US20190292176A1 - Bicyclic heteroaryl substituted compounds - Google Patents

Bicyclic heteroaryl substituted compounds Download PDF

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US20190292176A1
US20190292176A1 US16/317,248 US201716317248A US2019292176A1 US 20190292176 A1 US20190292176 A1 US 20190292176A1 US 201716317248 A US201716317248 A US 201716317248A US 2019292176 A1 US2019292176 A1 US 2019292176A1
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methylquinoxalin
methoxy
thiazol
oxy
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Xiaojun Zhang
Eldon Scott Priestley
J. Alex BATES
Oz Scott Halpern
Samuel Kaye REZNIK
Jeremy M. Richter
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention generally relates to bicyclic heteroaryl substituted compounds useful as inhibitors of platelet aggregation.
  • bicyclic heteroaryl substituted compounds useful as inhibitors of platelet aggregation.
  • compositions comprising such compounds, and methods of their use.
  • the invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful in preventing or treating thromboembolic disorders.
  • Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), synthetic pentasaccharides, and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®).
  • anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), synthetic pentasaccharides, and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®).
  • Alpha-thrombin is the most potent known activator of platelet aggregation and degranulation. Activation of platelets is causally involved in atherothrombotic vascular occlusions.
  • Thrombin activates platelets by cleaving G-protein coupled receptors termed protease activated receptors (PARs).
  • PARs provide their own cryptic ligand present in the N-terminal extracellular domain that is unmasked by proteolytic cleavage, with subsequent intramolecular binding to the receptor to induce signaling (tethered ligand mechanism; Coughlin, S. R., Nature, 407:258-264 (2000)).
  • Synthetic peptides that mimic the sequence of the newly formed N-terminus upon proteolytic activation can induce signaling independent of receptor cleavage.
  • Platelets are a key player in atherothrombotic events. Human platelets express at least two thrombin receptors, commonly referred to as PAR1 and PAR4. Inhibitors of PAR1 have been investigated extensively, and several compounds, including vorapaxar and atopaxar have advanced into late stage clinical trials. Recently, in the TRACER phase III trial in ACS patients, vorapaxar did not significantly reduce cardiovascular events, but significantly increased the risk of major bleeding (Tricoci, P. et al., N. Eng. J. Med., 366(1):20-33 (2012). Thus, there remains a need to discover new antiplatelet agents with increased efficacy and reduced bleeding side effects.
  • Compound 58 is also referred to as YD-3 in Wu, C-C. et al., “Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation by YD-3 ”, Thromb. Haemost., 87:1026-1033 (2002). Also, see Chen, H. S. et al., “Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives”, Bioorg. Med. Chem., 16:1262-1278 (2008).
  • EP1166785 A1 and EP0667345 disclose various pyrazole derivatives which are useful as inhibitors of platelet aggregation.
  • potent compounds that have activity as PAR4 inhibitors. These compounds are provided to be useful as pharmaceuticals with desirable potency, stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.
  • bicyclic heteroaryl substituted compounds in accordance with the present invention are PAR4 antagonists which inhibit platelet aggregation in gamma-thrombin induced platelet aggregation assays.
  • the present invention provides bicyclic heteroaryl substituted compounds that are PAR4 antagonists and are useful as selective inhibitors of platelet aggregation, including stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the present invention also provides a method for the treatment or prophylaxis of thromboembolic disorders comprising administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the present invention also provides the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.
  • the present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment or prophylaxis of a thromboembolic disorder.
  • the first aspect of the present invention provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII):
  • R 1 is F, Cl, —OH, C 1-4 alkyl, C 1-4 fluoroalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 fluorocycloalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 2-4 hydroxyalkoxy, C 3-6 cycloalkoxy, (C 1-3 alkoxy)-(C 1-3 alkylene), (C 1-3 alkoxy)-(C 1-3 fluoroalkylene), (C 1-3 deuteroalkoxy)-(C 1-3 deuteroalkylene), (C 1-3 fluoroalkoxy)-(C 1-3 alkylene), (C 1-3 fluoroalkoxy)-(C 1-3 fluoroalkylene), —(CH 2 ) 1-3 O(phenyl), —(CH 2 ) 1-3 NR a R a , —C(O)O(C 1-6 alkyl),
  • R 2 is independently H, F, Cl, Br, —OH, —CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-3 aminoalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 fluorocycloalkyl, C 1-6 alkoxy, C 1-3 fluoroalkoxy, C 1-3 alkylthio, C 1-3 fluoroalkylthio, (C 1-3 alkoxy)-(C 1-3 alkylene), (C 1-3 fluoroalkoxy)-(C 1-3 alkylene), —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —C(O)O(C 1-6 alkyl), —C(O)NH(CH 2 CH 2 O(C 1-3 alkyl)),
  • R 3 is a bicyclic group selected from indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzofuranyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[
  • R 3a at each occurrence, is independently:
  • R 4 is H, F, Cl, or —CH 3 ;
  • R a at each occurrence, is independently H, C 1-4 alkyl, or C 1-4 fluoroalkyl
  • R c at each occurrence, is independently C 1-3 alkyl or C 1-3 hydroxyalkyl, or two R c along with the nitrogen atom to which they are attached form a heterocyclyl or bicyclic heterocyclyl;
  • R d is independently C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-6 hydroxyalkyl, (C 1-4 alkoxy)-(C 1-3 alkylene), (C 1-2 fluoroalkoxy)-(C 1-2 alkylene), (C 3-6 cycloalkyl)-(C 0-2 alkylene), aryl(C 1-2 alkylene), heteroaryl(C 1-2 alkylene), aryloxy-(C 1-2 alkylene), aryl-CH 2 O—(C 1-2 alkylene), or heteroaryloxy-(C 1-2 alkylene); and
  • n zero, 1, or 2.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein
  • R 1 is —OH, C 1-2 alkyl, —CHFCH 3 , —CH ⁇ CH 2 , C 1-3 alkoxy, C 1-2 fluoroalkoxy, —OCH 2 CH 2 OH, —CH 2 O(C 1-2 alkyl), —CD 2 OCD 3 , —CH 2 OCHF 2 , —CF 2 OCH 3 , —CH 2 O(phenyl), —CH(CH 3 )OCH 3 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , —C(O)NH(CH 2 CH 2 OH), —C(O)OCH 3 , —CH(CH 3 )OCH 3 , cyclopropyl, furanyl, or —O(cyclopropyl);
  • R 2 is independently H, F, Cl, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , —OCF 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH(CH 3 )OH, —C(CH 3 ) 2 OH, —CH(OH)CH 2 OH, —CH 2 NH 2 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)(piperidinyl), —C(O)OCH 3 , —C(O)NH(CH 2 CH 2 OCH 3 ), —CH(OH)(cyclopropyl), —CH(OH)(phenyl), —CH ⁇ CH 2 , —C(CH 3 ) ⁇ CH 2 , or —C ⁇ CH;
  • R 3 is:
  • R 3a at each occurrence, is independently:
  • One embodiment provides at least one compound of Formulas (I), (II), (III) or (IV) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect. Included in this embodiment are compounds in which R 3 is:
  • R 3a is defined in the first aspect. Also included in this embodiment are compounds in which R 4 is H, F, or —CH 3 .
  • One embodiment provides at least one compound of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formulas (I) or (II) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (I) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (II) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (III) or a salt thereof, wherein R 1 , R 2 , R 3 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (IV) or a salt thereof, wherein R 1 , R 2 , R 3 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (V) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (VI) or a salt thereof, wherein R 1 , R 2 , R 3 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (VII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (I) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect. Included in this embodiment are compounds in which R 3 is:
  • R 3a is defined in the first aspect. Also included in this embodiment are compounds in which R 4 is H, F, or —CH 3 .
  • One embodiment provides at least one compound of Formulas (I) or (II) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and n are defined in the first aspect. Included in this embodiment are compounds in which R 3 is:
  • R 3a is defined in the first aspect.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), or (VIII) or a salt thereof, wherein R 3 is:
  • R m is H or Cl
  • R k is H or F
  • R 1 , R 2 , R 3a , R 4 , and n are defined in the first aspect. Included in this embodiment are compounds of Formula (I).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 3 is:
  • R 1 , R 2 , R 3a , R 4 , and n are defined in the first aspect. Included in this embodiment are compounds of Formula (I).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 is —OH, C 1-2 alkyl, —CHFCH 3 , —CH ⁇ CH 2 , C 1-3 alkoxy, C 1-2 fluoroalkoxy, —OCH 2 CH 2 OH, —CH 2 O(C 1-2 alkyl), —CD 2 OCD 3 , —CH 2 OCHF 2 , —CF 2 OCH 3 , —CH 2 O(phenyl), —CH(CH 3 )OCH 3 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , —C(O)NH(CH 2 CH 2 OH), —C
  • R 2 at each occurrence, is independently H, F, Cl, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , —OCF 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH(CH 3 )OH, —C(CH 3 ) 2 OH, —CH(OH)CH 2 OH, —CH 2 NH 2 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)(piperidinyl), —C(O)OCH 3 , —C(O)NH(CH 2 CH 2 OCH 3 ), —CH(OH)(cyclopropyl), —CH(OH)(phenyl),
  • One embodiment provides at least one compound of Formula (I), (II), (V), and (VII) or a salt thereof, wherein R 4 is H, F, or —CH 3 ; and R 1 , R 2 , R 3 , and n are defined in the first aspect. Included in this embodiment are compounds in which R 4 is H and F. Also included in this compounds in which R 4 is H.
  • R 3a at each occurrence, is independently, (i) F, Cl, —CN, —OH, —CH 3 , —CF 3 , —CHFC(CH 3 ) 3 , cyclopropyl, —CH 2 OH, —CD 2 OH, —CH 2 CH 2 OH, —CH(OH)CH 3 , —C(CH 3 ) 2 OH, —CH(OH)C(CH 3 ) 3 , —CD(OH)C(CH 3 ) 3 , —CH(OH)CF 3 , —CH(OH)CH 2 CF 3 , —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl), —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclo
  • R 3 is substituted with one R 3a selected from (i) F, Cl, —CN, —OH, —CH 3 , —CF 3 , —CHFC(CH 3 ) 3 , cyclopropyl, —CH 2 OH, —CD 2 OH, —CH 2 CH 2 OH, —CH(OH)CH 3 , —C(CH 3 ) 2 OH, —CH(OH)C(CH 3 ) 3 , —CD(OH)C(CH 3 ) 3 , —CH(OH)CF 3 , —CH(OH)CH 2 CF 3 , —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl), —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcycl
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , R a , R b , R d , and n are defined in the first aspect with the proviso that at least one R 3a is F, Cl, —CN, —OH, C 1-3 alkyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-6 hydroxy-deuteroalkyl, C 1-6 hydroxy-fluoroalkyl, C 1-6 alkoxy, C 1-3 fluoroalkoxy, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, 3- to 6-membered heterocyclyl, —CH(OH)R y wherein R y is C 3-6 cycloalkyl, aryl, heteroaryl, or 3- to
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , R a , R b , R d , and n are defined in the first aspect with the proviso that at least one R 3a is —CH(OH)CR h R i R j wherein R h and R i are independently H, F, C 1-4 alkyl, C 1-3 alkoxy, or taken together with the carbon atom to which they are attached, form C 3-8 cycloalkyl or 4- to 7-membered heterocyclyl ring; and R j is H, C 1-6 alkyl, C 1-5 fluoroalkyl, (C 1-3 alkoxy)-(C 1-3 alkylene), C 3-8 cycloalkyl, C 3-8 heterocyclyl, aryl, or heteroaryl
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , R a , R b , R d , and n are defined in the first aspect with the proviso that at least one R 3a is —O(CH 2 ) 1-4 NR a S(O) 2 (C 1-3 alkyl) or —O(CH 2 ) 1-4 NR a S(O) 2 R w , wherein R w is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, Cl, cyano, C 1-3 alkyl, C 1-3 alkoxy, —OCF 3 , —OCHF 2 , and C 1-3 fluoroalkyl; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , R a , R b , R d , and n are defined in the first aspect with the proviso that at least one R 3a is —O(CH 2 ) 1-4 OC(O)NR a R x , —OCH(R d )(CH 2 ) 1-3 OC(O)NR a R x , —OCR d R d (CH 2 ) 1-3 OC(O)NR a R x , —O(CH 2 ) 1-3 CH(R d )OC(O)NR a R x , —O(CH 2 ) 1-3 CR d R d OC(O)NR a R x , —OCH(R d
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , and n are defined in the first aspect with the proviso that at least one R 3a is F, Cl, —CN, —OH, —CH 3 , —CF 3 , —CHFC(CH 3 ) 3 , cyclopropyl, —CH 2 OH, —CD 2 OH, —CH 2 CH 2 OH, —CH(OH)CH 3 , —C(CH 3 ) 2 OH, —CH(OH)C(CH 3 ) 3 , —CD(OH)C(CH 3 ) 3 , —CH(OH)CF 3 , —CH(OH)CH 2 CF 3 , —CH(OH)(cyclopropyl), —CH(OH)(methylcycloprop
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , and n are defined in the first aspect with the proviso that at least one R 3a is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —OCH 2 (phenyl), —OCH 2 (thiazolyl), —OCH 2 (oxazolidinonyl), —OCH 2 (amino isoxazolyl), —OCH 2 (imidazolyl substituted with phenyl), —OCH 2 CH 2 OH, —OCH 2 CH(CH 3 )OH, —OCH 2 CH 2 OCH 3 , —OCH(CH 3 )CH 2 OH, —OC
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , and n are defined in the first aspect with the proviso that at least one R 3a is —C(O)OH, —C(O)OCH 3 , or —C(O)OC(CH 3 ) 3 ; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , and n are defined in the first aspect with the proviso that at least one R 3a is —NHC(O)OCH 3 , —NHC(O)OC(CH 3 ) 3 , —NHC(O)OCH 2 (phenyl), —NHC(O)OCH 2 (tetrahydrofuranyl), or —NHC(O)O(tetrahydropyranyl); and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , and n are defined in the first aspect with the proviso that at least one R 3a is —OCH 2 CH 2 NHC(O)OCH 3 , —OCH 2 CH 2 NHC(O)O(tetrahydropyranyl), —OCH 2 CH 2 NHC(O)OCH 2 (phenyl), —OCH 2 CH 2 NHC(O)O(methoxyphenyl), —OCH 2 CH 2 NHC(O)O(tetrahydrofuranyl), —OCH 2 CH 2 NHC(O)OCH 2 (tetrahydrofuranyl), —OCH 2 CH 2 NHC(O)NH(pyridinyl), —OCH 2 CH 2 N(CH 3 )C(O
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , and n are defined in the first aspect with the proviso that at least one R 3a is —OCH 2 CH 2 NHS(O) 2 CH 3 or —OCH 2 CH 2 NHS(O) 2 R w wherein R w is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, Cl, and —CH 3 ; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 , R 3a , R 4 , and n are defined in the first aspect with the proviso that at least one R 3a is —OCH 2 CH 2 OC(O)NHR z , —OCH(CH 3 )CH 2 OC(O)NHR z , —OCH 2 CH(CH 3 )OC(O)NHR z , —OCH(CH 3 )CH(CH 3 )(CH 2 ) 0-2 OC(O)NHR z , —OCH 2 CH(CH 2 O(isobutyl))(CH 2 ) 0-2 OC(O)NHR z , —OCH 2 CH(CH 2 CH 3 )OC(O)NHR z , —OCH 2 CH(CH 2 O
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R 3 is substituted with zero to 1 R 3a . Included in this embodiment are compounds in which R 3 is unsubstituted.
  • One embodiment provides at least one compound of Formula (I) or a salt thereof, wherein R 1 is —OCH 3 , —OCHF 2 , —OCH 2 CH 3 , or —CH 2 OCH 3 ; R 2 , at each occurrence, is independently H, F, Cl, —CN, —CH 3 , —OCH 3 , or —CH 2 OH; and
  • R 3 is:
  • R 4 , R 3a , and p are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (II) or a salt thereof, wherein R 1 is —OH, —OCH 3 , —OCH 2 CH 3 , —OCHF 2 , —OCH 2 CHF 2 , —CH 2 OCH 3 , or —NH(CH 3 ); R 2 , at each occurrence, is independently F, Cl, —CN, —CH 3 , —CH 2 OH, —CH 2 F, —CHF 2 , or —OCH 3 ;
  • R 3 is:
  • R 3a at each occurrence, is independently F, Cl, —CH 3 , —OCH 3 , —CH(OH)(trifluoromethylcyclobutyl), —OCH 2 CH(CH 3 )OC(O)NHR z , or —OCH(CH 3 )CH(CH 3 )OC(O)NHR z , wherein R z is pyridinyl, pyrimidinyl, or benzo[d]oxazolonyl, each substituted with zero to 2 substituents independently selected from F, —OH, —CN, —CH 3 , —CF 3 , —CH 2 OH, —CH 2 CH 2 OH, —OCH 2 CH 2 OH, —OCH 3 , —CH 2 CH(CH 3 )OH, and —OCH 2 CH 2 C(CH 3 ) 2 OH; and R 4 and p are defined in the first aspect.
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is indolyl. Included in this embodiment is a compound of Formula (I) selected from 2-(difluoromethoxy)-5-(1H-indol-2-yl)-7-methylquinoxaline (5).
  • One embodiment provides compounds selected from one of the examples, more preferably, Examples 1 to 837, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is benzofuranyl. Included in this embodiment is a compound of Formulas (I), (II), (III), or (IV) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is benzo[b]thiophenyl. Included in this embodiment is a compound of Formula (I) selected from
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is benzo[d]imidazolyl. Included in this embodiment is a compound of Formula (I) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is benzo[d]oxazolyl. Included in this embodiment is a compound of Formula (I) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is benzo[d]thiazolyl. Included in this embodiment is a compound of Formula (I) to (III) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is imidazol[1,2-a]pyridinyl. Included in this embodiment is a compound of Formula (I) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is thiazolo[4,5-b]pyridinyl. Included in this embodiment is a compound of Formula (I) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is thiazolo[5,4-b]pyridinyl. Included in this embodiment is a compound of Formula (I) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is 4,5,6,7-tetrahydrobenzo[d]thiazolyl. Included in this embodiment is a compound of Formula (I) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is 4,5,6,7-tetrahydrobenzofuranyl. Included in this embodiment is a compound of Formula (I) selected from: tert-butyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl) carbamate (25).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is 6,7-tetrahydrothiazolo[5,4-c]pyridinyl.
  • R 3 is 6,7-tetrahydrothiazolo[5,4-c]pyridinyl.
  • a compound of Formula (I) selected from: tert-butyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (11) and methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (62).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is 5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl. Included in this embodiment is a compound of Formula (I) selected from:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R 3 is 5,6-dihydro-4H-cyclopenta[d]thiazolyl. Included in this embodiment is a compound of Formula (I) selected from:
  • references made in the singular may also include the plural.
  • references made in the singular may also include the plural.
  • “a” and “an” may refer to either one, or one or more.
  • a compound of Formula (I) includes a compound of Formula (I) and two or more compounds of Formula (I).
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • halo and halogen, as used herein, refer to F, Cl, Br, and I.
  • cyano refers to the group —CN.
  • amino refers to the group —NH 2 .
  • alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
  • Me methyl
  • Et ethyl
  • propyl e.g., n-propyl and i-propyl
  • butyl e.g., n-butyl, i-butyl, sec-butyl, and t-butyl
  • pentyl e.g., n-pentyl
  • C 1-4 alkyl denotes straight and branched chain alkyl groups with one to four carbon atoms.
  • fluoroalkyl as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms.
  • C 1-4 fluoroalkyl is intended to include C 1 , C 2 , C 3 , and C 4 alkyl groups substituted with one or more fluorine atoms.
  • Representative examples of fluoroalkyl groups include, but are not limited to, —CF 3 and —CH 2 CF 3 .
  • aminoalkyl as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more amino groups.
  • C 1-4 aminoalkyl is intended to include C 1 , C 2 , C 3 , and C 4 alkyl groups substituted with one or more amino groups.
  • Representative examples of aminoalkyl groups include, but are not limited to, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , and —CH 2 CH(NH 2 )CH 3 .
  • hydroxyalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups.
  • hydroxyalkyl includes —CH 2 OH, —CH 2 CH 2 OH, and C 1-4 hydroxyalkyl.
  • hydroxy-deuteroalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more deuterium atoms.
  • Representative examples of hydroxy-deuteroalkyl groups include, but are not limited to, —CD 2 OH and —CH(CD 3 ) 2 OH.
  • hydroxy-fluoroalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms.
  • Representative examples of hydroxy-fluoroalkyl groups include, but are not limited to, —CF 2 OH and —CF 2 CH 2 OH.
  • alkylene refers to a bivalent alkyl radical having the general formula —(CH 2 ) n —, where n is 1 to 10.
  • Non-limiting examples include methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.
  • C 1-6 alkylene denotes straight and branched chain alkylene groups with one to six carbon atoms.
  • C 0-4 alkylene denotes a bond and straight and branched chain alkylene groups with one to four carbon atoms.
  • deuteroalkylene refers to an alkylene group in which one or more hydrogen atoms have been replaced with deuterium atoms.
  • C 1-6 deuteroalkylene denotes straight and branched chain deuteroalkylene groups with one to six carbon atoms.
  • fluoroalkylene refers to an alkylene group substituted with one or more fluorine atoms.
  • C 1-6 fluoroalkylene denotes straight and branched chain fluoroalkylene groups with one to six carbon atoms.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl.
  • C 2-6 alkenyl denotes straight and branched chain alkenyl groups with two to six carbon atoms.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl.
  • C 2-6 alkynyl denotes straight and branched chain alkynyl groups with two to six carbon atoms.
  • cycloalkyl refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom.
  • Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.
  • the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain.
  • C 3-6 cycloalkyl denotes cycloalkyl groups with three to six carbon atoms.
  • fluorocycloalkyl refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by fluoro group(s).
  • hydroxycycloalkyl refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by hydroxyl group(s).
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (—OCH 3 ).
  • —OCH 3 methoxy group
  • C 1-3 alkoxy denotes alkoxy groups with one to three carbon atoms.
  • fluoroalkoxy and “—O(fluoroalkyl)” represent a fluoroalkyl group as defined above attached through an oxygen linkage (—O—).
  • C 1-4 fluoroalkoxy is intended to include C 1 , C 2 , C 3 , and C 4 fluoroalkoxy groups.
  • hydroxyalkoxy represent a hydroxyalkyl group as defined above attached through an oxygen linkage (—O—).
  • C 1-4 hydroxyalkoxy is intended to include C 1 , C 2 , C 3 , and C 4 hydroxyalkoxy groups.
  • hydroxy-fluoroalkoxy represent a hydroxy-fluoroalkyl group as defined above attached through an oxygen linkage (—O—).
  • C 1-4 hydroxy-fluoroalkoxy is intended to include C 1 , C 2 , C 3 , and C 4 hydroxy-fluoroalkoxy groups.
  • cycloalkoxy refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom, for example, cyclopropoxy group (—O(cyclopropyl)).
  • alkoxyalkoxy refers to an alkoxy group attached through an alkoxy group to the patent molecular moiety.
  • (C 1-3 alkoxy)-(C 1-6 alkoxy) denotes a C 1-3 alkoxy group attached through a C 1-6 alkoxy group to the parent molecular moiety.
  • alkoxyalkylene refers to an alkoxy group attached through an alkylene group to the patent molecular moiety.
  • (C 1-3 alkoxy)-(C 1-3 alkylene) denotes a C 1-3 alkoxy group attached through a C 1-3 alkylene to the parent molecular moiety.
  • fluoroalkoxyalkylene refers to a fluoroalkoxy group attached through an alkylene group.
  • (C 1-2 fluoroalkoxy)-(C 1-2 alkylene) denotes a C 1-2 fluoroalkoxy group attached through a C 1-2 alkylene to the parent molecular moiety.
  • alkoxy-fluoroalkylene refers to an alkoxy group attached through a fluoroalkylene group to the patent molecular moiety.
  • (C 1-3 alkoxy)-(C 1-3 fluoroalkylene) denotes a C 1-3 alkoxy group attached through a C 1-3 fluoroalkylene to the parent molecular moiety.
  • deuteroalkoxy-deuteroalkylene refers to a deuteroalkoxy group attached through a deuteroalkylene group to the patent molecular moiety.
  • (C 1-3 deuteroalkoxy)-(C 1-3 deuteroalkylene) denotes a C 1-3 deuteroalkoxy group attached through a C 1-3 deuteroalkylene to the parent molecular moiety.
  • alkylthio refers to an alkyl group attached to the parent molecular moiety through a sulfur atom, for example, methylthio group (—SCH 3 ).
  • methylthio group —SCH 3
  • C 1-3 alkylthio denotes alkylthio groups with one to three carbon atoms.
  • fluoroalkylthio refers to a fluoroalkyl group attached to the parent molecular moiety through a sulfur atom, for example, trifluoromethylthio group (—SCF 3 ).
  • SCF 3 trifluoromethylthio group
  • C 1-3 fluoroalkylthio denotes fluoroalkylthio groups with one to three carbon atoms.
  • aryl refers to a group of atoms derived from a molecule containing aromatic ring(s) by removing one hydrogen that is bonded to the aromatic ring(s).
  • Representative examples of aryl groups include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, and 1,2,3,4-tetrahydronaphth-5-yl.
  • the aryl ring may be unsubstituted or may contain one or more substituents as valence allows.
  • benzyl refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group.
  • the phenyl ring may be unsubstituted or may contain one or more substituents as valence allows.
  • aryloxy refers to an aryl group attached through an oxygen group.
  • phenoxy refers to a phenyl group attached through an oxygen group (—O-phenyl).
  • the phenyl ring may be unsubstituted or may contain one or more substituents as valence allows.
  • heteroatom refers to oxygen (O), sulfur (S), and nitrogen (N).
  • heterocyclo or “heterocyclyl” may be used interchangeably and refer to non-aromatic 3- to 7-membered monocyclic groups and 6- to 11-membered bicyclic groups, in which at least one of the rings has at least one heteroatom (0, S or N), said heteroatom containing ring preferably having 1 to 3 heteroatoms independently selected from 0, S, and/or N.
  • Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom.
  • the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized.
  • the fused rings completing the bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
  • the heterocyclo group may be attached at any available nitrogen or carbon atom.
  • the heterocyclo ring may be unsubstituted or may contain one or more substituents as valence allows.
  • Exemplary monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.
  • Exemplary bicyclic heterocyclo groups include quinuclidiny
  • heteroaryl refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N.
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • the fused rings completing the bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
  • the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized.
  • Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
  • the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
  • the heteroaryl ring system may be unsubstituted or may contain one or more substituents.
  • Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • heteroaryloxy refers to a heteroaryl group attached through an oxygen group to the patent molecular moiety.
  • arylalkylene refers to an aryl group attached through an alkylene group to the patent molecular moiety.
  • aryl(C 1-2 alkylene) refers to an aryl group attached through a C 1-2 alkylene to the parent molecular moiety.
  • heteroarylalkylene refers to a heteroaryl group attached through an alkylene group to the patent molecular moiety.
  • heteroaryl(C 1-2 alkylene) refers to a heteroaryl group attached through a C 1-2 alkylene to the parent molecular moiety.
  • aryloxyalkylene refers to an aryloxy group attached through an alkylene group to the patent molecular moiety.
  • aryloxy-(C 1-2 alkylene) refers to an aryloxy group attached through a C 1-2 alkylene to the parent molecular moiety.
  • heteroaryloxyalkylene refers to a heteroaryloxy group attached through an alkylene group to the patent molecular moiety.
  • heteroaryloxy-(C 1-2 alkylene) refers to a heteroaryloxy group attached through a C 1-2 alkylene to the parent molecular moiety.
  • the compounds of the present invention can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds as amorphous solids.
  • solvates e.g., hydrates of the Compounds of the invention are also within the scope of the present invention.
  • the term “solvate” means a physical association of a compound of Formulas (I) to (VIII) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.
  • compounds of Formulas (I) to (VIII), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formulas (I) to (VIII) (“substantially pure”), which is then used or formulated as described herein.
  • substantially pure compounds of Formulas (I) to (VIII) are also contemplated herein as part of the present invention.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the present invention is intended to embody stable compounds.
  • the compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium (D) and tritium (T).
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • methyl (—CH 3 ) also includes deuterated methyl groups such as —CD 3 .
  • PAR4 antagonist denotes an inhibitor of platelet aggregation which binds PAR4 and inhibits PAR4 cleavage and/or signaling.
  • PAR4 activity is reduced in a dose dependent manner by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to such activity in a control cell.
  • the control cell is a cell that has not been treated with the compound.
  • PAR4 activity is determined by any standard method in the art, including those described herein (for example calcium mobilization in PAR4 expressing cells, platelet aggregation, platelet activation assays measuring e.g., calcium mobilization, P-selectin or CD40L release, or thrombosis and hemostasis models).
  • platelet activation is measured by changes in the platelet cytoplasm, by changes of the platelet membrane, by changes in the levels of analytes released by platelets, by the changes in the morphology of the platelet, by the ability of platelets to form thrombi or platelet aggregates in flowing or stirred whole blood, by the ability of platelets to adhere to a static surface which is derivatized with relevant ligands (e.g., von Willebrand Factor, collagen, fibrinogen, other extracellular matrix proteins, synthetic fragments of any of the proteins, or any combination thereof), by changes in the shape of the platelets, or any combinations thereof.
  • relevant ligands e.g., von Willebrand Factor, collagen, fibrinogen, other extracellular matrix proteins, synthetic fragments of any of the proteins, or any combination thereof.
  • platelet activation is measured by changes in the levels of one or more analytes released by platelets.
  • the one or more analytes released by platelets can be P-selectin (CD62p), CD63, ATP, or any combination thereof.
  • platelet activation is measured by the level of binding of fibrinogen or GPIIbIIIa antibodies to platelets.
  • platelet activation is measured by the degree of phosphorylation of vasodilator-stimulated phosphoprotein (VASP) upon platelet activation.
  • VASP vasodilator-stimulated phosphoprotein
  • platelet activation is measured by the level of platelet-leukocyte aggregates.
  • platelet activation is measured by proteomics profiling.
  • PAR4 antagonist also includes a compound that inhibits both PAR1 and PAR4.
  • compounds of the invention have IC 50 s in the PAR4 FLIPR Assay (described hereinafter) of about 10 ⁇ M, preferably 1 ⁇ M or less, more preferably 100 nM or less, and even more preferably 10 nM or less.
  • PAR4 FLIPR assay data for compounds of the present invention is presented in the Table.
  • the present invention provides a pharmaceutical composition, which includes a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I-VIII, preferably, a compound selected from one of the examples, more preferably, Examples 1 to 837, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, alone or in combination with another therapeutic agent.
  • the present invention provides a pharmaceutical composition which further includes another therapeutic agent(s).
  • the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent(s) are an anti-platelet agent or a combination thereof.
  • the anti-platelet agent(s) are P2Y12 antagonists and/or aspirin.
  • the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel.
  • the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent(s) are an anticoagulant or a combination thereof.
  • the anticoagulant agent(s) are a FXa inhibitor, a thrombin inhibitor, or a FXIa inhibitor.
  • the FXa inhibitors are apixaban, rivaroxaban, edoxaban, or betrixaban.
  • the thrombin inhibitor is dabigatran.
  • patient encompasses all mammalian species.
  • the term “subject” refers to any human or nonhuman organism that could potentially benefit from treatment with a PAR4 antagonist.
  • exemplary subjects include human beings of any age with risk factors for cardiovascular disease, or patients that have already experienced one episode of cardiovascular disease.
  • Common risk factors include, but are not limited to, age, male sex, hypertension, smoking or smoking history, elevation of triglycerides, elevation of total cholesterol or LDL cholesterol.
  • the subject is a species having a dual PAR1/PAR4 platelet receptor repertoire.
  • dual PAR1/PAR4 platelet receptor repertoire means that a subject expresses PAR1 and PAR4 in platelets or their precursors.
  • Exemplary subjects having a dual PAR1/PAR4 platelet receptor repertoire include human beings, non-human primates, and guinea pigs.
  • the subject is a species having a dual PAR3/PAR4 platelet receptor repertoire.
  • dual PAR3/PAR4 platelet receptor repertoire means that a subject expresses PAR3 and PAR4 in platelets or their precursors.
  • Exemplary subjects having a dual PAR3/PAR4 platelet receptor repertoire include rodents and rabbits.
  • treating cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e; arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.
  • “prophylaxis” or “prevention” cover the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. “Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
  • risk reduction covers therapies that lower the incidence of development of a clinical disease state.
  • primary and secondary prevention therapies are examples of risk reduction.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit and/or antagonize PAR4 and/or to prevent or treat the disorders listed herein. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.
  • thrombosis refers to formation or presence of a thrombus (pl. thrombi) within a blood vessel that may cause ischemia or infarction of tissues supplied by the vessel.
  • emblism refers to sudden blocking of an artery by a clot or foreign material that has been brought to its site of lodgment by the blood current.
  • thromboembolism refers to obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel.
  • thromboembolic disorders entails both “thrombotic” and “embolic” disorders (defined above).
  • thromboembolic disorders as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.
  • thromboembolic disorders as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • the medical implants or devices include, but are not limited to: prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, ventricular assist devices and artificial hearts or heart chambers, and vessel grafts.
  • the procedures include, but are not limited to: cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis.
  • thromboembolic disorders includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.
  • the present invention provides a method for the treatment of a thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis,
  • the present invention provides a method for the treatment of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, venous thrombosis, atrial fibrillation, and thrombosis resulting from medical implants and devices.
  • the present invention provides a method for the primary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease,
  • the present invention provides a method for the primary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, venous thrombosis, and thrombosis resulting from medical implants and devices.
  • the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombo
  • the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, atrial fibrillation and venous thrombosis.
  • stroke refers to embolic stroke or atherothrombotic stroke arising from occlusive thrombosis in the carotid communis, carotid interna, or intracerebral arteries.
  • thrombosis includes vessel occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty).
  • the thromboembolic disorders may result from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of pregnancy.
  • Thromboembolic disorders are frequently associated with patients with atherosclerosis.
  • Risk factors for atherosclerosis include but are not limited to male gender, age, hypertension, lipid disorders, and diabetes mellitus. Risk factors for atherosclerosis are at the same time risk factors for complications of atherosclerosis, i.e., thromboembolic disorders.
  • Atrial fibrillation is frequently associated with thromboembolic disorders.
  • Risk factors for atrial fibrillation and subsequent thromboembolic disorders include cardiovascular disease, rheumatic heart disease, nonrheumatic mitral valve disease, hypertensive cardiovascular disease, chronic lung disease, and a variety of miscellaneous cardiac abnormalities as well as thyrotoxicosis.
  • Diabetes mellitus is frequently associated with atherosclerosis and thromboembolic disorders.
  • Risk factors for the more common type 2 include but are not limited to family history, obesity, physical inactivity, race/ethnicity, previously impaired fasting glucose or glucose tolerance test, history of gestational diabetes mellitus or delivery of a “big baby”, hypertension, low HDL cholesterol, and polycystic ovary syndrome.
  • Thrombosis has been associated with a variety of tumor types, e.g., pancreatic cancer, breast cancer, brain tumors, lung cancer, ovarian cancer, prostate cancer, gastrointestinal malignancies, and Hodgkins or non-Hodgkins lymphoma. Recent studies suggest that the frequency of cancer in patients with thrombosis reflects the frequency of a particular cancer type in the general population. (Levitan, N. et al., Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N Engl. J Med., 334(11):677-681 (1996); Blom, J. W.
  • VTE venous thromboembolism
  • composition means any composition, which contains at least one therapeutically or biologically active agent and is suitable for administration to the patient. Any of these formulations can be prepared by well-known and accepted methods of the art. See, for example, Gennaro, A. R., ed., Remington: The Science and Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa. (2000).
  • the invention includes administering to a subject a pharmaceutical composition that includes a compound that binds to PAR4 and inhibits PAR4 cleavage and/or signaling (referred to herein as a “PAR4 antagonist” or “therapeutic compound”).
  • a pharmaceutical composition that includes a compound that binds to PAR4 and inhibits PAR4 cleavage and/or signaling (referred to herein as a “PAR4 antagonist” or “therapeutic compound”).
  • the pharmaceutical composition is administered using methods known in the art.
  • the compound is administered orally, rectally, nasally, by inhalation, topically or parenterally, e.g., subcutaneously, intraperitoneally, intramuscularly, and intravenously.
  • the compound is optionally formulated as a component of a cocktail of therapeutic drugs to treat a thromboembolic disorder.
  • the pharmaceutical composition is administered orally.
  • a PAR4 antagonist is formulated in a capsule or a tablet for oral administration.
  • Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose.
  • Tablets may be formulated in accordance with conventional procedures by compressing mixtures of a therapeutic compound with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite.
  • the compound is administered in the form of a hard shell tablet or a capsule containing a binder, e.g., lactose or mannitol, a conventional filler, and a tableting agent.
  • compositions of the invention are also useful for parenteral administration, such as intravenous, subcutaneous, intramuscular, and intraperitoneal.
  • parenteral administration such as intravenous, subcutaneous, intramuscular, and intraperitoneal.
  • formulations suitable for parenteral administration include aqueous solutions of the active agent in an isotonic saline solution, a 5% glucose solution, or another standard pharmaceutically acceptable excipient.
  • Standard solubilizing agents such as PVP or cyclodextrins are also utilized as pharmaceutical excipients for delivery of the therapeutic compounds.
  • the preferred dose of the PAR4 antagonist is a biologically active dose.
  • a biologically active dose is a dose that will inhibit cleavage and/or signaling of PAR4 and have an anti-thrombotic effect.
  • the PAR4 antagonist has the ability to reduce the activity of PAR4 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% below untreated control levels.
  • the levels of PAR4 in platelets is measured by any method known in the art, including, for example, receptor binding assay, platelet aggregation, platelet activation assays (e.g., p-selectin expression by FACS), Western blot or ELISA analysis using PAR4 cleavage sensitive antibodies.
  • the biological activity of PAR4 is measured by assessing cellular signaling elicited by PAR4 (e.g., calcium mobilization or other second messenger assays).
  • a therapeutically effective amount of a PAR4 compound is preferably from about less than 100 mg/kg, 50 mg/kg, 10 mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more preferred embodiment, the therapeutically effective amount of the PAR4 compound is less than 5 mg/kg. In a most preferred embodiment, the therapeutically effective amount of the PAR4 compound is less than 1 mg/kg. Effective doses vary, as recognized by those skilled in the art, depending on route of administration and excipient usage.
  • the activity of the PAR4 antagonists of the present invention can be measured in a variety of in vitro assays. Exemplary assays are shown below.
  • the Fluorometric Imaging Plate Reader (FLIPR) assay is an exemplary in vitro assay for measuring the activity of the PAR4 antagonists of the present invention.
  • FLIPR Fluorometric Imaging Plate Reader
  • AYPGKF is a known PAR4 agonist.
  • An alternative PAR4 agonist is H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 .
  • H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 was validated as a PAR4 agonist in the FLIPR assay.
  • H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 has improved agonist activity as compared to AYPGKF with an EC 50 that is 10 fold lower than the EC 50 for AYPGKF in the FLIPR assay.
  • H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 can be synthesized using methods well known to those of skill in the art.
  • the FLIPR assay can also be used as a counterscreen to test agonist activity or PAR1 antagonist activity in a cell line that expresses both PAR1 and PAR4.
  • the PAR1 antagonist activity can be tested by the ability of the compound to inhibit calcium mobilization induced by the PAR1 agonist peptide SFLLRN or other PAR1 agonist peptides.
  • the compounds of the current invention can be tested in vitro for their ability to inhibit platelet aggregation induced by gamma-thrombin as shown below.
  • Gamma-thrombin a proteolytic product of alpha-thrombin which no longer interacts with PAR1, selectively cleaves and activates PAR4 (Soslau, G. et al., “Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib”, J. Biol. Chem., 276:21173-21183 (2001)).
  • Platelet aggregation can be monitored in a 96-well microplate aggregation assay format or using standard platelet aggregometer.
  • the aggregation assay can also be employed to test the selectivity of the compound for inhibiting platelet aggregation induced by PAR4 agonist peptides, PAR1 agonist peptide, ADP, or thromboxane analogue U46619.
  • the compounds of the current invention can be tested in vitro for their ability to inhibit platelet aggregation induced by alpha-thrombin as shown below.
  • Alpha-thrombin activates both PAR1 and PAR4.
  • the ability of a selective PAR4 antagonist of the present invention to inhibit platelet aggregation can be measured using a standard optical aggregometer.
  • the compounds of the current invention can be tested in vitro for their ability to inhibit platelet aggregation induced by tissue factor as shown below.
  • the conditions in this assay mimic the physiological events during thrombus formation.
  • platelet aggregation in human platelet rich plasma (PRP) is initiated by the addition of tissue factor and CaCl 2 .
  • Tissue factor the initiator of the extrinsic coagulation cascade, is highly elevated in human atherosclerotic plaque. Exposure of blood to tissue factor at the atherosclerotic site triggers a robust generation of thrombin and induces the formation of obstructive thrombi.
  • the activity of the PAR4 antagonists of the present invention can also be measured in a variety of in vivo assays.
  • Exemplary mammals that can provide models of thrombosis and hemostasis to test the effectiveness of the PAR4 antagonists of the present invention as antithrombotic agents include, but are not limited to, guinea pigs and primates.
  • Relevant efficacy models include, but are not limited to, electrically-induced carotid arterial thrombosis, FeCl 3 -induced carotid artery thrombosis and arteriovenous-shunt thrombosis.
  • Models of kidney bleeding time, renal bleeding time and other bleeding time measurements can be used to assess the bleeding risk of the antithrombotic agents described in the current invention.
  • SFFLRR is a known high affinity PAR1 selective agonist peptide.
  • the PAR4 agonist peptides AYPGKF and H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 were synthesized.
  • H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 showed improved PAR4 agonist activity over AYPGKF in the FLIPR assay (EC 50 value of 8 ⁇ M for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 and 60 ⁇ M for AYPGKF) and in washed platelet aggregation assay (EC 50 value of 0.9 ⁇ M for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 and 12 ⁇ M for AYPGKF).
  • HEK293 cells stably expressing PAR4 were generated by a standard method of transfection of human PAR4 (F2R23) cDNA expression vector and selected based on PAR4 protein expression or mRNA expression. Those cells demonstrated functional responses to PAR4 agonist peptide-induced intracellular calcium elevation using FLIPR® (Fluorometric Imaging Plate Reader; Molecular Devices Corp.). These cells also express endogenous PAR1 and can elicit calcium signal upon stimulation with PAR1 agonist peptide. Therefore, the same cells were also used to determine selectivity against PAR1 and agonist activity for both receptors. Cells from HEK293 PAR4 Clone 1.2A (BMS Arctic ID 383940) were propagated and used for calcium mobilization studies.
  • Human blood was collected in 3.8% sodium citrate at a ratio of 1 ml per 9 ml blood and centrifuged in a Sorvall® RT6000B centrifuge at 900 revolution per minute (rpm) at room temperature (RT) for 15 minutes.
  • PRP was collected and used for aggregation assay.
  • Refludan (Berlex Labs, Wayne, N.J.), a recombinant hirudin, at a final concentration of 1 unit/mL was added to the sample to selectively prevent PAR1 activation induced by residual alpha-thrombin contamination.
  • the remaining blood sample was centrifuged at 2500 rpm at room temperature for 5 minutes to collect platelet-poor plasma (PPP).
  • Human blood was collected in ACD (85 mM tri-sodium citrate, 78 mM citric acid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml per 10 ml blood.
  • ACD 85 mM tri-sodium citrate, 78 mM citric acid, 110 mM D-glucose, pH 4.4
  • PRP was isolated by centrifugation at 170 g for 14 minutes and platelets were further pelleted by centrifugation at 1300 g for 6 minutes. Platelets were washed once with 10 ml ACD containing 1 mg/ml bovine serum albumin.
  • Platelets were resuspended at ⁇ 2.5 ⁇ 10 8 /ml in Tyrode's Buffer (137 mM NaCl, 2 mM KCl, 1.0 mM MgCl 2 , 1 mM CaCl 2 , 5 mM glucose, 20 mM HEPES pH 7.4).
  • FLIPR-based calcium mobilization assay in HEK293 cells was used to measure PAR4 antagonism, agonism, and selectivity against PAR1.
  • the activity of the PAR4 antagonists of the present invention were tested in PAR4 expressing cells by monitoring H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 -induced intracellular calcium mobilization. Counter screens for agonist activity and PAR1 antagonist activity were also performed.
  • PAR1/PAR4-expressing HEK293 cells were grown in DMEM (Life Technology, Grand Island, N.Y.) containing 10% heat-inactivated FBS, 1% Penicillin-Streptomycin, 10 ⁇ g/mL blasticidin, and 100 ⁇ g/mL Zeocin at 37° C. with 5% CO 2 .
  • Cells were plated overnight prior to the experiment in a black 384-well Purecoat Amine clear bottom plate (Becton Dickinson Biosciences, San Jose, Calif.) at 10,000 cells/well in 30 ⁇ L growth medium and incubated in a humidified chamber at 37° C. with 5% CO 2 overnight.
  • HBSS Hank's Balanced Saline Solution
  • DMSO dimethyl sulfoxide
  • the cells were then incubated for 30 minutes at room temperature followed by addition of 20 ⁇ L of agonist peptide for antagonist activity measurement.
  • the PAR4 agonist peptide H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2
  • the PAR1 agonist peptide SFFLRR
  • Compound potency was derived from 11-point concentration-response curves.
  • the ability of the compounds of the current invention to inhibit platelet aggregation induced by gamma-thrombin was tested in a 96-well microplate aggregation assay format. Briefly, 90 ⁇ L of PRP or washed platelets were pre-incubated for 5 minutes at 37° C. with 3-fold serially diluted test compound, which was prepared as a 100-fold stock solution in dimethyl sulfoxide (DMSO). Aggregation was initiated by addition of 10 ⁇ L of gamma-thrombin (Haematologic Technologies, Inc. Essex Junction, Vt.) at 50-100 nM final concentration, which was titrated daily to achieve 80% platelet aggregation.
  • DMSO dimethyl sulfoxide
  • the plate was then placed into a SpectraMax® Plus Plate Reader (Molecular Devices) at 37° C. Platelet aggregation was monitored at a wavelength of 405 nm using a kinetic analysis mode. Prior to the first data collection time point, the plate was shaken for 10 seconds to allow thorough mixing. Data was subsequently collected every 10 seconds for up to 7 minutes total. Data was collected using SoftMax® 5.4.1 software and exported to Microsoft Excel for analysis. The optical density (OD) values at the time point that achieved 75% platelet activation by agonist alone were used for analysis. The OD value from a PRP sample without any treatment served as ODmaximum, and the OD value from a PPP sample containing no platelets served as the ODminimum.
  • OD optical density
  • % IPA (100-100*[ODcompound ⁇ ODminimum]/[ODmaximum ⁇ ODminimum]).
  • the aggregation assays were also employed to test the selectivity of the compound against other platelet receptors by using SFFLRR for PAR1, collagen (Chrono-Log, Havertown, Pa.) for collagen receptors, ADP for P2Y1 and P2Y12 and U46619 (Cayman Chemical, Ann Arbor, Mich.) for thromboxane receptors.
  • the ability of PAR4 antagonists to inhibit platelet aggregation induced by alpha-thrombin can be tested using human washed platelets.
  • the antagonists are pre-incubated with washed platelets for 20 min. Aggregation is initiated by addition of 1.5 nM alpha-thrombin (Haematologic Technologies, Essex Junction, Vt.) to 300 ⁇ l of washed platelets at stirring speed of 1000 rpm. Platelet aggregation is monitored using an Optical Aggregometer (Chrono-Log, Havertown, Pa.) and the area under the curve (AUC) at 6 min was measured. IC 50 values are calculated using vehicle control as 0% inhibition.
  • the ability of PAR1 or PAR4 antagonists to inhibit platelet aggregation induced by endogenous thrombin can be tested in a tissue factor driven aggregation assay. Aggregation is initiated by addition of CaCl 2 and recombinant human tissue factor, which results in the generation of thrombin through activation of the coagulation pathway in the plasma. Anticoagulant agents such as corn trypsin inhibitor (Haematologic Technologies, Essex Junction, Vt.) at 50 ⁇ g/ml and PEFABLOC® FG (Centerchem, Norwalk, Conn.) are also added to the sample to prevent fibrin clot formation during the time of the study. Platelet aggregation is monitored using standard instrumentation including optical aggregometer or impedance aggregometer.
  • the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reaction mixtures are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • compounds of Formula I can also be prepared from palladium catalyzed cross coupling of arylboronic acids of Formula Ib with halides R 3 —X shown in Scheme 2.
  • a regio specific synthesis of quinoxalines of Formula Ia and Ib is shown in Scheme 4.
  • a properly protected ortho-nitro aniline Ie is alkylated with methyl bromoacetate to yield compound If.
  • Deprotection of compound If and reduction of compound Ig should initiate cyclization to give rise to compound Ih.
  • Compound Ih can be oxidized to quinoxaline-2-one of Formula Ii, which can be converted to the intermediate Ij with oxophosphorus halides.
  • the halides in compound Ij can be displaced with a nucleophile containing an R 1 group to compound Ia, and compounds of Formula Ia can be converted to corresponding boronic acids of Formula Ib via Suzuki-Miyaura reaction.
  • Intermediate Ii could also be converted to Ik by condensation reaction with sodium chlorodifluoroacetate in the presence of a base such as K 2 CO 3 .
  • the difluoroalkoxy may be displaced with a nucleophile containing an R 1 group to compound Ia.
  • Compounds of Formula II of this invention can be obtained as shown in Scheme 5.
  • Compound IIa can be condensed with dicarbonyl IIb to give compound IIc.
  • Acid catalyzed cyclization provides the key bromide IId.
  • Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes compound II.
  • Compounds of Formula IV of this invention can be obtained as shown in Scheme 7.
  • Compound IVa can be condensed with dimethylacetal IVb to give compound IVc.
  • Acid catalyzed cyclization and triflate formation provides the key coupling partner IVd.
  • Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes the compound of Formula IV.
  • Compounds of Formula V of this invention can be obtained as shown in Scheme 8.
  • Compound Va can be condensed with acid chloride Vb to give compound Vc.
  • Acid catalyzed cyclization and carbonyl alkylation provides the key bromide Vd.
  • Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes the compound of Formula V.
  • compounds of Formula VII can be obtained through the synthetic route shown in Scheme 10. Beginning with aryl chloride VIIa, palladium catalyzed cross coupling of various boronic acids or stannanes yields substituted anilines of structure VIIb. Nitration of compound VIIb and reduction of compound VIIc allows access to compounds of Formula VIId. Base mediated condensation of dianiline VIId with substituted bromo-ketones provides heterocycles of Formula VIIe. A final palladium-catalyzed cross coupling with aryl boronic acids or stannanes then furnishes the compounds of Formula VII.
  • Compounds of Formula VIII of this invention can be obtained by palladium catalyzed cross coupling of aryl boronic acids or stannanes with aryl chloride VIIIc as shown in Scheme 11.
  • Compound Villa can be condensed with amidines to give compound VIIIb.
  • Phosphorous oxychloride conversion of compound VIIIb to aryl chloride VIIIc followed by palladium-catalyzed cross coupling with aryl boronic acids or stannanes furnishes the compound of Formula VIII.
  • 2-halo benzothiazole XXI A synthesis of 2-halo benzothiazole XXI is shown in Scheme 12. Beginning with the appropriately substituted aniline XIX, the 2-amino benzothiazole XX is formed via addition and oxidative cyclization of a thiocyanate. Subsequent Sandmeyer chemistry is employed to generate the desired 2-halo benzothiazole XXI. With XXI in hand, various compounds of Formula I with structure XXIIa are prepared with boronic acid Ib via Suzuki cross-coupling.
  • Substitution at the 4-position of the benzothiazole R 3 group can be accomplished from intermediates XXVa and XXVb as shown in Scheme 14. Lithiation of XXVa followed by its addition to a variety of aldehydes provides XXVI, as does Grignard addition to benzaldehyde XXVb. XXVI is then coupled to Ib as described above to provide compounds of Formula I with structure XXVII.
  • chloroformate XXIX is synthesized from compounds with formulas analogous to XXVIII using phosgene. These chloroformates are then reacted with a variety of nucleophiles to generate compounds of structure XXX.
  • Compounds of structure XXXII are synthesized from amines such as XXXI using sulfonyl chloride reagents.
  • Method A PHENOMENEX® Luna C18 column (4.6 ⁇ 50 mm or 4.6 ⁇ 75 mm) eluted at 4 mL/min with 2, 4 or 8 min gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
  • Method B PHENOMENEX® Luna C18 column (4.6 ⁇ 50 mm) eluted at 4 mL/min with a 4 min gradient from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).
  • Method C PHENOMENEX® Luna C18 column (4.6 ⁇ 50 mm or 4.6 ⁇ 75 mm) eluted at 4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% H 3 PO 4 ; B: 10% water, 89.9% methanol, 0.1% H 3 PO 4 , UV 220 nm).
  • Method D PHENOMENEX® Luna C18 column (4.6 ⁇ 50 mm or 4.6 ⁇ 75 mm) eluted at 4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% NH 4 OAc; B: 10% water, 89.9% methanol, 0.1% NH 4 OAc, UV 220 nm).
  • Method E BEH C18 2.1 ⁇ 50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0% B to 100% B in 1 minute, gradient time 1.5 min.
  • Method F BEH C18 2.1 ⁇ 50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0% B to 50% B in 1 minute, gradient time 1.5 min.
  • Method G BEH C18 2.1 ⁇ 50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 50% B to 100% B in 1 minute, gradient time 1.5 min.
  • Reverse phase preparative HPLC was carried out using a Shimadzu Preparative HPLC system running Discovery VP software using one of the following methods.
  • Method A PHENOMENEX® Axia Luna 5 ⁇ M C18 30 ⁇ 75 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).
  • Method B YMC Sunfire 5 ⁇ M C18 30 ⁇ 100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
  • Method C XBridge C18, 19 ⁇ 200 mm column, 5- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Flow: 20 mL/min.
  • Method D Waters XBridge C18, 19 ⁇ 100 mm column, 5- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Flow: 20 mL/min.
  • Method E PHENOMENEX® Luna 5 ⁇ M C18 30 ⁇ 100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).
  • Method F PHENOMENEX® Luna 5 ⁇ M C18 30 ⁇ 100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
  • Method G Waters XBridge C18, 19 ⁇ 200 mm, 5- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% formic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% formic acid; Flow: 20 mL/min.
  • Method A A linear gradient using solvent A (10% acetonitrile, 90% water, 0.1% of TFA) and solvent B (90% acetonitrile, 10% water, 0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of solvent B over 1 min.
  • Method B A linear gradient using solvent A (10% methanol, 90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA); 0-100% of solvent B over 4 min and then 100% of solvent B over 1 min.
  • Method C A linear gradient using solvent A (10% methanol, 90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of solvent B over 1 min.
  • Method D A linear gradient using solvent A (10% methanol, 90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of solvent B over 1 min.
  • Method E 30-95% acetonitrile in water with 0.1% TFA in 8 min run, Waters Xbridge 4.6 ⁇ 50 mm 5 um C18, flow rate 1.2 mL/min and UV detection was set to 220 nm.
  • the LC column was maintained at room temperature.
  • Method F 10-95% methanol in water, 0.1% TFA in a 10 min run, PHENOMENEX® Onyx Monolithic 4.6 ⁇ 100 mm 5 um C18, flow rate 2.0 mL/mL and UV detection was set to 220 nm.
  • the LC column was maintained at room temperature.
  • Method G 5-95% acetonitrile in water, 10 mM of modifier in 6 min run, Waters Xbridge 2.1 ⁇ 50 mm 5 um C18, flow rate 1.0 mL/min and UV detection was set to 220 nm.
  • the LC column was maintained at room temperature.
  • Method H BEH C18 2.1 ⁇ 50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 2 to 98% B.
  • Method I BEH C18 2.1 ⁇ 50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 2 to 52% B.
  • Method J BEH C18 2.1 ⁇ 50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 48 to 98% B.
  • Method K Column: Waters Acquity UPLC BEH C18, 2.1 ⁇ 50 mm, 1.7- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • Method L Column: Waters Acquity UPLC BEH C18, 2.1 ⁇ 50 mm, 1.7- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • Method A Two analytical LC/MS injections were used to determine the final purity. Injection1 condition: A linear gradient using solvent A (5% acetonitrile, 95% water, 0.05% TFA) and solvent B (95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent B over 10 min and then 100% of solvent B over 5 min.
  • Injection 2 conditions A linear gradient using solvent A (5% acetonitrile, 95% water, 0.05% TFA) and solvent B (95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent B over 10 min and then 100% of solvent B over 5 min.
  • Method B Two analytical LC/MS injections were used to determine the final purity.
  • Injection 1 conditions Column: Waters Acquity UPLC BEH C18, 2.1 ⁇ 50 mm, 1.7- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • Injection 2 conditions Column: Waters Acquity UPLC BEH C18, 2.1 ⁇ 50 mm, 1.7- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • Procedure B To a vial containing the appropriate 5-bromopyrimidine (1.0 equiv.), palladium(II) acetate (0.1 equiv.), BINAP (0.2 equiv.), cesium carbonate (1.2 equiv.) and diphenylmethanimine (1.1 equiv.) was added toluene (0.5 M). The vial was sealed, evacuated and backfilled with Ar 3 ⁇ , and the reaction mixture was heated to 105° C. for 18 hours. The reaction mixture was then diluted with EtOAc and washed with 1M aqueous NaOH (1 ⁇ ) and brine (1 ⁇ ). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being purified by silica gel chromatography to provide the desired material.
  • Procedure C The 4-((diphenylmethylene)amino)pyrimidine intermediate (1.0 equiv.) was dissolved in 1:1 MeOH/THF (0.06M). 1M aqueous HCl (2.5 equiv.) was added to the reaction mixture at room temperature. The reaction mixture was allowed to stir at room temperature for 1 hour then diluted with water and extracted with 5:1 EtOAc/Hexanes (3 ⁇ ). The aqueous phase was concentrated and azeotroped with toluene 3 ⁇ to yield the desired 4-aminopyrimidine which was brought forward without further purification.
  • Procedure D 4-bromo-2-fluoropyridine (1.0 equiv.) was dissolved in DMF (1.1 M) along with the appropriate diol (1.5 equiv.). 60% sodium hydride in mineral oil (2.0 equiv.) was added to the reaction mixture portion-wise at 0° C. and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then quenched with saturated ammonium chloride solution and extracted with EtOAc (3 ⁇ ). The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being purified by silica gel chromatography to provide the desired material.
  • Procedure E N1,N2-dimethylethane-1,2-diamine (1.0 equiv.), 2,2,2-trifluoroacetamide (2.0 equiv.), copper(I) iodide (0.2 equiv.), potassium carbonate (2.0 equiv.) and the 4-boromo-2-alkoxypyridine intermediate (1.0 equiv.) were dissolved in dioxane (0.6 M) in a sealed vial. The vial was evacuated and backfilled with Ar 3 ⁇ then the reaction mixture was stirred at 75° C. for 2 hours. 3 mL of 1:1 MeOH/H 2 O was added to the mixture which was stirred at room temperature for 2 h then at 40° C. for 1 h.
  • reaction mixture was then diluted with water and extracted with EtOAc (3 ⁇ ). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride before being purified by silica gel chromatography to provide the desired material.
  • Procedure F The ester (1.0 equiv.) was dissolved in THF (0.2 M) and the solution was cooled to ⁇ 78° C. 1M DIBAL-H in toluene (3.0 equiv.) was added to the mixture which was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was then quenched saturated Rochelle's salt and allowed to stir for 18 h at room temperature. The mixture was then diluted with water and extracted with EtOAc (3 ⁇ ). The combined organic layer was washed with brine (1 ⁇ ), dried with sodium sulfate, filtered and concentrated yield the desired product.
  • Procedure I The alcohol (1.0 equiv.), imidazole (2.2 equiv.) and TBS-Cl (2.0 equiv.) were dissolved in THF or DCM (0.1 M). The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was then diluted with 1.5 M dipotassium phosphate solution and extracted with EtOAc (3 ⁇ ). The combined organic layer was washed with brine (1 ⁇ ), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride and purified by silica gel chromatography to yield the desired product.
  • Procedure K The acetonide intermediate (1.0 equiv.) was dissolved in a mixture of 4:3:2 THF/MeOH/concentrated aqueous HCl (0.01 M), and the solution was stirred at room temperature. The resulting mixture was monitored by LCMS, and after completion of the reaction (10 min-12 hours) the mixture was diluted with EtOAc, washed with 1.5 M K 2 HPO 4 , dried over sodium sulfate, filtered, concentrated, dissolved in DMF and purified by preparative HPLC to yield the desired example.
  • the mixture was diluted with EtOAc/water, insoluble material was removed by filtration.
  • the filtrate was extracted with EtOAc, washed with brine and dried over sodium sulfate, concentrated.
  • the crude product was purified by flash chromatography (loading in chloroform, 0% to 20% dichloromethane in MeOH over 15 min using a 40 g silica gel cartridge).
  • the desired fractions were combined and concentrated and further purified by prep HPLC (method A, 10-80% B in 8 mins; with a flow rate of 40 mL/min). The desired fractions were placed in a SpeedVac overnight to remove solvent.
  • tert-butyl (2-hydroxyethyl)carbamate (3.0 g, 18.61 mmol) was dissolved in DMF (20 mL) and mixed with 4-fluoro-2-methyl-1-nitrobenzene (2.89 g, 18.61 mmol).
  • K 2 CO 3 (7.72 g, 55.8 mmol) was added. Then the mixture was stirred at 100° C. overnight. On the next day, the reaction mixture was poured into ice water (50 mL) and was extracted with EtOAc (50 mL ⁇ 2).
  • CD 3 ONa was prepared by dissolving sodium metal (60 mg, 2.500 mmol) in CD 3 OD (0.405 mL, 10 mmol) for 30 minutes.
  • Intermediate I-25B (207 mg, 0.625 mmol) was dissolved in THF (12 mL).
  • the filtrate was concentrated on a rotary evaporator and then partitioned between 150 mL of EtOAc and 30 mL of water. Next, 4M NaOH (aqueous) was added to adjust the pH to 12. The solid was filtered on a Celite pad and the filter cake was washed with EtOAc. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with saturated NaHCO 3 (aqueous), brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give additional product.
  • 4M NaOH aqueous
  • a microwave tube was charged with Pd 2 (dba) 3 (48.9 mg, 0.053 mmol), X-Phos (102 mg, 0.214 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (814 mg, 3.21 mmol), and potassium acetate (315 mg, 3.21 mmol).
  • the tube was capped and then evacuated and backfilled with argon 3 times.
  • Intermediate I-35K (240 mg, 1.068 mmol) in 1,4-dioxane (10 mL) was added via syringe, followed by flushing the reaction mixture with N 2 for 10 minutes. The reaction mixture was heated at 110° C.
  • Degussa grade Pd/C (1.125 g, 1.058 mmol) was added to a 250 mL round bottom flask previously purged with argon. The Pd was carefully wetted with a few milliliters of MeOH before the full amount of solvent (42.3 ml) was added. The head space of the flask was evacuated until the solvent began to slightly bubble and then back-filled 3 ⁇ with N 2 . 2,3-difluoro-1-methoxy-4-nitrobenzene (2.0 g, 10.58 mmol) was added to the black suspension, and a balloon of Hz gas was attached. The heterogeneous mixture was sparged with H 2 for 30 min, before being allowed to stir under an atmosphere of H 2 for an additional 4 h.

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Abstract

Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
Figure US20190292176A1-20190926-C00001
Figure US20190292176A1-20190926-C00002

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is entitled to priority pursuant to 35 U.S.C. § 119(e) to U.S. provisional patent application No. 62/362,113, filed Jul. 14, 2016, which is incorporated herein in its entirety.
    • FIELD OF THE INVENTION
  • The present invention generally relates to bicyclic heteroaryl substituted compounds useful as inhibitors of platelet aggregation. Provided herein are bicyclic heteroaryl substituted compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful in preventing or treating thromboembolic disorders.
    • BACKGROUND OF THE INVENTION
  • Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), synthetic pentasaccharides, and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®).
  • Current anti-platelet therapies have limitations including increased risk of bleeding as well as partial efficacy (relative cardiovascular risk reduction in the 20 to 30% range). Thus, discovering and developing safe and efficacious oral or parenteral antithrombotics for the prevention and treatment of a wide range of thromboembolic disorders remains an important goal.
  • Alpha-thrombin is the most potent known activator of platelet aggregation and degranulation. Activation of platelets is causally involved in atherothrombotic vascular occlusions. Thrombin activates platelets by cleaving G-protein coupled receptors termed protease activated receptors (PARs). PARs provide their own cryptic ligand present in the N-terminal extracellular domain that is unmasked by proteolytic cleavage, with subsequent intramolecular binding to the receptor to induce signaling (tethered ligand mechanism; Coughlin, S. R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic the sequence of the newly formed N-terminus upon proteolytic activation can induce signaling independent of receptor cleavage. Platelets are a key player in atherothrombotic events. Human platelets express at least two thrombin receptors, commonly referred to as PAR1 and PAR4. Inhibitors of PAR1 have been investigated extensively, and several compounds, including vorapaxar and atopaxar have advanced into late stage clinical trials. Recently, in the TRACER phase III trial in ACS patients, vorapaxar did not significantly reduce cardiovascular events, but significantly increased the risk of major bleeding (Tricoci, P. et al., N. Eng. J. Med., 366(1):20-33 (2012). Thus, there remains a need to discover new antiplatelet agents with increased efficacy and reduced bleeding side effects.
  • There are several early reports of preclinical studies of PAR4 inhibitors. Lee, F-Y. et al., “Synthesis of 1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole Analogues as Novel Antiplatelet Agents”, J. Med. Chem., 4-(((22):3746-3749 (2001) discloses in the abstract that the compound
  • Figure US20190292176A1-20190926-C00003
  • “was found to be a selective and potent inhibitor or protease-activated receptor type 4 (PAR4)-dependent platelet activation.” Compound 58 is also referred to as YD-3 in Wu, C-C. et al., “Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation by YD-3”, Thromb. Haemost., 87:1026-1033 (2002). Also, see Chen, H. S. et al., “Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives”, Bioorg. Med. Chem., 16:1262-1278 (2008).
  • EP1166785 A1 and EP0667345 disclose various pyrazole derivatives which are useful as inhibitors of platelet aggregation.
  • The PCT publications WO 2013/163279, WO 2013/163244, and WO 2013/163241 disclose various PAR4 antagonists that are useful as inhibitors of platelet aggregation.
  • There still remains a need for compounds useful as inhibitors of platelet aggregation.
  • Applicants have found potent compounds that have activity as PAR4 inhibitors. These compounds are provided to be useful as pharmaceuticals with desirable potency, stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.
    • SUMMARY OF THE INVENTION
  • It has been found that bicyclic heteroaryl substituted compounds in accordance with the present invention are PAR4 antagonists which inhibit platelet aggregation in gamma-thrombin induced platelet aggregation assays.
  • Accordingly, the present invention provides bicyclic heteroaryl substituted compounds that are PAR4 antagonists and are useful as selective inhibitors of platelet aggregation, including stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • The present invention also provides a method for the treatment or prophylaxis of thromboembolic disorders comprising administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • The present invention also provides the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.
  • The present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment or prophylaxis of a thromboembolic disorder.
  • Other features and advantages of the invention will be apparent from the following detailed description and claims.
    • DETAILED DESCRIPTION
  • The first aspect of the present invention provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII):
  • Figure US20190292176A1-20190926-C00004
    Figure US20190292176A1-20190926-C00005
  • or a salt thereof; wherein
  • R1 is F, Cl, —OH, C1-4 alkyl, C1-4 fluoroalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, C2-4 hydroxyalkoxy, C3-6 cycloalkoxy, (C1-3 alkoxy)-(C1-3 alkylene), (C1-3 alkoxy)-(C1-3 fluoroalkylene), (C1-3 deuteroalkoxy)-(C1-3 deuteroalkylene), (C1-3 fluoroalkoxy)-(C1-3 alkylene), (C1-3 fluoroalkoxy)-(C1-3 fluoroalkylene), —(CH2)1-3O(phenyl), —(CH2)1-3 NRaRa, —C(O)O(C1-6 alkyl), —C(O)NRaRa, —C(O)NRbRb, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —NH(C1-6 hydroxyalkyl), azetidinyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, piperazinyl, —S(O)2(C1-3 alkyl), —S(O)2NRaRa, C1-3 alkylthio, or C1-3 fluoroalkylthio;
  • R2, at each occurrence, is independently H, F, Cl, Br, —OH, —CN, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 aminoalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, C1-6 alkoxy, C1-3 fluoroalkoxy, C1-3 alkylthio, C1-3 fluoroalkylthio, (C1-3 alkoxy)-(C1-3 alkylene), (C1-3 fluoroalkoxy)-(C1-3 alkylene), —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —C(O)O(C1-6 alkyl), —C(O)NH(CH2CH2O(C1-3 alkyl)), —C(O)NRbRb, —C(O)(piperidinyl), —CH(OH)(C3-6 cycloalkyl), —CH(OH)(phenyl), —CH(OH)(pyridyl), —S(O)2(C1-3 alkyl), —S(O)2NRaRa, or a cyclic group selected from phenyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein said cyclic group is substituted with zero to 5 substituents independently selected from F, Cl, hydroxy, C1-3 alkyl, C1-3 alkoxy, cyclopropyl, and —CN;
  • R3 is a bicyclic group selected from indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzofuranyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, 6,7-dihydrothiazolo[5,4-c]pyridinyl, 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazinyl, 4,5,6,7-tetrahydrobenzothiophenyl, furo[3,2-b]pyridinyl, and furo[2,3-b]pyridinyl, each bicyclic group substituted with zero to 3 R3a;
  • R3a, at each occurrence, is independently:
  • (i) F, Cl, —CN, —OH, C1-3 alkyl, C1-6 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxy-fluoroalkyl, C1-6 alkoxy, C1-3 fluoroalkoxy, C3-6 cycloalkyl, C3-6 fluorocycloalkyl, 4- to 7-membered heterocyclyl, —CH(OH)Ry wherein Ry is C3-6 cycloalkyl, aryl, heteroaryl, or 4- to 7-membered heterocyclyl; (C1-3 alkoxy)-(C1-3 alkylene), —(CH2)1-3NRaRa, —(CH2)1-3 NHS(O)2(aryl), —O(CH2)1-3 (aryl), —O(CH2)1-3 (thiazolyl), —O(CH2)1-3 (oxazolidinonyl), —O(CH2)1-3 (amino isoxazolyl), —O(CH2)1-3 (imidazolyl substituted with phenyl), C1-6 hydroxyalkoxy, (C1-3 alkoxy)-(C1-6 alkoxy), —O(CH2)1-4O(aryl), —O(CH2)1-4O(CH2)1-3 (aryl), —O(CH2)1-4NRaRa, —O(CH2)1-3CHRaNRa(methoxy pyrimidinyl), —O(CH2)1-4 NHS(O)2(C1-3 alkyl), —O(CH2)1-4 NHS(O)2(aryl), —O(CH2)1-4C(O)OH, —O(CH2)1-4C(O)O(C1-6 alkyl), —O(CH2)1-4C(O)NRa(CH2)0-3 (aryl), —O(CH2)1-4C(O)NRa(CH2)0-3 (heteroaryl), —O(CH2)1-4C(O)(morpholinyl), —O(CH2)1-4OC(O)O(C1-3 alkyl), —O(CH2)1-3 CHRaOC(O)NRa(CH2)1-4C(O)NRaRa, —CH2CHRdOC(O)NRa(heteroaryl), —O(CH2)1-4OC(O)NRa(heteroaryl), —O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C1-6 alkyl), —NRaC(O)(furanyl), —NRaC(O)(pyranyl), —NRaC(O)O(C1-6 alkyl), —NRaC(O)O(CH2)1-4(aryl), —O(CH2)1-4NRaC(O)O(C1-6 alkyl), —O(CH2)1-4NRaC(O)O(CH2)0-4(tetrahydropyranyl), —O(CH2)1-4NRaC(O)O(CH2)0-4(aryl), —O(CH2)1-4NRaC(O)O(CH2)0-4(heteroaryl), or —O(CH2)1-4NRaC(O)O(CH2)0-4(tetrahydrofuranyl), wherein each of said aryl, heteroaryl, and 3- to 6-membered heterocyclyl is substituted with zero to 5 substituents independently selected from F, Cl, —CN, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy, —OCF3, —OCHF2, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —C(O)O(C1-3 alkyl), C1-3 hydroxyalkoxy, phenyl, —CONRcRc, and —S(O)2NRcRc;
    (ii) —CH(OH)CRhRiRj wherein Rh and Ri are independently H, F, C1-4 alkyl, C1-4 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, or taken together with the carbon atom to which they are attached, form C3-8 cycloalkyl or 4- to 7-membered heterocyclyl ring; and Rj is H, C1-6 alkyl, C1-5 fluoroalkyl, (C1-3 alkoxy)-(C1-3 alkylene), C3-8 cycloalkyl, C3-8 heterocyclyl, aryl, or heteroaryl;
    (iii) —O(CH2)1-4NRaS(O)2(C1-4 alkyl) or —O(CH2)1-4NRaS(O)2Rw, wherein Rw is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, Cl, cyano, C1-3 alkyl, C1-3 alkoxy, —OCF3, —OCHF2, and C1-3 fluoroalkyl; or
    (iv) —O(CH2)1-4OC(O)NRaRx, —OCH(Rd)(CH2)1-3OC(O)NRaRx, —OCRdRd(CH2)1-3OC(O)NRaRx, —O(CH2)1-3 CH(Rd)OC(O)NRaRx, —O(CH2)1-3CRdRdOC(O)NRaRx, —OCH(Rd)CH(Rd)(CH2)0-2OC(O)NRaRx, or —OCRdRdCRdRd(CH2)0-2OC(O)NRaRx, wherein Rx is selected from H, C1-4 alkyl, C1-4 fluoroalkyl, aryl, heteroaryl, and —CH2(heteroaryl), each aryl and heteroaryl substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxyalkoxy, C1-6 hydroxy-fluoroalkoxy, C1-3 alkoxy, —C(O)OH, —(CH2)0-3C(O)O(C1-3 alkyl), —(CH2)1-3OP(O)(OH)2, —CH2(morpholinyl), —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —C(O)NRa(C1-6 hydroxyalkyl), —C(O)NRbRb, —S(O)2NRaRa, —NH2, —NH(C1-6 alkyl), —NRa(C1-6 hydroxyalkyl), —N(C1-6 alkyl)2, —NRaC(O)(C1-6 alkyl), —NRaC(O)(chloro, fluorophenyl), —NRaS(O)2(C1-3 alkyl), —C(O)NRa(CH2)0-1(hydroxymethyloxetanyl), —C(O)NRa(CH2)0-1 (hydroxymethyl C3-6 cycloalkyl), —C(O)NRa(CH2)0-1(hydroxy C3-6 cycloalkyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl;
  • R4 is H, F, Cl, or —CH3;
  • Ra, at each occurrence, is independently H, C1-4alkyl, or C1-4 fluoroalkyl;
  • two Rb along with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo ring having 1 to 2 nitrogen atoms and 0-1 oxygen or sulfur atoms;
  • Rc, at each occurrence, is independently C1-3 alkyl or C1-3 hydroxyalkyl, or two Rc along with the nitrogen atom to which they are attached form a heterocyclyl or bicyclic heterocyclyl;
  • Rd, at each occurrence, is independently C1-6 alkyl, C1-4 fluoroalkyl, C1-6 hydroxyalkyl, (C1-4 alkoxy)-(C1-3 alkylene), (C1-2 fluoroalkoxy)-(C1-2 alkylene), (C3-6 cycloalkyl)-(C0-2 alkylene), aryl(C1-2 alkylene), heteroaryl(C1-2 alkylene), aryloxy-(C1-2 alkylene), aryl-CH2O—(C1-2 alkylene), or heteroaryloxy-(C1-2 alkylene); and
  • n is zero, 1, or 2.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein
  • R1 is —OH, C1-2 alkyl, —CHFCH3, —CH═CH2, C1-3 alkoxy, C1-2 fluoroalkoxy, —OCH2CH2OH, —CH2O(C1-2 alkyl), —CD2OCD3, —CH2OCHF2, —CF2OCH3, —CH2O(phenyl), —CH(CH3)OCH3, —NH(CH3), —N(CH3)2, —CH2N(CH3)2, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)OCH3, —CH(CH3)OCH3, cyclopropyl, furanyl, or —O(cyclopropyl);
  • R2, at each occurrence, is independently H, F, Cl, —CN, —CH3, —CH2F, —CHF2, —CF3, —OCH3, —OCF3, —CH2OH, —CH2CH2OH, —CH(CH3)OH, —C(CH3)2OH, —CH(OH)CH2OH, —CH2NH2, —C(O)NH2, —C(O)N(CH3)2, —C(O)(piperidinyl), —C(O)OCH3, —C(O)NH(CH2CH2OCH3), —CH(OH)(cyclopropyl), —CH(OH)(phenyl), —CH═CH2, —C(CH3)═CH2, or —C≡CH;
    • R3 is:
  • Figure US20190292176A1-20190926-C00006
  • R3a, at each occurrence, is independently:
    • (i) F, Cl, —CN, —OH, —CH3, —CF3, —CHFC(CH3)3, cyclopropyl, —CH2OH, —CD2OH, —CH2CH2OH, —CH(OH)CH3, —C(CH3)2OH, —CH(OH)C(CH3)3, —CD(OH)C(CH3)3, —CH(OH)CF3, —CH(OH)CH2CF3, —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substituted with phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl), —CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl), —CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted with phenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl), —CH(OH)(phenyl), —CH(OH)(isopropylphenyl), —CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl), —CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl), —CH(OH)(methyltetrahydropyranyl), —CH2OCH3, —CH2N(CH3)2, —CH2NHS(O)2(phenyl), or —CH(OH)CH2(phenyl);
    • (ii) —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCHF2, —OCH2(phenyl), —OCH2(thiazolyl), —OCH2(oxazolidinonyl), —OCH2(amino isoxazolyl), —OCH2(imidazolyl substituted with phenyl), —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2CH2OCH3, —OCH(CH3)CH2OH, —OCH2CH(OH)CH3, —OCH(CH3)CH(OH)CH3, —OCH2C(CH3)2OH, —OCH2CH2O(phenyl), —OCH2CH2OCH2(phenyl), —OCH2CH2NH(CH3), —OCH2CH(CH3)NH(methoxy pyrimidinyl), —OCH2C(O)OH, —OCH2C(O)OCH3, —OCH2C(O)OCH2CH3, —OCH2C(O)OC(CH3)3, —OCH2C(O)NH(phenyl), —OCH2C(O)NHCH2(phenyl), —OCH2C(O)(morpholinyl), —OCH2CH2CH2C(O)NH(pyridinyl), —OCH2CH2OC(O)OCH3, —OCH2CH(CH3)OC(O)NHCH2CH2C(O)NH2, —OCH2CH(CH2CH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OC(CH3)3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2(phenyl))OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyrimidinyl), or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(methyl pyrimidinyl);
    • (iii) —C(O)OH, —C(O)OCH3, or —C(O)OC(CH3)3;
    • (iv) —NHC(O)OCH3, —NHC(O)OC(CH3)3, —NHC(O)OCH2(phenyl), —NHC(O)OCH2(tetrahydrofuranyl), or —NHC(O)O(tetrahydropyranyl);
    • (v) —OCH2CH2NHC(O)OCH3, —OCH2CH2NHC(O)O(tetrahydropyranyl), —OCH2CH2NHC(O)OCH2(phenyl), —OCH2CH2NHC(O)O(methoxyphenyl), —OCH2CH2NHC(O)O(tetrahydrofuranyl), —OCH2CH2NHC(O)OCH2(tetrahydrofuranyl), —OCH2CH2NHC(O)NH(pyridinyl), —OCH2CH2N(CH3)C(O)NH(methylpyrimidinyl), or —OCH2CH(CH3)OC(O)OCH2(aminopyridinyl);
    • (vi) —OCH2CH2NHS(O)2CH3 or —OCH2CH2NHS(O)2Rw wherein Rw is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, Cl, and —CH3; or
    • (vii) —OCH2CH2OC(O)NHRz, —OCH(CH3)CH2OC(O)NHRz, —OCH2CH(CH3)OC(O)NHRz, —OCH(CH3)CH(CH3)OC(O)NHRz, —OCH2CH(CH2O(isobutyl))OC(O)NHRz, —OCH2CH(CH2CH3)OC(O)NHRz, —OCH2CH(CH2OCH3)OC(O)NHRz, or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NHRz
      wherein Rz is H, —CH2CF3, phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH2(pyrazolyl), —CH2(imidazolyl), or —CH2(pyridinyl), each substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, —CH3, —CH2CH2CH3, —CF3, —CH2OH, —CD2OH, —CH(CH3)OH, —CH2CH2OH, —CH2CH2CH2OH, —C(CH3)2OH, —CH2CH(CH3)OH, —CH2C(CH3)2OH, —CH2CH2C(O)OCH3, —CH2OP(O)(OH)2, —CH2CH2OP(O)(OH)2, —CH2(morpholinyl), —OCH3, —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2C(CH3)2OH, —OCH2CH2C(CH3)2OH, —OCH(CH3)CH2OH, —OCH2CH(OH)CH2OH, —OCH2CF2OH, —OCH2CF2CH2OH, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)NH(CH2CH(CH3)OH), —C(O)NH(CH2C(CH3)2OH), —C(O)NH(CH2C(CH3)2CH2OH), —C(O)NH(CH2CH2C(CH3)2OH), —C(O)N(CH3)CH2CH2OH, —C(O)N(CH3)CH2C(CH3)2OH, —C(O)NHCH2(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl), —C(O)NHCH2(hydroxycyclobutyl), —C(O)NHCH2(hydroxymethylcyclobutyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH2, —N(CH3)2, —NHC(O)CH3, —NHC(O)(chloro, fluorophenyl), —NH(CH2C(CH3)2OH), —N(CH3)S(O)2CH3, pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl;
      R4 is H, F, or —CH3; and
      p is zero, 1, 2, or 3.
  • One embodiment provides at least one compound of Formulas (I), (II), (III) or (IV) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
  • Figure US20190292176A1-20190926-C00007
  • p is zero, 1, 2, or 3; and R3a is defined in the first aspect. Also included in this embodiment are compounds in which R4 is H, F, or —CH3.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formulas (I) or (II) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (I) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (II) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (III) or a salt thereof, wherein R1, R2, R3, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (IV) or a salt thereof, wherein R1, R2, R3, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (V) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (VI) or a salt thereof, wherein R1, R2, R3, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (VII) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (VIII) or a salt thereof, wherein R1, R2, R3, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (I) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
  • Figure US20190292176A1-20190926-C00008
  • p is zero, 1, 2, or 3; and R3a is defined in the first aspect. Also included in this embodiment are compounds in which R4 is H, F, or —CH3.
  • One embodiment provides at least one compound of Formulas (I) or (II) or a salt thereof, wherein R1, R2, R3, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
  • Figure US20190292176A1-20190926-C00009
  • p is zero, 1, 2, or 3; and R3a is defined in the first aspect.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), or (VIII) or a salt thereof, wherein R3 is:
  • Figure US20190292176A1-20190926-C00010
  • Rm is H or Cl; Rk is H or F; and R1, R2, R3a, R4, and n are defined in the first aspect. Included in this embodiment are compounds of Formula (I).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R3 is:
  • Figure US20190292176A1-20190926-C00011
  • and R1, R2, R3a, R4, and n are defined in the first aspect. Included in this embodiment are compounds of Formula (I).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1 is —OH, C1-2 alkyl, —CHFCH3, —CH═CH2, C1-3 alkoxy, C1-2 fluoroalkoxy, —OCH2CH2OH, —CH2O(C1-2 alkyl), —CD2OCD3, —CH2OCHF2, —CF2OCH3, —CH2O(phenyl), —CH(CH3)OCH3, —NH(CH3), —N(CH3)2, —CH2N(CH3)2, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)OCH3, —CH(CH3)OCH3, cyclopropyl, furanyl, or —O(cyclopropyl); and R2, R3, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R1 is —CH2OCH3, —OCH3, or —OCHF2.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R2, at each occurrence, is independently H, F, Cl, —CN, —CH3, —CH2F, —CHF2, —CF3, —OCH3, —OCF3, —CH2OH, —CH2CH2OH, —CH(CH3)OH, —C(CH3)2OH, —CH(OH)CH2OH, —CH2NH2, —C(O)NH2, —C(O)N(CH3)2, —C(O)(piperidinyl), —C(O)OCH3, —C(O)NH(CH2CH2OCH3), —CH(OH)(cyclopropyl), —CH(OH)(phenyl), —CH═CH2, —C(CH3)═CH2, or —C≡CH; and R1, R3, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R2 is F, Cl, —CN, —CH3, or —CH2OH. Also included in this embodiment are compounds in which R2 is —CH3.
  • One embodiment provides at least one compound of Formula (I), (II), (V), and (VII) or a salt thereof, wherein R4 is H, F, or —CH3; and R1, R2, R3, and n are defined in the first aspect. Included in this embodiment are compounds in which R4 is H and F. Also included in this compounds in which R4 is H.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R3a, at each occurrence, is independently, (i) F, Cl, —CN, —OH, —CH3, —CF3, —CHFC(CH3)3, cyclopropyl, —CH2OH, —CD2OH, —CH2CH2OH, —CH(OH)CH3, —C(CH3)2OH, —CH(OH)C(CH3)3, —CD(OH)C(CH3)3, —CH(OH)CF3, —CH(OH)CH2CF3, —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substituted with phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl), —CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl), —CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted with phenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl), —CH(OH)(phenyl), —CH(OH)(isopropylphenyl), —CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl), —CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl), —CH(OH)(methyltetrahydropyranyl), —CH2OCH3, —CH2N(CH3)2, —CH2NHS(O)2(phenyl), or —CH(OH)CH2(phenyl); (ii) —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCHF2, —OCH2(phenyl), —OCH2(thiazolyl), —OCH2(oxazolidinonyl), —OCH2(amino isoxazolyl), —OCH2(imidazolyl substituted with phenyl), —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2CH2OCH3, —OCH(CH3)CH2OH, —OCH2CH(OH)CH3, —OCH(CH3)CH(OH)CH3, —OCH2C(CH3)2OH, —OCH2CH2O(phenyl), —OCH2CH2OCH2(phenyl), —OCH2CH2NH(CH3), —OCH2CH(CH3)NH(methoxy pyrimidinyl), —OCH2C(O)OH, —OCH2C(O)OCH3, —OCH2C(O)OCH2CH3, —OCH2C(O)OC(CH3)3, —OCH2C(O)NH(phenyl), —OCH2C(O)NHCH2(phenyl), —OCH2C(O)(morpholinyl), —OCH2CH2CH2C(O)NH(pyridinyl), —OCH2CH2OC(O)OCH3, —OCH2CH(CH3)OC(O)NHCH2CH2C(O)NH2, —OCH2CH(CH2CH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OC(CH3)3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2(phenyl))OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyrimidinyl), or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(methyl pyrimidinyl); (iii) —C(O)OH, —C(O)OCH3, or —C(O)OC(CH3)3; (iv) —NHC(O)OCH3, —NHC(O)OC(CH3)3, —NHC(O)OCH2(phenyl), —NHC(O)OCH2(tetrahydrofuranyl), or —NHC(O)O(tetrahydropyranyl); (v) —OCH2CH2NHC(O)OCH3, —OCH2CH2NHC(O)O(tetrahydropyranyl), —OCH2CH2NHC(O)OCH2(phenyl), —OCH2CH2NHC(O)O(methoxyphenyl), —OCH2CH2NHC(O)O(tetrahydrofuranyl), —OCH2CH2NHC(O)OCH2(tetrahydrofuranyl), —OCH2CH2NHC(O)NH(pyridinyl), —OCH2CH2N(CH3)C(O)NH(methylpyrimidinyl), or —OCH2CH(CH3)OC(O)OCH2(aminopyridinyl); (vi) —OCH2CH2NHS(O)2CH3 or —OCH2CH2NHS(O)2Rw wherein Rw is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, Cl, and —CH3; or (vii) —OCH2CH2OC(O)NHRz, —OCH(CH3)CH2OC(O)NHRz, —OCH2CH(CH3)OC(O)NHRz, —OCH(CH3)CH(CH3)(CH2)0-2OC(O)NHRz, —OCH2CH(CH2O(isobutyl))(CH2)0-2OC(O)NHRz, —OCH2CH(CH2CH3)OC(O)NHRz, —OCH2CH(CH2OCH3)OC(O)NHRz, or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NHRz wherein Rz is H, —CH2CF3, phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH2(pyrazolyl), —CH2(imidazolyl), or —CH2(pyridinyl), each substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, —CH3, —CH2CH2CH3, —CF3, —CH2OH, —CD2OH, —CH(CH3)OH, —CH2CH2OH, —CH2CH2CH2OH, —C(CH3)2OH, —CH2CH(CH3)OH, —CH2C(CH3)2OH, —CH2CH2C(O)OCH3, —CH2OP(O)(OH)2, —CH2CH2OP(O)(OH)2, —CH2(morpholinyl), —OCH3, —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2C(CH3)2OH, —OCH2CH2C(CH3)2OH, —OCH(CH3)CH2OH, —OCH2CH(OH)CH2OH, —OCH2CF2OH, —OCH2CF2CH2OH, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)NH(CH2CH(CH3)OH), —C(O)NH(CH2C(CH3)2OH), —C(O)NH(CH2C(CH3)2CH2OH), —C(O)NH(CH2CH2C(CH3)2OH), —C(O)N(CH3)CH2CH2OH, —C(O)N(CH3)CH2C(CH3)2OH, —C(O)NHCH2(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl), —C(O)NHCH2(hydroxycyclobutyl), —C(O)NHCH2(hydroxymethylcyclobutyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH2, —N(CH3)2, —NHC(O)CH3, —NHC(O)(chloro, fluorophenyl), —NH(CH2C(CH3)2OH), —N(CH3)S(O)2CH3, pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl; and R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R3 is substituted with one R3a selected from (i) F, Cl, —CN, —OH, —CH3, —CF3, —CHFC(CH3)3, cyclopropyl, —CH2OH, —CD2OH, —CH2CH2OH, —CH(OH)CH3, —C(CH3)2OH, —CH(OH)C(CH3)3, —CD(OH)C(CH3)3, —CH(OH)CF3, —CH(OH)CH2CF3, —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substituted with phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl), —CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl), —CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted with phenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl), —CH(OH)(phenyl), —CH(OH)(isopropylphenyl), —CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl), —CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl), —CH(OH)(methyltetrahydropyranyl), —CH2OCH3, —CH2N(CH3)2, —CH2NHS(O)2(phenyl), or —CH(OH)CH2(phenyl); (ii) —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCHF2, —OCH2(phenyl), —OCH2(thiazolyl), —OCH2(oxazolidinonyl), —OCH2(amino isoxazolyl), —OCH2(imidazolyl substituted with phenyl), —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2CH2OCH3, —OCH(CH3)CH2OH, —OCH2CH(OH)CH3, —OCH(CH3)CH(OH)CH3, —OCH2C(CH3)2OH, —OCH2CH2O(phenyl), —OCH2CH2OCH2(phenyl), —OCH2CH2NH(CH3), —OCH2CH(CH3)NH(methoxy pyrimidinyl), —OCH2C(O)OH, —OCH2C(O)OCH3, —OCH2C(O)OCH2CH3, —OCH2C(O)OC(CH3)3, —OCH2C(O)NH(phenyl), —OCH2C(O)NHCH2(phenyl), —OCH2C(O)(morpholinyl), —OCH2CH2CH2C(O)NH(pyridinyl), —OCH2CH2OC(O)OCH3, —OCH2CH(CH3)OC(O)NHCH2CH2C(O)NH2, —OCH2CH(CH2CH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OC(CH3)3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2(phenyl))OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyrimidinyl), or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(methyl pyrimidinyl); (iii) —C(O)OH, —C(O)OCH3, or —C(O)OC(CH3)3; (iv) —NHC(O)OCH3, —NHC(O)OC(CH3)3, —NHC(O)OCH2(phenyl), —NHC(O)OCH2(tetrahydrofuranyl), or —NHC(O)O(tetrahydropyranyl); (v) —OCH2CH2NHC(O)OCH3, —OCH2CH2NHC(O)O(tetrahydropyranyl), —OCH2CH2NHC(O)OCH2(phenyl), —OCH2CH2NHC(O)O(methoxyphenyl), —OCH2CH2NHC(O)O(tetrahydrofuranyl), —OCH2CH2NHC(O)OCH2(tetrahydrofuranyl), —OCH2CH2NHC(O)NH(pyridinyl), —OCH2CH2N(CH3)C(O)NH(methylpyrimidinyl), or —OCH2CH(CH3)OC(O)OCH2(aminopyridinyl); (vi) —OCH2CH2NHS(O)2CH3 or —OCH2CH2NHS(O)2Rw wherein Rw is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, Cl, and —CH3; or (vii) —OCH2CH2OC(O)NHRz, —OCH(CH3)CH2OC(O)NHRz, —OCH2CH(CH3)OC(O)NHRz, —OCH(CH3)CH(CH3)(CH2)0-2OC(O)NHRz, —OCH2CH(CH2O(isobutyl))(CH2)0-2OC(O)NHRz, —OCH2CH(CH2CH3)OC(O)NHRz, —OCH2CH(CH2OCH3)OC(O)NHRz, or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NHRz wherein Rz is H, —CH2CF3, phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH2(pyrazolyl), —CH2(imidazolyl), or —CH2(pyridinyl), each substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, —CH3, —CH2CH2CH3, —CF3, —CH2OH, —CD2OH, —CH(CH3)OH, —CH2CH2OH, —CH2CH2CH2OH, —C(CH3)2OH, —CH2CH(CH3)OH, —CH2C(CH3)2OH, —CH2CH2C(O)OCH3, —CH2OP(O)(OH)2, —CH2CH2OP(O)(OH)2, —CH2(morpholinyl), —OCH3, —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2C(CH3)2OH, —OCH2CH2C(CH3)2OH, —OCH(CH3)CH2OH, —OCH2CH(OH)CH2OH, —OCH2CF2OH, —OCH2CF2CH2OH, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)NH(CH2CH(CH3)OH), —C(O)NH(CH2C(CH3)2OH), —C(O)NH(CH2C(CH3)2CH2OH), —C(O)NH(CH2CH2C(CH3)2OH), —C(O)N(CH3)CH2CH2OH, —C(O)N(CH3)CH2C(CH3)2OH, —C(O)NHCH2(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl), —C(O)NHCH2(hydroxycyclobutyl), —C(O)NHCH2(hydroxymethylcyclobutyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH2, —N(CH3)2, —NHC(O)CH3, —NHC(O)(chloro, fluorophenyl), —NH(CH2C(CH3)2OH), —N(CH3)S(O)2CH3, pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl; and zero to 2 R3a independently selected from F, Cl, —CN, —CH3, —CF3, and —OCH3; and R1, R2, R3, R4, and n are defined in the first aspect.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, Ra, Rb, Rd, and n are defined in the first aspect with the proviso that at least one R3a is F, Cl, —CN, —OH, C1-3 alkyl, C1-6 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxy-fluoroalkyl, C1-6 alkoxy, C1-3 fluoroalkoxy, C3-6 cycloalkyl, C3-6 fluorocycloalkyl, 3- to 6-membered heterocyclyl, —CH(OH)Ry wherein Ry is C3-6 cycloalkyl, aryl, heteroaryl, or 3- to 6-membered heterocyclyl; (C1-3 alkoxy)-(C1-3 alkylene), —(CH2)1-3NRaRa, —(CH2)1-3 NHS(O)2(aryl), —O(CH2)1-3 (aryl), —O(CH2)1-3 (thiazolyl), —O(CH2)1-3 (oxazolidinonyl), —O(CH2)1-3 (amino isoxazolyl), —O(CH2)1-3 (imidazolyl substituted with phenyl), C1-6 hydroxyalkoxy, (C1-3 alkoxy)-(C1-6 alkoxy), —O(CH2)1-4O(aryl), —O(CH2)1-4O(CH2)1-3 (aryl), —O(CH2)1-4NRaRa, —O(CH2)1-3CHRaRa(methoxy pyrimidinyl), —O(CH2)1-4 NHS(O)2(C1-3 alkyl), —O(CH2)1-4NHS(O)2(aryl), —O(CH2)1-4C(O)OH, —O(CH2)1-4C(O)O(C1-6 alkyl), —O(CH2)1-4C(O)NRa(CH2)0-3 (aryl), —O(CH2)1-4C(O)NRa(CH2)0-3 (heteroaryl), —O(CH2)1-4C(O)(morpholinyl), —O(CH2)1-4OC(O)O(C1-3 alkyl), —O(CH2)1-3 CHRaOC(O)NRa(CH2)1-4C(O)NRaRa, —CH2CHRdOC(O)NRa(heteroaryl), —O(CH2)1-4OC(O)NRa(heteroaryl), —O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C1-6 alkyl), —NRaC(O)(furanyl), —NRaC(O)(pyranyl), —NRaC(O)O(C1-6 alkyl), —NRaC(O)O(CH2)1-4 (aryl), —O(CH2)1-4NRaC(O)O(C1-6 alkyl), —O(CH2)1-4NRaC(O)O(CH2)0-4 (tetrahydropyranyl), —O(CH2)1-4NRaC(O)O(CH2)0-4 (aryl), —O(CH2)1-4NRaC(O)O(CH2)0-4 (heteroaryl), or —O(CH2)1-4NRaC(O)O(CH2)0-4(tetrahydrofuranyl), wherein each of said aryl, heteroaryl, and 3- to 6-membered heterocyclyl is substituted with zero to 5 substituents independently selected from F, Cl, —CN, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy, —OCF3, —OCHF2, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —C(O)O(C1-3 alkyl), C1-3 hydroxyalkoxy, phenyl, —CONRcRc, and —S(O)2NRcRc.
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, Ra, Rb, Rd, and n are defined in the first aspect with the proviso that at least one R3a is —CH(OH)CRhRiRj wherein Rh and Ri are independently H, F, C1-4 alkyl, C1-3 alkoxy, or taken together with the carbon atom to which they are attached, form C3-8 cycloalkyl or 4- to 7-membered heterocyclyl ring; and Rj is H, C1-6 alkyl, C1-5 fluoroalkyl, (C1-3 alkoxy)-(C1-3 alkylene), C3-8 cycloalkyl, C3-8 heterocyclyl, aryl, or heteroaryl; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, Ra, Rb, Rd, and n are defined in the first aspect with the proviso that at least one R3a is —O(CH2)1-4NRaS(O)2(C1-3 alkyl) or —O(CH2)1-4NRaS(O)2Rw, wherein Rw is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, Cl, cyano, C1-3 alkyl, C1-3 alkoxy, —OCF3, —OCHF2, and C1-3 fluoroalkyl; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, Ra, Rb, Rd, and n are defined in the first aspect with the proviso that at least one R3a is —O(CH2)1-4OC(O)NRaRx, —OCH(Rd)(CH2)1-3OC(O)NRaRx, —OCRdRd(CH2)1-3OC(O)NRaRx, —O(CH2)1-3 CH(Rd)OC(O)NRaRx, —O(CH2)1-3CRdRdOC(O)NRaRx, —OCH(Rd)CH(Rd)(CH2)0-2OC(O)NRaRx, or —OCRdRdCRdRd(CH2)0-2OC(O)NRaRx, wherein Rx is selected from H, C1-4 alkyl, C1-4 fluoroalkyl, aryl, heteroaryl, and —CH2(heteroaryl), each aryl and heteroaryl substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxyalkoxy, C1-6 hydroxy-fluoroalkoxy, C1-3 alkoxy, —C(O)OH, —(CH2)0-3C(O)O(C1-3 alkyl), —(CH2)1-3OP(O)(OH)2, —CH2(morpholinyl), —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —C(O)NRa(C1-6 hydroxyalkyl), —C(O)NRbRb, —S(O)2NRaRa, —NH2, —NH(C1-6 alkyl), —NRa(C1-6 hydroxyalkyl), —N(C1-6 alkyl)2, —NRaC(O)(C1-6 alkyl), —NRaC(O)(chloro, fluorophenyl), —NRaS(O)2(C1-3 alkyl), —C(O)NRa(CH2)0-1(hydroxymethyloxetanyl), —C(O)NRa(CH2)0-1 (hydroxymethyl C3-6 cycloalkyl), —C(O)NRa(CH2)0-1 (hydroxy C3-6 cycloalkyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is F, Cl, —CN, —OH, —CH3, —CF3, —CHFC(CH3)3, cyclopropyl, —CH2OH, —CD2OH, —CH2CH2OH, —CH(OH)CH3, —C(CH3)2OH, —CH(OH)C(CH3)3, —CD(OH)C(CH3)3, —CH(OH)CF3, —CH(OH)CH2CF3, —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substituted with phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl), —CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl), —CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted with phenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl), —CH(OH)(phenyl), —CH(OH)(isopropylphenyl), —CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl), —CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl), —CH(OH)(methyltetrahydropyranyl), —CH2OCH3, —CH2N(CH3)2, —CH2NHS(O)2(phenyl), or —CH(OH)CH2(phenyl); and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCHF2, —OCH2(phenyl), —OCH2(thiazolyl), —OCH2(oxazolidinonyl), —OCH2(amino isoxazolyl), —OCH2(imidazolyl substituted with phenyl), —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2CH2OCH3, —OCH(CH3)CH2OH, —OCH2CH(OH)CH3, —OCH(CH3)CH(OH)CH3, —OCH2C(CH3)2OH, —OCH2CH2O(phenyl), —OCH2CH2OCH2(phenyl), —OCH2CH2NH(CH3), —OCH2CH(CH3)NH(methoxy pyrimidinyl), —OCH2C(O)OH, —OCH2C(O)OCH3, —OCH2C(O)OCH2CH3, —OCH2C(O)OC(CH3)3, —OCH2C(O)NH(phenyl), —OCH2C(O)NHCH2(phenyl), —OCH2C(O)(morpholinyl), —OCH2CH2CH2C(O)NH(pyridinyl), —OCH2CH2OC(O)OCH3, —OCH2CH(CH3)OC(O)NHCH2CH2C(O)NH2, —OCH2CH(CH2CH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OC(CH3)3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2(phenyl))OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyrimidinyl), or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(methyl pyrimidinyl); and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is —C(O)OH, —C(O)OCH3, or —C(O)OC(CH3)3; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is —NHC(O)OCH3, —NHC(O)OC(CH3)3, —NHC(O)OCH2(phenyl), —NHC(O)OCH2(tetrahydrofuranyl), or —NHC(O)O(tetrahydropyranyl); and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is —OCH2CH2NHC(O)OCH3, —OCH2CH2NHC(O)O(tetrahydropyranyl), —OCH2CH2NHC(O)OCH2(phenyl), —OCH2CH2NHC(O)O(methoxyphenyl), —OCH2CH2NHC(O)O(tetrahydrofuranyl), —OCH2CH2NHC(O)OCH2(tetrahydrofuranyl), —OCH2CH2NHC(O)NH(pyridinyl), —OCH2CH2N(CH3)C(O)NH(methylpyrimidinyl), or —OCH2CH(CH3)OC(O)OCH2(aminopyridinyl); and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is —OCH2CH2NHS(O)2CH3 or —OCH2CH2NHS(O)2Rw wherein Rw is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, Cl, and —CH3; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R1, R2, R3, R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is —OCH2CH2OC(O)NHRz, —OCH(CH3)CH2OC(O)NHRz, —OCH2CH(CH3)OC(O)NHRz, —OCH(CH3)CH(CH3)(CH2)0-2OC(O)NHRz, —OCH2CH(CH2O(isobutyl))(CH2)0-2OC(O)NHRz, —OCH2CH(CH2CH3)OC(O)NHRz, —OCH2CH(CH2OCH3)OC(O)NHRz, or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NHRz wherein Rz is H, —CH2CF3, phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH2(pyrazolyl), —CH2(imidazolyl), or —CH2(pyridinyl), each substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, —CH3, —CH2CH2CH3, —CF3, —CH2OH, —CD2OH, —CH(CH3)OH, —CH2CH2OH, —CH2CH2CH2OH, —C(CH3)2OH, —CH2CH(CH3)OH, —CH2C(CH3)2OH, —CH2CH2C(O)OCH3, —CH2OP(O)(OH)2, —CH2CH2OP(O)(OH)2, —CH2(morpholinyl), —OCH3, —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2C(CH3)2OH, —OCH2CH2C(CH3)2OH, —OCH(CH3)CH2OH, —OCH2CH(OH)CH2OH, —OCH2CF2OH, —OCH2CF2CH2OH, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)NH(CH2CH(CH3)OH), —C(O)NH(CH2C(CH3)2OH), —C(O)NH(CH2C(CH3)2CH2OH), —C(O)NH(CH2CH2C(CH3)2OH), —C(O)N(CH3)CH2CH2OH, —C(O)N(CH3)CH2C(CH3)2OH, —C(O)NHCH2(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl), —C(O)NHCH2(hydroxycyclobutyl), —C(O)NHCH2(hydroxymethylcyclobutyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH2, —N(CH3)2, —NHC(O)CH3, —NHC(O)(chloro, fluorophenyl), —NH(CH2C(CH3)2OH), —N(CH3)S(O)2CH3, pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl; and p is 1, 2, or 3. Included in this embodiment are compounds of Formulas (I), (II), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R3 is substituted with zero to 1 R3a. Included in this embodiment are compounds in which R3 is unsubstituted.
  • One embodiment provides at least one compound of Formula (I) or a salt thereof, wherein R1 is —OCH3, —OCHF2, —OCH2CH3, or —CH2OCH3; R2, at each occurrence, is independently H, F, Cl, —CN, —CH3, —OCH3, or —CH2OH; and
    • R3 is:
  • Figure US20190292176A1-20190926-C00012
  • and R4, R3a, and p are defined in the first aspect.
  • One embodiment provides at least one compound of Formula (II) or a salt thereof, wherein R1 is —OH, —OCH3, —OCH2CH3, —OCHF2, —OCH2CHF2, —CH2OCH3, or —NH(CH3); R2, at each occurrence, is independently F, Cl, —CN, —CH3, —CH2OH, —CH2F, —CHF2, or —OCH3;
    • R3 is:
  • Figure US20190292176A1-20190926-C00013
  • and R3a, at each occurrence, is independently F, Cl, —CH3, —OCH3, —CH(OH)(trifluoromethylcyclobutyl), —OCH2CH(CH3)OC(O)NHRz, or —OCH(CH3)CH(CH3)OC(O)NHRz, wherein Rz is pyridinyl, pyrimidinyl, or benzo[d]oxazolonyl, each substituted with zero to 2 substituents independently selected from F, —OH, —CN, —CH3, —CF3, —CH2OH, —CH2CH2OH, —OCH2CH2OH, —OCH3, —CH2CH(CH3)OH, and —OCH2CH2C(CH3)2OH; and R4 and p are defined in the first aspect.
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is indolyl. Included in this embodiment is a compound of Formula (I) selected from 2-(difluoromethoxy)-5-(1H-indol-2-yl)-7-methylquinoxaline (5).
  • One embodiment provides compounds selected from one of the examples, more preferably, Examples 1 to 837, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is benzofuranyl. Included in this embodiment is a compound of Formulas (I), (II), (III), or (IV) selected from:
    • 5-(benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (1);
    • 2-(difluoromethoxy)-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline (2);
    • 2-(difluoromethoxy)-5-(4,5-dimethoxybenzofuran-2-yl)-7-methylquinoxaline (6);
    • 5-(7-chlorobenzofuran-2-yl)-2-methoxy-7-methylquinoxaline (37);
    • 2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate (38);
    • N-(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl)benzenesulfonamide (39);
    • 2-(difluoromethoxy)-5-(7-methoxybenzofuran-2-yl)-7-methylquinoxaline (41);
    • 2-(difluoromethoxy)-5-(4-methoxybenzofuran-2-yl)-7-methylquinoxaline (42);
    • 5-(4-(benzyloxy)benzofuran-2-yl)-2-methoxy-7-methylquinoxaline (43);
    • 5-(5-(benzyloxy) benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (44); methyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethylcarbamate (46);
    • tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy) acetate (49);
    • 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)-N-methylethanamine (54);
    • 2-methoxy-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline (56);
    • 5-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline (120);
    • 5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline (121);
    • 5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline (122);
    • 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate (123);
    • (8-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol (124); (8-(6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol (125);
    • 2-((6-fluoro-2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate (126);
    • 5-(benzofuran-2-yl)-7-methyl-2-vinylquinoxaline (131);
    • 5-(benzofuran-2-yl)-2-ethyl-7-methylquinoxaline (132);
    • 5-(benzofuran-2-yl)-2-(difluoromethoxy)-8-methylquinoxaline (133);
    • 5-(benzofuran-2-yl)-2-(furan-3-yl)-7-methylquinoxaline (135);
    • 5-(benzofuran-2-yl)-2-methoxy-7-methylquinoxaline (175); methyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate (176);
    • 5-(benzofuran-2-yl)-2-(1-methoxyethyl)-7-methylquinoxaline (184);
    • 5-(benzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline (195); and
    • 5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline (661).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is benzo[b]thiophenyl. Included in this embodiment is a compound of Formula (I) selected from
    • 5-(benzo[b]thiophen-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (40).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is benzo[d]imidazolyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 5-(1H-benzo[d]imidazol-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (47); and
    • 2-(difluoromethoxy)-5-(5-methoxy-1H-benzo[d]imidazol-2-yl)-7-methylquinoxaline (50).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is benzo[d]oxazolyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]oxazole (3).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is benzo[d]thiazolyl. Included in this embodiment is a compound of Formula (I) to (III) selected from:
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole (4);
    • 6-(benzyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole (7);
    • 4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole (8);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole (10);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxy-4-methylbenzo[d]thiazole (12);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-difluoro-7-methoxybenzo[d]thiazole (13);
    • tert-butyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl) carbamate (14);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(thiazol-4-ylmethoxy)benzo[d]thiazole (15);
    • tetrahydrofuran-3-yl (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate (16);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-phenoxyethoxy)benzo[d]thiazole (17);
    • 7-(2-(benzyloxy)ethoxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole (18);
    • (tetrahydrofuran-2-yl)methyl (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl)carbamate (19);
    • tetrahydro-2H-pyran-4-yl (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl)carbamate (20);
    • tetrahydro-2H-pyran-4-yl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-7-yl)carbamate (21);
    • (tetrahydrofuran-2-yl) methyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-7-yl)carbamate (22);
    • 4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (26);
    • N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (27);
    • N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (28);
    • 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (29);
    • N-(2-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethyl)-4-fluorobenzenesulfonamide (30);
    • N-(2-((2-(2-ethyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (31);
    • methyl 5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate (32);
    • N-(2-((2-(2-cyclopropoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (33);
    • 4-fluoro-N-(2-((2-(2-(fluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (34);
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-6-((2-phenyl-1H-imidazol-5-yl)methoxy)benzo[d]thiazole (35);
    • N-benzyl-2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetamide (36);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazole (48);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzo[d]thiazole (51);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (52);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazole (53);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thiazole (55);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxybenzo[d]thiazole (58);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluoro-6-methoxybenzo[d]thiazole (59);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazole (60);
    • methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole-7-carboxylate (61);
    • N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide (63); (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methanol (64);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(methoxymethyl)benzo[d]thiazole (65);
    • N-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methyl)benzenesulfonamide (66);
    • N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy) ethyl) benzenesulfonamide (67);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole (68); methyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethylcarbamate (69);
    • methyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethylcarbamate (70);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(thiazol-4-ylmethoxy)benzo[d]thiazole (71);
    • N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide (72);
    • N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)benzenesulfonamide (73);
    • 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethanol (74);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole (75);
    • benzyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ylcarbamate (76);
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole (77);
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole (78);
    • N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide (79);
    • methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-7-ylcarbamate (80);
    • N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-4-fluorobenzenesulfonamide (81);
    • 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-7-yloxy)-N-phenylacetamide (82);
    • N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-4-(trifluoromethyl) benzenesulfonamide (83);
    • N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-2,4-difluorobenzenesulfonamide (84);
    • N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-3,4-difluorobenzenesulfonamide (85);
    • 4-chloro N (2 (2 (2 (difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide (86);
    • N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-4-methylbenzenesulfonamide (87);
    • 4-fluoro N (2 (2 (2 (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide (89);
    • 4-fluoro N (2 (2 (2 methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide (90);
    • N-(2-(2-(2-cyclopropyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide (91);
    • benzyl 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethylcarbamate (92);
    • 4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (93);
    • 5-(5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline (94);
    • N-(2-(4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide (95);
    • 2-fluoro N (2 (2 (2 (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide (96);
    • 3-fluoro N (2 (2 (2 (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide (97);
    • N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl) methanesulfonamide (98);
    • N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)benzenesulfonamide (99);
    • N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)-2-fluorobenzenesulfonamide (100);
    • N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)-4-fluorobenzenesulfonamide (101);
    • N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)-3-fluorobenzenesulfonamide (102);
    • 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carbonitrile (103);
    • N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide (104);
    • N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide (105);
    • N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)benzenesulfonamide (106);
    • 4-fluoro N (2 (2 (2 (methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide (107);
    • 4-fluoro N (2 (2 (2 (1 fluoroethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide (108);
    • N-(2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide (109);
    • 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl phenylcarbamate (110);
    • 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl pyridin-3-ylcarbamate (111);
    • 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 6-methoxypyridin-3-ylcarbamate (112);
    • 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylpyridin-4-ylcarbamate (113);
    • N-(2-(2-(2-((difluoromethoxy)methyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide (114);
    • 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl 6-methoxypyridin-3-ylcarbamate (115);
    • 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 5-cyanopyridin-3-ylcarbamate (116);
    • 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-cyanopyridin-3-yl) carbamate (117);
    • 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (3-cyanophenyl)carbamate (118);
    • 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (2-chloropyrimidin-5-yl)carbamate (119);
    • 3-methoxy-8-(6-methoxybenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol (127);
    • 2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 6-methylpyridin-3-ylcarbamate (128);
    • 2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 2-methylpyridin-4-ylcarbamate (129);
    • methyl 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylate (152);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol (154);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) methanol (155);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) ethanol (156);
    • 2-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) propan-2-ol (157);
    • cyclopropyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazol-4-yl)methanol (158);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-N,N-dimethylmethanamine (159);
    • cyclopropyl(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) methanol (160);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) (phenyl)methanol (161);
    • 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylic acid (162);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(phenyl) methanol (163);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (164);
    • cyclohexyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol (165);
    • cyclobutyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol (166);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-2-yl)methanol (167);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) (pyridin-3-yl)methanol (168);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d1 (169);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-d5 (170);
    • 2,2,2-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol (171);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-4-yl)methanol (172);
    • 3,3,3-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-1-ol (173);
    • 2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) ethanol (174);
    • 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (183);
    • 2-(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole (186);
    • 6-methoxy-4-methyl-2-(7-methyl-2-(phenoxymethyl)quinoxalin-5-yl)benzo[d]thiazole (187);
    • 1-(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)-N,N-dimethyl methanamine (188);
    • 2-(2-(ethoxymethyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole (189);
    • N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethyl)-4-fluorobenzenesulfonamide (199);
    • N-(2-((2-(7-chloro-2-(methoxymethyl) quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (200);
    • 2-(7-chloro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxybenzo[d]thiazole (201);
    • 2-(7-chloro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxybenzo[d]thiazole (202);
    • 6-methoxy-2-(2-(methoxymethyl)-7-(trifluoromethoxy)quinoxalin-5-yl)-4-methylbenzo[d]thiazole (203);
    • methyl 8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl) quinoxaline-6-carboxylate (204);
    • methyl 8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxy methyl)quinoxaline-6-carboxylate (205);
    • 2-(7-fluoro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole (206);
    • 4-fluoro-N-(2-((2-(7-fluoro-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (207);
    • 6-methoxy-2-(2-(methoxymethyl)-7-(trifluoromethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazole (208);
    • 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(trifluoromethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (209);
    • 4-chloro-2-(7-chloro-2-(methoxymethyl) quinoxalin-5-yl)-6-methoxybenzo[d]thiazole (210);
    • 3-methoxy-8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)quinoxaline-6-carbonitrile (211);
    • 4-chloro-6-methoxy-2-(2-(methoxymethyl) quinoxalin-5-yl)benzo[d]thiazole (212);
    • 4-fluoro-N-(2-((2-(2-(methoxymethyl) quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (213);
    • 2-(7-chloro-2-methoxyquinoxalin-5-yl)-4,5-difluoro-6-methoxybenzo[d]thiazole (214);
    • 4-chloro-2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluoro-6-methoxybenzo[d]thiazole (215);
    • 4-chloro-5-fluoro-6-methoxy-2-(2-methoxy-6,7-dimethylquinoxalin-5-yl)benzo[d]thiazole (216);
    • 8-(4,5-difluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile (217);
    • (8-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol (218);
    • (3-methoxy-8-(6-methoxy-4,5-dimethylbenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol (219);
    • (8-(4,5-difluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol (220);
    • 8-(5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile (221);
    • (8-(5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol (222);
    • (8-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-5-fluoro-3-methoxyquinoxalin-6-yl)methanol (224);
    • 8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carboxamide (225);
    • 8-(6-(2-(4-fluorophenylsulfonamido) ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)-N,N-dimethylquinoxaline-6-carboxamide (226);
    • 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(piperidine-1-carbonyl) quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (227);
    • 8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-N-(2-methoxyethyl)-3-(methoxymethyl)quinoxaline-6-carboxamide (228);
    • 4-fluoro-N-(2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethyl) benzenesulfonamide (229);
    • N-(2-((2-(7-ethynyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (230);
    • N-(2-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (231);
    • N-(2-((2-(7-cyano-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl) oxy)ethyl)-4-fluorobenzenesulfonamide (232);
    • 8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carbonitrile (233);
    • 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (234);
    • 4-fluoro-N-(2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (235);
    • N-(2-((2-(7-(1,2-dihydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (236);
    • 4-fluoro-N-(2-((2-(7-(2-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (237);
    • N-(2-((2-(7-(aminomethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethyl)-4-fluorobenzenesulfonamide (238);
    • 4-fluoro-N-(2-((2-(7-(1-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (239);
    • 4-fluoro-N-(2-((2-(7-(hydroxy (phenyl)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (240);
    • 4-fluoro-N-(2-((2-(2-methoxy-7-(prop-1-en-2-yl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) benzenesulfonamide (241);
    • 4-fluoro-N-(2-((2-(7-(2-hydroxypropan-2-yl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (242);
    • (8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl) methanol (243); 1-(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl) ethanol (244);
    • (8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl) (phenyl)methanol (245);
    • cyclopropyl(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol (246);
    • 4-fluoro-N-(2-((2-(7-fluoro-2-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (247);
    • (8-(5-fluoro-6-isopropoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol (248);
    • N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethyl)pyridine-3-sulfonamide (249);
    • ethyl 2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) acetate (250);
    • 2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetic acid (251);
    • 2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethyl (6-methoxypyridin-3-yl)carbamate (252);
    • 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (253);
    • 4-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazole (254);
    • 6-ethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (255);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (256);
    • 4,6-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (257);
    • 4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (258);
    • 4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (259);
    • 4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (260);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (261);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl-6-(trifluoromethoxy)benzo[d]thiazole (262);
    • 6-(difluoromethoxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (263);
    • methyl 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole-6-carboxylate (264);
    • 4-chloro-7-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (265);
    • 4-chloro-6-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (266);
    • 4,5-difluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (267);
    • 5-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (268);
    • 5,6-difluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (269);
    • 6-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (270);
    • 5-fluoro-4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (271);
    • 6-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (272);
    • 4-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (273);
    • 6-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (274);
    • 4,6-dichloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (275);
    • 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole (276);
    • 5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (277);
    • 4,5-difluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (278);
    • 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole (279);
    • 5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (280);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol (281);
    • 4-chloro-5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (282);
    • 4-chloro-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (283);
    • 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazole (284);
    • methyl 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetate (285);
    • methyl 2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetate (286);
    • methyl 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)acetate (287);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol (288);
    • 2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol (289);
    • 5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol (290);
    • 4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-ol (291);
    • methyl 2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)acetate (292);
    • 2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol (293);
    • 5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (294);
    • 5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (295);
    • methyl 2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetate (296);
    • 2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethanol (297);
    • 4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole (298);
    • 4-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole (299);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)methanol (300);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)methanol (301);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-fluoropyridin-3-yl)carbamate (302);
    • 2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-fluoropyridin-3-yl) carbamate (303);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (6-fluoropyridin-3-yl)carbamate (304);
    • 2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl(6-fluoropyridin-3-yl)carbamate (305);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol (306);
    • 6-(benzyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (307);
    • (2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)methanol (308);
    • 6-(methoxymethyl)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (309);
    • 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-ol (310);
    • 5,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (311);
    • (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-yl) methanol (312);
    • 6-chloro-5-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazole (313);
    • 4-cyclopropyl-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (314);
    • 6-ethoxy-4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (315);
    • N-(2-((4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide (316);
    • N-(2-((4,5-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide (317);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol (318);
    • 1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)-2-methylpropan-2-ol (319);
    • 2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethyl methyl carbonate (320);
    • 2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-1-ol (racemate) (321);
    • 1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-2-ol (racemate) (322);
    • 3-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)butan-2-ol (diastereomeric) (323);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-1-morpholinoethanone (324);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl) methanol (bis-deuterated) (325);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)ethanol (326);
    • 2-((4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-6-yl)oxy)ethanol (327);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (racemate) (328);
    • 5-fluoro-6-isopropoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazole (329);
    • N-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (330);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-3-ylcarbamate (331);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (6-methoxypyridin-3-yl)carbamate (332);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (333);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2,2,2-trifluoroethyl)carbamate (334);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-4-ylcarbamate (335);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate (336);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (5-fluoropyridin-3-yl)carbamate (337);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)carbamate (338);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl pyridin-3-ylcarbamate (339);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (6-fluoropyridin-3-yl)carbamate (340);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (6-methoxypyridin-3-yl)carbamate (341);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-4-ylcarbamate (342);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (343);
    • (R)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl pyridin-3-ylcarbamate (344);
    • (S)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl pyridin-3-ylcarbamate (345);
    • (S)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)propan-2-ylpyridin-3-ylcarbamate (346);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyridin-3-ylcarbamate (347);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-fluoropyridin-3-yl)carbamate (348);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyridin-4-ylcarbamate (349);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (350);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) propan-2-yl (6-cyanopyridin-3-yl)carbamate (351);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (3-amino-3-oxopropyl) carbamate (352);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyridazin-4-ylcarbamate (353);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (354);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)propan-2-yl 1H-indol-5-ylcarbamate (355);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (1-methyl-1H-indol-5-yl)carbamate (356);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (357);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) ethyl carbamate (358);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (359);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl 1H-indol-5-ylcarbamate (360);
    • methyl 5-(((2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethoxy)carbonyl)amino)picolinate (361);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-methylpyrimidin-5-yl)carbamate (362);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (5-methoxy-1,2,4-thiadiazol-3-yl)carbamate (363);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl 1H-pyrazol-4-ylcarbamate (364);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) ethyl (1-methyl-1H-pyrazol-4-yl)carbamate (365);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (5-methyl-1,3,4-oxadiazol-2-yl) carbamate (366);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate (367);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) ethyl (pyridin-3-ylmethyl)carbamate (368);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (pyridin-4-ylmethyl)carbamate (369);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (5-methyl-1,3,4-thiadiazol-2-yl)carbamate (370);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-cyanopyridin-3-yl)carbamate (371);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyridin-3-ylcarbamate (372);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (373);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(trifluoromethyl)pyridin-3-yl)carbamate (374);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl 3H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (375);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (4-methylpyridin-3-yl) carbamate (376);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-methylpyridin-3-yl)carbamate (377);
    • methyl 4-(((2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethoxy)carbonyl)amino)-1-methyl-1H-pyrrole-2-carboxylate (378);
    • 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-yl pyridin-3-ylcarbamate (379);
    • 1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyridin-3-ylcarbamate (380);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate (racemate) (381);
    • (S)-2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate (382);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-chlorothiazol-4-yl)carbamate (383);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl thiazol-5-ylcarbamate (384);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate (385);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (386);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (387);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy) pyridin-4-yl)carbamate (388);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (389);
    • (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylamino)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (390);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-carbamoylpyridin-3-yl)carbamate (391);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((2-hydroxyethyl) carbamoyl)pyridin-3-yl)carbamate (392);
    • (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (393);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl ((1-methyl-1H-imidazol-4-yl)methyl)carbamate (394);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate (395);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (pyridin-2-ylmethyl)carbamate (396);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl ((1-methyl-1H-imidazol-4-yl)methyl)carbamate (397);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl ((1-methyl-1H-pyrazol-3-yl)methyl)carbamate (398);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl ((1-methyl-1H-pyrazol-4-yl)methyl)carbamate (399);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-cyanopyrimidin-5-yl)carbamate (400);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-chloropyrimidin-5-yl)carbamate (401);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-fluoro-5-methylpyridin-3-yl)carbamate (402);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-bromopyridin-3-yl)carbamate (403);
    • (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (404);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-methylpyridin-3-yl)carbamate (405);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (406);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methoxypyrimidin-5-yl)carbamate (407);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-methoxypyrimidin-5-yl)carbamate (408);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyrimidin-5-ylcarbamate (409);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl pyrimidin-5-ylcarbamate (410);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl phenylcarbamate (411);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methoxypyridin-4-yl)carbamate (412);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl pyridazin-4-ylcarbamate (413);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-propylpyrimidin-5-yl)carbamate (414);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(trifluoromethyl)pyrimidin-5-yl)carbamate (415);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-methylpyridazin-3-yl)carbamate (416);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-methylpyrazin-2-yl)carbamate (417);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-methylpyridazin-4-yl)carbamate (418);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-methylpyridin-3-yl)carbamate (419);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-methoxypyridin-3-yl)carbamate (420);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-cyanopyridin-3-yl)carbamate (421);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-methoxy-5-methylpyridin-3-yl)carbamate (422);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (423);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-methylpyrimidin-5-yl)carbamate (424);
    • (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (425);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate (426);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-carbamoylpyridin-4-yl)carbamate (427);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(methylcarbamoyl)pyridin-4-yl)carbamate (428);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-carbamoylpyrimidin-5-yl)carbamate (429);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(methylcarbamoyl)pyrimidin-5-yl)carbamate (430);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(dimethylcarbamoyl)pyrimidin-5-yl)carbamate (431);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(methylcarbamoyl)pyridin-3-yl)carbamate (432);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-carbamoylpyridin-3-yl)carbamate (433);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-carbamoylpyridin-3-yl)carbamate (434);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate (435);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(methylcarbamoyl)pyridin-3-yl)carbamate (436);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(morpholine-4-carbonyl)pyrimidin-5-yl)carbamate (437);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(dimethylcarbamoyl)pyridin-3-yl)carbamate (438);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (439);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(methylcarbamoyl)pyrimidin-5-yl)carbamate (440);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (441);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-((2-hydroxyethyl)carbamoyl)pyridin-4-yl)carbamate (442);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(methylcarbamoyl)pyridin-4-yl)carbamate (443);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-carbamoylpyridin-4-yl)carbamate (444);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)carbamate (445);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-3-yl)carbamate (446);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(dimethylcarbamoyl)pyridin-4-yl)carbamate (447);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate (448);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (449);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (450);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((2-hydroxyethyl)carbamoyl)pyridin-4-yl)carbamate (451);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropyl)carbamoyl)pyridin-4-yl)carbamate (452);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-carbamoylpyridin-4-yl)carbamate (453);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-carbamoylpyrimidin-5-yl)carbamate (454);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (455);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (456);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((2-hydroxy-2-methylpropyl)carbamoyl)pyrimidin-5-yl)carbamate (457);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((3-hydroxy-3-methylbutyl)carbamoyl)pyrimidin-5-yl)carbamate (458);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)carbamate (459);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate (460);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((S)-2-hydroxypropyl)carbamoyl)pyridin-4-yl)carbamate (461);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((S)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (462);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((1-hydroxycyclobutyl)methyl)carbamoyl)pyrimidin-5-yl)carbamate (463);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-3-yl)carbamate (464);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-4-yl)carbamate (465);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(methylcarbamoyl)pyridin-4-yl)carbamate (466);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(dimethylcarbamoyl)pyridin-4-yl)carbamate (467);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(dimethylcarbamoyl)pyrimidin-5-yl)carbamate (468);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (469);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(((3-(hydroxymethyl)oxetan-3-yl)methyl)carbamoyl)pyridin-3-yl)carbamate (470);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((2-hydroxyethyl)(methyl)carbamoyl)pyridin-3-yl)carbamate (471);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)pyridin-3-yl)carbamate (472);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate (473);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((2-hydroxy-2-methylpropyl)(methyl)carbamoyl)pyridin-3-yl)carbamate (474);
    • R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (475);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((R)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (476);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((S)-2-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate (477);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (478);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((S)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (479);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((R)-2-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate (480);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((S)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (481);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((S)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (482);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((R)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (483);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((S)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (484);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((R)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (485);
    • (2R,3S)-3-((2-(2,7-dimethylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((R)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate (486);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((S)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate (487);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((R)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate (488);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((S)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate (489);
    • (2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (490);
    • (2R,3S)-3-((5-fluoro-2-(7-methyl-2-propoxyquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (491);
    • (2R,3S)-3-((5-fluoro-2-(2-isopropoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate (492);
    • (2R,3S)-3-((5-fluoro-2-(2-(2-hydroxyethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (493);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(hydroxymethyl)pyridin-4-yl)carbamate (494);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(hydroxymethyl)pyridin-4-yl)carbamate (495);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (496);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)carbamate (497);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (498);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate (499);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (500);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)carbamate (501);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (502);
    • 4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (503);
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (504);
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (505);
    • 4-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (506);
    • 5-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (507);
    • 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (509);
    • 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole (510);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (512);
    • (2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (513);
    • (2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (514);
    • (2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (515);
    • 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-methoxypropan-2-yl pyridin-3-ylcarbamate (rac) (516);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (517);
    • 4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-N-(pyridin-3-yl)butanamide (518);
    • 1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) ethyl)-3-(pyridin-3-yl)urea (519);
    • 1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) ethyl)-1-methyl-3-(2-methylpyrimidin-5-yl)urea (520);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-yl (6-(morpholinomethyl)pyridin-3-yl)carbamate (521);
    • (2R,3S)-3-((2-(2-(dimethylamino)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (522);
    • 5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinic acid, TFA (523);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-yl carbamate (524);
    • 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-yl (2-methylpyrimidin-5-yl)carbamate (rac) (525);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (526);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate (527);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (528);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (529);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) propan-2-yl (6-((2-methyl-2-(phosphonooxy)propyl)carbamoyl)pyridin-3-yl)carbamate, TFA (530);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate, TFA (531);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((phosphonooxy)methyl)pyrimidin-5-yl)carbamate (532);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-hydroxypyridin-3-yl)carbamate (533);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-yl (5-(2-hydroxyethoxy)pyridin-3-yl)carbamate (534);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-1-hydroxyethyl)pyrimidin-5-yl)carbamate (535);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-yl (2-(((R)-1-hydroxyethyl)pyrimidin-5-yl)carbamate (536);
    • 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (537);
    • (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (538);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (539);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (540);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (541);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (542);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (543);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (5-(hydroxymethyl)-6-methylpyridin-3-yl)carbamate (544);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxyethyl)pyridin-4-yl)carbamate (545);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate (546);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyridin-4-yl)carbamate (547);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)carbamate (549);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropoxy)pyridin-4-yl)carbamate (550);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (552);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (553);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (554);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (555);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (556);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (557);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (558);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (559);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (560);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxy-2-methylpropyl)pyridin-4-yl)carbamate (561);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)carbamate (562);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (563);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (564);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (565);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (566);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (567);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (568);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (569);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (570);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (571);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (572);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (573);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (574);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxy-2-methylpropoxy)pyrimidin-5-yl)carbamate (575);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxy-2-methylpropoxy)pyrimidin-5-yl)carbamate (576);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxy-2-methylpropyl)pyrimidin-5-yl)carbamate (577);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (578);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (579);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (580);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (581);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (582);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(((R)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (583);
    • (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (584);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((S)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (585);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (586);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (587);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (588);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (589);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-methylpyridin-3-yl)carbamate (590);
    • (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyrimidin-5-ylcarbamate (591);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-methylpyridin-3-yl)carbamate (592);
    • methyl 3-(5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidin-2-yl)propanoate (593);
    • (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (594);
    • (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (595);
    • (R)-(5-aminopyridin-2-yl)methyl (1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl) carbonate (596);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (2-(dimethylamino)pyrimidin-5-yl)carbamate (597);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(dimethylamino)pyrimidin-5-yl)carbamate (598);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(dimethylamino)pyridin-3-yl)carbamate (599);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-oxooxazolidin-3-yl)pyridin-3-yl)carbamate (600);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-acetamidopyridin-3-yl)carbamate (601);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-aminopyridin-3-yl)carbamate (602);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-morpholinopyridin-3-yl)carbamate (603);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(3-chloro-4-fluorobenzamido)pyrimidin-5-yl)carbamate (604);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(pyrrolidin-1-yl)pyridin-3-yl)carbamate (605);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((2-hydroxy-2-methylpropyl)amino)pyrimidin-5-yl)carbamate (606);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(N-methylmethylsulfonamido)pyrimidin-5-yl)carbamate (607);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-morpholinopyrimidin-5-yl)carbamate (608);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(2-oxooxazolidin-3-yl)pyridin-3-yl)carbamate (609);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-acetamidopyridin-3-yl)carbamate (610);
    • (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (5-(hydroxymethyl)pyridin-3-yl)carbamate (611);
    • (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol (612);
    • (2R,3S)-3-((2-(2-carbamoyl-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate (613);
    • (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (614);
    • (2R,3S)-3-((2-(2-(dimethylcarbamoyl)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (615);
    • (2R,3S)-3-((5-fluoro-2-(2-((2-hydroxyethyl)carbamoyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (616);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-(hydroxymethyl)pyridin-3-yl)carbamate (617);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (618);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyridin-4-yl)carbamate (619);
    • (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(1-hydroxyethyl)pyrimidin-5-yl)carbamate (620);
    • 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl isothiazol-5-ylcarbamate (621);
    • (R)-5-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazolidin-2-one (622);
    • 4-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazol-2-amine (623);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-(phosphonooxy)ethyl)pyrimidin-5-yl)carbamate (624);
    • 2-(6-chloro-3-(methoxymethyl)quinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole (625);
    • 2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole (626);
    • 2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-2-ol (627);
    • 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (628);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) (phenyl)methanol (629);
    • 1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethyl propan-1-ol (630);
    • 1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2-phenylethanol (631);
    • 1-(5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (632);
    • 2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) ethanol (633);
    • 4-(1-fluoro-2,2-dimethylpropyl)-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benz o[d]thiazole (634);
    • 4-(benzyloxy)-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (635);
    • 1-(2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy benzo[d]thiazol-4-yl)-2,2-dimethyl propan-1-ol (636);
    • 1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethyl propan-1-ol (637);
    • 2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (5-cyanopyridin-3-yl)carbamate (638);
    • 8-(4-(1-hydroxy-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile (639);
    • 1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (640);
    • 2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol (641);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(3-(trifluoromethyl)phenyl)methanol (642);
    • (2-isopropylphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol (643);
    • ethyl 1-(hydroxy(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methyl)cyclobutanecarboxylate (644);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (645);
    • (1-(hydroxymethyl)cyclobutyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol (646);
    • (2R,3S)-3-((2-(6-chloro-3-ethylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (647);
    • (2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (648);
    • (2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (649);
    • (2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (650);
    • (2R,3S)-3-((2-(6-chloro-3-(2,2-difluoroethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (651);
    • (2R,3S)-3-((2-(6-chloro-3-(methylamino)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate (652);
    • (2R,3S)-3-((2-(6-(difluoromethyl)-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (653);
    • (2R,3S)-3-((5-fluoro-2-(6-(fluoromethyl)-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (654);
    • (2R,3S)-3-((2-(6-cyano-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (655);
    • (2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol (656);
    • (2R,3S)-3-((2-(3,6-dimethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (657);
    • 2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-4-ylcarbamate (658);
    • (2R,3S)-3-((2-(3-(difluoromethoxy)-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (659);
    • (2R,3S)-3-((2-(3-ethoxy-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (660);
    • 5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline (661);
    • 4-methoxyphenyl (2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate (662);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol (663);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol (664);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-phenylcyclobutyl)methanol (665);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methoxycyclobutyl)methanol (666);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclopropyl)methanol (667);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-phenylcyclopropyl)methanol (668);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol (669);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methylcyclopropyl)methanol (671);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methylcyclohexyl)methanol (672);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(thiazol-2-yl)methanol (673);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(4-methyltetrahydro-2H-pyran-4-yl)methanol (674);
    • (3-fluoro-5-methoxyphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol (675);
    • (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methylcyclohexyl)methanol (676);
    • 1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethan-1-ol (677);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-methylpyrimidin-5-yl)carbamate (678);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-methoxypyrimidin-5-yl)carbamate (679);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl pyridin-4-ylcarbamate (680);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (6-methylpyridin-3-yl)carbamate (681);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (5-fluoropyridin-3-yl)carbamate (682);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (683);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl pyridin-3-ylcarbamate (684);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (685);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-(3-hydroxypropyl)pyrimidin-5-yl)carbamate (686);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (687);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (688);
    • methyl (R)-5-((((1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate (689);
    • methyl (R)-5-((((1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate (690);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(2-hydroxyethyl)pyridin-3-yl)carbamate (691);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (692);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-(((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (693);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(hydroxymethyl)pyridin-3-yl)carbamate (694);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (695);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-(2-hydroxyethyl)pyridin-4-yl)carbamate (696);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (697);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl pyridazin-4-ylcarbamate (698);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (699);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (700);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (701);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (702);
    • (2R,3S)-3-((5-fluoro-2-(6-fluoro-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (772);
    • (2R,3S)-3-((5-fluoro-2-(6-(hydroxymethyl)-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (773);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate (782);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(trifluoromethyl)pyridin-3-yl)carbamate (783);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-methoxypyridin-3-yl)carbamate (784);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (5-methoxypyridin-3-yl)carbamate (785);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (5-cyanopyridin-3-yl)carbamate (786);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (5,6-dimethylpyridin-3-yl)carbamate (787);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (788);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-fluoropyridin-3-yl)carbamate (789);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-4-ylcarbamate (790);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (795);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (796);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-fluoropyridin-3-yl)carbamate (797);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-4-ylcarbamate (798);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (799);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (5,6-dimethylpyridin-3-yl)carbamate (800);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-methoxypyridin-3-yl)carbamate (801);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (5-cyanopyridin-3-yl)carbamate (802);
    • (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (5-methoxypyridin-3-yl)carbamate (803);
    • (2R,3S)-3-((4-chloro-5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate (804);
    • 1-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (806);
    • 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(methoxymethyl)benzo[d]thiazole (808);
    • 1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (817);
    • (R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl (6-cyanopyridin-3-yl)carbamate (818);
    • (R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (819);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methoxypyrimidin-5-yl)carbamate (820);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-methoxypyridin-3-yl)carbamate (821);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-methylpyridin-3-yl)carbamate (822);
    • (2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-methylpyridin-3-yl)carbamate (823);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (824);
    • (2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate (825);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(5-cyanopyridin-3-yl)carbamate (826);
    • (2R,3S)-3-((2-(2-(2,2-difluoroethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (827);
    • (2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-cyanopyridin-3-yl)carbamate (828);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-cyanopyridin-3-yl)carbamate (829);
    • methyl 5-(((((2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate (830);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate (831);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(methylcarbamoyl)pyridin-3-yl)carbamate (832);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-yl (6-carbamoylpyridin-3-yl)carbamate (833);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(dimethylcarbamoyl)pyridin-3-yl)carbamate (834);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (835);
    • (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (836); and
    • 2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole (837);
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is imidazol[1,2-a]pyridinyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-2-yl)-7-methylquinoxaline (45).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is thiazolo[4,5-b]pyridinyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazolo[4,5-b]pyridine (9);
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxythiazolo[4,5-c]pyridine (24);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine (146); and
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine (809).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is thiazolo[5,4-b]pyridinyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methoxythiazolo[5,4-b]pyridine (23);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine (147);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine (148);
    • 7-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine (149);
    • 5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine (150);
    • 7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine (151);
    • 5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine (179);
    • 6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine (180);
    • 5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine (181);
    • 6-fluoro-5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine (182);
    • 5-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine (191);
    • (5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl) methanol (192);
    • 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl) benzenesulfonamide (193);
    • 4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide (194);
    • 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)eth yl pyridin-3-ylcarbamate (196);
    • 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)eth yl (6-cyanopyridin-3-yl)carbamate (197);
    • 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate (198);
    • (3-methoxy-8-(5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-yl)quinoxalin-6-yl)methanol (223);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (708);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl pyridin-3-ylcarbamate (709);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-methylpyridin-3-yl)carbamate (710);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-methoxypyrimidin-5-yl)carbamate (711);
    • methyl 5-(((((2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate (712);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl pyridin-4-ylcarbamate (713);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate (714);
    • methyl 5-(((((2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate (715);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl pyrimidin-5-ylcarbamate (716);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyridin-4-yl)carbamate (717);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (718);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (719);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (720);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (721);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (722);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyridin-4-yl)carbamate (723);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (724);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (725);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (726);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (727);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (728);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (729);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (730);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (731);
    • (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl pyridin-3-ylcarbamate (733);
    • (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-fluoro-5-methylpyridin-3-yl)carbamate (734);
    • (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(5-cyanopyridin-3-yl)carbamate (735);
    • (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-chloropyrimidin-5-yl)carbamate (736);
    • (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-methylpyrimidin-5-yl)carbamate (737);
    • (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-methoxypyrimidin-5-yl)carbamate (738);
    • (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl pyridin-3-ylcarbamate (740);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate (741);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl
    • (6-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate (742);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (743);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (744);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (745);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(4-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (746);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (747);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (748);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-carbamoylpyrimidin-5-yl)carbamate (749);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (750);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-((2-hydroxy-2-methylpropyl)carbamoyl)pyrimidin-5-yl)carbamate (751);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (752);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(((S)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (753);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-carbamoylpyridin-3-yl)carbamate (754);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-carbamoylpyrimidin-5-yl)carbamate (755);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate (756);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl) oxy)butan-2-yl (6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (757);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (758);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(4-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (759);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate (760);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate (761);
    • N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) ethyl)-4-methylbenzenesulfonamide (762);
    • 6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine (763);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (764);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (765);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(1-hydroxyethyl)pyridin-3-yl)carbamate (766);
    • (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(1-hydroxyethyl)pyridin-3-yl)carbamate (767);
    • (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate (768);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (2-methylpyrimidin-5-yl)carbamate (769);
    • (R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)pro pan-2-yl (2-methylpyrimidin-5-yl)carbamate (770);
    • (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (771);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (774);
    • (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (775);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate (776);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (777);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (778);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (779);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (780);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (781);
    • (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate (791);
    • (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (792);
    • (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (793);
    • (R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)pro pan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (794);
    • 1-(5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl)-2,2-dimethylpropan-1-ol (807);
    • 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl pyridin-3-ylcarbamate (810);
    • 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) ethyl (6-fluoro-5-methylpyridin-3-yl)carbamate (811);
    • 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) ethyl (6-(thiophen-2-yl)pyridin-3-yl)carbamate (812);
    • (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate (813);
    • (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (814);
    • (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (815);
    • (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (816); and
    • 1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (817).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is 4,5,6,7-tetrahydrobenzo[d]thiazolyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol (138);
    • 7-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole (139);
    • 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole (140);
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (141);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol (143);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole (144);
    • 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol (145); and
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole (178).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is 4,5,6,7-tetrahydrobenzofuranyl. Included in this embodiment is a compound of Formula (I) selected from: tert-butyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl) carbamate (25).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is 6,7-tetrahydrothiazolo[5,4-c]pyridinyl. Included in this embodiment is a compound of Formula (I) selected from: tert-butyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (11) and methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (62).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is 5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazole (137).
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is 5,6-dihydro-4H-cyclopenta[d]thiazolyl. Included in this embodiment is a compound of Formula (I) selected from:
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole (136); and 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazol-5-yl) ethanol (142).
  • The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
    • Definitions
  • The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.
  • Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more.
  • As used herein, the phase “compounds” refers to at least one compound. For example, a compound of Formula (I) includes a compound of Formula (I) and two or more compounds of Formula (I).
  • Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference.
  • Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
  • Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.
  • In accordance with a convention used in the art,
  • Figure US20190292176A1-20190926-C00014
  • is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, and I.
  • The term “cyano” refers to the group —CN.
  • The term “amino” refers to the group —NH2.
  • The term “alkyl” as used herein, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscript after the symbol “C”, the subscript defines with more specificity the number of carbon atoms that a particular group may contain. For example, “C1-4 alkyl” denotes straight and branched chain alkyl groups with one to four carbon atoms.
  • The term “fluoroalkyl” as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, “C1-4 fluoroalkyl” is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, —CF3 and —CH2CF3.
  • The term “aminoalkyl” as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more amino groups. For example, “C1-4 aminoalkyl” is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more amino groups. Representative examples of aminoalkyl groups include, but are not limited to, —CH2NH2, —CH2CH2NH2, and —CH2CH(NH2)CH3.
  • The term “hydroxyalkyl” includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, “hydroxyalkyl” includes —CH2OH, —CH2CH2OH, and C1-4 hydroxyalkyl.
  • The term “hydroxy-deuteroalkyl” includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more deuterium atoms. Representative examples of hydroxy-deuteroalkyl groups include, but are not limited to, —CD2OH and —CH(CD3)2OH.
  • The term “hydroxy-fluoroalkyl” includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. Representative examples of hydroxy-fluoroalkyl groups include, but are not limited to, —CF2OH and —CF2CH2OH.
  • As used herein, “alkylene” refers to a bivalent alkyl radical having the general formula —(CH2)n—, where n is 1 to 10. Non-limiting examples include methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. For example, “C1-6 alkylene” denotes straight and branched chain alkylene groups with one to six carbon atoms. Further, for example, “C0-4 alkylene” denotes a bond and straight and branched chain alkylene groups with one to four carbon atoms.
  • As used herein, “deuteroalkylene” refers to an alkylene group in which one or more hydrogen atoms have been replaced with deuterium atoms. For example, “C1-6 deuteroalkylene” denotes straight and branched chain deuteroalkylene groups with one to six carbon atoms.
  • As used herein, “fluoroalkylene” refers to an alkylene group substituted with one or more fluorine atoms. For example, “C1-6 fluoroalkylene” denotes straight and branched chain fluoroalkylene groups with one to six carbon atoms.
  • The term “alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. For example, “C2-6 alkenyl” denotes straight and branched chain alkenyl groups with two to six carbon atoms.
  • The term “alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. For example, “C2-6 alkynyl” denotes straight and branched chain alkynyl groups with two to six carbon atoms.
  • The term “cycloalkyl,” as used herein, refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the symbol “C”, the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain. For example, “C3-6 cycloalkyl” denotes cycloalkyl groups with three to six carbon atoms.
  • The term “fluorocycloalkyl” refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by fluoro group(s).
  • The term “hydroxycycloalkyl” refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by hydroxyl group(s).
  • The term “alkoxy,” as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (—OCH3). For example, “C1-3 alkoxy” denotes alkoxy groups with one to three carbon atoms.
  • The terms “fluoroalkoxy” and “—O(fluoroalkyl)” represent a fluoroalkyl group as defined above attached through an oxygen linkage (—O—). For example, “C1-4 fluoroalkoxy” is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.
  • The term “hydroxyalkoxy” represent a hydroxyalkyl group as defined above attached through an oxygen linkage (—O—). For example, “C1-4 hydroxyalkoxy” is intended to include C1, C2, C3, and C4 hydroxyalkoxy groups.
  • The term “hydroxy-fluoroalkoxy” represent a hydroxy-fluoroalkyl group as defined above attached through an oxygen linkage (—O—). For example, “C1-4 hydroxy-fluoroalkoxy” is intended to include C1, C2, C3, and C4 hydroxy-fluoroalkoxy groups.
  • The term “cycloalkoxy,” as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom, for example, cyclopropoxy group (—O(cyclopropyl)).
  • The term “alkoxyalkoxy” as used herein, refers to an alkoxy group attached through an alkoxy group to the patent molecular moiety. For example, “(C1-3 alkoxy)-(C1-6 alkoxy)” denotes a C1-3 alkoxy group attached through a C1-6 alkoxy group to the parent molecular moiety.
  • The term “alkoxyalkylene” as used herein, refers to an alkoxy group attached through an alkylene group to the patent molecular moiety. For example, “(C1-3 alkoxy)-(C1-3 alkylene)” denotes a C1-3 alkoxy group attached through a C1-3 alkylene to the parent molecular moiety.
  • The term “fluoroalkoxyalkylene” as used herein, refers to a fluoroalkoxy group attached through an alkylene group. For example, “(C1-2 fluoroalkoxy)-(C1-2 alkylene)” denotes a C1-2 fluoroalkoxy group attached through a C1-2 alkylene to the parent molecular moiety.
  • The term “alkoxy-fluoroalkylene” as used herein, refers to an alkoxy group attached through a fluoroalkylene group to the patent molecular moiety. For example, “(C1-3 alkoxy)-(C1-3 fluoroalkylene)” denotes a C1-3 alkoxy group attached through a C1-3 fluoroalkylene to the parent molecular moiety.
  • The term “deuteroalkoxy-deuteroalkylene” as used herein, refers to a deuteroalkoxy group attached through a deuteroalkylene group to the patent molecular moiety. For example, “(C1-3 deuteroalkoxy)-(C1-3 deuteroalkylene)” denotes a C1-3 deuteroalkoxy group attached through a C1-3 deuteroalkylene to the parent molecular moiety.
  • The term “alkylthio,” as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfur atom, for example, methylthio group (—SCH3). For example, “C1-3 alkylthio” denotes alkylthio groups with one to three carbon atoms.
  • The term “fluoroalkylthio,” as used herein, refers to a fluoroalkyl group attached to the parent molecular moiety through a sulfur atom, for example, trifluoromethylthio group (—SCF3). For example, “C1-3 fluoroalkylthio” denotes fluoroalkylthio groups with one to three carbon atoms.
  • The term “aryl,” as used herein, refers to a group of atoms derived from a molecule containing aromatic ring(s) by removing one hydrogen that is bonded to the aromatic ring(s). Representative examples of aryl groups include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, and 1,2,3,4-tetrahydronaphth-5-yl. The aryl ring may be unsubstituted or may contain one or more substituents as valence allows.
  • The term “benzyl,” as used herein, refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group. The phenyl ring may be unsubstituted or may contain one or more substituents as valence allows.
  • The term “aryloxy,” as used herein, refers to an aryl group attached through an oxygen group.
  • The term “phenoxy,” as used herein, refers to a phenyl group attached through an oxygen group (—O-phenyl). The phenyl ring may be unsubstituted or may contain one or more substituents as valence allows.
  • The term “heteroatom” refers to oxygen (O), sulfur (S), and nitrogen (N).
  • The term “heterocyclo” or “heterocyclyl” may be used interchangeably and refer to non-aromatic 3- to 7-membered monocyclic groups and 6- to 11-membered bicyclic groups, in which at least one of the rings has at least one heteroatom (0, S or N), said heteroatom containing ring preferably having 1 to 3 heteroatoms independently selected from 0, S, and/or N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. The heterocyclo ring may be unsubstituted or may contain one or more substituents as valence allows.
  • Exemplary monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl. Exemplary bicyclic heterocyclo groups include quinuclidinyl.
  • The term “heteroaryl” refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents.
  • Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • The term “heteroaryloxy,” as used herein, refers to a heteroaryl group attached through an oxygen group to the patent molecular moiety.
  • The term “arylalkylene” refers to an aryl group attached through an alkylene group to the patent molecular moiety. For example, “aryl(C1-2 alkylene)” refers to an aryl group attached through a C1-2 alkylene to the parent molecular moiety.
  • The term “heteroarylalkylene” refers to a heteroaryl group attached through an alkylene group to the patent molecular moiety. For example, “heteroaryl(C1-2 alkylene)” refers to a heteroaryl group attached through a C1-2 alkylene to the parent molecular moiety.
  • The term “aryloxyalkylene” refers to an aryloxy group attached through an alkylene group to the patent molecular moiety. For example, “aryloxy-(C1-2 alkylene)” refers to an aryloxy group attached through a C1-2 alkylene to the parent molecular moiety.
  • The term “heteroaryloxyalkylene” refers to a heteroaryloxy group attached through an alkylene group to the patent molecular moiety. For example, “heteroaryloxy-(C1-2 alkylene)” refers to a heteroaryloxy group attached through a C1-2 alkylene to the parent molecular moiety.
  • The compounds of the present invention can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds as amorphous solids.
  • It should further be understood that solvates (e.g., hydrates) of the Compounds of the invention are also within the scope of the present invention. The term “solvate” means a physical association of a compound of Formulas (I) to (VIII) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.
  • In addition, compounds of Formulas (I) to (VIII), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formulas (I) to (VIII) (“substantially pure”), which is then used or formulated as described herein. Such “substantially pure” compounds of Formulas (I) to (VIII) are also contemplated herein as part of the present invention.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.
  • The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. For example, methyl (—CH3) also includes deuterated methyl groups such as —CD3.
    • BIOLOGY
  • The term “PAR4 antagonist” denotes an inhibitor of platelet aggregation which binds PAR4 and inhibits PAR4 cleavage and/or signaling. Typically, PAR4 activity is reduced in a dose dependent manner by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to such activity in a control cell. The control cell is a cell that has not been treated with the compound. PAR4 activity is determined by any standard method in the art, including those described herein (for example calcium mobilization in PAR4 expressing cells, platelet aggregation, platelet activation assays measuring e.g., calcium mobilization, P-selectin or CD40L release, or thrombosis and hemostasis models). In certain embodiments, platelet activation is measured by changes in the platelet cytoplasm, by changes of the platelet membrane, by changes in the levels of analytes released by platelets, by the changes in the morphology of the platelet, by the ability of platelets to form thrombi or platelet aggregates in flowing or stirred whole blood, by the ability of platelets to adhere to a static surface which is derivatized with relevant ligands (e.g., von Willebrand Factor, collagen, fibrinogen, other extracellular matrix proteins, synthetic fragments of any of the proteins, or any combination thereof), by changes in the shape of the platelets, or any combinations thereof. In one embodiment, platelet activation is measured by changes in the levels of one or more analytes released by platelets. For example, the one or more analytes released by platelets can be P-selectin (CD62p), CD63, ATP, or any combination thereof. In a particular embodiment, platelet activation is measured by the level of binding of fibrinogen or GPIIbIIIa antibodies to platelets. In other embodiments, platelet activation is measured by the degree of phosphorylation of vasodilator-stimulated phosphoprotein (VASP) upon platelet activation. In yet other embodiments, platelet activation is measured by the level of platelet-leukocyte aggregates. In certain embodiments, platelet activation is measured by proteomics profiling. The term “PAR4 antagonist” also includes a compound that inhibits both PAR1 and PAR4.
  • Preferably, compounds of the invention have IC50s in the PAR4 FLIPR Assay (described hereinafter) of about 10 μM, preferably 1 μM or less, more preferably 100 nM or less, and even more preferably 10 nM or less. PAR4 FLIPR assay data for compounds of the present invention is presented in the Table.
  • In some embodiments, the present invention provides a pharmaceutical composition, which includes a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I-VIII, preferably, a compound selected from one of the examples, more preferably, Examples 1 to 837, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, alone or in combination with another therapeutic agent.
  • In some embodiments, the present invention provides a pharmaceutical composition which further includes another therapeutic agent(s). In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent(s) are an anti-platelet agent or a combination thereof. Preferably, the anti-platelet agent(s) are P2Y12 antagonists and/or aspirin. Preferably, the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel. In another preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent(s) are an anticoagulant or a combination thereof. Preferably, the anticoagulant agent(s) are a FXa inhibitor, a thrombin inhibitor, or a FXIa inhibitor. Preferably, the FXa inhibitors are apixaban, rivaroxaban, edoxaban, or betrixaban. Preferably, the thrombin inhibitor is dabigatran.
  • It is desirable to find compounds with advantageous and improved characteristics compared with known anti-platelet agents, in one or more of the following categories that are given as examples, and are not intended to be limiting: (a) pharmacokinetic properties, including oral bioavailability, half life, and clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that decrease blood concentration peak-to-trough characteristics; (e) factors that increase the concentration of active drug at the receptor; (f) factors that decrease the liability for clinical drug-drug interactions; (g) factors that decrease the potential for adverse side-effects, including selectivity versus other biological targets; (h) improved therapeutic index with less propensity for bleeding; and (h) factors that improve manufacturing costs or feasibility.
  • As used herein, the term “patient” encompasses all mammalian species.
  • As used herein, the term “subject” refers to any human or nonhuman organism that could potentially benefit from treatment with a PAR4 antagonist. Exemplary subjects include human beings of any age with risk factors for cardiovascular disease, or patients that have already experienced one episode of cardiovascular disease. Common risk factors include, but are not limited to, age, male sex, hypertension, smoking or smoking history, elevation of triglycerides, elevation of total cholesterol or LDL cholesterol.
  • In some embodiments, the subject is a species having a dual PAR1/PAR4 platelet receptor repertoire. As used herein, the term “dual PAR1/PAR4 platelet receptor repertoire” means that a subject expresses PAR1 and PAR4 in platelets or their precursors. Exemplary subjects having a dual PAR1/PAR4 platelet receptor repertoire include human beings, non-human primates, and guinea pigs.
  • In other embodiments, the subject is a species having a dual PAR3/PAR4 platelet receptor repertoire. As used herein, the term “dual PAR3/PAR4 platelet receptor repertoire” means that a subject expresses PAR3 and PAR4 in platelets or their precursors. Exemplary subjects having a dual PAR3/PAR4 platelet receptor repertoire include rodents and rabbits.
  • As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e; arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.
  • As used herein, “prophylaxis” or “prevention” cover the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. “Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
  • As used herein, “risk reduction” covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit and/or antagonize PAR4 and/or to prevent or treat the disorders listed herein. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.
  • The term “thrombosis”, as used herein, refers to formation or presence of a thrombus (pl. thrombi) within a blood vessel that may cause ischemia or infarction of tissues supplied by the vessel. The term “embolism”, as used herein, refers to sudden blocking of an artery by a clot or foreign material that has been brought to its site of lodgment by the blood current. The term “thromboembolism”, as used herein, refers to obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel. The term “thromboembolic disorders” entails both “thrombotic” and “embolic” disorders (defined above).
  • The term “thromboembolic disorders” as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation. The term “thromboembolic disorders” as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. The medical implants or devices include, but are not limited to: prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, ventricular assist devices and artificial hearts or heart chambers, and vessel grafts. The procedures include, but are not limited to: cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In another embodiment, the term “thromboembolic disorders” includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.
  • In another embodiment, the present invention provides a method for the treatment of a thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention provides a method for the treatment of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, venous thrombosis, atrial fibrillation, and thrombosis resulting from medical implants and devices.
  • In another embodiment, the present invention provides a method for the primary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention provides a method for the primary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, venous thrombosis, and thrombosis resulting from medical implants and devices.
  • In another embodiment, the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, atrial fibrillation and venous thrombosis.
  • The term “stroke”, as used herein, refers to embolic stroke or atherothrombotic stroke arising from occlusive thrombosis in the carotid communis, carotid interna, or intracerebral arteries.
  • It is noted that thrombosis includes vessel occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty). The thromboembolic disorders may result from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of pregnancy.
  • Thromboembolic disorders are frequently associated with patients with atherosclerosis. Risk factors for atherosclerosis include but are not limited to male gender, age, hypertension, lipid disorders, and diabetes mellitus. Risk factors for atherosclerosis are at the same time risk factors for complications of atherosclerosis, i.e., thromboembolic disorders.
  • Similarly, atrial fibrillation is frequently associated with thromboembolic disorders. Risk factors for atrial fibrillation and subsequent thromboembolic disorders include cardiovascular disease, rheumatic heart disease, nonrheumatic mitral valve disease, hypertensive cardiovascular disease, chronic lung disease, and a variety of miscellaneous cardiac abnormalities as well as thyrotoxicosis.
  • Diabetes mellitus is frequently associated with atherosclerosis and thromboembolic disorders. Risk factors for the more common type 2 include but are not limited to family history, obesity, physical inactivity, race/ethnicity, previously impaired fasting glucose or glucose tolerance test, history of gestational diabetes mellitus or delivery of a “big baby”, hypertension, low HDL cholesterol, and polycystic ovary syndrome.
  • Thrombosis has been associated with a variety of tumor types, e.g., pancreatic cancer, breast cancer, brain tumors, lung cancer, ovarian cancer, prostate cancer, gastrointestinal malignancies, and Hodgkins or non-Hodgkins lymphoma. Recent studies suggest that the frequency of cancer in patients with thrombosis reflects the frequency of a particular cancer type in the general population. (Levitan, N. et al., Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N Engl. J Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA, 293(6):715-722 (2005).) Hence, the most common cancers associated with thrombosis in men are prostate, colorectal, brain, and lung cancer, and in women are breast, ovary, and lung cancer. The observed rate of venous thromboembolism (VTE) in cancer patients is significant. The varying rates of VTE between different tumor types are most likely related to the selection of the patient population. Cancer patients at risk for thrombosis may possess any or all of the following risk factors: (i) the stage of the cancer (i.e., presence of metastases), (ii) the presence of central vein catheters, (iii) surgery and anticancer therapies including chemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it is common clinical practice to dose patients having advanced tumors with heparin or low molecular heparin to prevent thromboembolic disorders. A number of low molecular weight heparin preparations have been approved by the FDA for these indications.
  • The term “pharmaceutical composition,” as used herein, means any composition, which contains at least one therapeutically or biologically active agent and is suitable for administration to the patient. Any of these formulations can be prepared by well-known and accepted methods of the art. See, for example, Gennaro, A. R., ed., Remington: The Science and Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa. (2000).
  • The invention includes administering to a subject a pharmaceutical composition that includes a compound that binds to PAR4 and inhibits PAR4 cleavage and/or signaling (referred to herein as a “PAR4 antagonist” or “therapeutic compound”).
  • The pharmaceutical composition is administered using methods known in the art. Preferably, the compound is administered orally, rectally, nasally, by inhalation, topically or parenterally, e.g., subcutaneously, intraperitoneally, intramuscularly, and intravenously. The compound is optionally formulated as a component of a cocktail of therapeutic drugs to treat a thromboembolic disorder. In one embodiment, the pharmaceutical composition is administered orally.
  • The therapeutic compounds described herein are formulated into pharmaceutical compositions utilizing conventional methods. For example, a PAR4 antagonist is formulated in a capsule or a tablet for oral administration. Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose. Tablets may be formulated in accordance with conventional procedures by compressing mixtures of a therapeutic compound with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. The compound is administered in the form of a hard shell tablet or a capsule containing a binder, e.g., lactose or mannitol, a conventional filler, and a tableting agent. Other formulations include an ointment, suppository, paste, spray, patch, cream, gel, resorbable sponge, or foam. Such formulations are produced using methods well known in the art. The compositions of the invention are also useful for parenteral administration, such as intravenous, subcutaneous, intramuscular, and intraperitoneal. Examples of formulations suitable for parenteral administration include aqueous solutions of the active agent in an isotonic saline solution, a 5% glucose solution, or another standard pharmaceutically acceptable excipient. Standard solubilizing agents such as PVP or cyclodextrins are also utilized as pharmaceutical excipients for delivery of the therapeutic compounds.
  • The preferred dose of the PAR4 antagonist is a biologically active dose. A biologically active dose is a dose that will inhibit cleavage and/or signaling of PAR4 and have an anti-thrombotic effect. Desirably, the PAR4 antagonist has the ability to reduce the activity of PAR4 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% below untreated control levels. The levels of PAR4 in platelets is measured by any method known in the art, including, for example, receptor binding assay, platelet aggregation, platelet activation assays (e.g., p-selectin expression by FACS), Western blot or ELISA analysis using PAR4 cleavage sensitive antibodies. Alternatively, the biological activity of PAR4 is measured by assessing cellular signaling elicited by PAR4 (e.g., calcium mobilization or other second messenger assays).
  • In some embodiments, a therapeutically effective amount of a PAR4 compound is preferably from about less than 100 mg/kg, 50 mg/kg, 10 mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more preferred embodiment, the therapeutically effective amount of the PAR4 compound is less than 5 mg/kg. In a most preferred embodiment, the therapeutically effective amount of the PAR4 compound is less than 1 mg/kg. Effective doses vary, as recognized by those skilled in the art, depending on route of administration and excipient usage.
  • The activity of the PAR4 antagonists of the present invention can be measured in a variety of in vitro assays. Exemplary assays are shown below.
  • The Fluorometric Imaging Plate Reader (FLIPR) assay is an exemplary in vitro assay for measuring the activity of the PAR4 antagonists of the present invention. In this assay, intracellular calcium mobilization is induced in PAR4 expressing cells by a PAR4 agonist and calcium mobilization is monitored.
  • AYPGKF is a known PAR4 agonist. An alternative PAR4 agonist is H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2. As shown in Example B of WO2013/163279, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2 was validated as a PAR4 agonist in the FLIPR assay. A side-by-side comparison of the IC50 values of ˜180 compounds were performed using AYPGKF versus H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2. The results demonstrated a strong correlation between the two assays. Additionally, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2 has improved agonist activity as compared to AYPGKF with an EC50 that is 10 fold lower than the EC50 for AYPGKF in the FLIPR assay. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2 can be synthesized using methods well known to those of skill in the art.
  • The FLIPR assay can also be used as a counterscreen to test agonist activity or PAR1 antagonist activity in a cell line that expresses both PAR1 and PAR4. The PAR1 antagonist activity can be tested by the ability of the compound to inhibit calcium mobilization induced by the PAR1 agonist peptide SFLLRN or other PAR1 agonist peptides.
  • The compounds of the current invention can be tested in vitro for their ability to inhibit platelet aggregation induced by gamma-thrombin as shown below. Gamma-thrombin, a proteolytic product of alpha-thrombin which no longer interacts with PAR1, selectively cleaves and activates PAR4 (Soslau, G. et al., “Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib”, J. Biol. Chem., 276:21173-21183 (2001)). Platelet aggregation can be monitored in a 96-well microplate aggregation assay format or using standard platelet aggregometer. The aggregation assay can also be employed to test the selectivity of the compound for inhibiting platelet aggregation induced by PAR4 agonist peptides, PAR1 agonist peptide, ADP, or thromboxane analogue U46619.
  • The compounds of the current invention can be tested in vitro for their ability to inhibit platelet aggregation induced by alpha-thrombin as shown below. Alpha-thrombin activates both PAR1 and PAR4. The ability of a selective PAR4 antagonist of the present invention to inhibit platelet aggregation can be measured using a standard optical aggregometer.
  • The compounds of the current invention can be tested in vitro for their ability to inhibit platelet aggregation induced by tissue factor as shown below. The conditions in this assay mimic the physiological events during thrombus formation. In this assay, platelet aggregation in human platelet rich plasma (PRP) is initiated by the addition of tissue factor and CaCl2. Tissue factor, the initiator of the extrinsic coagulation cascade, is highly elevated in human atherosclerotic plaque. Exposure of blood to tissue factor at the atherosclerotic site triggers a robust generation of thrombin and induces the formation of obstructive thrombi.
  • The activity of the PAR4 antagonists of the present invention can also be measured in a variety of in vivo assays. Exemplary mammals that can provide models of thrombosis and hemostasis to test the effectiveness of the PAR4 antagonists of the present invention as antithrombotic agents include, but are not limited to, guinea pigs and primates. Relevant efficacy models include, but are not limited to, electrically-induced carotid arterial thrombosis, FeCl3-induced carotid artery thrombosis and arteriovenous-shunt thrombosis. Models of kidney bleeding time, renal bleeding time and other bleeding time measurements can be used to assess the bleeding risk of the antithrombotic agents described in the current invention.
    • ASSAYS Materials
  • 1) PAR1 and PAR4 Agonist Peptides
  • SFFLRR is a known high affinity PAR1 selective agonist peptide. (Reference: Seiler, S. M., “Thrombin receptor antagonists”, Seminars in Thrombosis and Hemostasis, 22(3):223-232 (1996).) The PAR4 agonist peptides AYPGKF and H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2 were synthesized. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2 showed improved PAR4 agonist activity over AYPGKF in the FLIPR assay (EC50 value of 8 μM for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2 and 60 μM for AYPGKF) and in washed platelet aggregation assay (EC50 value of 0.9 μM for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2 and 12 μM for AYPGKF).
    • 2) PAR4 Expressing Cells
  • HEK293 cells stably expressing PAR4 were generated by a standard method of transfection of human PAR4 (F2R23) cDNA expression vector and selected based on PAR4 protein expression or mRNA expression. Those cells demonstrated functional responses to PAR4 agonist peptide-induced intracellular calcium elevation using FLIPR® (Fluorometric Imaging Plate Reader; Molecular Devices Corp.). These cells also express endogenous PAR1 and can elicit calcium signal upon stimulation with PAR1 agonist peptide. Therefore, the same cells were also used to determine selectivity against PAR1 and agonist activity for both receptors. Cells from HEK293 PAR4 Clone 1.2A (BMS Arctic ID 383940) were propagated and used for calcium mobilization studies.
    • 3) Preparation of Platelet Rich Plasma (PRP)
  • Human blood was collected in 3.8% sodium citrate at a ratio of 1 ml per 9 ml blood and centrifuged in a Sorvall® RT6000B centrifuge at 900 revolution per minute (rpm) at room temperature (RT) for 15 minutes. PRP was collected and used for aggregation assay. Refludan (Berlex Labs, Wayne, N.J.), a recombinant hirudin, at a final concentration of 1 unit/mL was added to the sample to selectively prevent PAR1 activation induced by residual alpha-thrombin contamination. The remaining blood sample was centrifuged at 2500 rpm at room temperature for 5 minutes to collect platelet-poor plasma (PPP).
    • 4) Preparation of Washed Platelets (WP)
  • Human blood was collected in ACD (85 mM tri-sodium citrate, 78 mM citric acid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml per 10 ml blood. PRP was isolated by centrifugation at 170 g for 14 minutes and platelets were further pelleted by centrifugation at 1300 g for 6 minutes. Platelets were washed once with 10 ml ACD containing 1 mg/ml bovine serum albumin. Platelets were resuspended at ˜2.5×108/ml in Tyrode's Buffer (137 mM NaCl, 2 mM KCl, 1.0 mM MgCl2, 1 mM CaCl2, 5 mM glucose, 20 mM HEPES pH 7.4).
    • FLIPR Assay in PAR4-Expressing HEK293 Cells
  • FLIPR-based calcium mobilization assay in HEK293 cells was used to measure PAR4 antagonism, agonism, and selectivity against PAR1. The activity of the PAR4 antagonists of the present invention were tested in PAR4 expressing cells by monitoring H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2-induced intracellular calcium mobilization. Counter screens for agonist activity and PAR1 antagonist activity were also performed. Briefly, PAR1/PAR4-expressing HEK293 cells were grown in DMEM (Life Technology, Grand Island, N.Y.) containing 10% heat-inactivated FBS, 1% Penicillin-Streptomycin, 10 μg/mL blasticidin, and 100 μg/mL Zeocin at 37° C. with 5% CO2. Cells were plated overnight prior to the experiment in a black 384-well Purecoat Amine clear bottom plate (Becton Dickinson Biosciences, San Jose, Calif.) at 10,000 cells/well in 30 μL growth medium and incubated in a humidified chamber at 37° C. with 5% CO2 overnight. Prior to compound addition, the cell medium was replaced with 40 μL of 1× calcium and magnesium-containing Hank's Balanced Saline Solution (HBSS) (with 20 mM HEPES) and 1:1000 diluted fluorescent calcium indicator (Codex Biosolutions, Gaithersburg, Md.). After a 30 minute incubation period at 37° C. and a further 30 minute incubation and equilibration period at room temperature, 20 μL test compound (diluted in 1×HBSS buffer) was added at various concentrations at 0.17% dimethyl sulfoxide (DMSO) final concentration. Changes in fluorescence intensity were measured using a Functional Drug Screening System (FDSS, Hamamatsu, Japan) to determine agonist activities. The cells were then incubated for 30 minutes at room temperature followed by addition of 20 μL of agonist peptide for antagonist activity measurement. The PAR4 agonist peptide (H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2) and the PAR1 agonist peptide (SFFLRR) were routinely tested to ensure a proper response at the EC50 value in the assay (˜5 μM for PAR4 agonist peptide and −2 μM for PAR1 agonist peptide). Compound potency was derived from 11-point concentration-response curves.
    • Gamma Thrombin Induced Platelet Aggregation Assays
  • The ability of the compounds of the current invention to inhibit platelet aggregation induced by gamma-thrombin was tested in a 96-well microplate aggregation assay format. Briefly, 90 μL of PRP or washed platelets were pre-incubated for 5 minutes at 37° C. with 3-fold serially diluted test compound, which was prepared as a 100-fold stock solution in dimethyl sulfoxide (DMSO). Aggregation was initiated by addition of 10 μL of gamma-thrombin (Haematologic Technologies, Inc. Essex Junction, Vt.) at 50-100 nM final concentration, which was titrated daily to achieve 80% platelet aggregation. The plate was then placed into a SpectraMax® Plus Plate Reader (Molecular Devices) at 37° C. Platelet aggregation was monitored at a wavelength of 405 nm using a kinetic analysis mode. Prior to the first data collection time point, the plate was shaken for 10 seconds to allow thorough mixing. Data was subsequently collected every 10 seconds for up to 7 minutes total. Data was collected using SoftMax® 5.4.1 software and exported to Microsoft Excel for analysis. The optical density (OD) values at the time point that achieved 75% platelet activation by agonist alone were used for analysis. The OD value from a PRP sample without any treatment served as ODmaximum, and the OD value from a PPP sample containing no platelets served as the ODminimum. Inhibition of platelet aggregation (IPA) was calculated based on the formula: % IPA=(100-100*[ODcompound−ODminimum]/[ODmaximum−ODminimum]). The IC50 value of the test compound was calculated by fitting the % IPA values to the one-site concentration response equation: Y=A+(B−A)/{1+(C/X){circumflex over ( )}D]}, using XLfit for 32 bit Excel® Version 2 Build 30 (ID Business Solutions Limited).
  • The aggregation assays were also employed to test the selectivity of the compound against other platelet receptors by using SFFLRR for PAR1, collagen (Chrono-Log, Havertown, Pa.) for collagen receptors, ADP for P2Y1 and P2Y12 and U46619 (Cayman Chemical, Ann Arbor, Mich.) for thromboxane receptors.
    • Alpha-thrombin Induced Platelet Aggregation Assays
  • The ability of PAR4 antagonists to inhibit platelet aggregation induced by alpha-thrombin can be tested using human washed platelets. The antagonists are pre-incubated with washed platelets for 20 min. Aggregation is initiated by addition of 1.5 nM alpha-thrombin (Haematologic Technologies, Essex Junction, Vt.) to 300 μl of washed platelets at stirring speed of 1000 rpm. Platelet aggregation is monitored using an Optical Aggregometer (Chrono-Log, Havertown, Pa.) and the area under the curve (AUC) at 6 min was measured. IC50 values are calculated using vehicle control as 0% inhibition.
    • Tissue Factor-Induced Platelet Aggregation Assay
  • The ability of PAR1 or PAR4 antagonists to inhibit platelet aggregation induced by endogenous thrombin can be tested in a tissue factor driven aggregation assay. Aggregation is initiated by addition of CaCl2 and recombinant human tissue factor, which results in the generation of thrombin through activation of the coagulation pathway in the plasma. Anticoagulant agents such as corn trypsin inhibitor (Haematologic Technologies, Essex Junction, Vt.) at 50 μg/ml and PEFABLOC® FG (Centerchem, Norwalk, Conn.) are also added to the sample to prevent fibrin clot formation during the time of the study. Platelet aggregation is monitored using standard instrumentation including optical aggregometer or impedance aggregometer.
  • The following table sets out the results obtained employing various compounds of the invention tested in the PAR4 FLIPR assay.
  • TABLE
    PAR4
    FLIPR
    assay
    (IC50,
    Ex. No. nM)
    1 29
    2 11
    3 240
    4 17
    5 880
    6 130
    7 800
    8 8.1
    9 220
    10 2.2
    11 1700
    12 2.0
    13 3.5
    14 6.8
    15 38
    16 80
    17 13
    18 98
    19 41
    20 30
    21 3.3
    22 1.8
    23 5.3
    24 2.0
    25 130
    26 3.3
    27 5.4
    28 3.0
    29 1.4
    30 4.7
    31 240
    32 3.0
    33 120
    34 1.6
    35 54
    36 7.7
    37 22
    38 2.1
    39 10
    40 36
    41 400
    42 5.2
    43 170
    44 220
    45 99
    46 17
    47 34
    48 2.1
    49 9.7
    50 92
    51 180
    52 4.7
    53 9.8
    54 94
    55 14
    56 4.7
    58 3.0
    59 5.0
    60 19
    61 43
    62 100
    63 2.9
    64 7.4
    65 31
    66 28
    67 2.9
    68 120
    69 36
    70 34
    71 160
    72 1.0
    73 2.3
    74 9.3
    75 14
    76 2.1
    77 130
    78 39
    79 2.2
    80 21
    81 1.5
    82 280
    83 11
    84 2.5
    85 8.5
    86 7.2
    87 2.0
    89 1.4
    90 84
    91 62
    92 2.0
    93 0.3
    94 1.4
    95 0.8
    96 1.1
    97 1.7
    98 0.3
    99 0.6
    100 0.5
    101 0.2
    102 0.9
    103 2.5
    104 1.7
    105 8.1
    106 1.6
    107 2.8
    108 1100
    109 8.3
    110 12
    111 1.1
    112 2.0
    113 3.0
    114 1600
    115 1.3
    116 1.4
    117 0.5
    118 2.2
    119 16
    120 28
    121 0.7
    122 3.9
    123 1.5
    124 1.8
    125 2.0
    126 1.2
    127 8.3
    128 2.2
    129 3.2
    130 460
    131 890
    132 59
    133 570
    134 120
    135 2200
    136 29
    137 29
    138 33
    139 3.9
    140 21
    141 80
    142 5.6
    143 36
    144 0.3
    145 4.5
    146 7.0
    147 1.7
    148 48
    149 4.2
    150 94
    151 2000
    152 38
    153 16
    154 3.8
    155 0.8
    156 1.4
    157 31
    158 0.7
    159 25
    160 1.2
    161 0.7
    162 270
    163 0.5
    164 0.5
    165 1.2
    166 2.8
    167 4.5
    168 2.0
    169 0.4
    170 0.3
    171 0.6
    172 1.7
    173 2.7
    174 3.0
    175 23
    176 980
    177 190
    178 13
    179 18
    180 2.7
    181 1.2
    182 22
    183 0.6
    184 2300
    185 6.5
    186 17
    187 390
    188 580
    189 140
    190 1700
    191 6.4
    192 2.8
    193 1.2
    194 2.5
    195 32
    196 2.3
    197 1.3
    198 0.6
    199 2.5
    200 1.6
    201 1.3
    202 0.9
    203 4.1
    204 3.1
    205 51
    206 0.7
    207 0.9
    208 1.1
    209 1.1
    210 0.3
    211 21
    212 2.4
    213 5.8
    214 4.3
    215 2.9
    216 160
    217 18
    218 2.5
    219 5.5
    220 2.6
    221 21
    222 1.0
    223 10
    224 15
    225 54
    226 140
    227 160
    228 890
    229 3.9
    230 2.2
    231 1.0
    232 0.7
    233 0.4
    234 1.4
    235 2.2
    236 140
    237 170
    238 1300
    239 7.9
    240 72
    241 5.4
    242 120
    243 1.2
    244 2.0
    245 92
    246 140
    247 19
    248 19
    249 6.9
    250 31
    251 17
    252 0.5
    253 0.6
    254 1.5
    255 0.8
    256 1.2
    257 2.1
    258 2.8
    259 14
    260 4.8
    261 1.2
    262 0.8
    263 0.8
    264 8.3
    265 6.8
    266 2.2
    267 0.8
    268 0.9
    269 3.6
    270 17
    271 1.5
    272 3.2
    273 4.3
    274 5.7
    275 0.9
    276 1.2
    277 9.0
    278 4.6
    279 18
    280 4.3
    281 3.6
    282 1.1
    283 1.9
    284 5.9
    285 16
    286 0.5
    287 8.5
    288 8.6
    289 1.3
    290 6.0
    291 11
    292 0.8
    293 1.0
    294 5.2
    295 0.7
    296 1.2
    297 5.7
    298 2.1
    299 10
    300 0.9
    301 15
    302 3.2
    303 0.9
    304 2.3
    305 1.0
    306 1.0
    307 0.9
    308 3.6
    309 3.3
    310 9.1
    311 93
    312 6.7
    313 2.9
    314 10
    315 3.3
    316 4.9
    317 4.5
    318 7.8
    319 7.3
    320 3.4
    321 3.1
    322 5.1
    323 15
    324 42
    325 0.7
    326 1.1
    327 5.2
    328 1.4
    329 1.1
    330 57
    331 9.2
    332 2.4
    333 1.7
    334 29
    335 2.5
    336 5.5
    337 0.7
    338 2.0
    339 1.6
    340 1.5
    341 15
    342 11
    343 0.7
    344 11
    345 0.6
    346 3.7
    347 0.8
    348 4.4
    349 2.7
    350 2.8
    351 2.7
    352 390
    353 22
    354 1.2
    355 17
    356 2.1
    357 6.7
    358 270
    359 170
    360 160
    361 5.5
    362 4.1
    363 1700
    364 19
    365 2.5
    366 550
    367 12
    369 13
    370 5.8
    371 1.8
    372 1.3
    373 0.9
    374 110
    375 1.7
    376 72
    377 4.3
    378 8.7
    379 1.7
    380 2.3
    381 1.4
    382 1.3
    383 590
    384 18
    385 2.3
    386 7.8
    387 1.5
    388 0.7
    389 0.4
    390 3.6
    391 2.0
    392 3.1
    393 30
    394 130
    395 5.8
    396 4.6
    397 210
    398 8.6
    399 3.9
    400 2.0
    401 2.7
    402 3.7
    403 1.7
    404 2.2
    405 1.9
    406 3.5
    407 0.9
    408 3.2
    409 0.4
    410 0.3
    411 4.4
    412 0.3
    413 3.4
    414 7.0
    415 3.1
    416 32
    417 11
    418 1.3
    419 2.0
    420 2.2
    421 1.8
    422 2.2
    423 4.2
    426 5.4
    427 7.6
    428 5.9
    429 0.5
    430 0.9
    431 1.1
    432 0.4
    433 0.6
    434 1.4
    435 0.9
    436 1.5
    437 4.9
    438 1.9
    439 0.9
    440 0.8
    441 0.9
    442 0.8
    443 0.6
    444 0.8
    445 3.2
    446 2.3
    447 21
    448 2.1
    449 0.3
    450 0.5
    451 0.7
    452 0.4
    453 0.6
    454 1.3
    455 0.8
    456 0.7
    457 0.4
    458 0.5
    459 0.9
    460 0.9
    461 0.4
    462 0.2
    463 0.7
    464 1.5
    465 1.4
    466 0.7
    467 1.9
    468 0.8
    470 2.2
    471 5.2
    472 4.6
    473 3.4
    474 11
    475 4.8
    476 10
    477 3.0
    478 9.1
    479 1.4
    480 3.4
    481 0.6
    482 0.6
    483 0.8
    484 1.0
    485 1.6
    486 1.5
    487 1.3
    488 14
    489 9.1
    490 5.1
    491 0.4
    492 7.4
    493 21
    494 1.8
    495 15
    496 1.9
    497 1.3
    498 1.3
    499 4.4
    500 3.8
    501 4.0
    502 1.7
    512 1.2
    513 1.1
    514 1.9
    515 2.6
    516 2.0
    517 1.1
    518 13
    519 16
    520 77
    521 24
    522 20
    523 2.6
    524 84
    525 2.3
    526 2.0
    527 1.4
    528 5.0
    529 0.9
    530 1.8
    531 0.7
    532 1.7
    533 0.7
    534 0.9
    535 5.2
    536 4.9
    539 6.5
    540 3.0
    541 3.4
    542 1.6
    543 1.3
    544 34
    545 1.5
    546 14
    547 5.2
    549 1.0
    550 0.4
    552 0.7
    553 1.2
    554 0.7
    555 1.1
    556 0.7
    557 0.7
    558 1.5
    559 0.9
    560 1.4
    561 53
    562 1.6
    563 2.8
    564 3.7
    565 3.0
    566 1.8
    567 5.9
    568 2.4
    569 8.2
    570 6.6
    571 1.0
    572 0.9
    573 1.6
    574 2.0
    575 0.6
    576 1.2
    577 1.0
    578 5.8
    579 3.3
    580 1.1
    581 4.1
    582 5.3
    589 0.8
    590 25
    591 7.0
    592 0.7
    596 130
    597 15
    598 3.7
    599 5.6
    600 2.4
    601 3.5
    602 6.4
    603 2.1
    604 17
    605 0.7
    606 0.4
    607 0.2
    608 0.5
    609 1.9
    610 4.3
    611 2.1
    613 65
    614 30
    615 870
    616 4200
    618 3.8
    621 8.0
    622 350
    623 320
    624 0.7
    625 1.8
    626 7.2
    627 1400
    628 1.4
    629 2.2
    630 1.4
    631 5.3
    632 10
    633 2.6
    634 44
    635 10
    636 3.0
    637 2.1
    638 2.7
    639 1.4
    640 8.0
    641 250
    642 4.6
    643 5.3
    644 21
    645 4.9
    646 3.8
    647 19
    648 3.0
    649 7.4
    650 5.6
    651 4.3
    652 11
    653 0.83
    654 1.0
    655 1.1
    656 2.4
    657 1.1
    658 3.0
    659 2.1
    660 2.0
    661 55
    662 77
    663 7.0
    664 0.9
    665 1.7
    666 1.1
    667 5.6
    668 7.3
    669 2.3
    671 1.9
    672 1.9
    673 39
    674 20
    675 10
    676 3.2
    677 3.8
    678 1.0
    679 2.5
    680 0.8
    681 0.4
    682 0.9
    683 0.7
    684 0.7
    685 1.7
    686 9.9
    687 0.9
    688 4.5
    689 0.3
    690 0.3
    691 0.9
    692 1.8
    693 1.3
    694 2.1
    695 1.0
    696 2.6
    697 2.9
    698 17
    699 1.1
    700 0.9
    701 2.7
    702 4.3
    708 2.6
    709 0.4
    710 1.8
    711 2.4
    712 3.2
    713 1.8
    714 1.2
    715 0.9
    716 2.0
    717 1.6
    718 1.7
    719 1.7
    720 3.2
    721 2.6
    722 1.4
    723 2.4
    724 2.1
    725 0.8
    726 1.2
    727 1.7
    728 2.4
    729 2.8
    730 13
    731 0.9
    733 1.1
    734 1.0
    735 1.1
    736 5.3
    737 8.1
    738 10
    740 0.9
    741 2.1
    747 2.4
    748 2.9
    749 4.3
    750 1.1
    751 4.7
    752 14
    753 12
    754 0.3
    755 0.3
    762 1.4
    763 4.0
    764 1.7
    765 0.8
    766 2.9
    767 3.4
    768 10
    769 3.2
    770 1.9
    771 6.3
    772 1.5
    773 11
    774 1.2
    775 0.8
    776 2.5
    777 8.6
    778 3.4
    779 3.3
    780 5.0
    781 6.0
    782 2.7
    783 4.2
    784 2.8
    785 3.5
    786 2.2
    787 2.9
    788 3.1
    789 2.4
    790 4.4
    791 2.3
    792 11
    793 24
    794 10
    795 0.8
    796 1.3
    797 3.1
    798 2.5
    799 2.9
    800 2.5
    801 2.6
    802 2.0
    803 3.5
    804 2.8
    806 6.6
    807 2.6
    808 2.0
    809 54
    810 6.9
    811 1.5
    812 7.0
    813 1.0
    814 7.2
    815 6.4
    816 10
    817 3.6
    818 1.8
    819 1.2
    820 1.7
    821 4.6
    822 1.6
    823 5.1
    824 1.5
    825 8.0
    826 1.9
    827 6.2
    828 0.7
    829 0.6
    830 1.6
    831 2.2
    832 2.5
    833 1.6
    834 3.0
    835 0.5
    836 1.2
    837 17
    • Methods of Preparation
  • The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction mixtures are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Wuts et al. (Greene's Protective Groups In Organic Synthesis, 4th Edition, Wiley-Interscience (2006).
  • Compounds of Formula I of this invention can be obtained by palladium catalyzed cross coupling of aryl halides of Formula Ia with organometallic species R3-M as shown in Scheme 1.
  • Figure US20190292176A1-20190926-C00015
  • Alternatively, compounds of Formula I can also be prepared from palladium catalyzed cross coupling of arylboronic acids of Formula Ib with halides R3—X shown in Scheme 2.
  • Figure US20190292176A1-20190926-C00016
  • One way to prepare the quinoxalines of Formula Ia and Ib is through the condensation reaction of the diamine Ic with ketoaldehyde Id, as shown in Scheme 3. In general, the condensation will give two regioisomers that may be separated by chromatography. Structure of Formula Ia can be converted to boronic acid Ib via Suzuki-Miyaura reaction.
  • Figure US20190292176A1-20190926-C00017
  • A regio specific synthesis of quinoxalines of Formula Ia and Ib is shown in Scheme 4. A properly protected ortho-nitro aniline Ie is alkylated with methyl bromoacetate to yield compound If. Deprotection of compound If and reduction of compound Ig should initiate cyclization to give rise to compound Ih. Compound Ih can be oxidized to quinoxaline-2-one of Formula Ii, which can be converted to the intermediate Ij with oxophosphorus halides. The halides in compound Ij can be displaced with a nucleophile containing an R1 group to compound Ia, and compounds of Formula Ia can be converted to corresponding boronic acids of Formula Ib via Suzuki-Miyaura reaction. Intermediate Ii could also be converted to Ik by condensation reaction with sodium chlorodifluoroacetate in the presence of a base such as K2CO3. The difluoroalkoxy may be displaced with a nucleophile containing an R1 group to compound Ia.
  • Figure US20190292176A1-20190926-C00018
  • Compounds of Formula II of this invention can be obtained as shown in Scheme 5. Compound IIa can be condensed with dicarbonyl IIb to give compound IIc. Acid catalyzed cyclization provides the key bromide IId. Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes compound II.
  • Figure US20190292176A1-20190926-C00019
  • Compounds of Formula III of this invention can be obtained as shown in Scheme 6. Compound IIIa can be condensed with dimethylacetal IIIb to give compound IIIc. Acid catalyzed cyclization and triflate formation provides the key coupling partner IIId. Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes the compound of Formula III
  • Figure US20190292176A1-20190926-C00020
  • Compounds of Formula IV of this invention can be obtained as shown in Scheme 7. Compound IVa can be condensed with dimethylacetal IVb to give compound IVc. Acid catalyzed cyclization and triflate formation provides the key coupling partner IVd. Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes the compound of Formula IV.
  • Figure US20190292176A1-20190926-C00021
  • Compounds of Formula V of this invention can be obtained as shown in Scheme 8. Compound Va can be condensed with acid chloride Vb to give compound Vc. Acid catalyzed cyclization and carbonyl alkylation provides the key bromide Vd. Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes the compound of Formula V.
  • Figure US20190292176A1-20190926-C00022
  • Compounds of Formula VI of this invention can be obtained as shown in Scheme 9. Compound VIa can be condensed with dicarbonyl compound VIb to give compound VIc. Palladium catalyzed cross coupling reaction with an appropriate boronic acid furnishes the compound of Formula VI.
  • Figure US20190292176A1-20190926-C00023
  • In this invention, compounds of Formula VII can be obtained through the synthetic route shown in Scheme 10. Beginning with aryl chloride VIIa, palladium catalyzed cross coupling of various boronic acids or stannanes yields substituted anilines of structure VIIb. Nitration of compound VIIb and reduction of compound VIIc allows access to compounds of Formula VIId. Base mediated condensation of dianiline VIId with substituted bromo-ketones provides heterocycles of Formula VIIe. A final palladium-catalyzed cross coupling with aryl boronic acids or stannanes then furnishes the compounds of Formula VII.
  • Figure US20190292176A1-20190926-C00024
  • Compounds of Formula VIII of this invention can be obtained by palladium catalyzed cross coupling of aryl boronic acids or stannanes with aryl chloride VIIIc as shown in Scheme 11. Compound Villa can be condensed with amidines to give compound VIIIb. Phosphorous oxychloride conversion of compound VIIIb to aryl chloride VIIIc followed by palladium-catalyzed cross coupling with aryl boronic acids or stannanes furnishes the compound of Formula VIII.
  • Figure US20190292176A1-20190926-C00025
  • A synthesis of 2-halo benzothiazole XXI is shown in Scheme 12. Beginning with the appropriately substituted aniline XIX, the 2-amino benzothiazole XX is formed via addition and oxidative cyclization of a thiocyanate. Subsequent Sandmeyer chemistry is employed to generate the desired 2-halo benzothiazole XXI. With XXI in hand, various compounds of Formula I with structure XXIIa are prepared with boronic acid Ib via Suzuki cross-coupling. Intermediates for preparation of compounds of Formulas I-VIII containing bicyclic R3 groups other than benzothiazole are commercially available or can be prepared by one skilled in the art, and can be incorporated into compounds of Formulas I-VIII via cross coupling chemistry as shown in Scheme 12.
  • Figure US20190292176A1-20190926-C00026
  • When compounds of structure XXIIb are used as a starting material, several compounds of Formula I with structure XXIII are prepared through either alkylation or Mitsunobu chemistry as shown in Scheme 13. Compounds XXIVa are accessed via epoxide opening of a variety of mono-substituted epoxides, and compounds XXIVb are accessed through the opening of di-substituted cyclic sulfates.
  • Figure US20190292176A1-20190926-C00027
    Figure US20190292176A1-20190926-C00028
  • Substitution at the 4-position of the benzothiazole R3 group can be accomplished from intermediates XXVa and XXVb as shown in Scheme 14. Lithiation of XXVa followed by its addition to a variety of aldehydes provides XXVI, as does Grignard addition to benzaldehyde XXVb. XXVI is then coupled to Ib as described above to provide compounds of Formula I with structure XXVII.
  • Figure US20190292176A1-20190926-C00029
  • Many compounds derived from the core structures depicted above can be either acylated or sulfonylated using the strategy shown in Scheme 15. Thus, chloroformate XXIX is synthesized from compounds with formulas analogous to XXVIII using phosgene. These chloroformates are then reacted with a variety of nucleophiles to generate compounds of structure XXX. Compounds of structure XXXII are synthesized from amines such as XXXI using sulfonyl chloride reagents.
  • Figure US20190292176A1-20190926-C00030
    • General Methods
  • The following methods were used in the exemplified Examples, except where noted otherwise.
  • Products were analyzed by reverse phase analytical HPLC carried out on a Shimadzu Analytical HPLC system running Discovery VP software using one of the following methods
  • Method A: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at 4 mL/min with 2, 4 or 8 min gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
  • Method B: PHENOMENEX® Luna C18 column (4.6×50 mm) eluted at 4 mL/min with a 4 min gradient from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).
  • Method C: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at 4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% H3PO4; B: 10% water, 89.9% methanol, 0.1% H3PO4, UV 220 nm).
  • Method D: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at 4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% NH4OAc; B: 10% water, 89.9% methanol, 0.1% NH4OAc, UV 220 nm).
  • Method E: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0% B to 100% B in 1 minute, gradient time 1.5 min.
  • Method F: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0% B to 50% B in 1 minute, gradient time 1.5 min.
  • Method G: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; 50% B to 100% B in 1 minute, gradient time 1.5 min.
  • Reverse phase preparative HPLC was carried out using a Shimadzu Preparative HPLC system running Discovery VP software using one of the following methods.
  • Method A: PHENOMENEX® Axia Luna 5 μM C18 30×75 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).
  • Method B: YMC Sunfire 5 μM C18 30×100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
  • Method C: XBridge C18, 19×200 mm column, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Flow: 20 mL/min.
  • Method D: Waters XBridge C18, 19×100 mm column, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Flow: 20 mL/min.
  • Method E: PHENOMENEX® Luna 5 μM C18 30×100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).
  • Method F: PHENOMENEX® Luna 5 μM C18 30×100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
  • Method G: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% formic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% formic acid; Flow: 20 mL/min.
  • LCMS chromatograms were obtained on a Shimadzu HPLC system running Discovery VP software, coupled with a Waters ZQ mass spectrometer running MassLynx version 3.5 software using
  • Method A: A linear gradient using solvent A (10% acetonitrile, 90% water, 0.1% of TFA) and solvent B (90% acetonitrile, 10% water, 0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of solvent B over 1 min. Column: PHENOMENEX® Luna 3 u C18(2) (2.0×30 mm). Flow rate was 5 ml/min. And UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method B: A linear gradient using solvent A (10% methanol, 90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA); 0-100% of solvent B over 4 min and then 100% of solvent B over 1 min. Column: PHENOMENEX® Luna 5 u C18 (4.5×30 mm). Flow rate was 4 ml/min. And UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method C: A linear gradient using solvent A (10% methanol, 90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of solvent B over 1 min. Column: PHENOMENEX® Luna 3 u C18(2) (2.0×30 mm). Flow rate was 1 ml/min. And UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method D: A linear gradient using solvent A (10% methanol, 90% water, 0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA); 0-100% of solvent B over 2 min and then 100% of solvent B over 1 min. Column: PHENOMENEX® Luna 3 u C18(2) (4.5×30 mm). Flow rate was 5 ml/min. And UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method E: 30-95% acetonitrile in water with 0.1% TFA in 8 min run, Waters Xbridge 4.6×50 mm 5 um C18, flow rate 1.2 mL/min and UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method F: 10-95% methanol in water, 0.1% TFA in a 10 min run, PHENOMENEX® Onyx Monolithic 4.6×100 mm 5 um C18, flow rate 2.0 mL/mL and UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method G: 5-95% acetonitrile in water, 10 mM of modifier in 6 min run, Waters Xbridge 2.1×50 mm 5 um C18, flow rate 1.0 mL/min and UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method H: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 2 to 98% B.
  • Method I: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 2 to 52% B.
  • Method J: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 48 to 98% B.
  • Method K: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • Method L: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • In addition, the following orthogonal HPLC conditions were used to check the purity of the compounds
  • Method A: Two analytical LC/MS injections were used to determine the final purity. Injection1 condition: A linear gradient using solvent A (5% acetonitrile, 95% water, 0.05% TFA) and solvent B (95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent B over 10 min and then 100% of solvent B over 5 min. Column: Sunfire C18 3.5 um (4.6×150 mm). Flow rate was 2 ml/min. And UV detection was set to 220 nm. The LC column was maintained at room temperature. Injection 2 conditions: A linear gradient using solvent A (5% acetonitrile, 95% water, 0.05% TFA) and solvent B (95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent B over 10 min and then 100% of solvent B over 5 min. Column: Xbridge Phenyl 3.5 um (4.6×150 mm). Flow rate was 2 ml/min. And UV detection was set to 220 nm. The LC column was maintained at room temperature.
  • Method B: Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm. Injection 2 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
    • General Procedures
  • The following procedures were used during the synthesis of the Examples and Intermediates where indicated below.
  • Procedure A: 5-bromo-2-chloropyrimidine (1.0 equiv.) was solvated in DMF (0.2 M) along with the appropriate diol (2.0 equiv.). 60% sodium hydride in mineral oil (3.0 equiv.) was added to the reaction mixture portion-wise at 0° C., then the reaction mixture allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was then quenched with saturated ammonium chloride and diluted with EtOAc. The organic layer was washed with 10% aqueous LiCl solution (3×), brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being purified by silica gel chromatography to provide the desired material.
  • Procedure B: To a vial containing the appropriate 5-bromopyrimidine (1.0 equiv.), palladium(II) acetate (0.1 equiv.), BINAP (0.2 equiv.), cesium carbonate (1.2 equiv.) and diphenylmethanimine (1.1 equiv.) was added toluene (0.5 M). The vial was sealed, evacuated and backfilled with Ar 3×, and the reaction mixture was heated to 105° C. for 18 hours. The reaction mixture was then diluted with EtOAc and washed with 1M aqueous NaOH (1×) and brine (1×). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being purified by silica gel chromatography to provide the desired material.
  • Procedure C: The 4-((diphenylmethylene)amino)pyrimidine intermediate (1.0 equiv.) was dissolved in 1:1 MeOH/THF (0.06M). 1M aqueous HCl (2.5 equiv.) was added to the reaction mixture at room temperature. The reaction mixture was allowed to stir at room temperature for 1 hour then diluted with water and extracted with 5:1 EtOAc/Hexanes (3×). The aqueous phase was concentrated and azeotroped with toluene 3× to yield the desired 4-aminopyrimidine which was brought forward without further purification.
  • Procedure D: 4-bromo-2-fluoropyridine (1.0 equiv.) was dissolved in DMF (1.1 M) along with the appropriate diol (1.5 equiv.). 60% sodium hydride in mineral oil (2.0 equiv.) was added to the reaction mixture portion-wise at 0° C. and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then quenched with saturated ammonium chloride solution and extracted with EtOAc (3×). The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being purified by silica gel chromatography to provide the desired material.
  • Procedure E: N1,N2-dimethylethane-1,2-diamine (1.0 equiv.), 2,2,2-trifluoroacetamide (2.0 equiv.), copper(I) iodide (0.2 equiv.), potassium carbonate (2.0 equiv.) and the 4-boromo-2-alkoxypyridine intermediate (1.0 equiv.) were dissolved in dioxane (0.6 M) in a sealed vial. The vial was evacuated and backfilled with Ar 3× then the reaction mixture was stirred at 75° C. for 2 hours. 3 mL of 1:1 MeOH/H2O was added to the mixture which was stirred at room temperature for 2 h then at 40° C. for 1 h. The reaction mixture was then diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride before being purified by silica gel chromatography to provide the desired material.
  • Procedure F: The ester (1.0 equiv.) was dissolved in THF (0.2 M) and the solution was cooled to −78° C. 1M DIBAL-H in toluene (3.0 equiv.) was added to the mixture which was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was then quenched saturated Rochelle's salt and allowed to stir for 18 h at room temperature. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated yield the desired product.
  • Procedure G: The ester (1.0 equiv.) was dissolved in THF (0.2 M) and cooled to −78° C. To the cooled reaction mixture was added 1M DIBAL-H in toluene (3.0 equiv.) and the reaction mixture was allowed to stir at −78° C. for 1 hour. The reaction mixture was then quenched saturated Rochelle's salt and allowed to stir for 2 h at room temperature. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting aldehyde intermediate was then re-subjected to the conditions described above to ultimately yield the desired alcohol product.
  • Procedure H: To the ester (1.0 equiv.) dissolved in THF (0.06 M) at −78° C. was added methylmagnesium bromide (10.0 equiv.). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes at room temperature. The reaction mixture was then quenched with saturated ammonium chloride, diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was purified by reverse phase preparative HPLC to yield the desired product.
  • Procedure I: The alcohol (1.0 equiv.), imidazole (2.2 equiv.) and TBS-Cl (2.0 equiv.) were dissolved in THF or DCM (0.1 M). The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was then diluted with 1.5 M dipotassium phosphate solution and extracted with EtOAc (3×). The combined organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride and purified by silica gel chromatography to yield the desired product.
  • Procedure J: The silyl protected intermediate (1.0 equiv.) was dissolved in a mixture of 20:1 MeOH/concentrated aqueous HCl (0.01 M), and the reaction mixture was stirred at room temperature. The reaction was monitored by LCMS, and after completion of the reaction (10 min-12 hours) the reaction mixture was concentrated, dissolved in DMF and purified by preparative HPLC to yield the desired example.
  • Procedure K: The acetonide intermediate (1.0 equiv.) was dissolved in a mixture of 4:3:2 THF/MeOH/concentrated aqueous HCl (0.01 M), and the solution was stirred at room temperature. The resulting mixture was monitored by LCMS, and after completion of the reaction (10 min-12 hours) the mixture was diluted with EtOAc, washed with 1.5 M K2HPO4, dried over sodium sulfate, filtered, concentrated, dissolved in DMF and purified by preparative HPLC to yield the desired example.
    • EXAMPLES
  • The invention is further defined in the following Examples. It should be understood that the Examples are given by the way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather is defined by the claims appended hereto.
    • ABBREVIATIONS
    • AcOH acetic acid
    • ACN acetonitrile
    • BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthylene
    • Boc tert-butoxycarbonyl
    • BOC2O di(tert-butoxycarbonyl) ether
    • BuLi butyl lithium
    • DCE dichloroethane
    • DCM dichloromethane
    • DIAD diisopropyl azodicarboxylate
    • DIBAL-H diisobutylaluminium hydride
    • DIEA diisopropylethylamine
    • DMAP dimethylaminopyridine
    • DMF dimethylformamide
    • DMSO dimethylsulfoxide
    • EtOAc ethyl acetate
    • EtOH ethanol
    • HOBt hydroxybenzotriazole
    • mCPBA 3-chloroperbenzoic acid
    • MeCN acetonitrile
    • MeOH methanol
    • NH4OAc ammonium acetate
    • NMP N-methylpyrrolidinone
    • PdCl2(dppf)-CH2Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct
    • Pd(OAc)2 palladium acetate
    • Pd(Ph3P)4 tetrakis(triphenylphosphine)palladium
    • TBAF tetrabutylammonium fluoride
    • TBDMS-Cl tert-butyldimethylsilyl chloride
    • TEA triethylamine
    • TFA trifluoroacetate
    • THF tetrahydrofuran
    • HPLC high pressure liquid chromatography
    • MS mass spectrometry
    • g gram(s)
    • h or hr hour(s)
    • min. minute(s)
    • mL milliliter(s)
    • mmol millimole(s)
    • RT retention time
    INTERMEDIATE I-1 2-(difluoromethoxy)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline
  • Figure US20190292176A1-20190926-C00031
    • Intermediate I-1A: tert-butyl N-(2-bromo-4-methyl-6-nitrophenyl)-N-[(tert-butoxy) carbonyl]carbamate
  • Figure US20190292176A1-20190926-C00032
  • To a solution of 2-bromo-4-methyl-6-nitroaniline (9.6 g, 41.6 mmol) in THF (60 mL) was added DMAP (0.508 g, 4.16 mmol), followed by BOC2O (22.67 g, 104 mmol) as a solid. The mixture was stirred at room temperature overnight. Solvent was removed by vacuum. The crude product was dissolved in a small amount of chloroform and charged to a 120 g silica gel cartridge (2 separate columns) which was eluted with 5% EtOAc in hexanes for 4 min., then a 12 min gradient from 5% to 30% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate I-1A (17.12 g, 39.7 mmol, 96% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.80-7.79 (m, 1H), 7.73 (dd, J=1.9, 0.8 Hz, 1H), 2.48 (s, 3H), 1.42 (s, 18H); LC-MS: method A, RT=1.90 min, MS (ESI) m/z: 230.0 and 232.0 (M-2 Boc)+.
    • Intermediate I-1B: tert-butyl (2-bromo-4-methyl-6-nitrophenyl)carbamate
  • Figure US20190292176A1-20190926-C00033
  • To a solution of Intermediate I-1A (17.1 g, 39.6 mmol) in dichloromethane (60 mL) was added TFA (6.11 mL, 79 mmol) and the mixture was stirred at room temperature for 1.0 h. The reaction mixture was quenched by addition of saturated sodium bicarbonate, extracted with dichloromethane (3×), dried over sodium sulfate. After evaporation of solvent, Intermediate I-1B was obtained as a yellow solid (12.88 g, 88% yield): 1H NMR (500 MHz, chloroform-d) δ 7.71 (d, J=1.1 Hz, 1H), 7.68 (dd, J=1.9, 0.8 Hz, 1H), 2.42 (s, 3H), 1.51 (s, 9H); LC-MS: method A, RT=1.53 min, MS (ESI) m/z: 231.0 and 233.0 (M-Boc)+.
    • Intermediate I-1C: methyl 2-((2-bromo-4-methyl-6-nitrophenyl)(tert-butoxycarbonyl) amino)acetate
  • Figure US20190292176A1-20190926-C00034
  • Intermediate I-1B (12 g, 26.3 mmol) was dissolved in DMF (80 mL), cooled with a water bath. Cs2CO3 (25.8 g, 79 mmol) was added. The dark brown solution was stirred at room temperature for 10 min, then methyl 2-bromoacetate (4.37 mL, 47.6 mmol) was added dropwise. After addition of methyl bromoacetate, the brown color faded to yellow. The mixture was stirred at room temperature for 1.0 h, diluted with EtOAc, quenched with water. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 330 g silica gel cartridge which was eluted with 5% EtOAc in hexanes for 5 min., then a 12 min gradient from 5% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate I-1C (15.2 g, 37.7 mmol, 95% yield) as an yellow oil. 1H NMR (500 MHz, chloroform-d) indicated a mixture of rotamers: δ 7.75-7.67 (m, 2H), 4.61-3.97 (m, 2H), 3.76 and 3.69 (s, 3H), 2.48 and 2.43 (s, 3H), 1.55 and 1.37 (s, 9H); LC-MS: method A, RT=1.70 min, MS (ESI) m/z: 303.0 and 305.0 (M-Boc)+.
    • Intermediate I-1D: methyl 2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C00035
  • To Intermediate I-1C (15.2 g, 37.7 mmol) was added 4.0 N HCl in dioxane (47.1 ml, 188 mmol) and the mixture was stirred at room temperature overnight. Solvent was removed under vacuum, chased with EtOAc (2×) to give Intermediate I-1D (13.6 g, 40.1 mmol, 106% yield) as a yellow solid. 1H NMR (500 MHz, methanol-d4) δ 7.88 (dd, J=1.9, 0.6 Hz, 1H), 7.80 (dd, J=1.9, 0.6 Hz, 1H), 4.47 (d, J=17.3 Hz, 1H), 4.08 (d, J=17.1 Hz, 1H), 3.69 (s, 3H), 2.46 (s, 3H); LC-MS: Method A, RT=1.94 min, MS (ESI) m/z: 303.1 and 305.1 (M+H)+.
    • Intermediate I-1E: 5-bromo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00036
  • To a solution of Intermediate I-1D (13.6 g, 40.1 mmol) in MeOH (100 mL) in a 1 L flask cooled with water bath was added concentrated HCl (13.35 mL, 160 mmol), followed by tin(II) chloride dihydrate (36.1 g, 160 mmol). The mixture was stirred at 68° C. for 2.5 h. MeOH was removed by vacuum. The crude was partitioned in water (100 mL)/EtOAc (200 mL), and the pH was adjusted to neutral with 4.0 N NaOH (ca 90 mL). The white precipitate formed was very fine particle that was very hard to remove by filtration. The mixture was transferred to a separatory funnel. The organic layer was collected. The aqueous was further extracted (2×200 mL) with EtOAc. The combined organic layer was washed with water (2×) and brine (2×), dried over sodium sulfate. After evaporation of solvent, Intermediate I-1E (8.36 g, 34.7 mmol, 87% yield) was obtained as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 6.87 (dd, J=1.8, 0.7 Hz, 1H), 6.56 (dd, J=1.1, 0.6 Hz, 1H), 5.46 (s, 1H), 3.76 (d, J=2.2 Hz, 2H), 2.14 (s, 3H); LC-MS: method A, RT=1.66 min, MS (ESI) m/z: 241.0 and 243.0 (M+H)+.
    • Intermediate I-1F: 5-bromo-7-methylquinoxalin-2-ol
  • Figure US20190292176A1-20190926-C00037
  • To a suspension of Intermediate I-1E (6.7 g, 27.8 mmol) in MeOH (50 mL) in a 1 L flask was added 30% hydrogen peroxide (28.4 mL, 278 mmol), followed by 4.0 N NaOH (20.84 mL, 83 mmol). The mixture was stirred at room temperature for 5 min, then gently heated at 60° C. After 15 min heating, the reaction mixture turned strongly exothermic, suggesting an initiation of the reaction mixture. The heating bath was removed and stirring continued for 30 min until the mixture turned completely clear. After cooling to room temperature with a water bath, MeOH was removed by vacuum. The mixture was then neutralized with 2.0 N HCl (to pH 2-3) and ice cooling. The precipitate formed was collected by filtration, washed with water, dried under vacuum in the air for 1.0 h and then at vacuum at 60° C. for 2.0 h, and under high vacuum to give Intermediate I-1F (6.55 g, 27.4 mmol, 99% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.52 (br. s., 1H), 8.17 (s, 1H), 7.49 (d, J=1.1 Hz, 1H), 7.08 (s, 1H), 2.40 (s, 3H; LC-MS: method A, RT=1.62 min, MS (ESI) m/z: 239.0 and 241.0 (M+H)+.
    • Intermediate I-1G: 5-bromo-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00038
  • A mixture of Intermediate I-1F (7.4 g, 26.9 mmol) and potassium carbonate (18.56 g, 134 mmol) in DMF (120 mL) was heated at 100° C. for 5 min. Sodium 2-chloro-2,2-difluoroacetate (16.40 g, 107.6 mmol) was added in one portion, and the mixture was stirred at 100° C. for 10 min. The mixture turned from yellow slurry to brown. The mixture was cooled to room temperature, diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform/toluene and purified with a 330 g ISCO column eluted with 5% dichloromethane in hexanes for 3 min, then 5-70% DCM/hexanes for 40 min (12 min gradient time). The desired fractions were combined, concentrated to give Intermediate I-1G (6.0 g, 20.76 mmol, 77% yield) as a slightly yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.64 (s, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.68 (dd, J=1.8, 1.0 Hz, 1H), 7.63 (t, JHF=71.80 Hz, 1H), 2.59 (s, 3H); 19F NMR (471 MHz, chloroform-d) δ −89.82 (s, 2F); LC-MS: method A, RT=2.09 min, MS (ESI) m/z: 289.0 and 291.0 (M+H)+.
    • Intermediate I-1
  • A mixture of Intermediate I-1G (1.04 g, 3.60 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.370 g, 5.40 mmol), potassium acetate (0.883 g, 8.99 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.147 g, 0.180 mmol) in dioxane (14 mL) was degassed by bubbling argon for 10 min. The reaction mixture vial was sealed and heated in microwave reactor at 135° C. for 30 min. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of toluene and charged to a 40 g silica gel cartridge which was eluted with 5% EtOAc in hexanes for 2 min., then a 18 min gradient from 5% to 75% EtOAc in hexanes. The desired fractions were concentrated and lyophilized to give Intermediate I-1 (0.93 g, 72% yield) as a pale solid. 1H NMR was complicated by the presence of two sets of signals. 19F NMR indicated a single compound. 19F NMR (471 MHz, chloroform-d) δ −89.64 (s., 2F). LC-MS: method A, RT=2.01 min, MS (ESI) m/z: 225.0 (boronic acid)+.
    • Intermediate I-2 2-(methoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00039
    • Intermediate I-2A: 1-diazo-3-methoxypropan-2-one
  • Figure US20190292176A1-20190926-C00040
  • To 2-methoxyacetyl chloride (2.4 g, 22.12 mmol) in MeCN (40 mL) cooled with ice-bath was added (diazomethyl)trimethylsilane 2.0 M in diethyl ether (19.35 mL, 38.7 mmol). The mixture was allowed to stir at room temperature overnight. Solvent was removed under reduced pressure. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% EtOAc in hexane over 18 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated (bath temp below 35° C.) to yield Intermediate I-2A (1.82 g, 15.95 mmol, 72.1% yield) as a yellow liquid. 1H NMR (500 MHz, chloroform-d) δ 5.73 (br. s., 1H), 3.97 (br. s., 2H), 3.43 (s, 3H); LC-MS: method A, RT=0.43 min, MS (ESI) m/z: 137.0 (M+Na)+.
    • Intermediate I-2B: 1-bromo-3-methoxypropan-2-one
  • Figure US20190292176A1-20190926-C00041
  • To Intermediate I-2A (1.6 g, 14.02 mmol) in diethyl ether (20 mL) at 0° C. was added aqueous HBr 48% (2.380 mL, 21.03 mmol) dropwise. After stirring at 0° C. for 5 min and at room temperature for 10 min, the reaction mixture was diluted with EtOAc, washed with water, saturated sodium bicarbonate (2×) and brine. The organic layer was dried over sodium sulfate, concentrated (keep bath temp below 30° C.) to give Intermediate I-2B (1.5 g, 8.98 mmol, 64.1% yield) as a slightly yellow liquid. 1H NMR indicated >92% purity. The compound was used immediately for the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 4.24 (s, 2H), 4.03 (s, 2H), 3.45 (s, 3H), consistent with literature report (I Org. Chem. 1981, 217).
    • Intermediate I-2C: tert-butyl (2-bromo-4-methyl-6-nitrophenyl)(3-methoxy-2-oxopropyl)carbamate
  • Figure US20190292176A1-20190926-C00042
  • To Intermediate I-1B (1.98 g, 5.98 mmol) in DMF (20 mL) at 0° C. was added Cs2CO3 (3.41 g, 10.46 mmol). The brown solution was stirred at 0° C. for 10 min, followed by addition of Intermediate I-2B (1.498 g, 8.97 mmol) in acetonitrile (5.0 mL). The brown solution turned yellow. The mixture was stirred at 0° C. for 15 min., diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 60% EtOAc in hexane over 18 min using a 80 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate I-2C (2.4 g, 5.75 mmol, 96% yield) as a yellow oil. 1H NMR indicated presence of two rotamers. 1H NMR (500 MHz, chloroform-d) δ 7.70-7.65 (m, 2H), 4.55 (d, J=17.9 Hz, 1H), 4.18 (d, J=17.9 Hz, 1H), 4.32 and 4.14 (d, J=1.4 Hz, 2H), 3.44 and 3.40 (s, 3H), 2.45 and 2.40 (s, 3H), 1.49 and 1.35 (s, 9H); LC-MS: method A, RT=1.89 min, MS (ESI) m/z: 317 and 319 (M-Boc)+.
    • Intermediate I-2D 6-bromo-3-hydroxy-3-(methoxymethyl)-8-methyl-1-oxo-1,3,4,5-tetrahydrobenzo[c][1,2,5]oxadiazepin-1-ium
  • Figure US20190292176A1-20190926-C00043
  • To Intermediate I-2C (1.67 g, 4.00 mmol) in ethyl acetate (10 mL) was added 4.0 N HCl in dioxane (10.01 mL, 40.0 mmol) and the mixture was stirred at room temperature for 20 min. Solvent was removed under vacuum, chased with EtOAc once to give Intermediate I-2D (1.25 g, 99%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.75-7.66 (m, 2H), 4.13-3.98 (m, 1H), 3.78-3.56 (m, 3H), 3.50 and 3.44 (m, 3H), 2.39 (s, 3H); LC-MS: method A, RT=1.47 min, MS (ESI) m/z: 317.0 and 319.0 (M+H)+.
    • Intermediate I-2E: 5-bromo-2-(methoxymethyl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00044
  • Intermediate I-2D (1.25 g, 3.9 mmol) was dissolved in THF (30 mL). Concentrated HCl (0.986 mL, 12.01 mmol) was added, followed by tin(II) chloride dihydrate (3.61 g, 16.01 mmol). The mixture was placed and stirred in an oil bath pre-heated at 40° C. for 4.0 h. The reaction mixture was diluted with EtOAc/water, The organic phase was neutralized with saturated sodium bicarbonate and stirred at room temperature for 15 min, the precipitate was removed by filtration with a pad of wet celite. The filtrate was collected. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 60% EtOAc in hexane over 20 min using a 120 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate I-2D (0.57 g, 1.920 mmol, 48.0% yield) as a brown solid: 1H NMR (400 MHz, chloroform-d) δ 9.03 (s, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.84 (dd, J=1.8, 1.1 Hz, 1H), 4.84 (s, 2H), 3.56 (s, 3H), 2.60 (s, 3H); Intermediate I-2D was contaminated with ca 10% of a side product 5-bromo-2,7-dimethylquinoxaline.
    • Intermediate I-2
  • A mixture of Intermediate I-2E (900 mg, 3.37 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1369 mg, 5.39 mmol), potassium acetate (661 mg, 6.74 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (110 mg, 0.135 mmol) in dioxane (15 mL) was degassed by bubbling argon for 10 min. The reaction vial was sealed and heated in microwave reactor at 130° C. for 30 min. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine and dried over sodium sulfate, concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 20% dichloromethane in MeOH over 15 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated and further purified by prep HPLC (method A, 10-80% B in 8 mins; with a flow rate of 40 mL/min). The desired fractions were placed in a SpeedVac overnight to remove solvent. The material was dissolved in EtOAc, washed with diluted saturated sodium bicarbonate (to remove TFA), brine, dried over sodium sulfate, concentrated and lyophilized to give Intermediate I-2 (360 mg, 1.550 mmol, 46% yield) as a slightly colored solid. LC-MS: method A, RT=1.73 min, MS (ESI) m/z: 233.1 boronic acid (M+H)+.
    • Intermediate I-3 2-bromo-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00045
    • Intermediate I-3A: 6-methoxy-4-methylbenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00046
  • To 4-methoxy-2-methylaniline (209 mg, 1.524 mmol) in acetonitrile (8 mL) was added ammonium thiocyanate (174 mg, 2.285 mmol). The mixture was stirred at room temperature for 10 min. Then it was cooled with tap water, and benzyltrimethylammonium tribromide (594 mg, 1.524 mmol) in acetonitrile (3.0 mL) was added dropwise. The mixture was then stirred at room temperature overnight. HPLC and LCMS indicated a clean reaction. The mixture was diluted with EtOAc/saturated sodium bicarbonate. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform/MeOH, and charged to a 24 g silica gel cartridge which was eluted with 5% EtOAc in hexanes for 3 min., then a 12 min gradient from 5% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate I-3A (240 mg, 1.235 mmol, 81% yield) as a pale solid. 1H NMR (500 MHz, methanol-d4) δ 7.03 (d, J=2.5 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 3.79 (s, 3H), 2.46 (s, 3H); LC-MS: method A, RT=1.22 min, MS (ESI) m/z: 195.0 (M+H)+.
    • Intermediate I-3
  • t-Butyl nitrite (0.969 mL, 8.15 mmol) was added to copper(II) bromide (1820 mg, 8.15 mmol) in dry acetonitrile (20 mL) under argon. The mixture was stirred at room temperature for 10 min. A suspension of Intermediate I-3A (931 mg, 4.79 mmol) in acetonitrile (30 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.0 h. LCMS indicated a clean reaction. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc (30 mL) and 20 mL of 0.5M HCl (aqueous). After separation, organic layer was washed with 0.5 N HCl (20 mL×2), saturated sodium bicarbonate (15 mL), brine (15 mL) and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by ISCO (80 g silica gel column, 20% EtOAc/hexanes). Removing solvent gave Intermediate I-3 as white solid (1.13 g, 91%). 1H NMR (400 MHz, methanol-d4) δ 7.29 (d, J=2.5 Hz, 1H), 6.95-6.87 (m, 1H), 3.84 (s, 3H), 2.60 (s, 3H); LC-MS: (BEH C18 2.1×50 mm; A: 10% MeCN-90% H2O −0.1% TFA; B: 90% MeCN-10% H2O −0.1% TFA; wavelength 220/254 nm; flow rate 5 mL/min; gradient time 2 min; 2 to 98% B) 1.11 min, [M+1]+=258.0, 260.0;
    • Intermediate I-4 2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanamine
  • Figure US20190292176A1-20190926-C00047
    • Intermediate I-4A: 2-chlorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00048
  • Aluminum chloride (3.07 g, 22.99 mmol) was added to a solution of 2-chloro-6-methoxybenzo[d]thiazole (1.53 g, 7.66 mmol) in toluene (50 mL). The mixture was heated at 110° C. for 1.5 h. TLC indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water (3×), saturated sodium bicarbonate (3×), water (3×) and air-dried for 1.0 h under vacuum. It was further dried under high vacuum overnight to give Intermediate I-4A (1.18 g, 6.36 mmol, 83% yield) as a pale brown solid. 1H NMR (500 MHz, chloroform-d) δ 7.82 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H), 5.53 (s, 1H); LC-MS: method A, RT=1.62 min, MS (ESI) m/z: 186.0 and 188.0 (M+H)+.
    • Intermediate I-4B: 6-((tert-butyldimethylsilyl)oxy)-2-chlorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00049
  • To a stirred solution of Intermediate I-4A (1.15 g, 6.20 mmol) in DMF (20 mL) was added TBDMS-Cl (1.307 g, 8.67 mmol) and imidazole (0.738 g, 10.84 mmol). After stirring at room temperature for 1.0 h, the reaction mixture was partitioned between EtOAc/water. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 24 g silica gel cartridge which was eluted with hexanes for 3 min., then a 15 min gradient from 0% to 15% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate I-4B (1.78 g, 5.94 mmol, 96% yield) as a clear brownish oil. 1H NMR (500 MHz, chloroform-d) δ 7.81 (d, J=8.8 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 7.01 (dd, J=8.8, 2.5 Hz, 1H), 1.04 (s, 9H), 0.26 (s, 6H); LC-MS: Method A, 50 to 100% B. RT=2.34 min, MS (ESI) m/z: 300.0 and 302.0 (M+H)+.
    • Intermediate I-4C 6-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00050
  • To Intermediate I-1 (1.45 g, 4.31 mmol), Intermediate I-4B (1.488 g, 4.96 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.176 g, 0.216 mmol) was added toluene (9 mL) and EtOH (3 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate, 2M (4.53 mL, 9.06 mmol). The reaction mixture was heated in a microwave at 130° C. for 80 min. HPLC and LCMS indicated a clean reaction. To the reaction mixture was added EtOAc/water. The organic layers were collected, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of toluene/chloroform and charged to a 80 g silica gel cartridge which was eluted with 5% dichloromethane in hexanes for 3 min., then a 18 min gradient from 5% to 75% dichloromethane in hexanes (flow rate 50 mL/min). The desired fractions were combined and concentrated to give Intermediate I-4C (1.65 g, 3.48 mmol, 81% yield) as a bright yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.76 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.80 (dd, J=1.8, 1.0 Hz, 1H), 7.68 (t, JHF=71.80 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.07 (dd, J=8.7, 2.3 Hz, 1H), 2.70 (s, 3H), 1.07-1.05 (m, 9H), 0.30-0.28 (m, 6H); 19F NMR (471 MHz, chloroform-d) δ −89.74 (s, 2F); LC-MS: method A, RT=2.89 min, MS (ESI) m/z: 474.1 (M+H)+.
    • Intermediate I-4D: 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00051
  • To a solution of Intermediate I-4C (1.65 g, 3.48 mmol) in THF (15 mL) at room temperature was added acetic acid (0.439 mL, 7.66 mmol), followed by addition of 1.0 N TBAF in THF (4.53 mL, 4.53 mmol) dropwise. The mixture was stirred at room temperature for 40 min. HPLC and LCMS indicated a completion of reaction. The mixture was diluted with EtOAc, washed with water, saturated sodium bicarbonate (2×), brine, and dried over sodium sulfate. After evaporation of the solvent, the crude product was triturated with EtOAc/hexanes (1:4). The precipitate was collected by filtration to give Intermediate I-4D (1.13 g) of the desired product. 1H NMR (500 MHz, chloroform-d) δ 8.58 (d, J=1.9 Hz, 1H), 8.53 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.50 (t, JHF=71.80 Hz, 1H), 6.98 (s, 1H), 6.88 (dd, J=8.8, 2.5 Hz, 1H), 2.52 (s, 3H); 19F NMR (471 MHz, chloroform-d) δ −89.75 (s, 2F); LC-MS: method A, RT=2.24 min, MS (ESI) m/z: 360.0 (M+H)+.
    • Intermediate I-4E: tert-butyl (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00052
  • A solution of tert-butyl (2-hydroxyethyl)carbamate (1.252 g, 7.76 mmol) and DIAD (1.510 mL, 7.76 mmol) in THF (6 mL) was added to a mixture of Intermediate I-4D (0.93 g, 2.59 mmol) and triphenylphosphine (1.358 g, 5.18 mmol) in THF (10 mL) heated at 70° C. dropwise with a syringe pump in 3 h. At the end of addition, HPLC and LCMS indicated a complete conversion of starting material to the product. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate (2×), brine. The organic layers were collected, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 80 g silica gel cartridge which was eluted with dichloromethane for 5 min., then a 18 min gradient from 0% to 25% EtOAc in dichloromethane, flow rate 60 mL/min. The desired fractions were combined and purified with a second ISCO (80 g) column, to give Intermediate I-4E (1.0 g, 1.990 mmol, 77% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.80 (d, J=1.7 Hz, 1H), 8.71 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.8, 1.0 Hz, 1H), 7.68 (t, JHF=71.68 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.15 (dd, 2.5 Hz, 1H), 4.19-4.12 (m, 2H), 3.63 (d, J=5.0 Hz, 2H), 2.71 (s, 3H), 1.53-1.48 (s, 9H); 19F NMR (471 MHz, chloroform-d) δ −89.75 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.20 min, MS (ESI) m/z: 503.0 (M+H)+.
    • Intermediate I-4
  • Intermediate I-4E (1.2 g, 2.388 mmol) was added 4.0 N HCl in dioxane (41.8 ml, 167 mmol), followed by addition of EtOAc (10 mL) to rinse the solid residue on the flask wall. The mixture was left stirring at room temperature overnight. HPLC and LCMS indicated a clean reaction. Solvent was removed, chased twice with EtOAc, once with MeOH, and then dried under high vacuum over the weekend to give Intermediate I-4 (1.0 g, 2.279 mmol, 95% yield) as a bright yellow solid. 1H NMR (500 MHz, methanol-d4) δ 8.75 (d, J=1.7 Hz, 1H), 8.73 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.91-7.89 (m, 1H), 7.69 (t, JHF=71.53 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.29 (dd, J=8.9, 2.3 Hz, 1H), 4.38 (t, J=5.0 Hz, 2H), 3.42 (t, J=4.5 Hz, 2H), 2.71 (s, 3H); LC-MS: method A, RT=1.90 min, MS (ESI) m/z: 403.0 (M+H)+.
    • Intermediate I-5 N-(2-((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00053
    • Intermediate I-5A: tert-butyl (2-(3-methyl-4-nitrophenoxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00054
  • In a round bottom flask, tert-butyl (2-hydroxyethyl)carbamate (3.0 g, 18.61 mmol) was dissolved in DMF (20 mL) and mixed with 4-fluoro-2-methyl-1-nitrobenzene (2.89 g, 18.61 mmol). K2CO3 (7.72 g, 55.8 mmol) was added. Then the mixture was stirred at 100° C. overnight. On the next day, the reaction mixture was poured into ice water (50 mL) and was extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude product that was purified by flash chromatography (80 g silica gel column, eluted with 0-100% EtOAc/Hexane gradient). Collecting desired fractions and removing solvent gave the desired product as a yellow oil. (2.44 g, 8.2 mmol, 44.2%). 1H NMR (400 MHz, chloroform-d): δ 8.19-7.94 (m, 1H), 6.91-6.70 (m, 2H), 4.95 (br s, 1H), 4.14-4.05 (m, 2H), 3.56 (q, J=5.3 Hz, 2H), 2.64 (s, 3H), 1.46 (s, 9H); LC-MS: method H, RT=1.13 min, MS (ESI) m/z: 241.1 ([M+H—(CH3)3C]+).
    • Intermediate I-5B: tert-butyl (2-(4-amino-3-methylphenoxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00055
  • Intermediate I-5A (3.94 g, 13.30 mmol) was dissolved in MeOH (50 mL) and mixed with wet Pd—C (0.708 g, 0.665 mmol). After applying vacuum and refilling with H2 3×, the mixture was treated with 1 atm H2 for 4 h. The resulting mixture was filtered over celite and washed with a small amount of MeOH several times. Solvent was removed in vacuo to give Intermediate I-5B as yellow oil. (3.28 g, 93%). 1H NMR (500 MHz, CHLOROFORM-d) δ 6.67 (s, 1H), 6.62 (d, J=1.7 Hz, 2H), 5.00 (br. s., 1H), 3.95 (t, J=5.1 Hz, 2H), 3.49 (d, J=5.0 Hz, 2H), 3.37 (br. s., 2H), 2.16 (d, J=0.6 Hz, 3H), 1.46 (s, 9H); LC-MS: method H, RT=0.79 min, MS (ESI) m/z: 267.3).
    • Intermediate I-5C: tert-butyl (2-((2-amino-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) carbamate
  • Figure US20190292176A1-20190926-C00056
  • To Intermediate I-5B (3.28 g, 12.3 mmol) in acetonitrile (30 mL) was added ammonium thiocyanate (1.406 g, 18.5 mmol). The mixture was stirred at room temperature for 10 min, cooled in an ice water bath, and benzyltrimethylammonium tribromide (4.80 g, 12.3 mmol) in acetonitrile (20 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, and then diluted with EtOAc/saturated sodium bicarbonate (100 mL/30 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (30 mL×2). Then organic phases were combined, washed with saturated NaHCO3(aqueous, 30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated on a rotary evaporator to give Intermediate I-5C (3.972 g, 12.3 mmol, 100%) as a brown solid. The crude product was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d): δ 6.97 (d, J=2.4 Hz, 1H), 6.75 (s, 1H), 5.13 (br s, 2H), 5.00 (br s, 1H), 4.02 (t, J=5.1 Hz, 2H), 3.53 (d, J=4.8 Hz, 2H), 2.53 (d, J=0.4 Hz, 3H), 1.46 (s, 9H); LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 324.2.
    • Intermediate I-5D: tert-butyl (2((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) carbamate
  • Figure US20190292176A1-20190926-C00057
  • In a round bottom flask charged with a stirring bar, copper (II) bromide (441 mg, 1.976 mmol), and dry acetonitrile (5 mL) under argon, tert-butyl nitrite (204 mg, 1.976 mmol) was added. The mixture was stirred at room temperature for 10 min. A suspension of Intermediate I-5C (376 mg, 1.163 mmol) in dry acetonitrile (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.0 h, and the acetonitrile was removed under vacuum. The reaction mixture was diluted with EtOAc (50 mL) and 40 mL of 0.5M HCl (aqueous). After separation, the organic layer was washed with 0.5 N HCl (aqueous, 30 mL×2), saturated sodium bicarbonate (aqueous, 30 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The residue was purified by flash chromatography (40 g silica gel column, 0-50% EtOAc/hexane) to give the desired product as a colorless oil (340 mg, 1.50 mmol, 76%). 1H NMR (400 MHz, chloroform-d) δ 7.08 (d, J=2.2 Hz, 1H), 6.88 (d, J=1.5 Hz, 1H), 4.98 (br s, 1H), 4.06 (t, J=5.1 Hz, 2H), 3.56 (d, J=5.1 Hz, 2H), 2.67 (s, 3H), 1.46 (s, 9H); LC-MS: method H, RT=1.37 min, MS (ESI) m/z: 387.0, 389.0.
    • Intermediate I-5E: tert 2((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethanamine
  • Figure US20190292176A1-20190926-C00058
  • In a round bottom flask charged with a stirring bar, Intermediate I-5D (940 mg, 2.43 mmol) was dissolved in DCM (4 mL) and treated with TFA (2 ml, 26.0 mmol) at room temperature for 1 hour. Solvent and extra TFA were removed on a rotary evaporator and the residue was dissolved in 30 mL of DCM and was washed with 20 mL of saturated NaHCO3, 20 mL of brine, and dried over Na2SO4. Removing solvent gave the crude product used without purification in the next step. (657 mg, 2.28 mmol, 94%) LC-MS: method H, RT=0.85 min, MS (ESI) m/z: 87.0, 289.0.
    • Intermediate I-5
  • Intermediate I-5E (534 mg, 1.86 mmol) was dissolved in a mixture of THF (5 mL) and DIEA (1.30 mL, 7.45 mmol). 4-Fluorobenzene-1-sulfonyl chloride (362 mg, 1.862 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Solvent was removed on a rotary evaporator and the residue was purified by flash chromatography (40 g silica gel column, 0-100% EtOAc/hexane gradient) to give the title compound as a white solid (666 mg, 1.49 mmol, 80%). 1H NMR (400 MHz, chloroform-d) δ 7.96-7.87 (m, 2H), 7.23-7.14 (m, 2H), 6.99 (d, J=2.2 Hz, 1H), 6.79-6.76 (m, 1H), 4.05 (t, J=5.1 Hz, 2H), 3.46-3.36 (m, 2H), 2.66 (s, 3H); LC-MS: method H, RT=1.37 min, MS (ESI) m/z: 444.9 and 446.9.
    • Intermediate I-9 (2-methoxy-7-methylquinoxalin-5-yl)boronic acid
  • Figure US20190292176A1-20190926-C00059
    • Intermediate I-9A: 5-bromo-2-methoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00060
  • To Intermediate I-1G (3.13 g, 10.83 mmol) dissolved in THF (20 mL) and MeOH (15 mL) at room temperature was added 4.3 M sodium methoxide in MeOH (7.55 mL, 32.5 mmol). The reaction mixture was stirred at room temperature overnight. Methanol was removed under vacuum. The reaction mixture was diluted with EtOAc, quenched with 0.5 N HCl (30.0 mL). The organic layer was washed with saturated sodium bicarbonate, brine, dried and concentrated to give Intermediate I-9A (2.7 g, 10.67 mmol, 99% yield) as a slightly yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.48 (s, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.60 (dd, J=1.8, 1.0 Hz, 1H), 4.10 (s, 3H), 2.53 (s, 3H); LC-MS: Method A, 30 to 100% B. RT=1.71 min, MS (ESI) m/z: 253.0 and 255.0 (M+H)+.
    • Intermediate I-9
  • A mixture of Intermediate I-9A (700 mg, 2.77 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1053 mg, 4.15 mmol), potassium acetate (679 mg, 6.91 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (113 mg, 0.138 mmol) in dioxane (14 mL) was degassed by bubbling argon for 5 min. It was then heated at 130° C. for 40 min. The reaction mixture was mixed with EtOAc/water and stirred at room temperature for 15 min. The insoluble material was removed by filtration through a pad of wet celite. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 5% to 100% EtOAc in hexane over 15 min using a 80 g silica gel cartridge). The desired fractions were combined, concentrated and lyophilized to yield to yield Intermediate I-9 (362 mg, 1.659 mmol, 60 yield) as a solid. 1H NMR (500 MHz, methanol-d4) δ 8.41 (s, 1H), 7.69 (br. s., 1H), 7.49 (br. s., 1H), 4.10 (s, 3H), 2.56 (s, 3H). LC-MS: method H, RT=0.83 min, MS (ESI) m/z: 219.1 (M+H)+.
    • Intermediate I-12 2-methoxy-7-methylquinoxaline-5-carbothioamide
  • Figure US20190292176A1-20190926-C00061
    • Intermediate I-12A: 2-methoxy-7-methylquinoxaline-5-carbonitrile
  • Figure US20190292176A1-20190926-C00062
  • Intermediate I-9A (0.458 g, 1.810 mmol) and copper(I) cyanide (0.600 g, 6.70 mmol) were dissolved in DMF (18.10 mL) and heated to reflux for 20 hours. The reaction mixture was cooled to ambient temperature. The reaction mixture was diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer was further washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-12A (247 mg, 1.24 mmol, 68.5%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (s, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.78 (s, 1H), 4.11 (s, 3H), 2.58 (s, 3H); LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 200.1 (M+H)+.
    • Intermediate I-12
  • Intermediate I-12A (0.247 g, 1.240 mmol), sodium hydrosulfide (1.043 g, 18.60 mmol), and magnesium chloride (1.771 g, 18.60 mmol) were dissolved in DMF (12.40 mL) and stirred for 18 hours. The reaction mixture was diluted with water, which formed copious amounts of precipitates. The reaction mixture was extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The solid was sonicated with DCM then filtered. The resulting solution was concentrated in vacuo to give Intermediate I-12 (111 mg, 0.476 mmol, 38.4%) as an orange solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 11.86 (br. s., 1H), 9.04 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.32 (br. s., 1H), 7.82 (dd, J=1.9, 0.9 Hz, 1H), 4.11 (s, 3H), 2.61 (s, 3H); LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 234.0 (M+H)+.
    • Intermediate I-14 5-iodo-7-methylquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00063
    • Intermediate I-14A: 2-iodo-4-methyl-6-nitroaniline
  • Figure US20190292176A1-20190926-C00064
  • Iodine (4.59 g, 18.07 mmol) was dissolved in EtOH (65.7 mL). Next, 4-methyl-2-nitroaniline (2.5 g, 16.43 mmol) and then silver sulfate (5.64 g, 18.07 mmol) were added and the reaction mixture was allowed to stir for 18 hours. The reaction mixture was diluted with EtOAc, filtered through a sintered glass funnel, and concentrated in vacuo. The crude material was redissolved in EtOAc and washed with saturated Na2S2O3, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-14A (4.65 g, 16.72 mmol, 100%) as an orange solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (d, J=1.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 6.49 (br. s., 2H), 2.26 (s, 3H); LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 279.0 (M+H)+.
    • Intermediate I-14B: bis-tert-butyl (2-iodo-4-methyl-6-nitroaniline)bis carbamate
  • Figure US20190292176A1-20190926-C00065
  • Intermediate I-14A (4.65 g, 16.72 mmol), DMAP (0.204 g, 1.672 mmol), and Boc2O (9.71 mL, 41.8 mmol) were dissolved in THF (27.9 mL) and stirred for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 220 g silica gel column, 50 minute gradient from 0 to 100% EtOAc in hexanes), to give Intermediate I-14B (5.4 g, 11.29 mmol, 67.5%) as a light yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (s, 1H), 7.78 (s, 1H), 2.43 (s, 3H), 1.40 (s, 18H); LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: (bis-deboc mass observed) 278.9 (M+H)+.
    • Intermediate I-14C: methyl 2-((tert-butoxycarbonyl)(2-iodo-4-methyl-6-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C00066
  • Intermediate I-14B (5.4 g, 11.29 mmol) was dissolved in DCM (18.82 mL) and TFA (1.740 mL, 22.58 mmol) and stirred for 30 minutes. The reaction mixture was diluted with DCM, quenched with saturated NaHCO3, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was dissolved in DMF (18.82 mL). Cs2CO3 (9.20 g, 28.2 mmol) was added and stirred for 15 minutes. The reaction mixture turned deep red. Methyl bromoacetate (1.249 mL, 13.55 mmol) was added and the reaction mixture was allowed to stir 24 hours. The reaction mixture turned from deep red to yellow. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 220 g silica gel column, 50 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-14C (3.51 g, 7.80 mmol, 69.1%) as an orange solid: LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: (deboc mass observed) 350.9 (M+H)+.
    • Intermediate I-14D: methyl 2-((2-iodo-4-methyl-6-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C00067
  • Intermediate I-14C (3.51 g, 7.80 mmol) was dissolved in HCl in dioxane (4 M, 9.75 mL, 39.0 mmol) and stirred for 1 hour. The reaction mixture was concentrated in vacuo to give Intermediate I-14D, which was used directly in the subsequent step without purification: LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 350.9 (M+H)+.
    • Intermediate I-14E: 5-iodo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00068
  • Intermediate I-14D (2.73 g, 7.80 mmol) was dissolved in MeOH (28.4 mL). HCl (2.60 mL, 31.2 mmol) then tin(II) chloride dihydrate (7.04 g, 31.2 mmol) were added and the reaction mixture was heated to 65° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature, neutralized with 10 N NaOH and diluted with brine then EtOAc. Vigorous stirring was allowed for 15 minutes. The mixture was filtered through celite and concentrated in vacuo to give Intermediate I-14E (1.77 g, 6.14 mmol, 79.0%) as an orange solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (br. s., 1H), 7.17 (s, 1H), 6.48 (s, 1H), 4.17 (br. s., 1H), 4.02 (d, J=1.8 Hz, 2H), 2.21 (s, 3H); LC-MS: Method H, RT=0.82 min, MS (ESI) m/z: 289.0 (M+H)+.
    • Intermediate I-14
  • Intermediate I-14E (1.7696 g, 6.14 mmol) was suspended in MeOH (17.86 mL). 1 N NaOH (18.43 mL, 18.43 mmol) then H2O2 (30%)(3.23 mL, 36.9 mmol) were added and the reaction mixture stirred 24 hours. More H2O2 (3.23 mL, 36.9 mmol) was added and the reaction mixture was stirred for 24 hours. More H2O2 (3.23 mL, 36.9 mmol) was added and the reaction mixture was stirred for 24 hours. The reaction mixture was diluted with ca 50 mL of water then about 50 mL of brine. The mixture was evaporated under a nitrogen stream to remove MeOH. The aqueous material was extracted thrice with EtOAc. During the extractions, an off-white solid precipitated. This precipitate was collected by suction filtration as to give Intermediate I-14 (1.35 g, 4.72 mmol, 77.0%): 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br. s., 1H), 8.11 (s, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.09 (s, 1H), 2.37 (s, 3H); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 287.0 (M+H)+.
    • Intermediate I-15 (2-(ethoxycarbonyl)-7-methylquinoxalin-5-yl)boronic acid
  • Figure US20190292176A1-20190926-C00069
    • Intermediate I-15A: 3-bromo-5-methylbenzene-1,2-diamine
  • Figure US20190292176A1-20190926-C00070
  • 2-bromo-4-methyl-6-nitroaniline (5.00 g, 21.64 mmol) was dissolved in MeOH (148 mL) and THF (18.50 mL). Ammonium chloride (23.15 g, 433 mmol) then zinc (14.15 g, 216 mmol) were added and the reaction mixture was heated to 40° C. for 1 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo, re-dissolved in EtOAc and saturated Na2CO3, and stirred vigorously for 10 minutes. The mixture was filtered through a sintered glass funnel and washed with more EtOAc. The organic layer was further washed twice with water, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-15A (4.35 g, 21.63 mmol, 100% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.81 (s, 1H), 6.48 (s, 1H), 3.66 (br. s., 2H), 3.46 (br. s., 2H), 2.19 (s, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 201.0 (M+H)+.
    • Intermediate I-15B: ethyl 5-bromo-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00071
  • Intermediate I-15A (4.35 g, 21.63 mmol) and ethyl 3-bromo-2-oxopropanoate (3.63 mL, 26.0 mmol) were dissolved in NMP (72.1 mL) and allowed to stir at room temperature for 18 h open to air. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc (×3). The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified by ISCO column using 0-40% EtOAc in hexanes on a 220 g column to yield a mixture of regioisomers. The reaction mixture was purified by SFC on a Chiralcel OD-H, 30×250 mm, 5 micron column using 20% IPA/80% CO2 with 85 mL/min, 100 Bar, 40° C. to yield Intermediate I-15B (0.936 g, 3.17 mmol, 14.66% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.48 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 4.53 (q, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.44 (t, J=7.2 Hz, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 295.1 (M+H)+.
    • Intermediate I-15
  • A mixture of Intermediate I-15B (0.100 g, 0.339 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.129 g, 0.508 mmol), potassium acetate (0.083 g, 0.847 mmol) in dioxane (3.39 mL) were degassed by bubbling argon for 5 min. PdCl2(dppf)-CH2Cl adduct (0.014 g, 0.017 mmol) was added and the mixture was sealed and heated in microwave at 130° C. for 30 min. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield a brown oil. The reaction mixture was purified on Prep HPLC using Method A to yield Intermediate I-15 (0.027 g, 0.104 mmol, 30.6% yield) as an off white solid. LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 261.2 (M+H)+.
    • Intermediate I-16 (2-bromo-5-methoxy-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00072
    • Intermediate I-16A: 1-(6-methoxy-4-methylpyridin-3-yl)thiourea
  • Figure US20190292176A1-20190926-C00073
  • To a solution of 6-methoxy-4-methylpyridin-3-amine (0.150 g, 1.086 mmol) in acetone (1 mL) was added dropwise benzoyl isothiocyanate (0.161 mL, 1.194 mmol). The reaction mixture was allowed to stir at room temperature for 2.5h. The reaction mixture was concentrated under reduced pressure and re-dissolved in tetrahydrofuran (1 mL). To this solution was added sodium methoxide (0.5 M in MeOH) (3.26 mL, 1.628 mmol), and the reaction mixture was allowed to stir at room temperature for 30 min. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was triturated with Et2O and filtered. The solid was collected to yield Intermediate I-16A (0.148 g, 0.750 mmol, 69.1% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (s, 1H), 7.54 (br. s., 1H), 6.69 (s, 1H), 6.51-5.18 (m, 2H), 3.93 (s, 3H), 2.28 (s, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 198.1 (M+H)+.
    • Intermediate I-16B: 5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-amine
  • Figure US20190292176A1-20190926-C00074
  • To a solution of Intermediate I-16A (0.146 g, 0.740 mmol) in tetrahydrofuran (1 mL) was added benzyltrimethylammonium tribromide (0.289 g, 0.740 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on ISCO using 0-100% EtOAc in hexanes gradient on a 24 g column to yield Intermediate I-16B (0.035 g, 0.179 mmol, 24.22% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.53 (d, J=0.7 Hz, 1H), 5.00 (br. s., 2H), 3.91 (s, 3H), 2.49 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 196.1 (M+H)+.
    • Intermediate I-16
  • Copper (II) bromide (0.068 g, 0.305 mmol) and t-butyl nitrite (0.036 mL, 0.305 mmol) were dissolved in MeCN (0.717 mL) and allowed to stir 10 minutes. Intermediate I-16B (0.035 g, 0.179 mmol) was dissolved in MeCN (1.076 mL) and the copper solution was added. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated aqueous NaHCO3, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-16 (0.030 g, 0.116 mmol, 64.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.64 (d, J=1.1 Hz, 1H), 3.96 (s, 3H), 2.62 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 359.1 (M+H)+.
    • Intermediate I-17 2-bromo-6-fluoro-5-methoxythiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00075
    • Intermediate I-17A: N-((5-fluoro-6-methoxypyridin-3-yl)carbamothioyl)benzamide
  • Figure US20190292176A1-20190926-C00076
  • To a solution of 5-fluoro-6-methoxypyridin-3-amine (0.100 g, 0.704 mmol) in acetone (1 mL) was added dropwise benzoyl isothiocyanate (0.104 mL, 0.774 mmol). The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate I-17A (0.215 g, 0.704 mmol, 100% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 12.48 (br. s., 1H), 9.12 (br. s., 1H), 8.06 (d, J=2.0 Hz, 1H), 8.01 (dd, J=10.8, 2.2 Hz, 1H), 7.91 (d, J=1.1 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.60-7.54 (m, 2H), 4.06 (s, 3H). LC-MS: method H, RT=1.18 min, MS (ESI) m/z: 306.1 (M+H)+.
    • Intermediate I-17B: 1-(5-fluoro-6-methoxypyridin-3-yl)thiourea
  • Figure US20190292176A1-20190926-C00077
  • To a solution of Intermediate I-17A (0.215 g, 0.704 mmol) in tetrahydrofuran (1 mL) was added dropwise sodium methoxide (0.5 M in MeOH) (2.112 mL, 1.056 mmol). The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was triturated with Et2O, and the solid was collected to yield Intermediate I-17B (0.09 g, 0.447 mmol, 63.5% yield) as a pale yellow solid. LC-MS: method H, RT=0.81 min, MS (ESI) m/z: 202.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J=2.2 Hz, 1H), 7.63 (br. s., 2H), 7.32 (s, 1H), 4.03 (s, 3H).
    • Intermediate I-17C: 6-fluoro-5-methoxythiazolo[5,4-b]pyridin-2-amine
  • Figure US20190292176A1-20190926-C00078
  • To a solution of Intermediate I-17B (0.078 g, 0.338 mmol) in tetrahydrofuran (1 mL) was added benzyltrimethylammonium tribromide (0.151 g, 0.388 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on Prep HPLC using Method A to yield Intermediate I-17C (0.028 g, 0.141 mmol, 36.3% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (br. s., 2H), 7.59 (d, J=9.7 Hz, 1H), 4.05 (s, 3H) LC-MS: method H, RT=0.84 min, MS (ESI) m/z: 200.1 (M+H)+.
  • Intermediate I-17
  • Copper (II) bromide (0.055 g, 0.247 mmol) and t-butyl nitrite (0.029 mL, 0.247 mmol) were dissolved in MeCN (0.582 mL) and allowed to stir 10 minutes. Intermediate I-17C (0.029 g, 0.146 mmol) was dissolved in MeCN (0.873 mL) and the copper solution was added. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated aqueous NaHCO3, then brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-17 (0.035 g, 0.133 mmol, 91% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J=9.9 Hz, 1H), 4.09 (s, 3H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 263.0 (M+H)+.
    • Intermediate I-20 2-bromo-6-methoxybenzo[d]thiazole-4-carbaldehyde
  • Figure US20190292176A1-20190926-C00079
    • Intermediate I-20A: Methyl 2-amino-5-methoxybenzoate
  • Figure US20190292176A1-20190926-C00080
  • 2-amino-5-methoxybenzoic acid (250 mg, 1.496 mmol) was dissolved in MeOH (7478 μL). Thionyl chloride (327 μL, 4.49 mmol) was added and the reaction mixture was heated to reflux for 3 days. The reaction mixture was concentrated in vacuo. The crude material was dissolved in EtOAc and washed with 1 N NaOH, then water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-20A (190 mg, 1.049 mmol, 70.1%) as a brown oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (d, J=3.1 Hz, 1H), 6.98 (dd, J=9.0, 3.1 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.43 (br. s., 2H), 3.90 (s, 3H), 3.79 (s, 3H); LC-MS: Method H, RT=0.89 min, MS (ESI) m/z: 182.1 (M+H)+.
    • Intermediate I-20B: Methyl 2-amino-6-methoxybenzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00081
  • Intermediate I-20A (190 mg, 1.049 mmol) was dissolved in MeCN (5243 μL). Ammonium thiocyanate (120 mg, 1.573 mmol) was added, followed by benzyltrimethylammonium tribromide (409 mg, 1.049 mmol). After 4 hours, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-20B (100 mg, 0.42 mmol, 40%) as a brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.51 (d, J=2.6 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 5.89 (br. s., 2H), 3.99 (s, 3H), 3.88 (s, 3H); LC-MS: Method H, RT=0.82 min, MS (ESI) m/z: 239.1 (M+H)+.
    • Intermediate I-20C: Methyl 2-bromo-6-methoxybenzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00082
  • Copper(II) bromide (159 mg, 0.713 mmol) and t-butyl nitrite (85 μL, 0.713 mmol) were dissolved in MeCN (1679 μL) and allowed to stir 10 minutes. Intermediate I-20B (100 mg, 0.420 mmol) was dissolved in MeCN (2518 μL) and the copper solution was added. After 2 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-20C (100.6 mg, 0.333 mmol, 79%) as a red solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.68 (d, J=2.6 Hz, 1H), 7.46 (d, J=2.6 Hz, 1H), 4.05 (s, 3H), 3.93 (s, 3H); LC-MS: Method H, The compound did not ionize.
    • Intermediate I-20D: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)methanol
  • Figure US20190292176A1-20190926-C00083
  • Intermediate I-20C (93.5 mg, 0.309 mmol) was dissolved in toluene (2063 μL) and THF (1032 μL) and cooled to −78° C. DIBAL-H (681 μL, 0.681 mmol) was added and the reaction mixture was warmed to ambient temperature for 1 hour. The reaction was quenched with 1 N HCl (1 mL), diluted with EtOAc, filtered through celite, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-20D (28.1 mg, 0.103 mmol, 33%) as an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.17 (d, J=2.6 Hz, 1H), 7.04 (d, J=2.6 Hz, 1H), 5.05 (d, J=6.6 Hz, 2H), 3.87 (s, 3H), 3.00 (t, J=6.5 Hz, 1H); LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 274/276 (M+H)+.
    • Intermediate I-20
  • Intermediate I-20D (188.8 mg, 0.689 mmol) was dissolved in CHCl3 (4591 μL). Manganese dioxide (359 mg, 4.13 mmol) was added and the reaction mixture was allowed to stir for 24 hours. More manganese dioxide (359 mg, 4.13 mmol) was added and the reaction mixture was allowed to stir for 3 days. The reaction mixture was filtered through celite and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-20 (136.3 mg, 0.501 mmol, 72.7%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 10.90-10.84 (m, 1H), 7.63-7.59 (m, 1H), 7.57-7.51 (m, 1H), 3.93 (s, 3H); LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 272/274 (M+H)+.
    • Intermediate I-22 4-bromo-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00084
  • 2-Bromo-4-methoxyaniline (10 g, 49.5 mmol) was dissolved in MeCN (247 mL). Ammonium thiocyanate (5.65 g, 74.2 mmol) was added, followed by benzyltrimethylammonium tribromide (19.3 g, 49.5 mmol). After stirring for 2 days, the reaction mixture was diluted with saturated NaHCO3 and the resulting solid was collected by suction filtration. The solid was washed with water to give Intermediate I-22 (10.75 g, 41.5 mmol, 84% yield) as a light brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.19 (d, J=2.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 3.78 (s, 3H); LC-MS: Method H, RT=0.70 min, MS (ESI) m/z: 259/261 (M+H)+.
    • Intermediate I-25 2-(methoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline, D5
  • Figure US20190292176A1-20190926-C00085
    • Intermediate I-25A: (5-bromo-7-methylquinoxalin-2-yl)methanol
  • Figure US20190292176A1-20190926-C00086
  • NaBH4 (135 mg, 3.56 mmol) and calcium chloride (197 mg, 1.779 mmol) were dissolved in THF (5270 μl). A solution of Intermediate I-15B (500 mg, 1.779 mmol) in THF (1318 μl) was added dropwise, and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with EtOAc, washed with water, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to yield Intermediate I-25A (0.263 g, 1.04 mmol, 58%) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.85 (s, 1H), 7.92 (d, J=1.7 Hz, 1H), 7.79 (dd, J=1.7, 1.1 Hz, 1H), 5.04 (s, 2H), 3.73 (br. s., 1H), 2.58 (s, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 253.1 (M+H)+.
    • Intermediate I-25B: (5-bromo-7-methylquinoxalin-2-yl)methyl methanesulfonate
  • Figure US20190292176A1-20190926-C00087
  • Intermediate I-25A (262.5 mg, 1.037 mmol) and TEA (0.434 mL, 3.11 mmol) were dissolved in DCM (20 mL) and methanesulfonic anhydride (217 mg, 1.245 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-25B (0.343 g, 1.04 mmol, 100%) as an orange solid. The material will be used crude in the next step. LC-MS: method H, RT=1.00 min, MS (ESI) m/z: 331.0 (M+H)+.
    • Intermediate I-25C: 5-bromo-2-(methoxymethyl)-7-methylquinoxaline, d5
  • Figure US20190292176A1-20190926-C00088
  • CD3ONa was prepared by dissolving sodium metal (60 mg, 2.500 mmol) in CD3OD (0.405 mL, 10 mmol) for 30 minutes. Intermediate I-25B (207 mg, 0.625 mmol) was dissolved in THF (12 mL). CD3ONa (71.3 mg, 1.250 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was partially concentrated in vacuo to remove THF, diluted with EtOAc and washed with water, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-25C (0.118 g, 0.432 mmol, 69% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.01 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.82 (dd, J=1.8, 0.9 Hz, 1H), 2.58 (s, 3H). LC-MS: method H, RT=0.90 min, MS (ESI) m/z: 272.1 (M+H)+.
    • Intermediate I-25
  • Intermediate I-25C (117.6 mg, 0.432 mmol), bis(pinacolato)diboron (165 mg, 0.648 mmol), and potassium acetate (106 mg, 1.080 mmol) were dissolved in dioxane (4321 μl) and degassed for 5 minutes by bubbling with argon. PdCl2(dppf)-CH2Cl2 adduct (28.2 mg, 0.035 mmol) was added and the reaction mixture was degassed for an additional 10 minutes. The reaction mixture was heated to 130° C. in the microwave for 45 minutes. The reaction mixture was diluted with EtOAc and water and filtered. The reaction mixture was further extracted twice with EtOAc. The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate I-25 (0.097 g, 0.302 mmol, 70% yield). LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 238.2 (M+H)+. Observed the mass of the boronic acid in LC/MS.
    • Intermediate I-26 (R)-(2-chloro-4-methyl-7,8-dihydro-[1,4]dioxino[2′,3′: 3,4]benzo[1,2-d]thiazol-7-yl)methyl acetate
  • Figure US20190292176A1-20190926-C00089
    • Intermediate I-26A: (R)-5-methyl-2-(oxiran-2-ylmethoxy)benzaldehyde
  • Figure US20190292176A1-20190926-C00090
  • To a solution of 2-hydroxy-5-methylbenzaldehyde (5 g, 36.7 mmol) in DMF (80 mL) was added (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (10.47 g, 40.4 mmol) and Cs2CO3 (35.9 g, 110 mmol). The mixture was stirred at room temperature overnight. LCMS indicated a completion of the reaction mixture. The mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude sample was purified with a 120 g ISCO column eluted with 0-100% EtOAc/hexanes for 40 min. The desired fractions were collected and concentrated to give Intermediate I-26A (7 g, 36.4 mmol, 99% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 10.50 (s, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.35 (ddd, J=8.6, 2.4, 0.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 4.36 (dd, J=11.1, 3.0 Hz, 1H), 4.05 (dd, J=11.1, 5.6 Hz, 1H), 3.40 (ddt, J=5.6, 4.1, 2.8 Hz, 1H), 2.94 (dd, J=4.7, 4.1 Hz, 1H), 2.80 (dd, J=4.8, 2.6 Hz, 1H), 2.32 (s, 3H); LC-MS: method C, RT=1.59 min, MS (ESI) m/z: 193.0 (M+H)+.
    • Intermediate I-26B: (S)-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol
  • Figure US20190292176A1-20190926-C00091
  • To a stirred solution of Intermediate I-26A (7 g, 36.4 mmol) in dichloromethane (100 mL) cooled with an ice bath was added mCPBA (12.36 g, 53.7 mmol). Next, trifluoroacetic acid (2.81 mL, 36.4 mmol) in dichloromethane (10 mL) was added dropwise. Ice bath was removed and the mixture was stirred at room temperature for 1.0 h. TLC and LCMS indicated no starting material remaining. The reaction mixture was quenched by addition of saturated sodium bicarbonate, followed by 10% sodium thiosulfite (20.0 mL), extracted with dichloromethane. The organic layers were collected, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in MeOH (100 mL), and K2CO3 (15.10 g, 109 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc, the combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude sample was purified with a 120 g ISCO column eluted with 0-100% EtOAc/hexanes for 40 min. The desired fractions were combined and concentrated to give Intermediate I-26B (4.65 g, 25.8 mmol, 70.9% yield). 1H NMR (400 MHz, chloroform-d) δ 6.78 (d, J=8.1 Hz, 1H), 6.73 (d, J=1.3 Hz, 1H), 6.69-6.63 (m, 1H), 4.33-4.21 (m, 2H), 4.15-4.05 (m, 1H), 3.96-3.76 (m, 2H), 2.26 (s, 3H). LC-MS: method C, RT=1.55 min, MS (ESI) m/z: 209.0 (M+H)+.
    • Intermediate I-26C: (R)-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl acetate
  • Figure US20190292176A1-20190926-C00092
  • To a solution of Intermediate I-26B (4.6 g, 25.5 mmol) in THF (100 mL) at 0° C. was added TEA (8.89 mL, 63.8 mmol), followed by acetyl chloride in DCM (31.9 mL, 31.9 mmol) dropwise. The mixture was stirred at 0° C. for 10 min, and at room temperature for 1.0 h. The mixture was diluted with EtOAc, washed with water. The organic layer was washed with 0.5 N HCl, saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, Intermediate I-26C (5.3 g, 23.85 mmol, 93% yield) was obtained as a yellow oil. It was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 6.76 (d, J=8.1 Hz, 1H), 6.72 (d, J=1.3 Hz, 1H), 6.68-6.61 (m, 1H), 4.40-4.33 (m, 1H), 4.30 (dd, J=5.1, 4.4 Hz, 2H), 4.25 (dd, J=11.3, 2.3 Hz, 1H), 4.03 (dd, J=11.4, 6.8 Hz, 1H), 2.25 (s, 3H), 2.11 (s, 3H). LC-MS: method C, RT=1.92 min, MS (ESI) m/z: 245.0 (M+H)+.
    • Intermediate I-26D: (R)-(7-methyl-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl acetate
  • Figure US20190292176A1-20190926-C00093
  • To a solution of Intermediate I-26C (4.15 g, 18.67 mmol) in acetic acid (40 mL) cooled at 0° C. with an ice-bath was added fuming nitric acid (4.36 mL, 93 mmol) dropwise. The mixture was stirred at 0° C. for 1 h, then at room temperature for 30 min. TLC (PMA stain) indicated a completion of the reaction. It was quenched with ice water. The aqueous was removed and the organic layer was washed with saturated sodium bicarbonate (3×), brine and dried over sodium sulfate. After evaporation of solvent, Intermediate I-26D (4.6 g, 17.21 mmol, 92% yield) was obtained as an off-white solid which was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.71 (s, 1H), 6.83 (s, 1H), 4.54-4.45 (m, 1H), 4.39-4.28 (m, 3H), 4.09 (dd, J=11.9, 7.0 Hz, 1H), 2.55 (d, J=0.4 Hz, 3H), 2.13 (s, 3H). LC-MS: method C, RT=1.90 min, MS (ESI) m/z: 290.0 (M+H)+.
    • Intermediate I-26E: (R)-(6-amino-7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl acetate
  • Figure US20190292176A1-20190926-C00094
  • To a solution of Intermediate I-26D (5.3 g, 19.83 mmol) in MeOH (80 mL) and THF (80 mL) cooled with an ice bath was added ammonium chloride (16.97 g, 317 mmol) and zinc dust (10.37 g, 159 mmol). The mixture was stirred at 0° C. for 30 min, and at room temperature for 1.0 h. MeOH and THF were removed under vacuum. The residue was diluted with EtOAc/saturated sodium bicarbonate and stirred at room temperature for 3 min. The mixture was filtered through a pad of wet celite to remove insoluble material. The filtrate was collected, organic layer was washed with brine, dried over sodium sulfate, concentrated to give Intermediate I-26E (4.7 g, 19.81 mmol, 100% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ 6.63 (s, 1H), 6.25 (s, 1H), 4.38-4.20 (m, 4H), 4.06-3.95 (m, 1H), 3.35 (br. s., 2H), 2.11 (s, 3H), 2.09 (s, 3H). LC-MS: method C, RT=1.14 min, MS (ESI) m/z: 238.0 (M+H)+.
    • Intermediate I-26F (R)-(2-amino-4-methyl-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl acetate
  • Figure US20190292176A1-20190926-C00095
  • To Intermediate I-26E (4.7 g, 19.81 mmol) dissolved in acetonitrile (120 mL) was added ammonium thiocyanate (2.262 g, 29.7 mmol). The mixture was stirred at room temperature for 10 min. Benzyltrimethylammonium tribromide (8.11 g, 20.80 mmol) in acetonitrile (20 mL) was added dropwise (5 min). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc/THF/saturated sodium bicarbonate. The insoluble material was removed by filtration. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate I-26F (5.8 g, 19.71 mmol, 99% yield) was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 6.73 (d, J=0.7 Hz, 1H), 5.10 (s, 2H), 4.47-4.28 (m, 4H), 4.14 (dd, J=11.3, 6.9 Hz, 1H), 2.45 (d, J=0.7 Hz, 3H), 2.12 (s, 3H). LC-MS: method C, RT=1.46 min, MS (ESI) m/z: 295.0 (M+H)+.
    • Intermediate I-26
  • To a suspension of Intermediate I-26F (5.8 g, 19.71 mmol) in dry acetonitrile (80 mL) was added copper (II) chloride (4.5 g, 33.5 mmol), followed by tert-butyl nitrite (4.56 mL, 34.5 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 h. LCMS indicated a completion of the reaction. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was purified with a 220 g ISCO column eluted with 0% to 70% EtOAc in hexanes over 60 min. The desired fraction was collected and concentrated to yield Intermediate I-26 (3.9 g, 12.43 mmol, 63.1% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 6.89 (d, J=0.7 Hz, 1H), 4.55-4.28 (m, 4H), 4.18 (dd, J=11.4, 7.0 Hz, 1H), 2.59 (s, 3H), 2.13 (s, 3H). LC-MS: method C, RT=2.18 min, MS (ESI) m/z: 314.0 (M+H)+.
    • Intermediate I-27 7-((tert-butyldimethylsilyloxy)methyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00096
    • Intermediate I-27A: 8-bromo-3-methoxyquinoxaline-6-carbaldehyde
  • Figure US20190292176A1-20190926-C00097
  • To a solution of Intermediate I-9A (1 g, 3.95 mmol) in CCl4 (20 mL) was added NBS (1.547 g, 8.69 mmol) and benzoic peroxide (0.115 g, 0.474 mmol). The mixture was heated at reflux (95° C. oil bath) for 3 h. TLC and LCMS indicated a completion of the reaction. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to a yellow solid. The crude sample was dissolved in THF (10 ml) and silver nitrate (6.71 g, 39.5 mmol) in water (10 ml) was added. The mixture was stirred at 95° C. for 1 h. LCMS indicated a completion of the reaction. The mixture was cooled to room temperature and poured to 60 ml of water. The mixture was filtered and the filter cake was washed with CHCl3 for 3 times. The combined filtrate was extracted with CHCl3 and the organic layer was combined, washed with NaHCO3 and brine dried over MgSO4 and concentrated to Intermediate I-27A (1 g, 3.74 mmol, 95% yield). The crude sample was used for next step without purification. LC-MS: method C, RT=1.84 min, MS (ESI) m/z: 267 and 269 (M+H)+.
    • Intermediate I-27B: (8-bromo-3-methoxyquinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00098
  • Intermediate I-27A (1.055 g, 3.95 mmol) suspended in THF (10 mL) and MeOH (10 mL) was treated with NaBH4 (0.149 g, 3.95 mmol) at room temperature for 15 min. The reaction mixture turned to a clear solution. LCMS indicated a completion of the reaction. Saturated NH4Cl was added to quench the reaction. After stirring at room temperature for 10 min, it was diluted with EtOAc and water. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified with a 120 g ISCO column eluted with 0-100% EtOAc in hexanes. The desired fraction was collected and concentrated to give Intermediate I-27B (380 mg, 1.412 mmol, 35.7% yield). 1H NMR (400 MHz, chloroform-d) δ 8.54 (s, 1H), 8.01-7.77 (m, 2H), 4.90 (s, 2H), 4.13 (s, 3H). LC-MS: method C, RT=1.64 min, MS (ESI) (m/z) 269 and 271 (M+H)+.
    • Intermediate I-27C 5-bromo-7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxaline
  • Figure US20190292176A1-20190926-C00099
  • To a stirred solution of Intermediate I-27B (380 mg, 1.412 mmol) in DMF (5 mL) was added TBDMS-Cl (319 mg, 2.118 mmol) and imidazole (173 mg, 2.54 mmol). The reaction mixture was stirred at room temperature for 1.0 h. TLC and LCMS indicated a clean reaction. The mixture was partitioned between EtOAc/water. The organic layer was washed with water, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g silica gel cartridge which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 15% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate I-27C (480 mg, 1.252 mmol, 89% yield) as a white solid. LC-MS: method C, RT=2.74 min, MS (ESI) (m/z) 383 and 385 (M+H)+.
    • Intermediate I-27
  • A mixture of Intermediate I-27C (100 mg, 0.261 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (99 mg, 0.391 mmol), potassium acetate (64.0 mg, 0.652 mmol) in dioxane (2 mL) was degassed with argon for 5 min, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (10.65 mg, 0.013 mmol) was added. The mixture was sealed and heated in microwave reactor at 130° C. for 30 min. LCMS indicated a clean reaction. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of toluene and charged to a 40 g silica gel cartridge which was eluted with 5% EtOAc in hexanes for 2 min., then a 18 min gradient from 5% to 75% EtOAc in hexanes. The desired fractions were combined, concentrated and lyophilized to give Intermediate I-27 (105 mg, 0.244 mmol, 94% yield) as a pale solid. 1H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.96 (dt, J=2.0, 1.0 Hz, 1H), 4.96 (s, 2H), 4.13 (s, 3H), 1.45 (s, 12H), 1.00 (s, 9H), 0.16 (s, 6H). LC-MS: method C, RT=2.73 min, MS (ESI) (m/z) 349 (M+H)+ (boronic acid).
    • Intermediate I-28 7-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00100
    • Intermediate I-28A: 2-bromo-4-chloro-6-nitroaniline
  • Figure US20190292176A1-20190926-C00101
  • A solution of 4-chloro-2-nitroaniline (10 g, 57.9 mmol) in acetic acid (50 mL) was cooled to 0° C. with an ice bath. Bromine (3.28 mL, 63.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hr, and then poured into ice water. The precipitated solid was filtered and was washed with water several times. The filter cake was re-dissolved in EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (14.66 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J=2.4 Hz, 1H), 8.02 (d, J=2.6 Hz, 1H), 7.27 (br s, 2H); LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 250.9 and 252.9 (M+H)+.
    • Intermediate I-28B: tert-butyl N-(2-bromo-4-chloro-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
  • Figure US20190292176A1-20190926-C00102
  • In a round bottom flask charged with a stirring bar, Intermediate I-28A (5 g, 19.88 mmol) was dissolved in THF (30 mL). DMAP (0.243 g, 1.988 mmol) was added, followed by di-tert-butyl dicarbonate (11.54 mL, 49.7 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (120 g silica gel column eluted with 0-100% EtOAc/Hexane) to give the title compound as a white solid (8.2 g, 18.1 mmol, 91%). 1H NMR (400 MHz, chloroform-d): 7.97 (d, J=2.4 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 1.42 (s, 18H); LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 250.9 and 252.9 (M+H-2Boc)+.
    • Intermediate I-28C: tert-butyl (2-bromo-4-chloro-6-nitrophenyl)carbamate
  • Figure US20190292176A1-20190926-C00103
  • To a solution of Intermediate I-28B (8.2 g, 18.15 mmol) in DCM (50 mL) was added TFA (2.80 mL, 36.3 mmol) and the mixture was stirred at room temperature for 1 hour. Saturated NaHCO3(aqueous 30 mL) was added to the mixture. After stirring at room temperature for 10 minutes, the layers were separated and the aqueous layer was extracted by DCM (30 mL×2). The combined organic solution was washed with brine, dried over Na2SO4 and concentrated to give the title compound as a yellow solid (6.32 g, 18.0 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H), 1.43 (br s, 9H); LC-MS: method H, RT=0.82 min, MS (ESI) m/z: 250.9 and 252.9 (M+H-Boc)+.
    • Intermediate I-28D: methyl 2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C00104
  • To a solution of Intermediate I-28C (6.32 g, 18.0 mmol) in DMF (30 mL) was added Cs2CO3 (14.64 g, 44.9 mmol. Methyl 2-bromoacetate (5.50 g, 36.0 mmol) was added dropwise and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with 100 mL of EtOAc and 50 mL of water. After separation, the aqueous layer was extracted by EtOAc (50 mL), and the combined organic layers were washed with brine and concentrated. The residue was purified by flash chromatography (120 g silica gel column, eluted with 0-50% EtOAc/Hex) to give the title compound (7.55 g, 17.8 mmol, 99%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.92-7.81 (m, 2H), 4.58 (d, J=17.6 Hz, 1H), 3.99 (d, J=17.4 Hz, 1H), 3.69 (s, 3H), 1.38 (s, 9H); LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 366.9 and 368.9 (M+H-56)+.
    • Intermediate I-28E: methyl 2-((2-bromo-4-chloro-6-nitrophenyl)amino)acetate, TFA salt
  • Figure US20190292176A1-20190926-C00105
  • Intermediate I-28D (5.6 g, 13.22 mmol) was dissolved in DCM (30 mL) and was treated with TFA (10.18 mL, 132 mmol) at room temperature overnight. On the next day, the solvent was removed and the crude product was used in the next step without purification. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 323.0 and 324.9 (M+H)+.
    • Intermediate I-28F: 5-bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00106
  • In a round bottom flask charged with a stirring bar, Intermediate I-28E (6.0 g, 18.55 mmol) was dissolved in MeOH (60 mL), and concentrated HCl (4.64 mL, 55.6 mmol) was added, followed by SnCl2 (14.07 g, 74.2 mmol). The reaction mixture was stirred at 60° C. overnight. On the next day, after cooling to room temperature, another 2 equivalents of SnCl2 was added to the reaction mixture. After 2 h at 60° C., the reaction mixture was cooled to room temperature; the precipitate was filtered, washed with small amount of MeOH, and dried to give a white solid as desired product. The filtrate was concentrated on a rotary evaporator and then partitioned between 150 mL of EtOAc and 30 mL of water. Next, 4M NaOH (aqueous) was added to adjust the pH to 12. The solid was filtered on a Celite pad and the filter cake was washed with EtOAc. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with saturated NaHCO3(aqueous), brine, dried over Na2SO4, filtered, and concentrated in vacuo to give additional product. Combining material gave 5-bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one (3.55 g, 13.58 mmol, 73.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.12 (d, J=2.2 Hz, 1H), 6.85-6.66 (m, 1H), 5.83 (s, 1H), 3.82 (d, J=2.0 Hz, 2H); LC-MS: method H, RT=1.02 min, MS (ESI) m/z: 261.0 and 263.0 (M+H)+.
    • Intermediate I-28G: 5-bromo-7-chloroquinoxalin-2-ol
  • Figure US20190292176A1-20190926-C00107
  • In 1 L round bottom flask charged with a stirring bar, Intermediate I-28F (3.84 g, 14.7 mmol) was suspended in MeOH (50 mL), and H2O2 (15.00 mL, 147 mmol, 30% in water) was added, followed by 4N NaOH (11.01 mL, 44.1 mmol). The mixture was stirred at room temperature for 5 minutes, and then heated at 60° C. for 15 minutes. Heating was removed and the reaction mixture was stirred at room temperature over the weekend. Another 5 mL of H2O2 was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated on a rotary evaporator. The residual mixture was cooled in an ice bath, and 6 N HCl was added to adjust the pH value to 2-3, followed by 200 mL of EtOAc. After shaking and separation, the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic phases were combined and dried over Na2SO4. Removing solvent in vacuo gave the title compound as a brown solid. (2.51 g, 9.70 mmol, 66%). 1H NMR (400 MHz, DMSO-d6): δ 12.63 (br s, 1H), 8.23 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H); LC-MS: method H, RT=1.01 min, MS (ESI) m/z: 258.9 and 260.9 (M+H)+.
    • Intermediate I-28H: 5-bromo-7-chloro-2-methoxyquinoxaline
  • Figure US20190292176A1-20190926-C00108
  • In a round bottom flask charged with a stirring bar, Intermediate I-28G (1.60 g, 6.17 mmol) was suspended in POCl3 (10 mL, 107 mmol), and the mixture was refluxed for 2 h. Excess POCl3 was removed on a rotary evaporator and the residue was dried in vacuo for 30 minutes to give a brown solid. This brown solid was suspended in MeOH (30 mL), and anhydrous K2CO3 (1.704 g, 12.33 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then refluxed for 2 h. After cooling to room temperature, the solvent was removed on a rotary evaporator. The residue was dissolved in 100 ml of EtOAc, washed with water, brine, dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography (80 g silica gel column, 0-50% EtOAc/Hexane) to give Intermediate I-28H (1.02 g, 3.73 mmol, 60.5% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d): δ 8.53 (s, 1H), 7.87-7.83 (m, 2H), 4.12 (s, 3H); LC-MS: method J, RT=0.96 min, MS (ESI) m/z: 273.0 and 275.0 (M+H)+.
    • Intermediate I-28
  • In a microwave vial charged with a stirring bar, Intermediate I-28H (330 mg, 1.207 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (460 mg, 1.810 mmol), potassium acetate (296 mg, 3.02 mmol) were mixed with 1,4-dioxane (10 mL). After degassing with bubbling N2 for 10 minutes, PdCl2(dppf)-CH2Cl2 adduct (49.3 mg, 0.060 mmol) was added. The vial was sealed and was heated by microwave to 120° C. for 60 minutes. After cooling to room temperature, the reaction mixture was diluted by adding 40 mL of EtOAc and 30 mL of water. After separation, the aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by flash chromatography (40 g silica gel column, 0-100% EtOAc/hexane gradient in 10 minutes, 100% EtOAc for 10 minutes) to give Intermediate I-28 as a yellow solid. (293 mg, 76%). 1H NMR (400 MHz, chloroform-d): 8.53 (s, 1H), 7.92-7.85 (m, 2H), 4.08 (s, 3H), 1.45 (s, 12H); LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 239.1 (M+H-82)+.
    • Intermediate I-29 7-chloro-2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00109
    • Intermediate I-29A: tert-butyl (2-bromo-4-chloro-6-nitrophenyl)(3-methoxy-2-oxopropyl)carbamate
  • Figure US20190292176A1-20190926-C00110
  • To Intermediate I-28C (2.0 g, 5.69 mmol) in DMF (20 mL) at 0° C. was added cesium carbonate (3.24 g, 9.96 mmol). The brown solution was stirred at 0° C. for 10 min, followed by addition of Intermediate I-2B (1.140 g, 6.83 mmol) in DMF (5.0 mL). The brown solution turned yellow. The mixture was stirred at 0° C. for 15 min. The mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (80 g silica gel column, 0% to 60% EtOAc/hexane over 18 min) to yield the desired product (2.01 g, 81%) as a yellow oil. 1H NMR (400 MHz, chloroform-d): δ 7.95-7.80 (m, 2H), 4.65 (d, J=18.3 Hz, 1H), 4.22 (d, J=18.0 Hz, 1H), 4.09 (s, 2H), 3.42 (s, 3H), 1.37 (s, 9H); LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 383.0 (M+H-54)+.
    • Intermediate I-29B: 5-bromo-7-chloro-2-(methoxymethyl)quinoxaline
  • Figure US20190292176A1-20190926-C00111
  • To Intermediate I-29A (2.0 g, 4.57 mmol) in ethyl acetate (10 mL) was added HCl in 1,4-dioxane (11.42 mL, 45.7 mmol) and the mixture was stirred at room temperature for 20 min. LCMS indicated a clean reaction. Solvent was removed under vacuum, and chased with EtOAc once to give the deprotected intermediate as yellow oil. The deprotected intermediate was dissolved in THF (40 mL). Concentrated HCl (aqueous) (1.142 mL, 13.71 mmol) was added, followed by SnCl2 (3.47 g, 18.28 mmol). The mixture was stirred in an oil bath at 40° C. for 4.0 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL)/water (50 mL). The organic phase was neutralized with saturated sodium bicarbonate, stirred at room temperature for 15 min, and the precipitate was removed by filtration with a pad of wet Celite. The organic solution was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 40% EtOAc in hexane over 20 min using an 80 g silica gel cartridge) to yield a brown solid (0.48 g, 36.5%). 1H NMR (400 MHz, chloroform-d) δ 9.07 (s, 1H), 8.06 (s, 2H), 4.83 (s, 2H), 3.56 (s, 3H); LC-MS: method J, RT=1.20 min, MS (ESI) m/z: 287.1, 289.0 (M+H)+.
    • Intermediate I-29
  • In a microwave vial charged with a stirring bar, Intermediate I-29B (475 mg, 1.652 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (629 mg, 2.478 mmol) and potassium acetate (405 mg, 4.13 mmol) were mixed in 1,4-dioxane (10 mL). After degassing with bubbling N2 for 10 minutes, Pd(dppf)2Cl2.CH2Cl2 (67.5 mg, 0.083 mmol) was added. The vial was sealed and was irradiated in the microwave at 120° C. for 60 minutes. Solvent was removed and the residue was purified by flash chromatography (24 g silica gel column, 0-100% EtOAc/Hexane) to give Intermediate I-29 (432 mg, 76%) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 9.07 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 4.78 (s, 2H), 3.51 (s, 3H), 1.24 (s, 12H); LC-MS: method J, RT=1.20 min, MS (ESI) m/z: 253.0 (M+H-82)+.
    • Intermediate I-30 to Intermediate I-34
  • Intermediate I-30 to Intermediate I-34 were synthesized by following the general procedures described in Intermediate I-28 and I-29.
  • LCMS LCMS
    [M + H]+ RT (Min)/
    Intermediate Structure m/z Method NMR
    I-30
    Figure US20190292176A1-20190926-C00112
         		237.1* 1.00/H
    I-31
    Figure US20190292176A1-20190926-C00113
         		287.2* 0.61/J
    I-32
    Figure US20190292176A1-20190926-C00114
         		303.2* 0.73/J
    I-33
    Figure US20190292176A1-20190926-C00115
         		277.1* 0.92/J
    I-34
    Figure US20190292176A1-20190926-C00116
         		219.1* 0.86/H
    *(M + H)+ of boronic acid
    • Intermediate I-35 (7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)boronic acid
  • Figure US20190292176A1-20190926-C00117
    • Intermediate I-35A: 4-bromo-2-chloro-6-nitroaniline
  • Figure US20190292176A1-20190926-C00118
  • A mixture of 4-bromo-2-nitroaniline (10.82 g, 49.9 mmol) and NCS (8.32 g, 62.3 mmol) in DMF (100 mL) was heated to 100° C. for 1 h. After cooling to room temperature, the solution was poured into ice water. The yellow precipitate was collected by filtration and was washed with water. The solid was dissolved in dichloromethane (100 mL) and the organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated to yield the title compound (11.54 g, 45.9 mmol, 92% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.26 (d, J=2.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 6.57 (br s, 2H).
    • Intermediate I-35B: tert-butyl N-(4-bromo-2-chloro-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
  • Figure US20190292176A1-20190926-C00119
  • Intermediate I-35B (11.75 g, 87%) was made as a yellow solid from Intermediate I-35A (7.52 g, 29.9 mmol) via the same procedure as Intermediate I-28B. 1H NMR (400 MHz, chloroform-d) δ 8.08 (d, J=2.2 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 1.42 (s, 18H).
    • Intermediate I-35C: tert-butyl (4-bromo-2-chloro-6-nitrophenyl)carbamate
  • Figure US20190292176A1-20190926-C00120
  • Intermediate I-35C (5.2 g, 14.8 mmol, 98%) was made as a brown waxy solid from Intermediate I-35B (6.8 g, 15.0 mmol) via the same procedure as Intermediate I-28C. 1H NMR (400 MHz, chloroform-d) δ 8.00 (d, J=2.2 Hz, 1H), 7.81 (d, J=2.2 Hz, 1H), 6.92 (br s, 1H), 1.50 (s, 9H)
    • Intermediate I-35D: methyl 2-((4-bromo-2-chloro-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate
  • Figure US20190292176A1-20190926-C00121
  • Intermediate I-35D (5.4 g, 12.8 mmol, 87%) was made as a yellow oil from Intermediate I-35C (5.2 g, 14.8 mmol) via the same procedure as Intermediate I-28D. 1H NMR (400 MHz, chloroform-d) δ 7.99 (d, J=2.2 Hz, 1H), 7.88-7.85 (m, 1H), 4.49 (d, J=17.4 Hz, 1H), 4.07 (d, J=17.4 Hz, 1H), 3.71-3.67 (m, 3H), 1.37 (s, 9H); LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 323.0 and 325.0 (M+H-100)+.
    • Intermediate I-35E: methyl 2-((4-bromo-2-chloro-6-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C00122
  • Intermediate I-35E (4.15 g, 12.8 mmol, 100%) was made as a brown oil from Intermediate I-35D (5.44 g, 12.8 mmol) via the same procedure as Intermediate I-28E. LC-MS: method H, RT=1.0 min, MS (ESI) m/z: 323.1 and 325.0 (M+H)+.
    • Intermediate I-35F: 7-bromo-5-chloro-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00123
  • Intermediate I-35F (3.02 g, 11.55 mmol, 73%) was made as a white solid from Intermediate I-35E (5.1 g, 15.8 mmol) via the same procedure as Intermediate I-28F. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.02 (s, 1H), 3.82 (d, J=1.8 Hz, 2H); LC-MS: method H, RT=0.84 min, MS (ESI) m/z: 261.0 and 263.0 (M+H)+.
    • Intermediate I-35G: 7-bromo-5-chloroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00124
  • Intermediate I-35G (3.40 g, 13.10 mmol, 70%) was made as an off-white solid from Intermediate I-35F (4.85 g, 18.5 mmol) via the same procedure as Intermediate I-28G. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.21 (d, J=2.2 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H); LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 259.1 and 261.1 (M+H)+.
    • Intermediate I-35H: 7-bromo-5-chloro-2-methoxyquinoxaline
  • Figure US20190292176A1-20190926-C00125
  • Intermediate I-35H (2.13 g, 7.79 mmol, 86%) was made as a yellow solid from Intermediate I-35G (2.34 g, 9.02 mmol) via the same procedure as Intermediate I-28H. 1H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 4.12 (s, 3H); LC-MS: method H, RT=1.07 min, MS (ESI) m/z: 273.1 and 275.1 (M+H)+.
    • Intermediate I-35I: 5-chloro-2-methoxy-7-vinylquinoxaline
  • Figure US20190292176A1-20190926-C00126
  • To a vial charged with a stirring bar was added Intermediate I-35H (0.7 g, 2.56 mmol), potassium vinyltrifluoroborate (0.377 g, 2.82 mmol), cesium carbonate (1.668 g, 5.12 mmol), (s)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.159 g, 0.256 mmol) and diacetoxypalladium (0.029 g, 0.128 mmol). After applying vacuum and refilling with N2 3 times, DMF (10 mL) was added and N2 was bubbled through the solution for 10 minutes. The vial was sealed, stirred at room temperature for 10 minutes, and then heated at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with 60 mL of EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-50% EtOAc/Hexane in 12 minutes, 50-100% EtOAc/hexane in 6 minutes, 40 g silica gel column) to give the title compound (470 mg, 2.130 mmol, 83% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 8.51 (s, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 6.83 (dd, J=17.5, 10.9 Hz, 1H), 5.96 (d, J=17.4 Hz, 1H), 5.48 (d, J=11.0 Hz, 1H), 4.12 (s, 3H); LC-MS: method H, RT=1.02 min, MS (ESI) m/z: 221.1.
    • Intermediate I-35J: 8-chloro-3-methoxyquinoxaline-6-carbaldehyde
  • Figure US20190292176A1-20190926-C00127
  • In a round bottom flask charged with a stirring bar, Intermediate I-351 (470 mg, 2.130 mmol) was dissolved in THF (20 mL)/water (6 mL), and treated with sodium periodate (1367 mg, 6.39 mmol) and osmium tetroxide (4% by wt. in water) (0.271 mL, 0.043 mmol). The mixture was stirred at room temperature for 4 h, and then reaction mixture was diluted by adding 40 mL of EtOAc and 20 mL of water. The organic phase was washed with saturated Na2S2O3 (aqueous, 3×) and brine, dried over Na2SO4, and filtered. The filtrate was concentrated on a rotary evaporator to give the title compound (457 mg, 2.053 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 10.17 (s, 1H), 8.67 (s, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 4.17 (s, 3H); LC-MS: method H, RT=0.88 min, MS (ESI) m/z: 223.2.
    • Intermediate I-35K: (8-chloro-3-methoxyquinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00128
  • In a round bottom flask charged with a stirring bar, Intermediate I-35J (421 mg, 1.89 mmol) was dissolved in toluene (10 mL) and mixed with sodium triacetoxyborohydride (882 mg, 4.16 mmol). The mixture was stirred at 60° C. for 4 h. After cooling to room temperature, the solvent was removed on a rotary evaporator. The residue was dissolved in 30 mL of EtOAc and 20 mL of water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated on a rotary evaporator to give the title compound (0.415 g, 1.847 mmol, 98% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H), 7.79-7.75 (m, 1H), 7.70 (d, J=1.8 Hz, 1H), 4.89 (s, 2H), 4.12 (s, 3H), 1.94 (br s, 1H); LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 225.2.
    • Intermediate I-35
  • A microwave tube was charged with Pd2(dba)3 (48.9 mg, 0.053 mmol), X-Phos (102 mg, 0.214 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (814 mg, 3.21 mmol), and potassium acetate (315 mg, 3.21 mmol). The tube was capped and then evacuated and backfilled with argon 3 times. Intermediate I-35K (240 mg, 1.068 mmol) in 1,4-dioxane (10 mL) was added via syringe, followed by flushing the reaction mixture with N2 for 10 minutes. The reaction mixture was heated at 110° C. in a microwave reactor for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (40 g silica gel, 0-100% EtOAc, then 0-10% MeOH/DCM) to give Intermediate I-35 (121 mg, 0.517 mmol, 48.4% yield) as a grey solid. LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 235.2.
    • Intermediate I-36 2-methoxy-6,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00129
    • Intermediate I-36A: 2-bromo-3,4-dimethyl-6-nitroaniline
  • Figure US20190292176A1-20190926-C00130
  • From commercially available 4,5-dimethyl-2-nitroaniline (5.76 g, 34.7 mmol), Intermediate I-36A was prepared as a yellow solid (7.78 g, 31.7 g, 114%) via the same procedure as Intermediate I-28A. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.11 (br s, 2H), 2.38 (s, 3H), 2.26 (s, 3H); LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 245.1 and 247.0 (M+H)+.
    • Intermediate I-36B: t-butyl N-(2-bromo-3,4-dimethyl-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
  • Figure US20190292176A1-20190926-C00131
  • Intermediate I-36B (9.2 g, 19.2 mmol, 65.1%) was made as a yellow solid from Intermediate I-36A (7.78 g, 20.66 mmol) via the same procedure as Intermediate I-28B. 1H NMR (400 MHz, chloroform-d) δ 7.83 (s, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 1.41 (s, 18H); LC-MS: method J, RT=1.03 min, MS (ESI) m/z: 445.1 and 447.0 (M+H)+.
    • Intermediate I-36C: tert-butyl (2-bromo-3,4-dimethyl-6-nitrophenyl)carbamate
  • Figure US20190292176A1-20190926-C00132
  • Intermediate I-36C (6.6 g, 19.1 mmol, 93%) was made as a yellow solid from Intermediate I-36B (9.2 g, 1.30 mmol) via the same procedure as Intermediate I-28C. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (br s, 1H), 7.80 (s, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 1.50-1.22 (m, 9H); LC-MS: method J, RT=0.88 min, MS (ESI) m/z: 245.0 and 247.0 (M+H-100)+.
    • Intermediate I-36D: methyl 2-((2-bromo-3,4-dimethyl-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate
  • Figure US20190292176A1-20190926-C00133
  • Intermediate I-36D (3.21 g, 7.69 mmol, 87%) was made as an orange oil from Intermediate I-36C (3.05 g, 8.84 mmol) via the same procedure as Intermediate I-28D. LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 317.0 and 319.1 (M+H-100)+.
    • Intermediate I-36E: methyl 2-((2-bromo-3,4-dimethyl-6-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C00134
  • Intermediate I-36E (2.43 g, 7.67 mmol, 100%) was made as a brown solid from Intermediate I-36D (3.2 g, 7.67 mmol) via the same procedure as Intermediate I-28E. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 317.0 and 319.0 (M+H)+.
    • Intermediate I-36F: 5-bromo-6,7-dimethyl-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00135
  • Intermediate I-36F (1.69 g, 6.62 mmol, 86%) was made as a white solid from Intermediate I-36E (2.43 g, 7.67 mmol) via the same procedure as Intermediate I-28F. LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 255.1 and 257.0 (M+H)+.
    • Intermediate I-36G: 5-bromo-6,7-dimethylquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00136
  • Intermediate I-36G (1.12 g, 4.43 mmol, 86%) was made as a white solid from Intermediate I-36F (1.26 g, 4.94 mmol) via the same procedure as Intermediate I-28G. LC-MS: method H, RT=1.03 min, MS (ESI) m/z: 253.0 and 255.1 (M+H)+.
    • Intermediate I-36H: 5-bromo-2-methoxy-6,7-dimethylquinoxaline
  • Figure US20190292176A1-20190926-C00137
  • Intermediate I-36H (0.79 g, 2.97 mmol, 67.2%) was made as a white solid from Intermediate I-36G (1.12 g, 4.43 mmol) via the same procedure as Intermediate I-28H. 1H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 7.61 (s, 1H), 4.10 (s, 3H), 2.61 (s, 3H), 2.53 (s, 3H); LC-MS: method H, RT=1.19 min, MS (ESI) m/z: 267.0 and 268.8 (M+H)+.
    • Intermediate I-36
  • Intermediate I-36 (0.50 g, 2.14 mmol, 72.5%) was made as a brown solid from Intermediate I-36H (0.79 g, 2.96 mmol) via the same procedure as Intermediate I-281. LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 232.9 (M+H-82)+.
    • Intermediate I-37 2 (5-fluoro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-6-yl) methanol
  • Figure US20190292176A1-20190926-C00138
    • Intermediate I-37A: 4-bromo-6-chloro-3-fluoro-2-nitroaniline
  • Figure US20190292176A1-20190926-C00139
  • A mixture of 4-bromo-3-fluoro-2-nitroaniline (1.0 g, 4.26 mmol), NCS (0.710 g, 5.32 mmol) in DMF (10 mL) was heated to 100° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted by adding 40 mL of DCM and 30 mL of water. After shaking and separation, aqueous layer was extracted with DCM (20 mL×2). Then organic phases were combined and washed with brine, dried over Na2SO4, filtered concentrated on a rotary evaporator, dried on a high vacuum pump to give 4-bromo-6-chloro-3-fluoro-2-nitroaniline (1.22 g, 4.53 mmol, 106% yield) as brown oil. 1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=6.4 Hz, 1H), 6.02 (br s, 2H); 19F NMR (376 MHz, chloroform-d) δ −109.56 (s, 1F)
    • Intermediate I-37B: t-butyl N-(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
  • Figure US20190292176A1-20190926-C00140
  • Intermediate I-37A (1.22 g, 4.53 mmol) was dissolved in THF (10 mL) and mixed with di-tert-butyl dicarbonate (1.976 g, 9.06 mmol) at room temperature, DMAP (0.055 g, 0.453 mmol) was added. The mixture was stirred at room temperature overnight. the next day, solvent was removed on a rotary evaporator and residue was purified by flash chromatography for purification (40 g silica gel column, 0-50% EtOAc/Hexane gradient) to give the title compound (1.141 g, 2.429 mmol, 53.7% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.86 (d, J=6.4 Hz, 1H), 1.43 (s, 18H); 19F NMR (376 MHz, chloroform-d) δ −114.28 (s, 1F).
    • Intermediate I-37C: tert-butyl (4-bromo-6-chloro-3-fluoro-2-nitrophenyl)carbamate
  • Figure US20190292176A1-20190926-C00141
  • Intermediate I-37C (0.85 g, 2.3 mmol, 95%) was made as a yellow solid from Intermediate I-37B (9.2 g, 1.30 mmol) via the same procedure as Intermediate I-28C. 1H NMR (400 MHz, chloroform-d) δ 7.82 (d, J=6.4 Hz, 1H), 6.61 (br s, 1H), 1.50 (s, 9H); 19F NMR (376 MHz, chloroform-d) δ −112.58 (br s, 1F).
    • Intermediate I-37D: methyl 2-((4-bromo-6-chloro-3-fluoro-2-nitrophenyl)(tert-butoxycarbonyl)amino)acetate
  • Figure US20190292176A1-20190926-C00142
  • Intermediate I-37D (0.68 g, 1.55 mmol, 68%) was made as a colorless oil from Intermediate I-37C (0.85 g, 2.30 mmol) via the same procedure as Intermediate I-28D. 1H NMR (400 MHz, chloroform-d) δ 7.85 (d, J=6.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 3.96-3.89 (m, 1H), 3.74 (s, 3H), 1.40 (s, 9H); 19F NMR (376 MHz, chloroform-d) δ −114.08 (s, 1F); LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 341.1 and 343.0 (M+H-100)+.
    • Intermediate I-37E: methyl 2-((4-bromo-6-chloro-3-fluoro-2-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C00143
  • Intermediate I-37E (0.53 g, 1.55 mmol, 100%) was made as brown oil from Intermediate I-37D (0.68 g, 1.55 mmol) via the same procedure as Intermediate I-28E. LC-MS: method H, RT=1.01 min, MS (ESI) m/z: 341.1 and 343.0 (M+H)+.
    • Intermediate I-37F: 7-bromo-5-chloro-8-fluoro-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00144
  • Intermediate I-37F (0.34 g, 1.22 mmol, 79%) was made as a yellow oil from Intermediate I-37E (0.53 g, 1.55 mmol) via the same procedure as Intermediate I-28F. 1H NMR (400 MHz, Acetone) δ 9.51 (br s, 1H), 7.17 (d, J=6.4 Hz, 1H), 5.72 (br s, 1H), 4.05-3.97 (m, 2H); 19F NMR (376 MHz, Acetone) δ 47.90 (br s, 1F); LC-MS: method I, RT=1.17 min, MS (ESI) m/z: 279.0 and 281.1 (M+H)+.
    • Intermediate I-37G: 7-bromo-5-chloro-8-fluoroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00145
  • Intermediate I-37G (0.31 g, 1.10 mmol, 90%) was made as a yellow solid from Intermediate I-37F (0.34 g, 1.22 mmol) via the same procedure as Intermediate I-28G. LC-MS: method H, RT=0.77 min, MS (ESI) m/z: 277.0 and 279.0 (M+H)+.
    • Intermediate I-37H: 7-bromo-5-chloro-8-fluoro-2-methoxyquinoxaline
  • Figure US20190292176A1-20190926-C00146
  • Intermediate I-37G (306 mg, 1.103 mmol) was treated with POCl3 (3 mL, 32.2 mmol) and heated to refluxing for 1 hour. After cooling to room temperature, extra POCl3 was removed on a rotary evaporator and the residue was dried on HVAC for 1 hour. Then the material was dissolved in anhydrous MeOH (10 mL) and K2CO3 (517 mg, 3.74 mmol) was added. After stirring at room temperature for 10 minutes, the mixture was refluxed for 2 h. Then reaction mixture was cooled to room temperature. Most of MeOH was removed on a rotary evaporator and residue was dissolved in 30 mL of EtOAc and 15 mL of H2O. After separation, organic phase was washed with brine, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The residue was purified by flash chromatography column (40 g silica gel, 0-100% EtOAc/Hexane gradient). Removing solvent gave 7-bromo-5-chloro-8-fluoro-2-methoxyquinoxaline (85 mg, 0.292 mmol, 26.4% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.60 (s, 1H), 7.82 (d, J=6.2 Hz, 1H), 4.18 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ −119.01 (s, 1F); LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 291.0 and 293.1 (M+H)+.
    • Intermediate I-37I: 5-chloro-8-fluoro-2-methoxy-7-vinylquinoxaline
  • Figure US20190292176A1-20190926-C00147
  • To a vial charged with a stirring bar was added Intermediate I-37H (83 mg, 0.285 mmol), potassium trifluoro(vinyl)borate (36.2 mg, 0.270 mmol), cesium carbonate (186 mg, 0.569 mmol), (s)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (35.5 mg, 0.057 mmol) and Pd(OAc)2 (6.39 mg, 0.028 mmol). After applying vacuum and refilling with N2 3 times, DMF (1.0 mL) was added and the mixture was degassed with bubbling N2 for 10 minutes. The vial was sealed and the reaction mixture was stirred at room temperature for 10 minutes, then heated at 120° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted by adding 20 mL of EtOAc and washed with water and brine, dried over Na2SO4 and filtered. Removing solvent gave crude product that was purified by flash chromatography (24 g silica gel column, 0-100% EtOAc/Hexane gradient in 10 minutes). Removing solvent gave 5-chloro-8-fluoro-2-methoxy-7-vinylquinoxaline (43 mg, 0.180 mmol, 63.3% yield) as a yellow solid. LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 239.0 (M+H)+.
    • Intermediate I-37J: 8-chloro-5-fluoro-3-methoxyquinoxaline-6-carbaldehyde
  • Figure US20190292176A1-20190926-C00148
  • Intermediate I-37I (43 mg, 0.180 mmol) was dissolved in THF (3 mL))/water (1 mL). Sodium periodate (116 mg, 0.541 mmol) was added, followed by osmium tetroxide (0.023 mL, 3.60 μmol). The mixture was stirred at room temperature for 6 h. Then the reaction mixture was diluted by adding 30 mL of EtOAc and 20 mL of water. After separation, organic phase was washed with saturated Na2S2O3 (aqueous) 3 times, brine, dried over Na2SO4 and filtered. Concentration on a rotary evaporator gave 8-chloro-5-fluoro-3-methoxyquinoxaline-6-carbaldehyde (32 mg, 0.133 mmol, 73.8% yield) as light yellow solid. 1H NMR (400 MHz, chloroform-d) δ 10.58 (s, 1H), 8.70 (s, 1H), 8.07 (d, J=5.9 Hz, 1H), 4.22 (s, 3H); LC-MS: method H, RT=0.90 min, MS (ESI) m/z: 241.0 (M+H)+.
    • Intermediate I-37K: (8-chloro-5-fluoro-3-methoxyquinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00149
  • Intermediate I-37J (32 mg, 0.133 mmol) was dissolved in toluene (1 mL) and mixed with sodium triacetoxyborohydride (62.0 mg, 0.293 mmol). The mixture was stirred at 60° C. for 4 hour. Then reaction mixture was cooled to room temperature, solvent was removed on a rotary evaporator. The residue was dissolved in 20 mL of EtOAc and 10 mL of water. After separation, organic phase was washed with brine, passed over Na2SO4, concentrated on a rotary evaporator to give (8-chloro-5-fluoro-3-methoxyquinoxalin-6-yl)methanol (26 mg, 0.107 mmol, 81% yield) as a solid. 1H NMR (400 MHz, chloroform-d) δ 8.58 (s, 1H), 7.80 (d, J=6.2 Hz, 1H), 4.97 (d, J=4.4 Hz, 2H), 4.17 (s, 3H), 2.10-2.03 (m, 1H); LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 243.0 (M+H)+.
    • Intermediate I-37
  • In a microwave tube was charged with Pd2(dba)3 (4.91 mg, 5.36 μmol), XPhos (10.22 mg, 0.021 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (82 mg, 0.321 mmol) and potassium acetate (31.5 mg, 0.321 mmol). The microwave tube was capped, evacuated and backfilled with argon (this sequence was carried out two times). Intermediate I-37J (26 mg, 0.107 mmol) in 1,4-dioxane (1 ml) was added via syringe, followed by flushing the reaction mixture with N2 for 10 minutes. The microwave tube was sealed and the reaction mixture was heated at 130° C. in a microwave reactor for 30 minutes. After cooling to room temperature, the reaction mixture was removed. The crude material Intermediate I-37 was used without purification in the next step. LC-MS: method H, RT=0.65 min, MS (ESI) m/z: 253.1 (M+H)+.
    • Intermediate I-38 3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-6-carbonitrile
  • Figure US20190292176A1-20190926-C00150
    • Intermediate I-38A: 8-bromo-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • Figure US20190292176A1-20190926-C00151
  • Intermediate I-38A was synthesized from 4-amino-3-nitrobenzonitrile via the route described for Intermediate I-28. LC-MS: method I, RT=0.94 min, MS (ESI) m/z: 252.0 and 253.9 (M+H)+.
    • Intermediate I-38B: 8-bromo-3-oxo-3,4-dihydroquinoxaline-6-carbonitrile
  • Figure US20190292176A1-20190926-C00152
  • In a round bottom flask charged with a stirring bar, Intermediate I-38A (394 mg, 1.563 mmol) was suspended in DMF (10 mL), and manganese dioxide (1359 mg, 15.63 mmol) was added. The mixture was stirred at room temperature for 60 minutes. LCMS showed starting material remained. Another 10 equivalents of manganese dioxide (1359 mg, 15.63 mmol) was added, and the mixture was stirred at room temperature overnight. The next day, the solid was filtered and solvent was removed on a rotary evaporator and dried on HVAC to give the title compound (100 mg, 0.400 mmol, 25.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.95 (d, J=2.6 Hz, 1H), 7.65 (s, 1H); LC-MS: method A, RT=2.42 min, MS (ESI) m/z: 248.0 and 250.0 (M+H)+.
    • Intermediate I-38
  • Intermediate I-38 was synthesized in two steps from Intermediate I-38B via the route described in Intermediate I-28. LC-MS: method A, RT=0.97 min, MS (ESI) m/z: 230.1 (M+H)+ of boronic acid.
    • Intermediate I-39 Ethyl 2-((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00153
  • Intermediate I-39 was made from Intermediate I-40 following the procedure described in I-49. 1H NMR (400 MHz, chloroform-d) δ 7.08 (d, J=2.2 Hz, 1H), 6.95-6.92 (m, 1H), 4.66 (s, 2H), 4.29 (q, J=7.3 Hz, 2H), 2.67 (s, 3H), 1.31 (t, J=7.2 Hz, 3H; LC-MS: method H, RT=1.37 min, MS (ESI) m/z: 330.0 and 332.0.
    • Intermediate I-40 2-bromo-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00154
  • Intermediate I-3 (100 mg, 0.387 mmol) was solvated in DCM (3.87 mL) and cooled to 0° C. Boron tribromide (1.0 M in Hexanes) (0.415 mL, 0.415 mmol) was slowly added dropwise. After 1 h of stirring, the reaction mixture was allowed to thaw to room temperature. Once at room temperature, the reaction mixture was recooled to 0° C. and quenched with saturated NH4Cl. The resulting mixture was extracted twice with DCM and the organic phase was dried over MgSO4, filtered and concentrated. The crude product was purified by ISCO (12 g, 0-30% EtOAc/Hexanes, 18 min. Product at 18%) to give clean Intermediate I-40 (54 mg, 0.221 mmol, 57.1% yield) as a white solid. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 244.0, 246.0 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.06 (d, J=2.2 Hz, 1H), 6.79 (s, 1H), 2.57 (s, 1H).
    • Intermediate I-41 2-bromo-4,5-difluoro-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00155
    • Intermediate I-41A: 2,3-difluoro-4-methoxyaniline
  • Figure US20190292176A1-20190926-C00156
  • Degussa grade Pd/C (1.125 g, 1.058 mmol) was added to a 250 mL round bottom flask previously purged with argon. The Pd was carefully wetted with a few milliliters of MeOH before the full amount of solvent (42.3 ml) was added. The head space of the flask was evacuated until the solvent began to slightly bubble and then back-filled 3× with N2. 2,3-difluoro-1-methoxy-4-nitrobenzene (2.0 g, 10.58 mmol) was added to the black suspension, and a balloon of Hz gas was attached. The heterogeneous mixture was sparged with H2 for 30 min, before being allowed to stir under an atmosphere of H2 for an additional 4 h. The reaction mixture was then filtered over celite to remove Pd/C. The celite was rinsed with EtOAc, and the filtrate was concentrated to afford Intermediate I-41A (1.63 g, 10.24 mmol, 97% yield) as a purple solid. LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 160.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.59 (td, J=8.6, 2.2 Hz, 1H), 6.49-6.43 (m, 1H), 3.83 (s, 3H), 3.51 (br. s., 2H).
    • Intermediate I-41B: 4,5-difluoro-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00157
  • To a solution of Intermediate I-41A (1.63 g, 10.24 mmol) in acetonitrile (51.2 ml) was added ammonium thiocyanate (1.014 g, 13.32 mmol). The mixture was stirred at room temperature for 10 min followed by the addition of benzyltrimethylammonium tribromide (4.39 g, 11.27 mmol). After 16 h, the reaction mixture was concentrated down and retaken in DCM. The organic phase was washed with saturated NaHCO3, concentrated and purified by ISCO (120 g, 0-100% EtOAc/Hexanes, 16 min. Product from 55%-100%) to afford Intermediate I-41B (398 mg, 1.843 mmol, 18% yield). LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 217.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.96 (dd, J=6.9, 2.1 Hz, 1H), 5.19 (br. s., 2H), 3.92 (s, 3H).
    • Intermediate I-41
  • To a solution of copper (II) bromide (289 mg, 1.295 mmol) and Intermediate I-41B (280 mg, 1.295 mmol) in acetonitrile (10 mL) was added t-Butyl nitrite (0.222 mL, 1.684 mmol) at room temperature. After 30 min, the crude mixture was diluted with EtOAc and washed with 1 M HCl. The organic phase was dried over MgSO4, filtered, concentrated and purified by ISCO flash chromatography (0-20% EtOAc/Hex, 19 min, 40 g silica gel cartridge. Product from 12% to 20%) to afford Intermediate I-41 (271 mg, 0.968 mmol, 74.7% yield) as an off-white solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 280.1, 282.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.11 (dd, J=6.6, 2.0 Hz, 1H), 3.98 (s, 3H).
    • Intermediate I-42 2-bromo-4,5-difluorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00158
  • A solution of Intermediate I-41 (220 mg, 0.785 mmol) solvated in DCM (20 ml) was cooled to 0° C. A solution of BBr3 (1.0 M hexanes) (1.571 ml, 1.571 mmol) was then added dropwise. After 5 min, the mixture was allowed to thaw to room temperature. After an additional 18 h, the reaction mixture was quenched with 1 M HCl (20.0 mL) and stirred vigorously for 20 min to fully cleave the boronate complex. The mixture was diluted with EtOAc and extracted. The organic phase was dried over MgSO4, filtered and concentrated to give Intermediate I-42 (208 mg, 0.785 mmol, 100% yield) which was taken forward without further purification. LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 266.0, 268.0 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.24 (dd, J=7.2, 2.1 Hz, 1H).
    • Intermediate I-43 2-bromo-4-chloro-5-fluoro-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00159
    • Intermediate I-43A: 2-chloro-3-fluoro-4-methoxy-1-nitrobenzene
  • Figure US20190292176A1-20190926-C00160
  • To a 0° C. solution of 1-chloro-2-fluoro-3-methoxybenzene (1.606 g, 10 mmol) in acetic acid (5.00 ml) was added fuming nitric acid (0.933 ml, 20.00 mmol) followed by the dropwise addition of sulfuric acid (2.132 ml, 40.0 mmol). After 30 min, the reaction mixture was poured into water and diluted with ethyl acetate. The organic phase was separated and washed 2× with saturated NaHCO3 followed by a final brine wash. The organic solution was then dried over MgSO4, filtered, concentrated and purify by ISCO (120 g, 10-50% EtOAc/Hexanes, 25 min. Desired regioisomer eluted second) affording Intermediate I-43A (1.10 g, 5.35 mmol, 53% yield) as a yellow solid. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: No Ionization Observed (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (dd, J=9.2, 2.2 Hz, 1H), 6.95 (dd, J=9.4, 7.6 Hz, 1H), 4.00 (s, 3H). Regiochemistry confirmed through NMR analysis of both regioisomeric products.
    • Intermediate I-43B: 2-chloro-3-fluoro-4-methoxyaniline
  • Figure US20190292176A1-20190926-C00161
  • To a solution of Intermediate I-43A (1.10 g, 5.35 mmol) in MeOH (26.7 mL, 0.2 M) was added NH4Cl (5.72 g, 107 mmol) and zinc dust (3.50 g, 53.5 mmol). The resulting mixture was allowed to stir at room temperature overnight. After 14 h, the MeOH solvent was removed in vacuo. The resulting residue was diluted with EtOAc and saturated sodium bicarbonate (0.2 M of each) and stirred vigorously for 1 hr and then filtered over celite. The organic layer was then separated, washed with brine, dried over MgSO4, filtered and concentrated to give Intermediate I-43B (710 mg, 4.04 mmol, 76% yield) as a dark brown solid. This material was taken on without further purification. LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 176.1, 178.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.76 (t, J=8.7 Hz, 1H), 6.49 (dd, J=9.0, 2.2 Hz, 1H), 3.86 (br. s, 2H), 3.82 (s, 3H).
    • Intermediate I-43C: 4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00162
  • To a solution of Intermediate I-43B (820 mg, 3.74 mmol) in acetonitrile (18.700 mL) was added ammonium thiocyanate (370 mg, 4.86 mmol). The mixture was stirred at room temperature for 10 min and then benzyltrimethylammonium tribromide (1457 mg, 3.74 mmol) was added. The resulting heterogeneous mixture was stirred vigorously overnight. After 16 h, the reaction mixture was concentrated and retaken in 30 mL saturated NaHCO3. This suspension was stirred vigorously and then filtered. The collected solid was washed with water and transferred to a new flask using acetone. This solution was concentrated in vacuo to afford Intermediate I-43C (863 mg, 3.67 mmol, 99% yield) as a yellow solid. This material was taken on without further purification. LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 233.1, 235.1 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.34 (d, J=7.5 Hz, 1H), 3.88 (s, 3H).
    • Intermediate I-43
  • To a solution of copper (II) bromide (835 mg, 3.74 mmol) and Intermediate I-43C (870 mg, 3.74 mmol) in acetonitrile (18.700 mL) was added t-butyl nitrite (0.642 mL, 4.86 mmol) at room temperature. After 30 min, the reaction mixture was diluted with EtOAc and washed with 1 M HCl followed by 1 M K2HPO4, then brine. The organic phase was concentrated and purified by ISCO flash chromatography (0-20% EtOAc/Hex over 30 min, 120 g silica gel cartridge-product at 10%) to afford Intermediate I-43 (723 mg, 2.267 mmol, 60.6% yield) as a yellow solid. LC-MS: Method H, RT=1.23 min, MS (ESI) m/z: 295.9, 297.9, 299.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.23 (d, J=7.3 Hz, 1H), 3.96 (s, 3H).
    • Intermediate I-44 2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00163
  • To a solution of Intermediate I-43 (72 mg, 0.243 mmol) in toluene (2428 μl) was added AlCl3 (97 mg, 0.728 mmol) and the mixture was heated to reflux. After 2 h, the solution was allowed to cool to room temperature, and the resulting mixture was diluted with 1 M HCl followed by EtOAc. The organic phase was separated, dried over MgSO4, filtered and concentrated to give Intermediate I-44 (38 mg, 0.135 mmol, 55.4% yield) as a brown solid. The isolated material was taken on without further purification. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 281.9, 284.0, 285.9 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.39 (d, J=7.7 Hz, 1H).
    • Intermediate I-45 2-bromo-5-fluoro-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00164
    • Intermediate I-45A: 1-chloro-3-fluoro-2-methoxy-4-methyl-5-nitrobenzene
  • Figure US20190292176A1-20190926-C00165
  • A solution of 1-chloro-3-fluoro-2-methoxy-4-methylbenzene (1 g, 5.73 mmol) in acetic acid (2.86 ml) was cooled to 0° C. To this cooled solution was added fuming nitric acid (0.535 ml, 11.45 mmol) followed by sulfuric acid (1.221 ml, 22.91 mmol) dropwise. After 30 min, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with 1 M K2HPO4 and then concentrated in vacuo to give Intermediate I-45A (1.26 g, 5.16 mmol, 90% yield) as a dark orange oil. This material was taken forward without further purification. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: None Observed (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (d, J=2.2 Hz, 1H), 4.08 (d, J=2.4 Hz, 3H), 2.50 (d, J=2.9 Hz, 3H).
    • Intermediate I-45B: 5-chloro-3-fluoro-4-methoxy-2-methylaniline
  • Figure US20190292176A1-20190926-C00166
  • A 250 mL round bottom flask containing Intermediate I-45A (1.26 g, 5.74 mmol) was evacuated and back-filled with N2. Degussa grade Pd/C (0.611 g, 0.574 mmol) was then added to the orange oil. This mixture was carefully wet with a few mL of MeOH before the full solvent volume (28.7 ml) was added. The head space of the flask was evacuated until the solvent began to slightly bubble and then back-filled with N2. A balloon of hydrogen gas was attached and the mixture was sparged with H2 for about 15 minutes through a vent needle. The vent was removed and the reaction mixture was stirred vigorously under an atmosphere of H2 overnight. After 14 h, the reaction mixture was filtered over Celite and rinsed with EtOAc to afford Intermediate I-45B (890 mg, 5.74 mmol, 100% yield) as a tan solid. This material was taken on to the next reaction without further purification. LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: 156.0 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.18-6.95 (m, 2H), 3.88 (s, 3H), 2.27 (d, J=2.4 Hz, 3H).
    • Intermediate I-45C: 5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00167
  • To a solution of Intermediate I-45B (1.03 g, 6.64 mmol) in acetonitrile (33.2 ml) was added ammonium thiocyanate (0.657 g, 8.63 mmol) followed by benzyltrimethylammonium tribromide (2.59 g, 6.64 mmol). The resulting mixture was stirred vigorously for 4 h before being diluted with saturated NaHCO3 and extracted 2× with DCM. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford Intermediate I-45C (920 mg, 4.33 mmol, 65.3% yield). This material was taken on without further purification. LC-MS: Method H, RT=0.84 min, MS (ESI) m/z: 213.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (br. s., 2H), 7.35 (d, J=8.1 Hz, 1H), 3.80 (s, 3H), 2.33 (d, J=2.2 Hz, 3H).
    • Intermediate I-45
  • To a heterogeneous solution of Intermediate I-45C (920 mg, 4.33 mmol) in acetonitrile (43.3 ml) was added copper (II) bromide (0.968 g, 4.33 mmol) followed by t-butyl nitrite (0.745 ml, 5.64 mmol). After 30 min, the reaction mixture was diluted with 1 M HCl and extracted 2× with EtOAc. The organic phase was dried over MgSO4, filtered over celite, concentrated and purified by ISCO (120 g, 0-10% EtOAc/Hexanes, 35 min. Product at 4%) to afford Intermediate I-45 (750 mg, 2.72 mmol, 62.7% yield) as a beige solid. LC-MS: Method H, RT=1.28 min, MS (ESI) m/z: 276.0, 278.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.15 (d, J=7.5 Hz, 1H), 3.93 (s, 3H), 2.61 (dd, J=2.4, 0.4 Hz, 3H).
    • Intermediate I-46 2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00168
  • To a solution of Intermediate I-45 (155 mg, 0.561 mmol) in toluene (2807 μl) was added AlCl3 (225 mg, 1.684 mmol). The mixture was heated to 90° C. for 30 min and then allowed to cool room temperature. The resulting mixture was diluted with EtOAc and washed 2× with 1 M HCl followed by Brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford Intermediate I-46 (123 mg, 0.399 mmol, 71.1% yield) as a brown solid. This material was taken on without further purification. LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 262.0, 264.0 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.23 (dd, J=7.9, 0.4 Hz, 1H), 2.54 (dd, J=2.4, 0.4 Hz, 3H).
    • Intermediate I-47 2-bromo-6-methoxy-4,5-dimethylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00169
    • Intermediate I-47A: 4-methoxy-2,3-dimethylaniline
  • Figure US20190292176A1-20190926-C00170
  • A 250 mL round bottom flask containing 1-methoxy-2,3-dimethyl-4-nitrobenzene (1 g, 5.52 mmol) was evacuated and back-filled with N2. The flask was then charged with Degussa grade Pd/C (0.587 g, 0.552 mmol). This mixture was carefully wet with a few milliliters of MeOH before the full solvent volume (27.6 ml) was added. The head space of the flask was evacuated until the solvent began to slightly bubble and then back-filled with N2. A balloon of hydrogen gas was attached and the mixture was sparged with H2 for about 15 minutes through a vent needle. The vent was removed and the reaction mixture was stirred vigorously under an atmosphere of H2 overnight. After 14 h, the reaction mixture was filtered over celite and rinsed with EtOAc to afford Intermediate I-47B (820 mg, 5.42 mmol, 98% yield) as a dark brown solid. This material was taken on to the next reaction without further purification. LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: 152.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.66-6.47 (m, 2H), 3.75 (s, 3H), 3.34 (br. s., 2H), 2.17 (s, 3H), 2.10 (s, 3H).
    • Intermediate I-47B: 6-methoxy-4,5-dimethylbenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00171
  • To a solution of Intermediate I-47A (100 mg, 0.661 mmol) in acetonitrile (18.700 mL) was added ammonium thiocyanate (370 mg, 4.86 mmol). The mixture was stirred at room temperature for 10 min and then benzyltrimethylammonium tribromide (1457 mg, 3.74 mmol) was added. After 2 h of vigorous stirring, the reaction mixture was concentrated and retaken in 5 mL saturated NaHCO3. This suspension was stirred vigorously and then filtered. The collected solid was washed with water and transferred to a new flask using acetone. This solution was concentrated in vacuo to afford Intermediate I-47B (136 mg, 0.654 mmol, 99% yield) as a tan solid. This material was taken on without further purification. LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 209.2 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.03 (s, 1H), 3.79 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).
    • Intermediate I-47
  • To a heterogeneous solution of crude Intermediate I-47B (136 mg, 0.65 mmol) in acetonitrile (6600 μl) was added copper (II) bromide (145 mg, 0.65 mmol) followed by t-butyl nitrite (113 μl, 0.858 mmol). After 30 min, the reaction mixture was diluted with 1 M HCl and EtOAc. The organic phase was dried over MgSO4, filtered, concentrated and purified by ISCO (24 g, 0-20% EtOAc/Hexanes, 25 min. Product at 5%) to afford Intermediate I-47 (45 mg, 0.165 mmol, 25.05% yield) as a beige solid. LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 272.1, 274.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.05 (s, 1H), 3.87 (s, 3H), 2.64 (s, 3H), 2.25 (s, 3H).
    • Intermediate I-48 2-bromo-4,5-dimethylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00172
  • To a solution of Intermediate I-47 (600 mg, 2.205 mmol) in toluene (22.000 mL) was added AlCl3 (588 mg, 4.41 mmol). The mixture was heated to 90° C. under an atmosphere of N2 for 1 h. The solution was then cooled to room temperature and 22 mL of 1 M HCl was added. The resulting mixture was stirred vigorously at room temperature for 1 h. The solution was then filtered to collect the off-white solid which had precipitated out of the mixture. These solids were washed with water, retaken in toluene and concentrated in vacuo to afford Intermediate I-48 (350 mg, 2.205 mmol, 61.5% yield), which was taken on without further purification. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 258.0, 260.0 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.06 (s, 1H), 2.57 (s, 3H), 2.24 (s, 3H).
    • Intermediate I-49 methyl 2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00173
  • To a solution of Intermediate I-48 (240 mg, 0.930 mmol) solvated in DMF (9297 μl) was added methyl 2-bromoacetate (132 μl, 1.395 mmol) followed by K2CO3 (257 mg, 1.859 mmol). The resulting mixture was stirred vigorously at room temperature for 30 min, before being diluted EtOAc, filtered over celite, concentrated and purified by ISCO (40 g, 0-30% EtOAc/Hexanes, 19 min. Product at 15%) to afford Intermediate I-49 (268 mg, 0.812 mmol, 87% yield) as a light pink solid. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 333.0, 332.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.96 (s, 1H), 4.69 (s, 2H), 3.82 (s, 3H), 2.65 (s, 3H), 2.33 (s, 3H).
    • Intermediate I-50 methyl 2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propanoate (racemate)
  • Figure US20190292176A1-20190926-C00174
  • To a solution of Intermediate I-48 (30 mg, 0.116 mmol) solvated in DMF (1162 μl) was added methyl 2-bromopropanoate (38.9 μl, 0.349 mmol) followed by K2CO3 (48.2 mg, 0.349 mmol). The mixture was stirred vigorously for 1.5 h before being diluted with EtOAc, filtered over celite, concentrated and purified by ISCO (12 g, 0-30% EtOAc/Hexanes, 16 min. Product at 15%) to afford Intermediate I-50 (rac) (37 mg, 0.107 mmol, 92% yield) as a light pink solid. LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 344.1, 346.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.93 (s, 1H), 4.76 (q, J=6.8 Hz, 1H), 3.76 (s, 3H), 2.64 (s, 3H), 2.31 (s, 3H), 1.67 (d, J=6.6 Hz, 3H).
    • Intermediate I-51 2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00175
  • A solution of Intermediate I-49 (170 mg, 0.515 mmol) in toluene (3432 μl) and THF (1716 μl) was cooled to −78° C. under an atmosphere of N2. To this cold solution was added DIBAL-H (1 M in Toluene) (1.13 mL, 1.13 mmol) dropwise. After 5 min of stirring, the reaction mixture was allowed to thaw to room temperature. Once this solution reached room temperature, 5 mL of 1 M HCl was added. The resulting slurry was stirred vigorously for 1 hr to fully cleave the aluminate complexes. The mixture was then diluted with EtOAc, extracted, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by ISCO (40 g, 0-100% EtOAc/Hexanes, 19 min. Product at 47%) to afford 2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy) ethanol (156 mg, 0.516 mmol, 100% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 302.1, 304.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.08 (s, 1H), 4.15-4.09 (m, 2H), 4.06-3.99 (m, 2H), 2.65 (s, 3H), 2.29 (s, 3H), 1.94 (t, J=6.3 Hz, 1H).
    • Intermediate I-52 Methyl 2((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00176
  • To a solution of Intermediate I-46 (105 mg, 0.341 mmol) solvated in DMF (3405 μl) was added methyl 2-bromoacetate (48.4 μl, 0.511 mmol) followed by K2CO3 (94 mg, 0.681 mmol). The reaction mixture was stirred vigorously at room temperature for 1 h before being diluted with EtOAc, filtered over celite and concentrated. The crude material was purified by ISCO (24 g, 0-50% EtOAc/Hexanes, 20 min. Product at 18%) to afford Intermediate I-52 (81 mg, 0.242 mmol, 71% yield) as a pink solid. LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 334.0, 336.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.15 (d, J=7.5 Hz, 1H), 4.74 (s, 2H), 3.82 (s, 3H), 2.62 (dd, J=2.4, 0.4 Hz, 3H).
    • Intermediate I-53 2-((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00177
  • This intermediate was prepared in a manner analogous to Intermediate I-51. Thus, Intermediate I-52 was reacted to afford Intermediate I-53 (82% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 306.0, 308.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.19 (d, J=7.5 Hz, 1H), 4.20-4.15 (m, 2H), 4.02 (dt, J=6.2, 4.5 Hz, 2H), 2.61 (d, J=2.4 Hz, 3H), 2.08 (t, J=6.4 Hz, 1H).
    • Intermediate I-54 (2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)methanol
  • Figure US20190292176A1-20190926-C00178
    • Intermediate I-54A: methyl 3-methoxy-2-methyl-6-nitrobenzoate
  • Figure US20190292176A1-20190926-C00179
  • This intermediate was prepared in a manner analogous to Intermediate I-43A. Thus, methyl 3-methoxy-2-methylbenzoate was reacted to afford Intermediate I-54A (56% yield) as the major regioisomer isolated from the reaction mixture (second eluting on silica gel). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: None Observed (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (d, J=9.0 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 2.20 (s, 3H).
    • Intermediate I-54B: methyl 6-amino-3-methoxy-2-methylbenzoate
  • Figure US20190292176A1-20190926-C00180
  • This intermediate was prepared in a manner analogous to Intermediate I-47A. Thus, Intermediate I-54A was reacted to afford Intermediate I-54B (100% yield) as a brown oil. LC-MS: Method H, RT=0.60 min, MS (ESI) m/z: 196.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.82 (d, J=8.8 Hz, 1H), 6.53 (dd, J=8.7, 0.6 Hz, 1H), 4.38 (br. s., 2H), 3.90 (s, 3H), 3.75 (s, 3H), 2.26 (s, 3H).
    • Intermediate I-54C: methyl 2-amino-6-methoxy-5-methylbenzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00181
  • This intermediate was prepared in a manner analogous to Intermediate I-47B. Thus, Intermediate I-54B was reacted to afford Intermediate I-54C (60% yield) as a brown solid. LC-MS: Method H, RT=0.66 min, MS (ESI) m/z: 252.9 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.29 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 2.17 (s, 3H).
    • Intermediate I-54D: methyl 2-bromo-6-methoxy-5-methylbenzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00182
  • This intermediate was prepared in a manner analogous to Intermediate I-47. Thus, Intermediate I-54C was reacted to afford Intermediate I-54D (70% yield) as a bright yellow solid. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 315.7, 317.7 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.22 (s, 1H), 4.03 (s, 3H), 3.90 (s, 3H), 2.29 (s, 3H).
    • Intermediate I-54
  • A solution of Intermediate I-54D (390 mg, 1.234 mmol) in toluene (8223 μl) and THF (4112 μl) was cooled to −78° C. under an atmosphere of N2. To this cooled solution was added DIBAL-H (1 M in toluene) (2714 μl, 2.71 mmol) dropwise. After 5 min of stirring, the mixture was allowed to thaw to room temperature. Once at room temperature, the reaction was quenched with 12 mL 1 M HCl and stirred vigorously for 30 min to fully cleave any aluminate complexes. The mixture was then diluted with EtOAc, extracted, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 33 min. SM peak recovered at 20%, Product peak) to afford Intermediate I-54 (213 mg, 0.739 mmol, 59.9% yield) as white powder. LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 287.8, 289.8 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.14 (s, 1H), 5.14 (d, J=6.4 Hz, 2H), 3.89 (s, 3H), 3.42 (t, J=6.3 Hz, 1H), 2.33 (s, 3H).
    • Intermediate I-55 2-bromo-6-methoxy-5-methylbenzo[d]thiazole-4-carbaldehyde
  • Figure US20190292176A1-20190926-C00183
  • To a solution of Intermediate I-54 (80 mg, 0.278 mmol) in DCE (2776 μl) was added manganese(IV) oxide (241 mg, 2.78 mmol). The solution was heated to reflux under an atmosphere of N2 for 4 h. The reaction mixture was allowed to cool to room temperature before being filtered over celite and washed with EtOAc. The filtrate was concentrate in vacuo to afford Intermediate I-55 (61 mg, 0.213 mmol, 77% yield) as an off-white solid. This material was taken on without further purification. LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 285.7, 287.7 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 11.12 (s, 1H), 7.42 (s, 1H), 3.93 (s, 3H), 2.63 (s, 3H).
    • Intermediate I-56 2-bromo-4-chloro-6-methoxy-5-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00184
    • Intermediate I-56A: 2-chloro-4-methoxy-3-methyl-1-nitrobenzene
  • Figure US20190292176A1-20190926-C00185
  • This intermediate was prepared in a manner analogous to Intermediate I-43A. Thus 1-chloro-3-methoxy-2-methylbenzene was reacted to afford Intermediate I-56A (52% yield) as the major regioisomer isolated from the reaction mixture (second eluting on silica gel). LC-MS: Method H, RT=0.85 min, MS (ESI) m/z: None Observed (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.80 (d, J=8.8 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H).
    • Intermediate I-56B: 2-chloro-4-methoxy-3-methylaniline
  • Figure US20190292176A1-20190926-C00186
  • This intermediate was prepared in a manner analogous to Intermediate I-43B. Thus, Intermediate I-56A was reacted to afford Intermediate I-56B (42% yield) as a purple oil. LC-MS: Method H, RT=0.91 min, MS (ESI) m/z: 172.1, 174.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.68-6.58 (m, 2H), 3.77 (br. s., 2H), 3.76 (s, 3H), 2.27 (s, 3H).
    • Intermediate I-56C: 4-chloro-6-methoxy-5-methylbenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00187
  • This intermediate was prepared in a manner analogous to Intermediate I-43C. Thus, Intermediate I-56B was reacted to afford Intermediate I-56C (81% yield) as a purple oil. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 229.1, 231.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.34 (s, 1H), 3.79 (s, 3H), 2.24 (s, 3H).
    • Intermediate I-56
  • This intermediate was prepared in a manner analogous to Intermediate I-43. Thus, Intermediate I-56C was reacted to afford Intermediate I-56 (51% yield) as a beige solid. LC-MS: Method H, RT=1.36 min, MS (ESI) m/z: 292.0, 294.0, 295.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.34 (s, 1H), 3.79 (s, 3H), 2.24 (s, 3H).
    • Intermediate I-57 methyl 2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00188
    • Intermediate I-57A: 2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-ol, hydrobromide
  • Figure US20190292176A1-20190926-C00189
  • A suspension of Intermediate I-43C (100 mg, 0.430 mmol) in acetic acid (2 mL) and HBr (48% in water) (2 mL, 17.68 mmol) was heated to 125° C. After 3 h of heating, the mixture was cooled to room temperature and concentrated in vacuo to give Intermediate I-57A (116 mg, 0.387 mmol, 90% yield) as its HBr salt. LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 218.9, 220.8 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.36 (d, J=7.3 Hz, 1H).
    • Intermediate I-57B: methyl 2-((2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) acetate
  • Figure US20190292176A1-20190926-C00190
  • To a solution of Intermediate I-57A (129 mg, 0.431 mmol) in DMF (5 mL) was added Cs2CO3 (631 mg, 1.938 mmol) followed by methyl bromoacetate (0.044 mL, 0.474 mmol). The reaction mixture was stirred vigorously for 30 min before being quenched with AcOH (0.247 mL, 4.31 mmol) followed by 5 mL deionized water. This solution was diluted with DCM and extracted 3×. The organic phase was concentrated and the crude residue was purified by ISCO (40 g, 0-10% DCM/MeOH, 17 min. Product at 5%) to afford Intermediate I-57B (135 mg, 0.418 mmol, 97% yield). LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 290.8, 292.7 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.33 (d, J=7.5 Hz, 1H), 4.77 (s, 2H), 3.78 (s, 3H).
    • Intermediate I-57C: methyl 2-((2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) acetate
  • Figure US20190292176A1-20190926-C00191
  • This intermediate was prepared in a manner analogous to Intermediate I-43. Thus, Intermediate I-57B was reacted to afford Intermediate I-57C (57% yield) as a beige solid. LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 353.9, 356.0, 357.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.25 (d, 1H-buried under CDCl3), 4.77 (s, 2H), 3.82 (s, 3H).
    • Intermediate I-58 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)acetic acid
  • Figure US20190292176A1-20190926-C00192
  • To a mixture of Intermediate I-57 (88 mg, 0.248 mmol) in THF (3.5 mL) and water (1.0 mL) was added LiOH monohydrate (51.2 mg, 1.241 mmol). After 30 min the reaction mixture was diluted with EtOAc and washed with 1 M HCl. The organic phase was concentrated to afford Intermediate I-58 (88 mg, 0.258 mmol, 104% yield) as a beige solid. This material was taken forward without further purification. LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 340.0, 342.0, 344.0 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.62 (d, J=7.5 Hz, 1H), 4.83 (s, 2H).
    • Intermediate I-59 2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00193
  • This intermediate was prepared in a manner analogous to Intermediate I-51. Intermediate I-57 was reacted to afford Intermediate I-59 (77% yield) as a yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 326.0, 327.9, 329.9 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.68 (d, J=7.3 Hz, 1H), 4.25-4.15 (m, 2H), 4.00-3.89 (m, 2H).
    • Intermediate I-60 2-bromo-5-fluorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00194
  • A solution of Intermediate 277B (502 mg, 1.915 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. To this mixture was slowly added BBr3 (1 M in Hexanes) (5.75 mL, 5.75 mmol) over 5 minutes. After this addition, the reaction mixture was allowed to thaw to room temperature overnight. After 16 h, the reaction mixture was poured into ice. The mixture was diluted with 30 mL of EtOAc and stirred vigorously for 10 min. The organic phase was separated and the aqueous phase was washed 2× with EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford Intermediate I-60 (468 mg, 1.887 mmol, 98% yield) as an off-white solid. LC-MS: Method H, RT=0.85 min, MS (ESI) m/z: 248.0, 249.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.84 (d, J=11.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ −135.05 (s, 1F).
    • Intermediate I-61 2((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00195
  • Intermediate I-61A: methyl 2-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00196
  • This intermediate was prepared in a manner analogous to Intermediate I-52. Thus, Intermediate I-60 was reacted to afford Intermediate I-61A (96% yield) as a white solid. LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 320.1, 322.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (d, J=11.0 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 4.76 (s, 2H), 3.82 (s, 3H).
    • Intermediate I-61
  • This intermediate was prepared in a manner analogous to Intermediate I-51. Thus, Intermediate I-61A was reacted to afford Intermediate I-61 (98% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 292.1, 294.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.70 (d, J=11.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 4.22-4.17 (m, 2H), 4.04 (dt, J=6.2, 4.5 Hz, 2H), 2.10-2.04 (m, 1H).
    • Intermediate I-62 2-((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-fluoropyridin-3-yl) carbamate
  • Figure US20190292176A1-20190926-C00197
  • To a solution of Intermediate I-53 (22 mg, 0.072 mmol) in THF (1.5 mL) was added DIEA (0.065 mL, 0.370 mmol) followed by a solution of phosgene (15% by wt. in toluene) (0.253 mL, 0.359 mmol) at room temperature. After 2 h of stirring, the crude chlorofomate intermediate was concentrated to remove excess phosgene and retaken in THF (1 mL). Another batch of DIEA (0.065 mL, 0.370 mmol) was added followed by 6-fluoropyridin-3-amine (24.90 mg, 0.222 mmol). After 15 min, the crude reaction mixture was concentrated and purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 16 min. Product at 35%) to afford Intermediate I-62 (28 mg, 0.070 mmol, 95% yield) as an off-white solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 443.1, 445.2 (M+H)+. 1H NMR (400 MHz, THF) δ 9.10 (br. s., 1H), 8.07 (br. s., 1H), 8.02-7.91 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 6.80 (dd, J=8.8, 3.5 Hz, 1H), 4.46-4.38 (m, 2H), 4.26-4.18 (m, 2H), 2.44 (dd, J=3.6, 2.5 Hz, 3H).
    • Intermediate I-63 2((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)ethyl(6-fluoropyridin-3-yl) carbamate
  • Figure US20190292176A1-20190926-C00198
  • This intermediate was prepared in a manner analogous to Intermediate I-62. Thus, Intermediate I-59 was reacted to afford Intermediate I-63 (90% yield) as an off-white solid. LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 464.0, 466.0, 468.0 (M+H)+. 1H NMR (400 MHz, THF) δ 9.22 (br. s., 1H), 8.19 (br. s., 1H), 8.12-8.02 (m, 1H), 7.70 (d, J=7.3 Hz, 1H), 6.92 (dd, J=8.8, 3.5 Hz, 1H), 4.56-4.53 (m, 2H), 4.41-4.37 (m, 2H).
    • Intermediate I-64 5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00199
    • Intermediate I-64A: 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00200
  • A microwave vial was charged with Intermediate I-1 (106 mg, 0.314 mmol), Intermediate I-60 (65 mg, 0.262 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (17.12 mg, 0.021 mmol). A solvent mixture of toluene (1638 μl), EtOH (546 μl) and 2.0 M Na2CO3 (197 μl, 0.393 mmol) was then added, and the resulting solution was sparged with argon for 10 min before being sealed and then heated in the microwave at 130° C. for 30 min. The crude reaction mixture was diluted with EtOAc and filtered over celite before being concentrated and purified by ISCO (24 g, 0-100% EtOAc/Hexanes, 16 min. Product at 35%.) to afford Intermediate I-64A (95 mg, 0.252 mmol, 96% yield) as a dark yellow solid. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 378.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=10.8 Hz, 1H), 7.80 (s, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 5.30 (d, J=5.1 Hz, 1H), 2.68 (s, 3H).
    • Intermediate I-64
  • To a solution of Intermediate I-64A (20 mg, 0.053 mmol) in THF (1 mL) was added a 0.5 M NaOMe solution in MeOH (0.530 mL, 0.265 mmol). After 1 h, the reaction mixture was diluted with EtOAc and quenched with 1.0 N HCl. The organic phase was extracted, dried over MgSO4, filtered and concentrated in vacuo to afford Intermediate I-64 (18 mg, 0.053 mmol, 99% yield) as a yellow solid. This material was taken on without further purification. LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 342.2 (M+H)+. 1H NMR (400 MHz, THF) δ 8.95 (br. s., 1H), 8.70 (d, J=1.3 Hz, 1H), 8.54 (s, 1H), 7.80-7.67 (m, 2H), 7.46 (d, J=8.6 Hz, 1H), 4.10 (s, 3H), 2.63 (s, 3H).
    • Intermediate I-65 4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00201
    • Intermediate I-65A 4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00202
  • This intermediate was prepared in a manner analogous to Intermediate I-64A. Thus, Intermediate I-1 was reacted with Intermediate I-44 to afford Intermediate I-65A (81% yield) as a bright yellow solid. LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 412.0, 414.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.94-9.01 (m, 1H), 8.69-8.78 (m, 1H), 7.72-8.10 (m, 2H), 7.64-7.70 (m, 1H), 2.70 (s, 3H).
    • Intermediate I-65
  • This intermediate was prepared in a manner analogous to Intermediate I-64. Thus, Intermediate I-65A was reacted to afford Intermediate I-65 (100% yield) as a dark orange solid. LC-MS: Method H, RT=1.36 min, MS (ESI) m/z: 376.0, 378.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.94-9.01 (m, 1H), 8.69-8.78 (m, 1H), 7.72-8.10 (m, 2H), 7.64-7.70 (m, 1H), 2.70 (s, 3H).
    • Intermediate I-66 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00203
    • Intermediate I-66A: 2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00204
  • This intermediate was prepared in a manner analogous to Intermediate I-64A. Thus, Intermediate I-1 was reacted with Intermediate I-61 to afford Intermediate I-66A (75% yield) as a yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 422.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=11.4 Hz, 1H), 7.80 (dd, J=1.8, 0.9 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 4.29-4.23 (m, 2H), 4.10-4.03 (m, 2H), 2.69 (s, 3H), 2.14 (t, J=6.4 Hz, 1H).
    • Intermediate I-66
  • This intermediate was prepared in a manner analogous to Intermediate I-64. Intermediate I-66A was reacted to afford Intermediate I-66 (43% yield) as a dark orange solid. LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 386.1 (M+H)+. 1H NMR (400 MHz, THF) δ 8.71 (d, J=1.8 Hz, 1H), 8.55 (s, 1H), 7.77-7.73 (m, 2H), 7.71 (d, J=8.1 Hz, 1H), 4.22-4.16 (m, 2H), 4.10 (s, 3H), 3.93-3.85 (m, 2H), 2.64 (s, 3H).
    • Intermediate I-67 (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C00205
  • To a suspension of Intermediate I-64 (30 mg, 0.088 mmol) neat in (R)-2-methyloxirane (1 mL, 14.29 mmol) was added tetrabutylammonium bromide (56.7 mg, 0.176 mmol) followed by K2CO3 (36.4 mg, 0.264 mmol). The reaction vessel was sealed, heated to 65° C. and stirred vigorously for 4 h. The reaction mixture was then cooled to room temperature and quenched with a few drops of AcOH. The resulting mixture was concentrated and purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 16 min. Product at 38%) to afford Intermediate I-67 (27 mg, 0.068 mmol, 77% yield) as a bright yellow solid. LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 400.1 (M+H)+. 1H NMR (400 MHz, THF) δ 8.70 (d, J=1.8 Hz, 1H), 8.56 (s, 1H), 7.78-7.73 (m, 2H), 7.71 (d, J=8.1 Hz, 1H), 4.10 (s, 3H), 4.16-4.07 (m, 1H), 4.07-4.00 (m, 1H), 4.00-3.92 (m, 1H), 2.64 (s, 3H), 2.55 (br. s, 1H), 1.26 (d, J=6.4 Hz, 3H).
    • Intermediate I-68 (S)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C00206
  • This intermediate was prepared in a manner analogous to Intermediate I-67. Intermediate I-64 was reacted with (S)-2-methyloxirane to afford Intermediate I-68 (73% yield) as a bright yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 422.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=11.4 Hz, 1H), 7.80 (dd, J=1.8, 0.9 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 4.29-4.23 (m, 2H), 4.10-4.03 (m, 2H), 2.69 (s, 3H), 2.14 (t, J=6.4 Hz, 1H).
    • Intermediate I-69 (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C00207
  • This intermediate was prepared in a manner analogous to Intermediate I-67. Thus, Intermediate I-65 was reacted with (R)-2-methyloxirane to afford Intermediate I-69 (74% yield) as a bright yellow solid. LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 434.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.88 (s, 1H), 5.00 (d, J=4.2 Hz, 1H), 4.10 (s, 3H), 4.10-4.00 (m, 3H), 2.67 (s, 3H), 1.22 (d, J=5.9 Hz, 3H).
    • Intermediate I-70 (S)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-1-ol
  • Figure US20190292176A1-20190926-C00208
    • Intermediate I-70A: (S)-6-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-fluoro-2-(2-methoxy-7-methyl quinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00209
  • A solution of Intermediate I-64 (30 mg, 0.088 mmol) and triphenylphosphine (92 mg, 0.352 mmol) in THF (1.0 mL) was heated to 65° C. To this mixture was added a solution of (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (84 mg, 0.439 mmol) mixed with DIAD (0.085 mL, 0.439 mmol) in THF (1.0 mL) dropwise over 1 h via syringe pump. At the end of addition, the crude mixture was allowed to cool to room temperature then was concentrated and purified by ISCO (12 g, 0-10% EtOAc/Hexanes, 16 min. Product at 7%) to afford Intermediate I-70A (31 mg, 0.060 mmol, 68.7% yield) as a yellow oil. LC-MS: Method H, RT=1.56 min, MS (ESI) m/z: 514.3 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.61 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 4.52 (sxt, J=5.9 Hz, 1H), 4.13 (s, 3H), 3.89 (dd, J=10.7, 5.8 Hz, 1H), 3.75 (dd, J=10.7, 5.0 Hz, 1H), 2.65 (s, 3H), 1.39 (d, J=6.2 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).
    • Intermediate I-70
  • To a solution of Intermediate I-70A (20 mg, 0.039 mmol) in THF (0.8 mL) and methanol (0.2 mL) was added several drops of concentrated HCl (12.1M, 0.016 mL, 0.195 mmol). After stirring for 5 min at room temperature, the reaction mixture was quenched with saturated NaHCO3. This solution was then diluted with DCM and extracted. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford Intermediate I-70 (15 mg, 0.039 mmol, 100% yield), which was taken on without further purification. LC-MS(ESI) m/z: 400.2 (M+H)+. RT=1.11 min (1 min gradient, ACN/water/TFA). 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.57 (d, J=1.7 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.82 (d, J=0.8 Hz, 1H), 4.96 (t, J=5.6 Hz, 1H), 4.63-4.55 (m, 1H), 4.08 (s, 3H), 3.68-3.61 (m, 1H), 3.61-3.55 (m, 1H), 2.63 (s, 3H), 2.51 (dt, J=3.5, 1.7 Hz, 8H), 1.30 (d, J=6.1 Hz, 3H).
    • Intermediate I-71 (R)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-1-ol
  • Figure US20190292176A1-20190926-C00210
    • Intermediate I-71A: (R)-6-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-fluoro-2-(2-methoxy-7-methyl quinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00211
  • This intermediate was prepared in a manner analogous to Intermediate I-70A. Intermediate I-64 was reacted with (S)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol to afford Intermediate I-71A (61% yield) as a yellow oil. LC-MS: Method H, RT=1.56 min, MS (ESI) m/z: 514.3 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.61 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 4.52 (sxt, J=5.9 Hz, 1H), 4.13 (s, 3H), 3.89 (dd, J=10.7, 5.8 Hz, 1H), 3.75 (dd, J=10.7, 5.0 Hz, 1H), 2.65 (s, 3H), 1.39 (d, J=6.2 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).
    • Intermediate I-71
  • This intermediate was prepared in a manner analogous to Intermediate I-70. Thus, Intermediate I-71A was reacted to afford Intermediate I-71 (94% yield). LC-MS(ESI) m/z: 400.2 (M+H)+. RT=1.11 min (1 min gradient, ACN/water/TFA). 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.57 (d, J=1.7 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.82 (d, J=0.8 Hz, 1H), 4.96 (t, J=5.6 Hz, 1H), 4.63-4.55 (m, 1H), 4.08 (s, 3H), 3.68-3.61 (m, 1H), 3.61-3.55 (m, 1H), 2.63 (s, 3H), 2.51 (dt, J=3.5, 1.7 Hz, 8H), 1.30 (d, J=6.1 Hz, 3H).
    • Intermediate I-72 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00212
    • Intermediate I-72A: (2R,3S)-3((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00213
  • To a solution of Intermediate I-60 (1.0 g, 4.03 mmol) in THF (26.9 ml) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (0.736 g, 4.84 mmol) followed by potassium carbonate (0.669 g, 4.84 mmol). The reaction mixture was sealed and heated to 65° C. for 16 h. The reaction mixture was cooled to 0° C. and concentrated sulfuric acid (0.430 ml, 8.06 mmol) was added (caution: significant bubbling observed) followed by water (0.218 ml, 12.09 mmol). The reaction mixture was allowed to thaw to room temperature for 10 min before being quenched with 1.5 M K2HPO4, extracted with EtOAc, washed with brine, dried over MgSO4, filtered over celite and concentrated down to afford Intermediate I-72A (1.29 g, 4.03 mmol) as beige solid. The crude material was taken on without further purification. LC-MS: Method H, RT=0.96 min, MS (ESI) m/z: 319.9, 321.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=8.1 Hz, 1H), 7.89 (d, J=11.4 Hz, 1H), 4.86 (d, J=5.3 Hz, 1H), 4.35-4.25 (m, 1H), 3.84-3.73 (m, 1H), 1.26 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −132.96.
    • Intermediate I-72B (2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00214
  • To a 250 mL round bottom flask charged with Intermediate I-1 (787 mg, 2.342 mmol) and Intermediate I-72A (750 mg, 2.342 mmol) was added toluene (8784 μl) and EtOH (2928 μl) followed by a 2M solution of sodium carbonate (1757 μl, 3.51 mmol). The mixture was stirred vigorously and sparged with argon for 10 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (191 mg, 0.234 mmol) was then added and the mixture was sparged with argon for an additional 5 min. The reaction mixture was heated to reflux under an atmosphere of argon. After 2 h of heating, the reaction mixture was diluted with EtOAc and filtered through celite before being concentrated, dry loaded onto celite and purified by ISCO (120 g, 0-100% DCM/EtOAc, Product at 25%) to afford Intermediate I-72B (470 mg, 1.046 mmol, 44.6% yield) as a bright yellow solid. LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 450.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 7.83 (d, J=11.4 Hz, 1H), 7.80 (dd, J=1.9, 1.0 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 4.40 (qd, J=6.3, 3.3 Hz, 1H), 4.18-4.06 (m, 1H), 2.69 (s, 3H), 2.14 (d, J=4.8 Hz, 1H), 1.38 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −89.77, −132.68.
    • Intermediate I-72
  • Intermediate I-72B (470 mg, 1.046 mmol) was co-evaporated with toluene to removed adventitious water. The crude solid was retake in THF (20.900 mL) and a 0.5 M solution sodium methoxide in MeOH (20.91 mL, 10.46 mmol) was added causing the solution to turn dark red. The reaction mixture was quenched after 30 min with 1.0 N HCl (21 mL) causing the solution to return to a bright yellow color. The reaction mixture was diluted with 150 mL EtOAc, extracted and washed with brine. The organic phase was dried over MgSO4, filtered over a pad of SiO2 gel and concentrated to afford Intermediate I-72 (430 mg, 1.040 mmol, 99% yield) as a yellow solid. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 414.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (d, J=1.8 Hz, 1H), 8.55 (s, 1H), 7.83 (d, J=11.2 Hz, 1H), 7.77 (d, J=0.9 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 4.43-4.34 (m, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 2.15 (d, J=4.8 Hz, 1H), 1.37 (d, J=6.2 Hz, 3H), 1.29 (d, J=6.6 Hz, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −133.04.
    • Intermediate I-73 (2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00215
  • To a solution of Intermediate I-72B (170 mg, 0.332 mmol) in THF (6.5 mL) was added a 15% phosgene solution in toluene (2354 μl, 3.34 mmol). The resulting slurry was allowed to stir at room temperature for 16 h before being concentrated down to the crude chloroformate intermediate. This crude residue was retaken in THF (6.5 mL) and 2-methylpyrimidin-5-amine (39.9 mg, 0.365 mmol) followed by pyridine (0.134 mL, 1.660 mmol) were added to the reaction mixture. After 10 min, the reaction mixture was concentrated and purified by ISCO (40 g, 0-100% EtOAc/Hex, Product at 85%) to afford Intermediate I-73 (182 mg, 0.311 mmol, 94% yield) as a yellow solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 585.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=2.0 Hz, 1H), 8.72 (br. s., 2H), 8.69 (s, 1H), 7.86-7.78 (m, 2H), 7.66 (t, J=71.8 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 6.49 (br. s., 1H), 5.21-5.12 (m, 1H), 4.63 (dd, J=6.4, 3.3 Hz, 1H), 2.69 (s, 3H), 2.68 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.44 (d, J=6.4 Hz, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −89.78 (s, 3F), −132.17 (s, 1F)
    • Intermediate I-74 Methyl 5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
  • Figure US20190292176A1-20190926-C00216
  • To a solution of Intermediate I-72 (30 mg, 0.073 mmol) in THF (1.5 mL) was added a 15% phosgene solution in toluene (512 μl, 0.726 mmol). The resulting slurry was allowed to stir at room temperature for 16 h before being concentrated down to the crude chloroformate intermediate. This crude residue was retaken in THF (1.5 mL) and methyl 5-aminopicolinate (13.25 mg, 0.087 mmol) was added followed by pyridine (0.059 mL, 0.726 mmol). After 10 min, the reaction mixture was concentrated and loaded directly onto an ISCO column (12 g, 0-60%, DCM/EtOAc, Product at 28%) to afford Intermediate I-74 (40 mg, 0.068 mmol, 93% yield) as a light yellow solid. LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 592.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.64-8.59 (m, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.6 Hz, 1H), 8.51 (s, 1H), 8.18-8.11 (m, 1H), 8.10-8.06 (m, 1H), 7.79 (d, J=11.2 Hz, 1H), 7.74 (d, J=0.9 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.18 (s, 1H), 5.16 (qd, J=6.5, 3.1 Hz, 1H), 4.65-4.57 (m, 1H), 4.12 (s, 3H), 3.95 (s, 3H), 2.63 (s, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.42 (d, J=6.4 Hz, 3H).
    • Intermediate I-75 Methyl 5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
  • Figure US20190292176A1-20190926-C00217
    • Intermediate I-75A: (ethyl 5-(5-fluoro-6-(((2S,3R)-3-hydroxybutan-2-yl)oxy) benzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00218
  • This intermediate was prepared in a manner analogous to Intermediate I-70A. Thus, Intermediate I-72A was reacted with Intermediate I-15 and purified by ISCO (0-100% EtOAc/Hex, Product at 60%) to afford Intermediate I-75A (79% yield) as a dark yellow solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 456.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.62 (s, 1H), 8.99 (d, J=2.0 Hz, 1H), 8.20 (s, 1H), 7.84 (d, J=11.2 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 4.67-4.58 (m, 2H), 4.47-4.36 (m, 1H), 4.17-4.08 (m, 1H), 2.74 (s, 3H), 2.14 (d, J=4.6 Hz, 1H), 1.56-1.53 (m, 3H), 1.38 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H).
    • Intermediate I-75
  • This intermediate was prepared in a manner analogous to Intermediate I-73. Thus Intermediate I-75A was reacted to afford Intermediate I-75 (50% yield) as a yellow solid. LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 591.8 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.97 (br. s., 1H), 9.46 (s, 1H), 8.85 (br. s., 1H), 8.73 (br. s., 2H), 8.18 (br. s., 1H), 8.05 (d, J=7.6 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 5.12 (br. s., 1H), 4.84 (br. s., 1H), 4.49 (d, J=6.7 Hz, 2H), 2.69 (br. s., 3H), 2.56 (s, 3H), 1.56-1.34 (m, 9H).
    • Intermediate I-76 (2R,3S)-3((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00219
    • Intermediate I-76A: (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2-oxide
  • Figure US20190292176A1-20190926-C00220
  • To a solution of thionyl chloride (5.37 ml, 73.5 mmol) in DCM (235 ml) was added (2R,3R)-butane-2,3iol (5.37 ml, 58.8 mmol). The reaction mixture immediately became opaque and bubbled. Over time, the solution became clear once again. After 30 min, the reaction mixture was carefully concentrated [Note: This product is volatile]. Intermediate I-76A (8.01 g, 58.8 mmol, 100% yield) was isolated as a light tan oil mixed with some residual DCM. The product was taken on to the subsequent sulfur oxidation without purification. 1H NMR (400 MHz, CDCl3) δ 4.68 (dq, J=9.0, 6.2 Hz, 1H), 4.11 (dq, J=8.9, 6.3 Hz, 1H), 1.57 (d, J=6.2 Hz, 3H), 1.48 (d, J=6.2 Hz, 3H).
    • Intermediate I-76B: (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide
  • Figure US20190292176A1-20190926-C00221
  • A solution of Intermediate I-76A in CCl4 (73.4 ml), acetonitrile (73.4 ml) and H2O (147 ml) was cooled to 0° C. Sodium periodate (18.85 g, 88 mmol) was added to the mixture followed by ruthenium(III) chloride (0.244 g, 1.175 mmol). The resulting mixture was stirred at 0° C. for 1 h, over which time it took on a reddish-brown hue. The reaction mixture was then diluted with 200 mL DI H2O and extracted with 500 mL EtOAc. The organic phase was washed with brine, dried over MgSO4, and filtered over a pad of silica gel. This organic solution was concentrated down to a black oil and retaken in DCM. This DCM solution was filtered over a second pad of silica gel which removed more of the ruthenium impurities. The resulting solution was concentrated to afford Intermediate I-76B (7.6 g, 49.9 mmol, 85% yield) as a brown tinged oil. [Note: This material can be stored as a frozen solid at −20° C.]. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.75-4.63 (m, 2H), 1.58-1.52 (m, 6H).
    • Intermediate I-76
  • To a solution of Intermediate I-60 (2.65 g, 10.68 mmol) in THF (42.7 ml) was added Intermediate I-76B followed by potassium carbonate (2.215 g, 16.02 mmol). A reflux condenser was attached, and the reaction mixture was heated to reflux (65° C.) overnight. After 15 h of refluxing, the solution was cooled to 0° C. Cleavage of the resulting sulfate intermediate was affected by the addition of concentrated sulfuric acid (1.708 ml, 32.0 mmol) followed by water (0.962 ml, 53.4 mmol) [Note: vigorous bubbling observed]. The reaction mixture was allowed to thaw to room temperature and stirred vigorously for 1 h. The reaction mixture was then quenched with 100 mL of a 1.5 M K2HPO4 solution, extracted with 300 mL EtOAc, washed with brine, dried over MgSO4, filtered and concentrated to afford a beige solid. This solid was dry loaded onto Celite and purified by ISCO (220 g, 0-50% EtOAc/DCM, 36 min. Product at 15%) to afford Intermediate I-76 (3.1 g, 9.68 mmol, 91% yield, 99% ee) as an off-white solid. LC-MS: Method H, RT=0.78 min, MS (ESI) m/z: 399.9, 401.9 (M+H)+-Sulfate Intermediate. LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 320.0, 322.0 (M+H)+-Desired Alcohol. Chiral HPLC: Chiral AD 10 micron 4.6×250 mm, Solvent A (heptane), Solvent B (1:1 MeOH/EtOH). Isocratic gradient at 16% B, product retention time 6.0 min. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=8.4 Hz, 1H), 7.91 (d, J=11.7 Hz, 1H), 4.90 (d, J=5.3 Hz, 1H), 4.35-4.26 (m, 1H), 3.85-3.73 (m, 1H), 1.27 (d, J=6.2 Hz, 3H), 1.16 (d, J=6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −132.96 (s, 1F).
    • Intermediate I-77 (2R,3S)-3-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00222
  • This intermediate was prepared in a manner analogous to Intermediate I-76. Thus, Intermediate I-44 was reacted with Intermediate I-76A to afford Intermediate I-77 (58% yield) as an off-white solid. LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 353.9, 355.9, 358.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=7.0 Hz, 1H), 4.38 (dd, J=6.3, 3.4 Hz, 1H), 4.16-4.03 (m, 1H), 2.01 (d, J=4.8 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.6 Hz, 3H).
    • Intermediate I-78 (2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00223
  • To a flask charged with Intermediate I-1 (254 mg, 0.756 mmol) and Intermediate I-76 (220 mg, 0.687 mmol) was added toluene (2577 μl) and EtOH (859 μl) followed by a 2 M aqueous solution of sodium carbonate (515 μl, 1.031 mmol). The mixture was stirred vigorously and sparged with argon for 10 minutes. [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (56.1 mg, 0.069 mmol) was then added and the mixture was sparged with argon for an additional 5 min. The flask was then heated to reflux under an atmosphere of argon. After 2 h of refluxing, the reaction mixture was diluted with EtOAc, filtered over Celite and concentrated. The crude residue was dry-loaded onto Celite and purified by ISCO (80 g, 0-70% DCM/EtOAc, product at 20%) to afford Intermediate I-78 (260 mg, 0.578 mmol, 84% yield) as a bright yellow foaming solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 450.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 7.83 (d, J=11.4 Hz, 1H), 7.80 (dd, J=1.9, 1.0 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 4.40 (qd, J=6.3, 3.3 Hz, 1H), 4.18-4.06 (m, 1H), 2.69 (s, 3H), 2.14 (d, J=4.8 Hz, 1H), 1.38 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ −89.77 (s, 2F), −132.68 (s, 1F).
    • Intermediate I-79 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-ol
  • Figure US20190292176A1-20190926-C00224
  • The starting material Intermediate I-78 (0.91 g, 2.025 mmol) was co-evaporated with toluene to remove any adventitious water. The dried solid was retaken in THF (40.5 ml) and a 0.5 M solution of sodium methoxide in methanol (40.5 ml, 20.25 mmol) was added. After 1 h of stirring, the reaction mixture was quenched with 1.0 N HCl (41 mL). The mixture was then diluted with 500 mL EtOAc and washed with 150 mL Brine. The organic phase was dried over MgSO4, filtered, and concentrated onto Celite for dry-load purification by ISCO (80 g, 0-100% DCM/EtOAc) to give Intermediate I-79 (0.73 g, 1.766 mmol, 87% yield) as a yellow foamy solid. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 414.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.58 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.95 (d, J=11.7 Hz, 1H), 7.83 (d, J=0.7 Hz, 1H), 4.91 (d, J=5.1 Hz, 1H), 4.38 (quin, J=5.8 Hz, 1H), 4.09 (s, 3H), 3.87-3.77 (m, 1H), 2.63 (s, 3H), 1.31 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.2 Hz, 3H)
    • Intermediate I-80 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-ol
  • Figure US20190292176A1-20190926-C00225
  • To a solution of Intermediate I-78 (370 mg, 0.823 mmol) in THF (6174 μl) was added ethanol (2058 μl) followed by the portion-wise addition of sodium hydride (329 mg, 8.23 mmol). After 10 minutes of stirring, the reaction mixture was quenched with saturated NH4Cl (˜2 mL), and the resulting mixture was concentrated onto Celite for dry loading and purified by ISCO (80 g, 0-70% DCM/EtOAc, 33 min, product at 20%) to afford Intermediate I-80 (320 mg, 0.749 mmol, 91% yield) as a bright yellow solid. LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 428.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.95 (d, J=11.7 Hz, 1H), 7.81 (s, 1H), 4.91 (d, J=5.3 Hz, 1H), 4.54 (q, J=7.0 Hz, 2H), 4.37 (quin, J=5.8 Hz, 1H), 3.87-3.78 (m, 1H), 2.63 (s, 3H), 1.45 (t, J=7.0 Hz, 3H), 1.31 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.4 Hz, 3H).
    • Intermediate I-81 (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00226
  • This intermediate was prepared in a manner analogous to Intermediate I-78. Thus, Intermediate I-9 was reacted with Intermediate I-77 to afford Intermediate I-81 (25% yield) as a yellow solid. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 447.9, 449.8 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.41 (d, J=7.0 Hz, 1H), 4.43-4.33 (m, 1H), 4.15-4.06 (m, 4H), 2.65 (s, 3H), 2.15 (d, J=4.2 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H).
    • Intermediate I-82 (R)-methyl 5-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate
  • Figure US20190292176A1-20190926-C00227
  • To a solution Intermediate I-67 (194 mg, 0.486 mmol) in THF (9714 μl) was added a 15% phosgene solution in toluene (3425 μl, 4.86 mmol). The resulting slurry was allowed to stir overnight before being concentrated down to a crude yellow residue. This intermediate chloroformate was retaken in THF (9714 μl) and added dropwise to a premixed solution of methyl 5-aminopicolinate (217 mg, 1.429 mmol) and pyridine (385 μl, 4.76 mmol) in THF (9526 μl). After 10 min of stirring, the reaction mixture was concentrated and loaded directly onto an ISCO cartridge for purification (40 g, 0-100% EtOAc/DCM, product at 35%) to afford Intermediate I-82 (250 mg, 0.433 mmol, 91% yield) as a yellow solid. LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 578.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.78-8.72 (m, 2H), 8.58 (d, J=1.8 Hz, 1H), 8.12-7.94 (m, 4H), 7.84 (s, 1H), 5.30 (td, J=6.2, 3.2 Hz, 1H), 4.47-4.36 (m, 1H), 4.35-4.24 (m, 1H), 4.09 (s, 3H), 3.84 (s, 3H), 2.64 (s, 3H), 1.45 (d, J=6.6 Hz, 3H).
    • Intermediate I-83 (R)-methyl 4-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate
  • Figure US20190292176A1-20190926-C00228
  • This intermediate was prepared in a manner analogous to Intermediate I-82. Thus, Intermediate I-67 was reacted with methyl 4-aminopicolinate to afford Intermediate I-83 (59% yield) as a yellow solid. LC-MS: Method H, RT=1.33 min, MS (ESI) m/z: 578.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.57 (m, 2H), 8.53 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.78-7.70 (m, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.14 (s, 1H), 5.43-5.33 (m, 1H), 4.30-4.17 (m, 2H), 4.12 (s, 3H), 3.98 (s, 3H), 2.64 (s, 3H), 1.51 (d, J=6.4 Hz, 3H).
    • Intermediate I-84 (R)-methyl 5-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C00229
  • This intermediate was prepared in a manner analogous to Intermediate I-82. Thus, Intermediate I-67 was reacted with Intermediate I-107 to afford Intermediate I-84 (66% yield) as a yellow solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 579.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (br. s., 1H), 9.01 (s, 2H), 8.76 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.99 (d, J=11.7 Hz, 1H), 7.85 (dd, 1.0 Hz, 1H), 5.31 (td, J=6.2, 3.2 Hz, 1H), 4.45-4.38 (m, 1H), 4.35-4.27 (m, 1H), 4.10 (s, 3H), 3.87 (s, 3H), 2.64 (s, 3H), 1.45 (d, J=6.6 Hz, 3H)
    • Intermediate I-85 Methyl 4-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
  • Figure US20190292176A1-20190926-C00230
  • This intermediate was prepared in a manner analogous to Intermediate I-82. Thus, Intermediate I-79 was reacted with methyl 4-aminopicolinate to afford Intermediate I-85 (46% yield) as a yellow solid. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 592.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=1.8 Hz, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.51 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.80 (d, J=11.4 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.69 (dd, J=5.6, 2.1 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.12 (s, 1H), 5.16 (qd, J=6.5, 3.0 Hz, 1H), 4.67-4.56 (m, 1H), 4.12 (s, 3H), 3.95 (s, 3H), 2.64 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H).
    • Intermediate I-86 Methyl 5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C00231
  • This intermediate was prepared in a manner analogous to Intermediate I-82. Thus, Intermediate I-67 was reacted with Intermediate I-107 to afford Intermediate I-86 (66% yield) as a yellow solid. LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 593.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 2H), 8.62 (br. s., 1H), 8.57 (d, J=1.8 Hz, 1H), 8.51 (s, 1H), 7.78 (d, J=11.4 Hz, 1H), 7.76-7.73 (m, 1H), 7.49 (d, J=7.7 Hz, 1H), 5.17 (qd, J=6.5, 3.1 Hz, 1H), 4.62 (qd, J=6.4, 2.9 Hz, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 2.64 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H).
    • Intermediate I-87 (R)-methyl 4-((((1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate
  • Figure US20190292176A1-20190926-C00232
  • This intermediate was prepared in a manner analogous to Intermediate I-82. Thus, Intermediate I-69 was reacted with methyl 4-aminopicolinate to afford Intermediate I-87 (58% yield) as a yellow solid. LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 612.2, 614.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=1.5 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.55 (s, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.80 (dd, J=2.0, 0.9 Hz, 1H), 7.75 (dd, 2.2 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.01 (s, 1H), 5.46-5.35 (m, 1H), 4.35-4.20 (m, 2H), 4.16 (s, 3H), 4.02 (s, 3H), 2.69 (s, 3H), 1.55 (d, J=6.6 Hz, 3H).
    • Intermediate I-88 (2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00233
    • Intermediate I-88A: (2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00234
  • To a solution Intermediate I-72A (780 mg, 2.436 mmol) in THF (24.4 mL, 0.1 M) was added 15% phosgene in toluene (8.59 mL, 12.18 mmol). The resulting slurry was allowed to stir at room temperature. After t=5 h, the resulting mixture was concentrated to remove the excess phosgene and afford Intermediate I-88A (824 mg, 2.436 mmol) as a yellow solid. Quantitative yield was assumed, and this material was telescope into the next reaction without purification. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 338.0, 339.9 (M+H)+.
    • Intermediate I-88B: (2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00235
  • To a solution of Intermediate I-97 (784 mg, 2.91 mmol) and pyridine (1.961 mL, 24.25 mmol) in DCM (48.5 mL, 0.05 M) was added crude Intermediate I-88A (820 mg, 2.425 mmol) dropwise from its own solution of DCM (48.500 mL). [Note: Addition funnel was used to add solution over 10 min]. Following the reagent addition, the reaction mixture was concentrated down to remove excess pyridine and purified by ISCO (0-100% EtOAc/Hex, product at 35%) to afford Intermediate I-88B (1.10 g, 1.63 mmol, 67% yield) as an off-white solid. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 571.0, 573.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.67-8.49 (m, 2H), 7.66 (dd, J=11.0, 3.5 Hz, 1H), 7.41-7.34 (m, 1H), 5.12 (dd, J=6.5, 3.0 Hz, 1H), 4.55 (dd, J=6.3, 3.0 Hz, 1H), 4.45-4.39 (m, 2H), 3.98 (t, J=5.5 Hz, 2H), 1.34 (d, J=6.4 Hz, 3H), 1.28 (d, J=6.6 Hz, 3H), 0.92-0.86 (m, 9H), 0.08 (s, 6H).
    • Intermediate I-88
  • To a solution of Intermediate I-88B (95 mg, 0.166 mmol) in THF (3327 μl) was added 1 M HCl (832 μl, 0.832 mmol) at room temperature (12 pm). After 1.5 h, the reaction was quenched with saturated NaHCO3, diluted with EtOAc, extracted, dried over MgSO4, filtered, concentrated, and purified by ISCO (12 g, 0-100% EtOAc/DCM, product at 85%) to afford Intermediate I-88 (50 mg, 0.109 mmol, 65.8% yield) as a colorless oil. LC-MS: Method H, RT=0.91 min, MS (ESI) m/z: 456.9, 458.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.61 (br. s., 2H), 7.64 (d, J=11.0 Hz, 1H), 7.43-7.32 (m, 1H), 7.00 (br. s., 1H), 5.12 (qd, J=6.5, 3.0 Hz, 1H), 4.56 (qd, J=6.4, 3.1 Hz, 1H), 4.51-4.44 (m, 2H), 4.23 (t, J=6.3 Hz, 1H), 3.98 (m, 2H), 1.43 (d, J=6.4 Hz, 3H), 1.39 (d, J=6.4 Hz, 3H).
    • Intermediate I-89 methyl 5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate
  • Figure US20190292176A1-20190926-C00236
  • This intermediate was prepared in a manner analogous to Intermediate I-82. Thus, Intermediate I-80 was reacted with methyl 5-aminopicolinate and purified by ISCO (0-100% EtOAc/DCM, product at 35%) to afford Intermediate I-89 (76% yield) as a yellow solid. LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 606.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 8.47 (s, 1H), 8.20-8.11 (m, 1H), 8.10-8.05 (m, 1H), 7.78 (d, J=11.4 Hz, 1H), 7.70 (dd, J=2.0, 0.9 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.24 (s, 1H), 5.16 (qd, J=6.5, 3.0 Hz, 1H), 4.65-4.58 (m, 1H), 4.55 (q, J=7.0 Hz, 2H), 3.95 (s, 3H), 2.62 (s, 3H), 1.49 (t, J=7.0 Hz, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H).
    • Intermediate I-90 methyl 5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C00237
  • This intermediate was prepared in a manner analogous to Intermediate I-82. Thus, Intermediate I-80 was reacted with Intermediate I-107 and purified by ISCO (0-80% EtOAc/DCM, product at 40%) to afford Intermediate I-90 (81% yield) as a yellow solid. LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 607.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 2H), 8.53 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.77 (d, J=11.2 Hz, 1H), 7.70 (dd, J=1.8, 0.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.45 (s, 1H), 5.17 (qd, J=6.5, 2.9 Hz, 1H), 4.65-4.58 (m, 1H), 4.58-4.51 (m, 2H), 4.02 (s, 3H), 2.62 (s, 3H), 1.49 (t, J=7.0 Hz, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.40 (d, J=6.6 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ −132.68 (s, 1F).
    • Intermediate I-91 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan
  • Figure US20190292176A1-20190926-C00238
  • This intermediate was prepared in a manner analogous to Intermediate I-78. Thus, Intermediate I-72A was reacted with Intermediate I-121 and purified by ISCO (0-70% EtOAc/DCM, product at 30%) to afford I-91 (55% yield) as a yellow solid. LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 433.0, 435.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J=3.1 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.03-7.94 (m, 3H), 4.89 (d, J=5.1 Hz, 1H), 4.43-4.34 (m, 1H), 4.01 (s, 3H), 3.88-3.77 (m, 1H), 1.32 (d, J=6.2 Hz, 3H), 1.20 (d, J=6.2 Hz, 3H)19F NMR (376 MHz, DMSO-d6) δ −133.13 (s, 1F).
    • Intermediate I-92 1-(5-aminopyridin-2-yl)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00239
    • Intermediate I-92A: 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00240
  • 5-bromo-2-methylpyridine (0.7 g, 4.07 mmol) was dissolved in anhydrous THF (20 mL). The solution was cooled to −78° C. and 2M LDA in THF (2.442 mL, 4.88 mmol) was added dropwise. The reaction mixture was stirred for 20 minutes at −78° C. then freshly distilled acetone (1.046 mL, 14.24 mmol) was added and the reaction mixture continued to stir for 20 minutes at −78° C. The reaction mixture was then quenched with saturated ammonium chloride and extracted with EtOAc (3×). The combined organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride before being charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane, The desired fractions were collected and concentrated to yield Intermediate I-92A (0.432 g, 1.877 mmol, 46.1% yield). LC-MS: Method H, MS (ESI) m/z: 232.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.1, 2.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.91 (s, 2H), 1.28-1.17 (m, 6H).
    • Intermediate I-92
  • To a solution of Intermediate I-92A (432 mg, 1.877 mmol) dissolved in DMSO (5 mL) was added L-proline (86 mg, 0.751 mmol), ammonium hydroxide (0.146 mL, 3.75 mmol), potassium carbonate (519 mg, 3.75 mmol) and copper(I) iodide (71.5 mg, 0.375 mmol). The reaction vessel was evacuated and backfilled with Ar 3× then stirred at 90° C. for 18 h. The reaction mixture was then diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-30% MeOH in methylene chloride. The desired fractions were collected and concentrated to yield Intermediate I-92 (47 mg, 0.283 mmol, 15% yield), as a white solid. LC-MS: Method H, MS (ESI) m/z: 167.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.00-6.96 (m, 1H), 6.95-6.90 (m, 1H), 2.81 (s, 2H), 1.22 (s, 6H).
    • Intermediate I-93 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine
  • Figure US20190292176A1-20190926-C00241
    • Intermediate I-93A: 2-((5-nitropyridin-2-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00242
  • Ethylene glycol (0.883 mL, 15.84 mmol) was dissolved in DMF (10 mL) at 0° C. Sodium hydride (253 mg, 6.33 mmol, 60% in mineral oil) was added to the reaction mixture portion wise and the reaction mixture was stirred for 10 minutes at 0° C. 2-fluoro-5-nitropyridine (450 mg, 3.17 mmol) dissolved in 1 mL of DMF was then added to the reaction mixture which was allowed to stir for 15 minutes at room temperature. The mixture was then quenched with saturated ammonium chloride and extracted with EtOAc (1×). The organic layer was then washed with 10% aqueous LiCl (3×), brine (1×), dried with sodium sulfate, filtered and concentrated to yield Intermediate I-93A, (530 mg, 2.88 mmol, 91% yield), as a clear oil which was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 185.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=2.9 Hz, 1H), 8.41 (dd, J=9.0, 2.9 Hz, 1H), 6.92 (dd, J=9.2, 0.4 Hz, 1H), 4.65-4.54 (m, 2H), 4.09-3.96 (m, 2H), 2.32 (t, J=5.9 Hz, 1H).
    • Intermediate I-93B: 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine
  • Figure US20190292176A1-20190926-C00243
  • Intermediate I-93A (530 mg, 2.88 mmol) was dissolved in dichloromethane (20 mL) along with TEA (0.521 mL, 3.74 mmol) and DMAP (70.3 mg, 0.576 mmol). TBS-Cl (521 mg, 3.45 mmol) was added to the reaction mixture which was allowed to stir at room temperature for 18 h. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate and extracted with DCM (2×). The organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 40 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. The desired fractions were collected and concentrated to yield Intermediate I-93B, (700 mg, 2.346 mmol, 82% yield), as a clear oil. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 299.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J=2.4 Hz, 1H), 8.27 (dd, J=9.0, 2.9 Hz, 1H), 6.80-6.72 (m, 1H), 4.47-4.35 (m, 2H), 3.90 (dd, 4.5 Hz, 2H), 0.84-0.73 (m, 9H), 0.03-0.01 (m, 6H).
    • Intermediate I-93
  • Intermediate I-93B (700 mg, 2.346 mmol) was dissolved in ethyl acetate (10 mL). Pd—C (125 mg, 0.117 mmol, 10% by wt.) was added to the reaction mixture which was evacuated and backfilled with 1 atm of hydrogen 3× and stirred under 1 atm of hydrogen at room temperature for 3 h. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated to yield Intermediate I-93, (561 mg, 2.090 mmol, 89% yield), as a yellow oil. The product was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 289.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.59-7.53 (m, 1H), 7.01-6.86 (m, 1H), 6.58-6.47 (m, 1H), 4.27-4.14 (m, 2H), 3.96-3.80 (m, 2H), 3.37-3.11 (m, 2H), 0.86-0.77 (m, 10H), 0.00 (s, 6H).
    • Intermediate I-94 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-4-amine
  • Figure US20190292176A1-20190926-C00244
    • Intermediate I-94A: 2-(4-bromopyridin-2-yl)ethanol
  • Figure US20190292176A1-20190926-C00245
  • 4-bromo-2-methylpyridine (2.5 g, 14.53 mmol) was dissolved in anhydrous THF (50 mL) at −78° C. LDA (25.4 mL, 50.9 mmol) was added to the reaction mixture which was allowed to stir at −78° C. for 30 minutes. Anhydrous DMF (3.38 mL, 43.6 mmol) was then added to the reaction mixture which continued to stir at −78° C. for an additional 45 minutes. A mixture of acetic acid (3.33 mL, 58.1 mmol)/MeOH (10 mL) was then added to the mixture at −78° C. followed by sodium borohydride (0.550 g, 14.53 mmol). The reaction mixture was then allowed to warm to room temperature and was stirred for 1 h then quenched with 10% aqueous citric acid solution at room temperature and stirred for an additional 10 minutes. The reaction mixture was extracted with EtOAc (3×). The organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated to yield Intermediate I-94A which was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 201.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J=5.3 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.49 (dd, J=5.4, 1.9 Hz, 1H), 3.78-3.70 (m, 1H), 2.89-2.86 (m, 2H), 2.28 (d, J=5.5 Hz, 1H).
    • Intermediate I-94B: 2-(4-bromopyridin-2-yl)ethyl acetate
  • Figure US20190292176A1-20190926-C00246
  • Intermediate I-94A (2.9 g, 14.35 mmol) was dissolved in THF (50 mL). Acetic anhydride (4.06 mL, 43.1 mmol) was added to the reaction mixture followed by DMAP (0.351 g, 2.87 mmol) and pyridine (3.48 mL, 43.1 mmol). The mixture was stirred at room temperature for 2 hours then diluted with EtOAc and 1.5M potassium diphosphate solution and extracted with EtOAc (3×). The organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to an 80 g silica gel cartridge which was eluted with a 30 min gradient from 0-80% EtOAc in hexane. The desired fractions were collected and concentrated to yield Intermediate I-94B (0.98 g, 4.01 mmol, 28.0% yield) as a yellow oil. LC-MS: Method H, MS (ESI) m/z: 246.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=5.5 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.36 (dd, J=5.3, 1.8 Hz, 1H), 4.48 (t, J=6.6 Hz, 2H), 3.11 (t, J=6.6 Hz, 2H), 2.08-1.99 (m, 3H).
    • Intermediate I-94
  • Intermediate I-94B (282 mg, 3.20 mmol), 2,2,2-trifluoroacetamide (722 mg, 6.39 mmol), 2-(4-bromopyridin-2-yl)ethyl acetate (780 mg, 3.20 mmol), 3 Å molecular sieves (250 mg, 3.20 mmol), copper(I) iodide (122 mg, 0.639 mmol) and potassium carbonate (883 mg, 6.39 mmol) were dissolved in dioxane (1 mL). The reaction vessel was evacuated and backfilled with Ar 3× then heated to 75° C. for 4 h. 5 mL of MeOH was then added to the reaction mixture which was allowed to stir for 30 minutes at room temperature. The reaction mixture was then filtered through celite and the filtrate was concentrated. The resulting residue was dissolved in THF (30 mL). 1M aqueous LiOH (12.05 mL, 12.05 mmol) was added to the mixture which was allowed to stir at room temperature for 18 h. The reaction mixture was then concentrated to dryness, redissolved in THF (30 mL) and filtered through a pad of celite. The celite pad was washed with excess THF. To the THF solution (˜50 mL) was added TBS-Cl (3028 mg, 20.09 mmol) and imidazole (1368 mg, 20.09 mmol). The reaction mixture was stirred at room temperature for 1 hour then filtered through a pad of celite and the filtrate was concentrated. The resulting residue was dissolved in methylene chloride before being charged to an 80 g silica gel cartridge which was eluted with a 30 min gradient from 0-25% MeOH in methylene chloride. The fractions containing desired product were concentrated and the resulting isolate was repurified on an 80 g column using 1M NH3 MeOH/DCM (0-20%, 30 min gradient). Fractions containing the desired product were concentrated to yield Intermediate I-94 (293 mg, 1.16 mmol, 29% yield). LC-MS: Method H, MS (ESI) m/z: 253.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=5.7 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 6.44 (dd, J=5.6, 2.3 Hz, 1H), 4.35-4.11 (m, 2H), 3.97 (t, J=6.6 Hz, 2H), 2.91 (t, J=6.5 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H).
    • Intermediate I-95 1-(4-aminopyridin-2-yl)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00247
    • Intermediate I-95A: 1-(4-bromopyridin-2-yl)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00248
  • To a stirred solution of 4-bromo-2-methylpyridine (0.7 g, 4.07 mmol) in anhydrous THF (20 mL) at −78° C. was added 2M LDA in THF (2.442 mL, 4.88 mmol) dropwise. The reaction mixture was stirred for 20 minutes at −78° C. Freshly distilled acetone (1.046 mL, 14.24 mmol) was then added to the reaction mixture which stirred for an additional 20 minutes at −78° C. The reaction mixture was then quenched with saturated ammonium chloride and was allowed to warm to room temperature. The reaction mixture was then diluted with water and extracted with EtOAc (3×). The organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. The desired fractions were collected and concentrated to yield Intermediate I-95A (0.588 g, 2.56 mmol, 62.8% yield). LC-MS: Method H, MS (ESI) m/z: 232.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=5.3 Hz, 1H), 7.42-7.34 (m, 2H), 5.35-5.01 (m, 1H), 2.92 (s, 2H), 1.25 (s, 6H).
    • Intermediate I-95
  • Intermediate I-95A (588 mg, 2.56 mmol) was dissolved in DMSO (5 mL) along with L-proline (118 mg, 1.022 mmol), ammonium hydroxide (0.199 mL, 5.11 mmol), potassium carbonate (706 mg, 5.11 mmol) and copper(I) iodide (97 mg, 0.511 mmol). The reaction mixture was evacuated and backfilled with argon three times before being sealed and heated to 90° C. for 5 hours. The reaction mixture was then filtered through celite, washed with MeOH and the filtrate was concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-30% MeOH in methylene chloride. Fractions containing desired product were concentrated and repurified by Prep HPLC using Method A to yield Intermediate I-95 (28 mg, 0.168 mmol, 7% yield). LC-MS: Method H, MS (ESI) m/z: 167.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.94 (d, J=7.0 Hz, 1H), 6.76 (dd, J=6.9, 2.3 Hz, 1H), 6.74-6.68 (m, 1H), 2.84 (s, 2H), 1.28 (s, 6H).
    • Intermediate I-96 1-((4-aminopyridin-2-yl)oxy)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00249
    • Intermediate I-96A: 1-((4-bromopyridin-2-yl)oxy)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00250
  • This intermediate was prepared according to Procedure D from 2-methylpropane-1,2-diol. Intermediate I-96A was afforded in 52% yield after column chromatography. LC-MS: Method H, MS (ESI) m/z: 247.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=5.5 Hz, 1H), 7.08 (dd, J=5.5, 1.5 Hz, 1H), 7.05 (d, J=1.3 Hz, 1H), 4.23 (s, 2H), 3.01 (s, 1H), 1.34 (s, 6H).
    • Intermediate I-96
  • This intermediate was prepared from Intermediate I-96A according to Procedure E. Intermediate I-96 was afforded in 66% yield. LC-MS: Method H, MS (ESI) m/z: 183.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.72-7.38 (m, 1H), 6.24-6.15 (m, 1H), 6.14-5.95 (m, 2H), 5.91-5.80 (m, 1H), 3.91 (s, 2H), 1.15 (s, 6H).
    • Intermediate I-97 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00251
    • Intermediate I-97A: 2-((5-nitropyrimidin-2-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00252
  • 2-chloro-5-nitropyrimidine (1 g, 6.27 mmol) was mixed with ethylene glycol (8 ml, 143 mmol) and DIEA (3.28 ml, 18.81 mmol) was added. The mixture was stirred at 80° C. for 20 minutes and was then poured into 30 mL of ice water. 40 mL of EtOAc was added to the mixture followed by 20 mL of 1N aqueous HCl. EtOAc (30 mL×3) was used to extract the aqueous layer. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated to give Intermediate I-97A in quantitative yield as a yellow oil. The product was brought forward without further purification. 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 2H), 4.73-4.51 (m, 2H), 4.08-3.96 (m, 2H), 2.41 (br. s., 1H).
    • Intermediate I-97B: 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyrimidine
  • Figure US20190292176A1-20190926-C00253
  • Intermediate I-97A, (1.23 g, 6.64 mmol), was mixed with tert-butylchlorodimethylsilane (2.003 g, 13.29 mmol) in DCM (20 ml). Imidazole (0.905 g, 13.29 mmol) was added to the reaction mixture and the reaction mixture stirred at room temperature for 30 minutes. The solid was filtered off and the filter cake was washed with a small amount of DCM. The filtrate was mixed with 30 g of silica gel, evaporated to dryness and loaded on CombiFlash (80 g column, 0-50% EtOAc/Hexane) for purification. The fractions containing desired product were collected and concentrated to give Intermediate I-97B, (1.73 g, 5.78 mmol, 87% yield), as a light yellow solid. LC-MS: Method H, MS (ESI) m/z: 300.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (2H, s), 4.61 (2H, dd, J=5.50, 4.62 Hz), 4.02 (2H, dd, J=5.61, 4.73 Hz), 0.88 (9H, s), 0.09 (6H, s).
    • Intermediate I-97
  • Intermediate I-97B, (1.73 g, 5.78 mmol), was dissolved in THF (40 ml). Wet Pd—C (0.307 g, 0.289 mmol, 10% by wt.) was then added to the solution. The mixture was then evacuated and backfilled with hydrogen 3×, and the mixture was stirred under 1 atm H2 for 7 hours at room temperature. The catalyst was filtered off over a pad of celite which was washed with a small amount of EtOAc. The filtrate was concentrated to yield Intermediate I-97, (1.53 g, 5.68 mmol, 98% yield), as a gray solid. LC-MS: Method H, MS (ESI) m/z: 270.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (2H, s), 4.35 (2H, t, J=5.50 Hz), 3.97 (2H, t, J=5.61 Hz), 1.69 (2H, d, J=5.06 Hz), 0.89 (9H, s), 0.08 (6H, s).
    • Intermediate I-98 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00254
    • Intermediate I-98A: 3-hydroxypropanimidamide, HCl
  • Figure US20190292176A1-20190926-C00255
  • To a mixture of MeOH (5 mL, 124 mmol)/toluene (30.1 mL) at 0° C. was added acetyl chloride (3.00 mL, 42.2 mmol) slowly over 10 minutes. The reaction mixture was allowed to stir at 0° C. for 10 minutes then at room temperature for 10 minutes. The reaction mixture was cooled to 0° C. and 3-hydroxypropanenitrile (1.5 g, 21.10 mmol) dissolved in 5 mL of toluene added and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was cooled to 0° C. and 7N ammonia in MeOH (15.07 mL, 106 mmol) was added carefully over 5 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for 18 h at room temperature. The mixture was then filtered through celite and the filter cake washed with 2:1 toluene/MeOH. The filtrate was concentrated to yield Intermediate I-98A in quantitative yield. The product was brought forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ 3.70 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
    • Intermediate I-98B: methyl 2-(2-hydroxyethyl)pyrimidine-5-carboxylate
  • Figure US20190292176A1-20190926-C00256
  • Intermediate I-98A (8.9 g, 71.4 mmol) was dissolved in DMF (200 ml). While the solution stirred at room temperature, sodium (Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (16.5 g, 83 mmol) was added in portion-wise and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated under reduced pressure and heat. The resulting residue was then suspended in 10:1 DCM:MeOH mixture and run through a pad of silica gel/celite which was washed with 500 mL of additional 10:1 DCM/MeOH solution. The filtrate was concentrated to yield Intermediate I-98B (10.5 g, 57.6 mmol, 81% yield), as a red oil. The product was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 183.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 2H), 4.69 (t, J=5.4 Hz, 1H), 4.03-3.79 (m, 5H), 3.12 (t, J=6.6 Hz, 2H).
    • Intermediate I-98C: methyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidine-5-carboxylate
  • Figure US20190292176A1-20190926-C00257
  • To the solution of Intermediate I-98B (4 g, 21.96 mmol) in THF (80 mL) was added DMAP (0.134 g, 1.098 mmol), TEA (7.65 mL, 54.9 mmol) and TBDPS-Cl (8.46 mL, 32.9 mmol). The reaction mixture was stirred for 18 h at room temperature. 5 mL of methanol was then added and the reaction mixture stirred for 10 minutes at room temperature followed by evaporation under reduced pressure. The crude product was purified by silica gel chromatography on a 120 g silica column using petroleum ether, chloroform and EtOAc as eluent. First an eluent of 0-100% chloroform in petroleum ether was used followed by an eluent of 0-100% EtOAc in chloroform. Fractions containing desired product were collected and concentrated to yield Intermediate I-98C (7.5 g, 17.9 mmol, 82% yield), as a colorless oil. LC-MS: Method H, MS (ESI) m/z: 421.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 2H), 7.73-7.28 (m, 10H), 4.22 (t, J=6.4 Hz, 2H), 3.97 (s, 4H), 3.30 (t, J=6.4 Hz, 2H), 0.98-0.94 (m, 9H).
    • Intermediate I-98D: 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidine-5-carboxylic acid
  • Figure US20190292176A1-20190926-C00258
  • Intermediate I-98C (2.14 g, 5.09 mmol) was dissolved in THF (60 mL). 1M aqueous LiOH (15.26 mL, 15.26 mmol) was added and the reaction mixture was allowed to stir at room temperature for 1 hour. The majority of the THF was concentrated under reduced pressure and the reaction mixture was acidified with 10% citric acid to pH 4-5 then extracted 3× with EtOAc. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated to yield Intermediate I-98D, (2.07 g, 5.09 mmol, 100% yield), as a clear glass. LC-MS: Method H, MS (ESI) m/z: 407.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 2H), 7.76-7.23 (m, 10H), 4.19 (t, J=6.3 Hz, 2H), 3.25 (t, J=6.3 Hz, 2H), 0.90 (s, 9H).
    • Intermediate I-98
  • Intermediate I-98D (5.5 g, 13.53 mmol) was dissolved in THF (350 mL). TEA (9.43 mL, 67.6 mmol) was added to the mixture followed by diphenyl phosphorazidate (9.31 g, 33.8 mmol) at room temperature. The reaction mixture was heated to 65° C. under a reflux condenser for 22 hours. The reaction mixture was then allowed to cool to room temperature and water (175 mL) was added. The mixture was stirred at room temperature for 2 hours and 15 minutes. The majority of THF was evaporated off under reduced pressure and the mixture was then diluted with water and a small amount of brine and extracted 3× with a total of ˜500 mL of EtOAc. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 330 g column which was eluted with a gradient from 0-20% MeOH/DCM. Fractions containing desired product were collected and concentrated to yield Intermediate I-98, (1.135 g, 3.01 mmol, 22% yield), as an orange oil. LC-MS: Method H, MS (ESI) m/z: 378.2. (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.59-7.53 (m, 4H), 7.47-7.31 (m, 6H), 5.76 (s, 2H), 4.02 (t, J=6.7 Hz, 2H), 2.97 (t, J=6.7 Hz, 2H), 0.92 (s, 9H).
    • Intermediate I-99 6-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)pyridin-3-amine
  • Figure US20190292176A1-20190926-C00259
    • Intermediate I-99A: 2,2-difluoro-3-((5-nitropyridin-2-yl)oxy)propan-1-ol
  • Figure US20190292176A1-20190926-C00260
  • 2,2-difluoropropane-1,3-diol (394 mg, 3.52 mmol) was dissolved in DMF (10 mL). Sodium hydride (77 mg, 1.934 mmol, 60% by wt.) was added to the mixture at 0° C. and the reaction mixture was stirred at 0° C. for 10 minutes. 2-fluoro-5-nitropyridine (250 mg, 1.758 mmol) dissolved in 1 mL of DMF was then added to the reaction mixture which was allowed to stir at room temperature for 1 hour. The mixture was then quenched with saturated ammonium chloride and diluted with EtOAc. The organic layer was washed with 10% aqueous LiCl (3×), and brine (1×), dried with sodium sulfate, filtered and concentrated to yield 2,2-difluoro-3-((5-nitropyridin-2-yl)oxy)propane as a yellow oil. To the crude intermediate dissolved in DCM (9 mL) was added TEA (1137 μl, 8.16 mmol) and DMAP (39.9 mg, 0.326 mmol) followed by TBS-Cl (738 mg, 4.89 mmol). The reaction mixture stirred for 18 h at room temperature. 5 mL of MeOH was then added to the reaction mixture which was allowed to stir for 10 minutes at room temperature. The reaction mixture was then quenched with saturated sodium bicarbonate and extracted DCM (3×). The organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride and charged to a 40 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractions containing desired product were concentrated to yield Intermediate I-99A (204 mg, 0.586 mmol, 36% yield) as a clear oil. LC-MS: Method H, MS (ESI) m/z: 349.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.01 (dd, J=2.9, 0.4 Hz, 1H), 8.34 (dd, J=9.1, 2.8 Hz, 1H), 6.86 (dd, J=9.0, 0.4 Hz, 1H), 4.66 (t, J=12.4 Hz, 2H), 3.85 (t, J=12.2 Hz, 2H), 0.81-0.78 (m, 9H), 0.00 (s, 6H).
    • Intermediate I-99
  • Intermediate I-99A (204 mg, 0.586 mmol) was dissolved in EtOAc (10 mL). Pd—C (18.69 mg, 0.176 mmol, 10% by wt.) was added to the solution and the flask was evacuated and backfilled with 1 atm of hydrogen 3×. The reaction mixture was stirred under 1 atm of hydrogen for 18 h and then filtered through celite and the celite pad washed with excess EtOAc. The filtrate was concentrated to yield Intermediate I-99 in quantitative yield as a green oil. The product was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 319. (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.60-7.54 (m, 1H), 7.02-6.95 (m, 1H), 6.63-6.50 (m, 1H), 4.45 (t, J=12.5 Hz, 2H), 3.86 (t, J=12.4 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H).
    • Intermediate I-100 4-((5-aminopyrimidin-2-yl)oxy)-2-methylbutan-2-ol, HCl
  • Figure US20190292176A1-20190926-C00261
    • Intermediate I-100A: 4-((5-bromopyrimidin-2-yl)oxy)-2-methylbutan-2-ol
  • Figure US20190292176A1-20190926-C00262
  • This intermediate was prepared according to Procedure A from 3-methylbutane-1,3-diol. Intermediate I-100A was afforded in 68% yield after silica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 263.0. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 4.56 (t, J=6.8 Hz, 2H), 2.05 (t, J=6.8 Hz, 2H), 1.34 (s, 6H).
    • Intermediate I-100B: 4-((5-((diphenylmethylene)amino)pyrimidin-2-yl)oxy)-2-methylbutan-2-ol
  • Figure US20190292176A1-20190926-C00263
  • This intermediate was prepared according to Procedure B from Intermediate I-100A. Intermediate I-100B was afforded in 81% yield after silica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 362.1.
    • Intermediate I-100
  • Intermediate I-100 was afforded from Intermediate I-100B in 77% yield according to Procedure C. LC-MS: Method H, MS (ESI) m/z: 198.1.
    • Intermediate I-101 2-(2-methyl-2-((triethylsilyl)oxy)propoxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00264
    • Intermediate I-101A: 1-((5-bromopyrimidin-2-yl)oxy)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00265
  • This intermediate was prepared according to Procedure A from 2-methylpropane-1,2-diol. Intermediate I-101A was afforded in 29% yield after silica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 249.0. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 2H), 4.25 (s, 2H), 1.38 (s, 6H).
    • Intermediate I-101B: 1-((5-((diphenylmethylene)amino)pyrimidin-2-yl)oxy)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00266
  • This intermediate was prepared according to Procedure B from Intermediate I-101A. Intermediate I-101B was afforded in 58% yield after silica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 348.2. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 2H), 7.81-7.67 (m, 2H), 7.58-7.35 (m, 6H), 7.19-7.02 (m, 2H), 4.17 (s, 2H), 1.34 (s, 6H).
    • Intermediate I-101
  • Intermediate I-101B (152 mg, 0.438 mmol) was dissolved in MeOH (5 mL)/THF (5.00 mL). 1M HCl (1.0 mL, 1.0 mmol) was added to the reaction mixture and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was then concentrated under reduced pressure and azeotroped with toluene 3×. The resulting residue was dissolved in anhydrous DCM (5 mL) along with Hunig's Base (0.534 mL, 3.06 mmol). The reaction mixture was then cooled to 0° C. and triethylsilyl trifluoromethanesulfonate (347 mg, 1.311 mmol) was added dropwise and the reaction mixture was allowed to stir at 0° C. for 30 minutes and then at room temperature for 30 minutes. The mixture was then quenched with saturated sodium bicarbonate and extracted with DCM (3×). The organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-25% MeOH in methylene chloride. The desired fractions were collected and concentrated to yield Intermediate I-101 (42 mg, 0.141 mmol, 32.3% yield). LC-MS: Method H, MS (ESI) m/z: 298.2. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 2H), 4.08 (s, 2H), 1.38 (s, 6H), 0.98-0.93 (m, 6H), 0.67-0.57 (m, 9H).
    • Intermediate I-102 1-(5-aminopyrimidin-2-yl)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C00267
    • Intermediate I-102A: 3-hydroxy-3-methylbutanimidamide, HCl
  • Figure US20190292176A1-20190926-C00268
  • This intermediate was synthesized from 3-hydroxy-3-methylbutanenitrile using the method described to synthesize Intermediate I-98A. Intermediate I-102A was afforded in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 2.54 (s, 2H), 1.36-1.00 (m, 6H).
    • Intermediate I-102B: methyl 2-(2-hydroxy-2-methylpropyl)pyrimidine-5-carboxylate
  • Figure US20190292176A1-20190926-C00269
  • This intermediate was synthesized from I-102A using the procedure described for Intermediate I-98B. Intermediate I-102B was afforded in 58% yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 211.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 2H), 4.70 (s, 1H), 3.91 (s, 3H), 3.09 (s, 2H), 1.17 (s, 6H).
    • Intermediate I-102C: methyl 2-(2-methyl-2-((triethylsilyl)oxy)propyl)pyrimidine-5-carboxylate
  • Figure US20190292176A1-20190926-C00270
  • To a solution of Intermediate I-102B (0.7 g, 3.33 mmol) and 2,6-lutidine (0.776 ml, 6.66 mmol) in DCM (16.65 ml) was added triethylsilyl trifluoromethanesulfonate (1.408 g, 5.33 mmol) dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with DCM (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride and charged to a 40 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractions containing the desired product were concentrated to yield Intermediate I-102C (0.629 g, 1.938 mmol, 58% yield) as a clear oil. LC-MS: Method H, MS (ESI) m/z: 325.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 2H), 4.00 (s, 3H), 3.24 (s, 2H), 1.37 (s, 6H), 0.94-0.81 (m, 9H), 0.56 (q, J=8.1 Hz, 7H).
    • Intermediate I-102D: 2-(2-methyl-2-((triethylsilyl)oxy)propyl)pyrimidine-5-carboxylic acid
  • Figure US20190292176A1-20190926-C00271
  • Intermediate I-102C (0.629 g, 1.938 mmol) was dissolved in THF (20 mL). 1M aqueous LiOH (5.82 mL, 5.82 mmol) was added to the reaction mixture which was allowed to stir at room temperature for 1 hour. Most of the THF was evaporated off and the reaction mixture was acidified to pH 4-5 with 10% citric acid and extracted with EtOAc (3×). The combined organic layer was washed with brine, filtered and concentrated to yield Intermediate I-102D (0.6 g, 1.623 mmol, 84% yield) as a clear glass. LC-MS: Method H, MS (ESI) m/z: 311.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 3.13 (s, 2H), 1.31 (s, 6H), 0.84 (t, J=7.9 Hz, 9H), 0.53-0.40 (m, 6H).
    • Intermediate I-102
  • This intermediate was synthesized from I-102D according to the procedure described for conversion of Intermediate I-98D to Intermediate I-98. Intermediate I-102 was afforded in 78% yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 168.1 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.16 (s, 2H), 2.94 (s, 2H), 1.22 (s, 6H).
    • Intermediate I-103 (R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00272
  • This intermediate was prepared from (R)-ethyl 2-hydroxypropanoate in the same manner as described for Intermediate I-104 below. LC-MS: Method H, MS (ESI) m/z: 284.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 4.20-4.06 (m, 2H), 4.01-3.93 (m, 1H), 3.29 (br. s., 2H), 1.17 (d, J=6.2 Hz, 3H), 0.81 (s, 9H), 0.01 (d, J=6.2 Hz, 6H). MS (ESI) m/z: 284.2 (M+H)+.
    • Intermediate I-104 (S)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00273
    • Intermediate I-104A: (S)-ethyl 2-((tert-butyldimethylsilyl)oxy)propanoate
  • Figure US20190292176A1-20190926-C00274
  • (S)-ethyl 2-hydroxypropanoate (1.50 g, 12.70 mmol) was reacted according to Procedure I using DCM as a solvent to afford Intermediate I-104A (2.3 g, 9.90 mmol, 78% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 4.35-4.28 (m, 1H), 4.18 (t, J=7.5 Hz, 2H), 1.40 (d, J=6.8 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H).
    • Intermediate I-104B: (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol
  • Figure US20190292176A1-20190926-C00275
  • Intermediate I-104A (2.2 g, 9.47 mmol) was dissolved in THF (100 ml) and the solution was cooled to −78° C. To the reaction mixture was added DIBAL-H (23.67 ml, 23.67 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 3 h at room temperature before being quenched with saturated Rochelle's salt. The quenched reaction mixture was stirred for 18 h at room temperature and then extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to yield Intermediate I-104B in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 3.87-3.77 (m, J=2.6 Hz, 1H), 3.46-3.37 (m, 1H), 3.32-3.21 (m, 1H), 1.03 (d, J=6.4 Hz, 3H), 0.82 (s, 9H), 0.00 (s, 6H).
    • Intermediate I-104C: (S)-5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidine
  • Figure US20190292176A1-20190926-C00276
  • Triphenylphosphine (2.88 g, 10.98 mmol) was dissolved in THF (143 ml) and the solution was cooled to 0° C. DIAD (1.941 ml, 9.98 mmol) was added and reaction mixture was allowed to stir for 5 minutes at 0° C. Intermediate I-104B (1.9 g, 9.98 mmol) was added to the reaction mixture and the reaction mixture was allowed to stir for 10 minutes at 0° C. 5-bromopyrimidin-2-ol (1.5 g, 8.57 mmol) was then added to the reaction mixture which was allowed to warm to room temperature slowly and stirred for 72 hours at room temperature. The reaction mixture was then diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride before being charged to an 80 g silica gel cartridge which was eluted with a 30 min gradient from 0-100% EtOAc in hexane. Fractions containing desired product were collected and concentrated to yield Intermediate I-104C (1.9 g, 5.47 mmol, 55% yield). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 2H), 4.34-4.26 (m, 1H), 4.18 (s, 1H), 4.15-4.05 (m, 1H), 1.24 (d, J=6.2 Hz, 3H), 0.87 (s, 9H), 0.07 (d, J=8.1 Hz, 5H). LC-MS: Method H, MS (ESI) m/z: 349.1 (M+H)+.
    • Intermediate I-104D (S)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)-N-(diphenylmethylene)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00277
  • This intermediate was synthesized from Intermediate I-104C using Procedure B. Intermediate I-104D was afforded in 78% yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 448.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 2H), 7.78-7.71 (m, 2H), 7.53-7.30 (m, 6H), 7.16-7.06 (m, 2H), 4.31-4.11 (m, 2H), 4.08-4.01 (m, 1H), 1.22 (d, J=5.9 Hz, 3H), 0.87 (s, 9H), 0.05 (d, J=9.9 Hz, 6H).
    • Intermediate I-104
  • Intermediate I-104D (1.9 g, 4.24 mmol) was dissolved in 90:10:0.1 MeOH/water/TFA (14 ml) and the solution stirred for 15 minutes at room temperature then basified with 1.5 M dipotassium phosphate solution and extracted with EtOAc (3×). The combined organic layer was washed with brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride and charged to an 80 g silica gel cartridge which was eluted with a 30 min gradient from 0-15% MeOH in methylene chloride. Fractions containing the desired product were concentrated to yield Intermediate I-104 (210 mg, 0.741 mmol, 17% yield). LC-MS: RT=1.01 min, LC-MS: Method H, MS (ESI) m/z: 284.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H), 4.93 (s, 2H), 4.16-3.83 (m, J=7.4, 5.6 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H).
    • Intermediate I-105 (S)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00278
  • This intermediate was prepared from (S)-propane-1,2-diol using the same reaction sequence as described for Intermediate I-106 below. LC-MS: Method H, MS (ESI) m/z: 284.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 5.04 (d, J=6.2 Hz, 1H), 3.78 (dd, J=10.3, 5.5 Hz, 1H), 3.60 (dd, J=10.3, 5.7 Hz, 1H), 1.28 (d, J=6.4 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 3H), −0.03 (s, 3H).
    • Intermediate I-106 (R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00279
    • Intermediate I-106A: (R)-2-((5-nitropyrimidin-2-yl)oxy)propan-1-ol, (R)-1-((5-nitropyrimidin-2-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C00280
  • To a vial containing 2-chloro-5-nitropyrimidine (300 mg, 1.9 mmol) was added DMF (3 mL) followed by (R)-propane-1,2-diol (0.5 mL, 6.81 mmol). Potassium carbonate (520 mg, 3.76 mmol) was then added to the reaction mixture which was allowed to stir vigorously at 65° C. for 1 h. The reaction mixture was then quenched with acetic acid (0.323 mL, 5.64 mmol), diluted with EtOAc and filtered over a pad of silica gel. The filtrate was concentrated before being purified by ISCO (40 g Gold Column, 0-100% EtOAc/Hex) to afford Intermediate I-106A as a mixture of regioisomers (64 mg, 0.32 mmol, 17% yield). LC-MS: Method H, MS (ESI) m/z: 199.6 (M+H)+.
    • Intermediate I-106B: (R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-nitropyrimidine
  • Figure US20190292176A1-20190926-C00281
  • Intermediate I-106A (64.0 mg, 0.321 mmol) was dissolved in THF (5 mL) along with TEA (0.224 mL, 1.607 mmol) and DMAP (7.85 mg, 0.064 mmol). TBS-Cl (242 mg, 1.607 mmol) was added to the reaction mixture which was allowed to stir for 18 h at room temperature. The reaction mixture was then concentrated and the resulting residue was dissolved in a small amount of methylene chloride and charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractions containing the desired product concentrated to yield Intermediate I-106B (67 mg, 0.214 mmol, 66.5% yield). LC-MS: Method H, MS (ESI) m/z: 314.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 2H), 5.38 (d, J=4.8 Hz, 1H), 3.83-3.64 (m, 2H), 0.80-0.77 (m, 9H), 0.00 (s, 3H), −0.03 (s, 3H). MS (ESI) m/z 314.1 (M+H).
    • Intermediate I-106
  • Intermediate I-106B (67 mg, 0.214 mmol) was dissolved in EtOAc (10 mL). Wet Pd—C (22.75 mg, 0.021 mmol, 10% by wt.) was added to the reaction mixture which was allowed to stir under 1 atm of hydrogen for 6 hours at room temperature. The reaction mixture was then filtered through celite. The filtrate was concentrated to yield Intermediate I-106 (55 mg, 0.194 mmol, 91% yield). The product was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 284.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 5.11-4.82 (m, 1H), 3.80-3.73 (m, 1H), 3.64-3.52 (m, 1H), 3.28 (br. s., 2H), 1.28 (d, J=6.2 Hz, 3H), 0.83-0.77 (m, 9H), 0.00 (s, 3H), −0.03 (s, 3H).
    • Intermediate I-107 Methyl 5-aminopyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C00282
    • Intermediate I-107A: methyl 5-((diphenylmethylene)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C00283
  • 5-bromopyrimidine-2-carboxylate was reacted according to Procedure B to afford Intermediate I-107A (3.1 g, 9.77 mmol, 70.7% yield) as a yellow solid. LC-MS: Method H, MS (ESI) m/z: 318.1 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 2H), 7.82 (d, J=6.3 Hz, 2H), 7.72-7.32 (m, 6H), 7.13 (br. s., 2H), 4.04 (s, 3H).
    • Intermediate I-107
  • Intermediate I-107A (0.2 g, 0.630 mmol) was solvated in a mixture of THF (5 ml) and MeOH (5.00 ml). To this solution was added 1M aqueous HCl (1.576 ml, 1.576 mmol). After 30 minutes of stirring at room temperature the reaction mixture was diluted with water and the aqueous phase was washed with 4:1 EtOAc/Hexanes (3×) then concentrated to afford the aminopyrimidine HCl salt intermediate. This crude intermediate was dissolved in MeOH and run through solid supported HCO3 − cartridge (PL-HCO3 MP SCE) to form the free base. The cartridge was washed with MeOH and the resulting solution was concentrated to yield Intermediate I-107 (0.065 g, 0.42 mmol, 67% yield). LC-MS: Method H, MS (ESI) m/z: 154.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 6.38 (s, 2H), 3.80 (s, 3H).
    • Intermediate I-108 4-((4-aminopyridin-2-yl)oxy)-2-methylbutan-2-ol
  • Figure US20190292176A1-20190926-C00284
    • Intermediate I-108A: 4-((4-bromopyridin-2-yl)oxy)-2-methylbutan-2-ol
  • Figure US20190292176A1-20190926-C00285
  • This intermediate was prepared according to Procedure D from 3-methylbutane-1,3-diol. Intermediate I-108A was afforded in 80% yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 261.9. (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=5.5 Hz, 1H), 7.05 (dd, J=5.5, 1.8 Hz, 1H), 6.96 (d, J=1.5 Hz, 1H), 4.52 (t, J=6.5 Hz, 2H), 2.00 (t, J=6.5 Hz, 2H), 1.32 (s, 6H).
    • Intermediate I-108
  • Intermediate I-108 was prepared from Intermediate I-108A according to Procedure E. Intermediate I-108 was afforded in 61% yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 197.0. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=5.7 Hz, 1H), 6.14 (dd, J=5.7, 2.0 Hz, 1H), 5.89 (s, 2H), 5.77 (d, J=1.8 Hz, 1H), 4.33 (s, 1H), 4.21 (t, J=7.4 Hz, 2H), 1.76 (t, J=7.4 Hz, 2H), 1.13 (s, 6H).
    • Intermediate I-109 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine
  • Figure US20190292176A1-20190926-C00286
    • Intermediate I-109A: methyl 2-(5-nitropyridin-2-yl)acetate
  • Figure US20190292176A1-20190926-C00287
  • Tert-butyl methyl malonate (2.64 g, 15.14 mmol) was dissolved in THF (50 mL). Sodium hydride (0.605 g, 15.14 mmol) was added portion-wise at 0° C. and the reaction mixture was allowed to stir for 15 min at room temperature. 2-chloro-5-nitropyridine (2.0 g, 12.61 mmol) dissolved in 10 mL of THF was then added to the mixture and the mixture was allowed to stir for 4 hours at room temperature before being quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in 30 mL of 2:1 DCM/TFA and stirred for 1.5 hours. The reaction mixture was then diluted with 1.5 M potassium phosphate solution and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to an 80 g silica gel cartridge which was eluted with a 30 min gradient from 0-100% EtOAc in hexane. Fractions containing the desired product were concentrated to yield Intermediate I-109A (1.06 g, 5.40 mmol, 42.8% yield), as a yellow oil. LC-MS: Method H, MS (ESI) m/z: 197.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.41 (d, J=2.6 Hz, 1H), 8.49 (dd, J=8.6, 2.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 4.02 (s, 2H), 3.78 (s, 3H).
    • Intermediate I-109B: 2-(5-nitropyridin-2-yl)ethanol
  • Figure US20190292176A1-20190926-C00288
  • This intermediate was prepared from Intermediate I-109A using Procedure F. Intermediate I-109B was afforded in quantitative yield and was brought forward without purification. LC-MS: Method H, MS (ESI) m/z: 169.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 9.30 (d, J=2.6 Hz, 1H), 8.51 (dd, J=8.6, 2.6 Hz, 1H), 7.64-7.49 (m, 1H), 3.96 (t, J=6.3 Hz, 2H), 3.12 (t, J=6.4 Hz, 2H).
    • Intermediate I-109C: 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitropyridine
  • Figure US20190292176A1-20190926-C00289
  • Intermediate I-109B was reacted according to Procedure I using THF as a solvent to afford Intermediate I-109C (0.150 g, 0.531 mmol, 89% yield) as a yellow oil. LC-MS: Method H, MS (ESI) m/z: 283.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J=2.6 Hz, 1H), 8.28 (dd, J=8.6, 2.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 3.92 (t, J=6.2 Hz, 2H), 3.01 (t, J=6.2 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H).
    • Intermediate I-109
  • Intermediate I-109C (0.150 g, 0.531 mmol) was dissolved in ethanol (5.3 ml) and Pd—C (0.113 g, 0.106 mmol, 10% by wt.) was added to the solution followed by ammonium formate (0.167 g, 2.66 mmol). The reaction mixture was allowed to stir at reflux for 3 hours and was then filtered over celite and concentrated under reduced pressure to yield Intermediate I-109 (0.075 g, 0.297 mmol, 56% yield). LC-MS: Method H, MS (ESI) m/z: 253.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=2.6 Hz, 1H), 7.02 (s, 1H), 6.99-6.94 (m, 1H), 3.94 (t, J=6.7 Hz, 2H), 3.69-3.54 (m, 2H), 2.92 (s, 2H), 0.89 (s, 9H), 0.00 (s, 6H).
    • Intermediate I-110 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-4-amine
  • Figure US20190292176A1-20190926-C00290
    • Intermediate I-110A: 2-((4-bromopyridin-2-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00291
  • This intermediate was prepared according to Procedure D from ethane-1,2-diol. Intermediate I-110A was afforded in 78% yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 219.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=5.5 Hz, 1H), 7.09 (dd, 1.5 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 4.51-4.47 (m, 2H), 4.01-3.87 (m, 2H), 3.16 (s, 1H).
    • Intermediate I-110
  • Intermediate I-110A was reacted according to Procedure E to afford the 4-aminopyridine intermediate which was brought forward without further purification. To a solution of the crude 4-aminopyridine intermediate (205 mg, 1.330 mmol) dissolved in THF (5 mL) was added DMAP (32.5 mg, 0.266 mmol) and TEA (0.927 mL, 6.65 mmol) followed by TBS-Cl (1002 mg, 6.65 mmol) and the mixture was allowed to stir for 18 h at room temperature. The mixture was then filtered through celite and the filtrate was concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-25% 2M NH3/MeOH in methylene chloride. The fractions containing desired product were extracted with saturated sodium bicarbonate (3×) to remove triethyl amine hydrochloride, washed with brine (1×), dried with sodium sulfate, filtered and concentrated to yield Intermediate I-110 (70 mg, 0.261 mmol, 20% yield), as a clear oil. LC-MS: Method H, MS (ESI) m/z: 269.4 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.89-7.58 (m, 1H), 6.27-6.08 (m, 1H), 6.02-5.63 (m, 1H), 4.28-4.18 (m, 2H), 3.91-3.80 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H).
    • Intermediate I-111 (R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-4-amine, (R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyridin-4-amine (regioisomeric mixture)
  • Figure US20190292176A1-20190926-C00292
    • Intermediate I-111A: (R)-1-((4-bromopyridin-2-yl)oxy)propan-2-ol, (R)-2-((4-bromopyridin-2-yl)oxy)propan-1-ol (mixture of regioisomer)
  • Figure US20190292176A1-20190926-C00293
  • This intermediate was prepared from (R)-propane-1,2-diol using Procedure D. Intermediate I-111A was afforded as mixture of regioisomers in quantitative yield. LC-MS: Method H, MS (ESI) m/z: 233.9 (M+H)+.
    • Intermediate I-111
  • Intermediate I-111A was reacted according to Procedure E to afford the 4-aminopyridine intermediates as a mixture of regioisomers. To the crude mixture of 4-aminopyridine regioisomers (302 mg, 1.8 mmol) dissolved in THF (5 mL) was added DMAP (43.9 mg, 0.359 mmol) and TEA (1.251 mL, 8.98 mmol) followed by TBS-Cl (1353 mg, 8.98 mmol) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was then filtered through celite and the filtrate was concentrated. The resulting residue was dissolved in methylene chloride before being charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-25% 2M NH3/MeOH in methylene chloride. Fractions containing the desired product were concentrated to yield Intermediate I-111 as a mixture (327 mg, 1.2 mmol, 65% yield). LC-MS: Method H, MS (ESI) m/z: 283.0 (M+H)+.
    • Intermediate I-112 5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-amine
  • Figure US20190292176A1-20190926-C00294
    • Intermediate I-112A: ethyl 5-((tert-butoxycarbonyl)amino)-2-methylnicotinate
  • Figure US20190292176A1-20190926-C00295
  • Tert-butyl carbamate (605 mg, 5.16 mmol), ethyl 5-bromo-2-methylnicotinate (420 mg, 1.72 mmol), xanthphos (100 mg, 0.172 mmol), Pd2(dba)3 (158 mg, 0.172 mmol), cesium carbonate (1121 mg, 3.44 mmol) and tert-butyl carbamate (605 mg, 5.16 mmol) were dissolved in dioxane (10 mL) in a pressure rated vial and evacuated and backfilled with Ar 3×. The reaction mixture was then heated at 85° C. for 18 h. The reaction mixture was then filtered through celite and the filtrate was concentrated. The resulting residue was dissolved in a small amount of methylene chloride before being charged to a 4 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractions containing the desired product were concentrated to yield Intermediate I-112A in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=2.6 Hz, 1H), 8.32-8.24 (m, 1H), 6.49-6.31 (m, 1H), 4.31 (q, J=7.3 Hz, 2H), 1.46 (s, 9H), 1.33 (t, J=7.2 Hz, 3H).
    • Intermediate I-112
  • Intermediate I-112A (555 mg, 1.4 mmol) was dissolved in DCM (10 mL)/TFA (2.5 mL) and the solution was stirred for 30 minutes at room temperature. The reaction mixture was then concentrated to yield the deprotected aminopyridine intermediate. This crude intermediate was dissolved in THF (20 mL) at 0° C. under Ar. 1M LAH in THF (12.94 mL, 12.94 mmol) was added dropwise to the reaction mixture and the reaction mixture was allowed to stir at room temperature for 1.5 hours. The reaction mixture was then cooled to 0° C. and quenched with 0.5 mL of water, 1 mL of 3N NaOH and then 5 mL of water. Magnesium sulfate was added to the quenched mixture, which stirred for 10 minutes before being filtered through celite and concentrated to yield the alcohol intermediate. To the crude alcohol dissolved in DCM (10 mL) was added imidazole (308 mg, 4.53 mmol) followed by TBS-Cl (634 mg, 4.21 mmol). The reaction mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. The resulting residue was dissolved in a small amount of methylene chloride before being charged to a 12 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractions containing desired product were concentrated to yield Intermediate I-112 (22 mg, 0.087 mmol, 3% yield). LC-MS: Method H, MS (ESI) m/z: 253.2 (M+H)+.
    • Intermediate I-113 (R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00296
    • Intermediate I-113A: (R)-5-bromo-2((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy) pyrimidine
  • Figure US20190292176A1-20190926-C00297
  • (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (189 mg, 1.429 mmol) was reacted with 5-bromopyrimidin-2-ol (250 mg, 1.429 mmol) according to the procedure described for Intermediate I-104C. After silica gel chromatography, Intermediate I-113A (315 mg, 1.089 mmol, 76% yield) was yielded as a colorless oil. LC-MS: Method H, MS (ESI) m/z: 290.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 4.54-4.46 (m, 1H), 4.46-4.40 (m, 1H), 4.38-4.31 (m, 1H), 4.15 (dd, J=8.6, 6.4 Hz, 1H), 3.93 (dd, J=8.5, 5.6 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H).
    • Intermediate I-113B: (R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(diphenylmethylene)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00298
  • Intermediate I-113A ((315 mg, 1.089 mmol) was reacted according to Procedure B to afford Intermediate I-113B, (300 mg, 1.089 mmol, 71% yield). LC-MS: Method H, MS (ESI) m/z: 390.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.79-7.72 (m, 1H), 7.53-7.47 (m, 1H), 7.45-7.39 (m, 2H), 7.38-7.31 (m, 3H), 7.16-7.09 (m, 2H), 4.50-4.42 (m, 1H), 4.38-4.31 (m, 1H), 4.29-4.23 (m, 1H), 4.15-4.08 (m, 1H), 3.91 (dd, J=8.6, 5.7 Hz, 1H), 1.45-1.41 (m, 3H), 1.39-1.35 (m, 3H).
    • Intermediate I-113
  • Intermediate I-113B (300 mg, 0.770 mmol) was solvated in MeOH with 0.1% TFA (8 mL) and the solution was stirred vigorously. After 30 min of stirring, the reaction mixture was passed through a PL-HCO3 ion exchange cartridge and washed with MeOH to remove the TFA. The resulting solution was concentrated and azeotroped with toluene to afford a 1:1 mixture of Intermediate I-113 and benzophenone (115 mg, 0.631 mmol, 82% yield). The intermediate was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 226.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 4.55-4.44 (m, 1H), 4.41-4.33 (m, 1H), 4.30-4.21 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.93 (dd, J=8.5, 5.8 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H).
    • Intermediate I-114 (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-5-amine
  • Figure US20190292176A1-20190926-C00299
  • Intermediate I-114 was prepared using the same reaction sequence as described for I-113. LC-MS: Method H, MS (ESI) m/z: 226.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 4.55-4.44 (m, 1H), 4.41-4.33 (m, 1H), 4.30-4.21 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.93 (dd, J=8.5, 5.8 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H).
    • Intermediate I-115 N2,N2-dimethylpyrimidine-2,5-diamine, 2 HCl
  • Figure US20190292176A1-20190926-C00300
    • Intermediate I-115A: N5-(diphenylmethylene)-N2,N2-dimethylpyrimidine-2,5-diamine
  • Figure US20190292176A1-20190926-C00301
  • 5-bromo-N,N-dimethylpyrimidin-2-amine (200 mg, 1.0 mmol) was reacted according to Procedure B to afford Intermediate I-115A, (70 mg, 0.23 mmol, 24% yield) after chromatography. LC-MS: Method H, MS (ESI) m/z: 303.2 (M+H)+.
    • Intermediate I-115
  • Intermediate I-115A was reacted according to Procedure C to afford Intermediate I-115 in quantitative yield. This intermediate was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 138.9 (M+H)+.
    • Intermediate I-116 N-(5-aminopyrimidin-2-yl)-N-methylmethanesulfonamide
  • Figure US20190292176A1-20190926-C00302
    • Intermediate I-116A: N-(5-bromopyrimidin-2-yl)-N-methylmethanesulfonamide
  • Figure US20190292176A1-20190926-C00303
  • To a solution of 5-bromo-N-methylpyrimidin-2-amine (2.55 g, 13.56 mmol) in DMF (30 mL) at 0° C. was added NaH (0.705 g, 17.63 mmol) portion-wise. The mixture was stirred for 30 min at 0° C. Methanesulfonyl chloride (1.864 g, 16.27 mmol) was then added dropwise. The mixture was warmed to room temperature and stirred for an additional 2 h at room temperature. The reaction mixture was then quenched with water (10 mL) at 0° C. and then extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. This resulting residue was dissolved in a small amount of methylene chloride before being charged to an 80 g column which was eluted with 1% MeOH in DCM. Fractions containing the desired product were concentrated to yield Intermediate I-116A (1.26 g, 35% yield). LC-MS: Method H, MS (ESI) m/z: 268.0 (M+H)+.
    • Intermediate I-116
  • Intermediate I-116A was reacted according to Procedure B to provide to the desired imine intermediate after silica gel chromatography. This imine intermediate was reacted according to Procedure C to afford the desired product which was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 203.0 (M+H)+.
    • Intermediate I-117 methyl 3-(5-aminopyrimidin-2-yl)propanoate
  • Figure US20190292176A1-20190926-C00304
    • Intermediate I-117A: 5-((diphenylmethylene)amino)pyrimidine-2-carbaldehyde
  • Figure US20190292176A1-20190926-C00305
  • Intermediate I-107A (1.1 g, 3.47 mmol) was dissolved in THF (50 ml) and the mixture was cooled to −78° C. DIBAL-H (10.40 ml, 10.40 mmol) was added to the mixture which was allowed to stir for 1 hour at −78° C. The reaction mixture was then quenched with saturated Rochelle's salt at −78° C. and the resulting slurry was allowed to stir overnight under a stream of Ar. The mixture was then extracted with EtOAc (3×) and the combined organic layer was washed with brine, dried with sodium sulfate, filtered through celite and concentrated to yield Intermediate I-117A in quantitative yield. LC-MS: Method H, MS (ESI) m/z: 154.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 2H), 3.80 (s, 3H).
    • Intermediate I-117B: (E)-methyl 3-(5-((diphenylmethylene)amino)pyrimidin-2-yl)acrylate
  • Figure US20190292176A1-20190926-C00306
  • Methyl 2-(dimethoxyphosphoryl)acetate (0.190 g, 1.044 mmol) was dissolved in THF (10 mL). 60% sodium hydride in mineral oil (0.042 g, 1.044 mmol) was added to the solution at 0° C. and the solution was allowed to stir at 0° C. for 20 minutes. Intermediate I-117A (0.25 g, 0.870 mmol) dissolved in 2 mL of THF was then added to the reaction mixture at 0° C. which was then allowed to warm to room temperature and stir for 5 minutes. The reaction mixture was then quenched with saturated ammonium chloride and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of methylene chloride and charged to a 24 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractions containing desired product were collected and concentrated to yield Intermediate I-117B (250 mg, 0.728 mmol, 84% yield) as a yellow solid. LC-MS: Method H, MS (ESI) m/z: 344.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 2H), 7.84-7.71 (m, 3H), 7.60 (d, J=15.8 Hz, 1H), 7.55-7.29 (m, 8H), 7.17-7.09 (m, 3H), 7.02 (d, J=15.6 Hz, 1H), 3.80 (s, 3H).
    • Intermediate I-117
  • Intermediate I-117B (170 mg, 0.495 mmol) was dissolved in MeOH (10 mL)/water (0.5 mL). TFA (0.038 mL, 0.495 mmol) was added to the solution which was allowed to stir at room temperature for 2.5 h. The reaction mixture was concentrated. The resulting free aniline intermediate was then dissolved in ethanol (10 mL)/ethyl acetate (10 mL) and Hunig's Base (0.432 mL, 2.473 mmol) was added to the solution. Wet Pd—C (25 mg, 0.235 mmol, 10% by wt.) was then added to the reaction mixture which was evacuated and backfilled with 1 atm of hydrogen 3×. The reaction mixture was allowed to stir for 1 h under 1 atm of hydrogen at room temperature. The mixture was then filtered through a pad of celite, concentrated and the resulting residue was dissolved in methylene chloride and charged to a 12 g silica gel cartridge which was eluted with a 15 min gradient from 0-20% MeOH in methylene chloride. Fractions containing the desired product were collected and concentrated to yield Intermediate I-117 (30 mg, 0.166 mmol, 34% yield). LC-MS: Method H, MS (ESI) m/z: 182.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 2H), 3.70 (s, 3H), 3.60 (br. s., 2H), 3.22 (t, J=7.4 Hz, 2H), 2.86 (t, J=7.4 Hz, 2H).
    • Intermediate I-118 methyl 5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)nicotinate
  • Figure US20190292176A1-20190926-C00307
  • Intermediate I-118 was prepared from Intermediate I-72 and methyl 5-aminonicotinate according to the procedure described in the table of carbamate examples below. LC-MS: Method H, MS (ESI) m/z: 593.0 (M+H)+.
    • Intermediate I-119 5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine
  • Figure US20190292176A1-20190926-C00308
  • Methyl 5-aminonicotinate (250 mg, 1.643 mmol) was dissolved in THF (20 mL) at 0° C. LAH (6.57 mL, 6.57 mmol, 1 M in THF) was added dropwise to the solution over 2 minutes. The reaction mixture was then allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The reaction mixture was then quenched water at 0° C. (1 mL), followed by addition of 1M NaOH (2 mL) and an additional 4 mL of water. The quenched reaction mixture was stirred for 10 minutes at room temperature then magnesium sulfate was added. The mixture was filtered through celite and the filtrate was concentrated to yield the intermediate alcohol. This crude alcohol intermediate was reacted according to Procedure I to yield Intermediate I-119 (251 mg, 1.05 mmol, 65% yield) after silica chromatography. LC-MS: Method H, MS (ESI) m/z: 239.2 (M+H)+.
    • Intermediate I-120 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-formylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00309
  • Intermediate I-86 (16 mg, 0.027 mmol) was dissolved in THF (5 mL) and cooled −78° C. DIBAL-H (0.135 mL, 0.135 mmol) was added to the reaction mixture dropwise which was then allowed to stir at −78° C. for 1 hour. The mixture was then quenched with saturated Rochelle's salt and stirred for 30 min. at room temperature. The resulting mixture was extracted with EtOAc (3×) and the combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated to yield Intermediate I-120 (5 mg, 8.89 μmol, 32.9% yield). The product was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 562.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 8.99 (s, 2H), 8.53-8.28 (m, 2H), 7.77-7.60 (m, 2H), 7.42 (d, J=7.7 Hz, 1H), 6.91 (s, 1H), 5.17-5.05 (m, 1H), 4.66-4.46 (m, 1H), 4.13-3.83 (m, 3H), 2.56 (s, 3H), 1.47-1.39 (m, 3H), 1.35-1.33 (m, 3H).
    • Intermediate I-121 6-chloro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00310
    • Intermediate I-121A: 8-bromo-6-chloro-3-methoxyquinoline
  • Figure US20190292176A1-20190926-C00311
  • Intermediate I-122 (2 g, 6.78 mmol), potassium carbonate (2.81 g, 20.3 mmol), and methyl iodide (0.848 mL, 13.6 mmol) were dissolved in acetone (67.8 mL) and heated to 50° C. in a sealed tube. After heating overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give I-121A (2.04 g, 7.48 mmol) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.6 Hz, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.29 (d, J=2.9 Hz, 1H), 3.97 (s, 3H); LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 272/274 (M+H)+.
    • Intermediate I-121
  • Intermediate I-121A (1 g, 3.67 mmol), bispinacolatodiboron (1.86 g, 7.34 mmol), potassium acetate (0.900 g, 9.17 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.240 g, 0.294 mmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (18.4 mL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in DCM, followed by 0 to 20% MeOH in DCM) to give Intermediate I-121 (368 mg, 1.15 mmol, 31.4%) as a brown solid: LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 237.9 (boronic acid mass observed, M+H)+.
    • Intermediate I-122 8-bromo-6-chloroquinolin-3-ol, HCl
  • Figure US20190292176A1-20190926-C00312
    • Intermediate I-122A: 3-(benzyloxy)-8-bromo-6-chloroquinoline
  • Figure US20190292176A1-20190926-C00313
  • Intermediate I-123 (5 g, 21.32 mmol), 2-(benzyloxy)acetaldehyde (3.20 g, 21.3 mmol), and sodium methoxide solution (0.5 M in MeOH, 46.9 mL, 23.5 mmol) were dissolved in MeOH (42.6 mL) and heated to reflux. After heating overnight, the reaction mixture was diluted with saturated NH4Cl, partially concentrated in vacuo and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 330 g silica gel column, 30 minute gradient from 0 to 17% EtOAc in hexanes) to give Intermediate I-122A (4.97 g, 14.3 mmol, 67%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=2.8 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.52-7.48 (m, 2H), 7.48-7.43 (m, 2H), 7.43-7.38 (m, 1H), 7.37 (d, J=2.8 Hz, 1H), 5.24 (s, 2H); LC-MS: Method H, RT=1.46 min, MS (ESI) m/z: 348/350 (M+H)+.
    • Intermediate I-122
  • Intermediate I-122A (4.87 g, 14 mmol) and pentamethylbenzene (14.5 g, 98 mmol) were dissolved in DCM (279 mL) and cooled to −78° C. Boron trichloride (1 M in heptane, 36.3 mL, 36.3 mmol) was then added and the reaction mixture was allowed to slowly warm to ambient temperature. After stirring overnight, the reaction mixture was diluted with hexanes and 1 N HCl and allowed to stir for 1 hour. The resulting solid was collected by suction filtration, rinsing with water and hexanes to give Intermediate I-122 (3.39 g, 11.5 mmol, 82%) as an off-white solid: 1H NMR (400 MHz, MeOH4) δ 8.59 (d, J=2.6 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H); LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 258/260 (M+H)+.
    • Intermediate I-123 2-amino-3-bromo-5-chlorobenzaldehyde
  • Figure US20190292176A1-20190926-C00314
    • Intermediate I-123A: methyl 2-amino-3-bromo-5-chlorobenzoate
  • Figure US20190292176A1-20190926-C00315
  • Methyl 2-amino-5-chlorobenzoate (18.1 g, 97 mmol) and NBS (17.3 g, 97 mmol) were dissolved in AcOH (195 mL) and heated to 120° C. After 1.5 hours, the reaction mixture was cooled to ambient temperature and diluted with EtOAc. The reaction was then quenched with vigorous stirring with saturated NaHCO3. The layers were separated and the organic layer further washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-123A (25.7 g, 97 mmol, 100%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 6.36 (br. s., 2H), 3.92 (s, 3H); LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 264/266 (M+H)+.
    • Intermediate I-123B: (2-amino-3-bromo-5-chlorophenyl)methanol
  • Figure US20190292176A1-20190926-C00316
  • Intermediate I-123A (25.7 g, 97 mmol) was dissolved in THF (324 mL). Lithium borohydride (4.23 g, 194 mmol) was added and the reaction mixture was heated to 50° C. After 2 hours, the reaction mixture was diluted with water and stirred for 30 minutes. All of the lithium borohydride had not dissolved, so concentrated HCl was added carefully to speed up the quenching process. The reaction mixture was then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-123B (23.9 g, 101 mmol, 100%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 4.72 (br. s., 2H), 4.68 (d, J=5.9 Hz, 2H), 1.63 (t, J=5.8 Hz, 1H); LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 236/238 (M+H)+.
    • Intermediate I-123
  • Intermediate I-123B (23.9 g, 101 mmol) was dissolved in CHCl3 (674 mL). Manganese dioxide (17.6 g, 202 mmol) was added and the reaction mixture was heated to 40° C. After heating for 2 days, more manganese dioxide (17.6 g, 202 mmol) was added and heating was continued. After heating overnight, the reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate I-123 (22 g, 94 mmol, 93%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 6.70 (br. s., 2H); LC-MS: Method H, RT=1.27 min, compound did not ionize.
    • Intermediate I-124 3-methoxy-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00317
  • Intermediate I-125 (183 mg, 0.726 mmol), bispinacolatodiboron (369 mg, 1.45 mmol), potassium acetate (178 mg, 1.82 mmol), and PdCl2(dppf)-CH2Cl2 adduct (47.4 mg, 0.058 mmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (7.26 mL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in DCM then 0 to 20% MeOH in DCM) to give Intermediate I-124 (108 mg, 0.36 mmol, 50%) as a brown solid: LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 218.0 (boronic acid observed, M+H)+.
    • Intermediate I-125 8-bromo-3-methoxy-6-methylquinoline
  • Figure US20190292176A1-20190926-C00318
    • Intermediate I-125A: methyl 2-amino-3-bromo-5-methylbenzoate
  • Figure US20190292176A1-20190926-C00319
  • 2-Amino-3-bromo-5-methylbenzoic acid (3.8 g, 16.5 mmol) was dissolved in MeOH (33.0 mL). Thionyl chloride (3.62 mL, 49.6 mmol) was added carefully dropwise and the reaction mixture was heated to 65° C. After stirring for 8 days, the reaction mixture was concentrated in vacuo. The crude material was redissolved in EtOAc, washed with 1 N NaOH, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-125A (3.38 g, 13.9 mmol, 84%) as an orange oil: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=1.1 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 6.14 (br. s., 2H), 3.88 (s, 3H), 2.22 (s, 3H); LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 244/246 (M+H)+.
    • Intermediate I-125B: (2-amino-3-bromo-5-methylphenyl)methanol
  • Figure US20190292176A1-20190926-C00320
  • Intermediate I-125A (3.38 g, 13.8 mmol) was dissolved in THF (46.2 mL). Lithium borohydride (0.603 g, 27.7 mmol) was added and the reaction mixture was heated to 50° C. After 1 hour, the reaction mixture was diluted with water and stirred for 30 minutes. All of the lithium borohydride had not dissolved, so concentrated HCl was added carefully to speed up the quenching process. The reaction mixture was then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-125B (2.85 g, 13.2 mmol, 95%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=1.1 Hz, 1H), 6.84 (d, J=1.3 Hz, 1H), 4.65 (s, 2H), 4.53 (br. s., 2H), 2.22 (s, 3H); LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 216/218 (M+H)+.
    • Intermediate I-125C: 2-amino-3-bromo-5-methylbenzaldehyde
  • Figure US20190292176A1-20190926-C00321
  • Intermediate I-125B (2.85 g, 13.2 mmol) was dissolved in CHCl3 (88 mL). Manganese dioxide (6.88 g, 79 mmol) was added and the reaction mixture was heated to 40° C. After heating overnight, the reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate I-125C (2.72 g, 12.7 mmol, 96%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.47 (d, J=1.5 Hz, 1H), 7.28-7.26 (m, 1H), 6.49 (br. s., 2H), 2.28 (s, 3H); LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 214/216 (M+H)+.
    • Intermediate I-125D: 3-(benzyloxy)-8-bromo-6-methylquinoline
  • Figure US20190292176A1-20190926-C00322
  • Intermediate I-125C (2.72 g, 12.7 mmol), 2-(benzyloxy)acetaldehyde (1.91 g, 12.7 mmol), and sodium methoxide (0.5 M in MeOH, 28.0 mL, 13.98 mmol) were dissolved in MeOH (50.8 mL) and heated to reflux. After heating overnight, the reaction mixture was diluted with saturated NH4Cl, partially concentrated in vacuo and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 220 g silica gel column, 41 minute gradient from 0 to 40% EtOAc in hexanes) to give Intermediate I-125D (1.86 g, 5.67 mmol, 45%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J=2.9 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.45-7.40 (m, 3H), 7.39-7.33 (m, 2H), 5.20 (s, 2H), 2.49 (s, 3H); LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 328/330 (M+H)+.
    • Intermediate I-125E: 8-bromo-6-methylquinolin-3-ol
  • Figure US20190292176A1-20190926-C00323
  • Intermediate I-125D (1.86 g, 5.67 mmol) and pentamethylbenzene (5.88 g, 39.7 mmol) were dissolved in DCM (113 mL) and cooled to −78° C. Boron trichloride (1 M in heptane, 14.7 mL, 14.7 mmol) was added and the reaction mixture was allowed to warm slowly to ambient temperature. After stirring overnight, the reaction mixture was diluted with hexanes and 1 N HCl and allowed to stir for 1 hour. The aqueous layer still contained product by LCMS. The aqueous layer was neutralized with NaOH until approximately pH 7 and copious amounts of precipitates were formed. The precipitate was collected by suction filtration to give I-125E (829 mg, 3.48 mmol, 62%) as an off-white solid: 1H NMR (400 MHz, MeOH4) δ 8.50 (d, J=2.6 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.43 (d, J=1.8 Hz, 1H), 2.47 (s, 3H); LC-MS: Method H, RT=0.82 min, MS (ESI) m/z: 238/240 (M+H)+.
    • Intermediate I-125
  • Intermediate I-125E (200 mg, 0.728 mmol), K2CO3 (302 mg, 2.18 mmol), and methyl iodide (91 μl, 1.46 mmol) were dissolved in acetone (7.29 mL) and heated to 50° C. in a sealed tube. After heating overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-125 (207 mg, 0.82 mmol, 100%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=2.9 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.46 (s, 1H), 7.29 (d, J=2.9 Hz, 1H), 3.95 (s, 3H), 2.50 (s, 3H); LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 252/254 (M+H)+.
    • Intermediate I-126 6-chloro-3-ethoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00324
    • Intermediate I-126A: 8-bromo-6-chloro-3-ethoxyquinoline
  • Figure US20190292176A1-20190926-C00325
  • Intermediate I-122 (300 mg, 1.02 mmol), K2CO3 (422 mg, 3.05 mmol), and iodoethane (163 μL, 2.03 mmol) were dissolved in Acetone (10 mL) and heated to 50° C. in a sealed tube. After heating overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-126A (319 mg, 1.11 mmol, 100%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=2.6 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.28-7.24 (m, 1H), 4.17 (q, J=6.9 Hz, 2H), 1.52 (t, J=7.0 Hz, 3H); LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 286/288 (M+H)+.
    • Intermediate I-126
  • Intermediate I-126A (319 mg, 1.11 mmol), bispinacolatodiboron (565 mg, 2.23 mmol), potassium acetate (273 mg, 2.78 mmol), and PdCl2(dppf)-CH2Cl2 adduct (72.7 mg, 0.089 mmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (5.67 mL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in DCM, followed by 0 to 20% MeOH in DCM) to give Intermediate I-126 (114 mg, 0.343 mmol, 31%) as a brown solid: LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 251.9 (boronic acid mass observed, M+H)+.
    • Intermediate I-127 6-chloro-3-(difluoromethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00326
    • Intermediate I-127A: 8-bromo-6-chloro-3-(difluoromethoxy)quinoline
  • Figure US20190292176A1-20190926-C00327
  • Intermediate I-122 (0.5 g, 1.7 mmol) and K2CO3 (1.17 g, 8.48 mmol) were suspended in DMF (17 mL) and heated to 100° C. Sodium 2-chloro-2,2-difluoroacetate (1.03 g, 6.78 mmol) was then added. After heating for 1 hour, the reaction mixture was cooled to ambient temperature, diluted with water, and extracted thrice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 50% EtOAc in hexanes) to give Intermediate I-127A (342 mg, 1.11 mmol, 66%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=2.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 6.88-6.49 (m, 1H); LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 308/310 (M+H)+.
    • Intermediate I-127
  • Intermediate I-127A (340 mg, 1.1 mmol), bispinacolatodiboron (560 mg, 2.2 mmol), potassium acetate (270 mg, 2.76 mmol), and PdCl2(dppf)-CH2Cl2 adduct (72.0 mg, 0.088 mmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (5.51 mL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in DCM, followed by 0 to 20% MeOH in DCM) to give Intermediate I-127 (175 mg, 0.492 mmol, 45%) as a brown solid: LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 274.1 (boronic acid mass observed, M+H)+.
    • Intermediate I-128 6-(difluoromethyl)-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00328
    • Intermediate I-128A: 8-bromo-3-methoxyquinoline-6-carbaldehyde
  • Figure US20190292176A1-20190926-C00329
  • Intermediate I-125 (152 mg, 0.602 mmol) and selenium dioxide (401 mg, 3.61 mmol) were suspended in 1,4-dioxane (3.01 mL) and heated to 180° C. in the microwave for 8 hours. The reaction mixture was filtered and concentrated in vacuo. The solids were then suspended in DCM and the insoluble material removed by suction filtration to give Intermediate I-128A (170 mg, 0.639 mmol, 100%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.93 (d, J=2.9 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.25 (d, J=1.5 Hz, 1H), 7.56 (d, J=2.9 Hz, 1H), 4.04 (s, 3H); LC-MS: Method H, RT=0.89 min, MS (ESI) m/z: 266/268 (M+H)+.
    • Intermediate I-128B: 8-bromo-6-(difluoromethyl)-3-methoxyquinoline
  • Figure US20190292176A1-20190926-C00330
  • Intermediate I-128A (50 mg, 0.188 mmol) and deoxofluor (104 μl, 0.564 mmol) were dissolved in DCM (940 μL). After stirring overnight, the reaction mixture was diluted carefully with water then extracted thrice with DCM. The combined organic layers were washed with saturated NaHCO3 then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-128B (37 mg, 0.129 mmol, 68%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J=2.9 Hz, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.89 (d, J=1.3 Hz, 1H), 7.46 (d, J=2.9 Hz, 1H), 6.96-6.64 (t, J=56 Hz, 1H), 4.02 (s, 1H); LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 288/290 (M+H)+.
    • Intermediate I-128
  • Intermediate I-128B (37 mg, 0.128 mmol), bispinacolatodiboron (65.2 mg, 0.257 mmol), potassium acetate (31.5 mg, 0.321 mmol), and PdCl2(dppf)-CH2Cl2 adduct (8.39 mg, 10.3 μmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (642 μL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-128. The crude material was used directly in the subsequent step: LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 254.1 (boronic acid mass observed, M+H)+.
    • Intermediate I-129 6-(fluoromethyl)-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00331
    • Intermediate I-129A: (8-bromo-3-methoxyquinolin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00332
  • Intermediate I-128A (50 mg, 0.188 mmol) was dissolved in MeOH (1.88 mL) and cooled to 0° C. Sodium borohydride (14.2 mg, 0.376 mmol) was then added. After 1 hour, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-129A (38.6 mg, 0.144 mmol, 77%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J=2.9 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=2.9 Hz, 1H), 4.89 (d, J=5.1 Hz, 2H), 4.00 (s, 3H), 1.89 (t, J=5.6 Hz, 1H); LC-MS: Method H, RT=0.73 min, MS (ESI) m/z: 268/270 (M+H)+.
    • Intermediate I-129B: 8-bromo-6-(fluoromethyl)-3-methoxyquinoline
  • Figure US20190292176A1-20190926-C00333
  • Intermediate I-129A (38 mg, 0.142 mmol) and Deoxofluor (78 μL, 0.425 mmol) were dissolved in DCM (709 μL). After stirring overnight, the reaction mixture was diluted carefully with water then extracted thrice with DCM. The combined organic layers were washed with saturated NaHCO3 then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-129B (29 mg, 0.109 mmol, 77%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=2.9 Hz, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.41 (d, J=2.6 Hz, 1H), 5.62-5.48 (t, J=48 Hz, 2H), 4.00 (s, 3H); LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 270/272 (M+H)+.
    • Intermediate I-129
  • Intermediate I-129B (29 mg, 0.107 mmol), bispinacolatodiboron (54.5 mg, 0.215 mmol), potassium acetate (26.3 mg, 0.268 mmol), and PdCl2(dppf)-CH2Cl2 adduct (7.01 mg, 8.59 μmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (537 μL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate I-129, which was used directly for the subsequent step: LC-MS: Method H, RT=0.68 min, MS (ESI) m/z: 236.1 (boronic acid mass observed, M+H)+
    • Intermediate I-130 (2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00334
  • Intermediate I-72A (300 mg, 0.937 mmol) was dissolved in THF (18.7 mL). Phosgene solution (15% in toluene, 7.14 mL, 9.37 mmol) was then added. After stirring overnight, the reaction mixture was concentrated in vacuo and stored on HIVAC for 3 hours. The reaction mixture was dissolved in THF (18.7 mL). 2-Methylpyrimidin-5-amine (123 mg, 1.12 mmol) and pyridine (758 μL, 9.37 mmol) were added. After 1 hour, the reaction mixture was concentrated in vacuo and purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate I-130 (327 mg, 0.796 mmol, 85%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.72 (br. s., 2H), 7.66 (d, J=11.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 6.55 (br. s., 1H), 5.14 (dd, J=6.5, 3.0 Hz, 1H), 4.60-4.49 (m, 1H), 2.71 (s, 3H), 1.44 (d, J=6.6 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H); LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 411.0 (M+H)+.
    • Intermediate I-131 (R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C00335
    • Intermediate I-131A: 6-fluoro-5-methoxythiazolo[5,4-b]pyridin-2-amine
  • Figure US20190292176A1-20190926-C00336
  • Potassium thiocyanate (0.738 g, 7.59 mmol) was dissolved in acetic acid (5 mL) and cooled to 0° C. 5-fluoro-6-methoxypyridin-3-amine (1.079 g, 7.59 mmol) was dissolved in acetic acid (1.667 mL) and added dropwise. Bromine (0.782 mL, 15.18 mmol) was dissolved in acetic acid (1.667 mL) and added dropwise to the reaction. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was diluted with water and neutralized with 1 N NaOH. The aqueous solution was extracted with EtOAc×3. The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate I-131A (1.496 g, 7.51 mmol, 99% yield). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=10.6 Hz, 1H), 5.14 (br. s., 2H), 4.03 (s, 3H). LC-MS: method H, RT=0.65 min, MS (ESI) m/z: 200.0 (M+H)+.
    • Intermediate I-131B: 2-amino-6-fluorothiazolo[5,4-b]pyridin-5-ol, 2hydrobromide
  • Figure US20190292176A1-20190926-C00337
  • Intermediate I-131A (0.500 g, 2.510 mmol) was dissolved in a solution of HBr in acetic acid (1.704 mL, 15.06 mmol, 33% by wt.) and the reaction mixture was stirred at 130° C. for 3h. The reaction mixture was concentrated under reduced pressure to yield Intermediate I-131B (0.88 g, 2.54 mmol, 101% yield) as a tan solid. 1H NMR (400 MHz, MeOH4) δ 7.66 (d, J=9.7 Hz, 1H) LC-MS: method H, RT=0.45 min, MS (ESI) m/z: 186.1 (M+H)+.
    • Intermediate I-131C (R)-1-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C00338
  • To a solution of Intermediate I-131B (1.00 g, 2.88 mmol) in tetrahydrofuran (23.05 ml) was added (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (0.478 g, 3.46 mmol) followed by potassium carbonate (1.195 g, 8.65 mmol). The reaction mixture was stirred vigorously at 60° C. for 3h then at room temperature for 48 hours. Sulfuric acid (0.768 ml, 14.41 mmol) followed by water (0.156 ml, 8.65 mmol) were added slowly to the reaction. The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with 1 N NaOH and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate I-131C (0.284 g, 1.167 mmol, 40.5% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=10.6 Hz, 1H), 5.09 (br. s., 2H), 4.40 (d, J=7.9 Hz, 1H), 4.23 (d, J=6.6 Hz, 2H), 2.58 (d, J=2.9 Hz, 1H), 1.30 (d, J=5.9 Hz, 3H). LC-MS: method H, RT=0.59 min, MS (ESI) m/z: 244.1 (M+H)+.
    • Intermediate I-131
  • Copper(II) chloride (0.658 g, 4.89 mmol) and t-butyl nitrite (0.582 ml, 4.89 mmol) were dissolved in MeCN (11.51 ml) and allowed to stir 10 minutes. Intermediate I-131C (0.700 g, 2.88 mmol) was dissolved in MeCN (17.27 ml) and the copper solution was added. The reaction mixture was stirred for 2.5 hours at 60° C. The reaction mixture was diluted with EtOAc, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using a 12 g column with 0-100% gradient of EtOAc in hexanes to Intermediate I-131 (0.698 g, 2.66 mmol, 92% yield). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=9.9 Hz, 1H), 4.45-4.34 (m, 1H), 4.26-4.19 (m, 2H), 3.86-3.71 (m, 1H), 2.25 (d, J=3.5 Hz, 1H), 1.39-1.24 (m, 3H). LC-MS: method H, RT=0.88 min, MS (ESI) m/z: 263.0 (M+H)+.
    • Intermediate I-132 (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00339
  • Intermediate I-132A: (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C00340
  • Intermediate I-9 (0.343 g, 1.142 mmol) and Intermediate I-131 (0.300 g, 1.142 mmol) were dissolved in DMF (11.42 ml). PdCl2(dppf)-CH2Cl2 adduct (0.056 g, 0.069 mmol) was added, and the reaction degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.381 ml, 1.142 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was purified on ISCO using a 24 g column eluting with 0-100% EtOAc in hexanes to yield Intermediate I-132A (0.223 g, 0.557 mmol, 48.8% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=12.5 Hz, 1H), 8.01 (d, J=10.1 Hz, 1H), 7.78 (br. s., 1H), 7.33-7.28 (m, 1H), 4.55 (d, J=11.2 Hz, 1H), 4.38 (br. s., 2H), 4.13 (s, 4H), 2.65 (br. s., 3H), 1.35 (d, J=5.9 Hz, 3H). LC-MS: method H, RT=1.25 min, MS (ESI) m/z: 401.1 (M+H)+.
    • Intermediate I-132
  • To a solution of (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol (0.098 g, 0.245 mmol) in THF (3 mL) at room temperature was added 15% phosgene in toluene (0.863 mL, 1.224 mmol) and the mixture was stirred at room temperature for 1 h. Solvent was completely removed and the sample was under vacuum overnight to give Intermediate I-132 (0.113 g, 0.244 mmol, 100% yield) as a yellow solid. This intermediate was used without further purification in the next step. LC-MS: method H, RT=1.37 min, MS (ESI) m/z: 463.0 (M+H)+.
    • Intermediate I-133 (2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00341
    • Intermediate I-133A: (2R,3S)-3-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-ol
  • Figure US20190292176A1-20190926-C00342
  • To a solution of Intermediate I-131B (150 mg, 0.432 mmol) in DMF (1729 μl) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (79 mg, 0.519 mmol) followed by potassium carbonate (179 mg, 1.297 mmol). The reaction mixture was stirred vigorously at 60° C. for 3h and then allowed to stir at room temperature for 48 h. The reaction mixture was then diluted with EtOAc and filtered. The resulting solution was concentrated under reduced pressure to yield a dark oil. This residue was dissolved in THF (1729 μl) and sulfuric acid (69.1 μl, 1.297 mmol) followed by water (23.36 μl, 1.297 mmol). This reaction mixture was allowed to stir at room temperature for 1 hour before being diluted with 1 N NaOH and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate I-133A (0.11 g, 0.428 mmol, 99% yield) as a yellow solid. 1H NMR (400 MHz, MeOH4) δ 7.42 (d, J=11.0 Hz, 1H), 5.12-5.02 (m, 1H), 3.96-3.88 (m, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.24 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.63 min, MS (ESI) m/z: 258.0 (M+H)+.
    • Intermediate I-133
  • Copper(II) chloride (0.588 g, 4.37 mmol) and t-butyl nitrite (0.589 ml, 4.96 mmol) were dissolved in MeCN (11.66 ml) and allowed to stir 10 minutes. Intermediate I-133A (0.750 g, 2.92 mmol) was dissolved in MeCN (17.49 ml) and the copper solution was added. The reaction mixture was stirred for 1.5h at 60° C. The reaction mixture was diluted with EtOAc, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using a 40 g column with 0-100% gradient of EtOAc in hexanes to yield Intermediate I-133 (0.722 g, 2.61 mmol, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=9.9 Hz, 1H), 5.31 (dd, J=6.4, 3.1 Hz, 1H), 4.12 (ddd, J=6.4, 4.7, 3.2 Hz, 1H), 2.14 (d, J=4.6 Hz, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=0.95, MS (ESI) m/z: 277.1 (M+H)+.
    • Intermediate I-134 (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00343
    • Intermediate I-134A: (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00344
  • Intermediate I-9 (0.067 g, 0.224 mmol) and Intermediate I-133 (0.062 g, 0.224 mmol) were dissolved in DMF (2.241 ml). PdCl2(dppf)-CH2Cl2 adduct (10.98 mg, 0.013 mmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.075 ml, 0.224 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. Purified on ISCO using a 40 g column eluting with 0-100% EtOAc in hexanes to yield Intermediate I-134A (0.090 g, 0.219 mmol, 95%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.99 (d, J=10.1 Hz, 1H), 7.77 (s, 1H), 5.37 (dd, J=6.4, 2.9 Hz, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 2.46 (d, J=4.8 Hz, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.39 (d, J=6.4 Hz, 1H), 1.30 (d, J=6.6 Hz, 5H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 415.1 (M+H)+.
    • Intermediate I-134
  • To a solution of Intermediate I-134A (0.045 g, 0.109 mmol) in THF (3 mL) at room temperature was added 15% phosgene solution in toluene (0.383 mL, 0.543 mmol) and the mixture was stirred room temperature overnight. Solvent was completely removed to yield Intermediate I-134 (0.052 g, 0.098 mmol, 90% yield) as a yellow solid. Used without further purification in the next step. LC-MS: method H, RT=1.46 min, MS (ESI) m/z: 477.0 (M+H)+.
    • Intermediate I-135 (2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00345
    • Intermediate I-135A: (2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00346
  • To a solution of Intermediate I-133 (0.030 g, 0.108 mmol) in THF (3 mL) at room temperature was added 15% phosgene solution in toluene (0.382 mL, 0.542 mmol), and the mixture was stirred at room temperature overnight. Solvent was completely removed to give Intermediate I-135A (0.035 g, 0.103 mmol, 95% yield) as a yellow solid. Used without further purification in the next step. LC-MS: method H, RT=1.46 min, MS (ESI) m/z: 340.0 (M+H)+.
    • Intermediate I-135
  • 2-Methylpyrimidin-5-amine (0.023 g, 0.206 mmol) and pyridine (0.083 mL, 1.032 mmol) were dissolved in DCM (2 mL) To this solution was added Intermediate I-135A (0.035 g, 0.103 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1h. The reaction mixture was concentrated under reduced pressure to yield Intermediate I-135 (0.040 g, 0.097 mmol, 94%). LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 412.0 (M+H)+.
    • Intermediate I-136 6-fluoro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00347
    • Intermediate I-136A: (2-amino-3-bromo-5-fluorophenyl)methanol
  • Figure US20190292176A1-20190926-C00348
  • Methyl 2-amino-3-bromo-5-fluorobenzoate (0.910 g, 3.67 mmol) was dissolved in THF (12.23 ml). LiBH4 (0.160 g, 7.34 mmol) was added and the reaction mixture was heated to 50° C. for 2 hours. The reaction mixture was diluted with water and stirred for 30 minutes. The reaction mixture was then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate I-136A (0.799 g, 3.63 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J=7.7, 2.9 Hz, 1H), 6.86 (dd, J=8.4, 2.9 Hz, 1H), 4.68 (s, 2H), 4.52 (d, J=12.8 Hz, 2H), 1.89-1.69 (m, 1H). LC-MS: method H, RT=0.94 min, MS (ESI) m/z: 219.9 (M+H)+.
    • Intermediate I-136B: 2-amino-3-bromo-5-fluorobenzaldehyde
  • Figure US20190292176A1-20190926-C00349
  • Intermediate I-136A (0.799 g, 3.63 mmol) was dissolved in CHCl3 (24.21 ml). Manganese dioxide (1.263 g, 14.52 mmol) was added and the reaction mixture was heated to 40° C. overnight. The reaction mixture was filtered through celite and concentrated in vacuo to yield Intermediate I-136B (0.750 g, 3.44 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.48 (dd, J=7.5, 2.9 Hz, 1H), 7.25 (dd, J=7.9, 2.9 Hz, 1H), 6.55 (br. s., 2H).
    • Intermediate I-136C: 3-(benzyloxy)-8-bromo-6-fluoroquinoline
  • Figure US20190292176A1-20190926-C00350
  • Intermediate I-136B (0.800 g, 3.67 mmol), 2-(benzyloxy)acetaldehyde (0.551 g, 3.67 mmol), and sodium methoxide (8.07 ml, 4.04 mmol) were dissolved in MeOH (7.34 ml) and heated to reflux overnight. The reaction mixture was diluted with saturated NH4Cl, partially concentrated in vacuo and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using 80 g column eluting with 0-60% gradient of EtOAc in hexanes to yield Intermediate I-136C (0.363 g, 1.093 mmol, 30%). 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J=2.5 Hz, 1H), 7.72 (dd, J=8.1, 2.6 Hz, 1H), 7.52-7.49 (m, 2H), 7.45 (t, J=7.3 Hz, 2H), 7.41 (d, J=2.8 Hz, 2H), 7.34 (dd, J=8.7, 2.6 Hz, 1H), 5.24 (s, 2H). LC-MS: method H, RT=1.38 min, MS (ESI) m/z: 331.9 (M+H)+.
    • Intermediate I-136D: 8-bromo-6-fluoroquinolin-3-ol
  • Figure US20190292176A1-20190926-C00351
  • Intermediate I-136C (0.363 g, 1.093 mmol) and pentamethylbenzene (1.134 g, 7.65 mmol) were dissolved in DCM (21.86 ml) and cooled to −78° C. Boron trichloride (1 M in heptane) (2.84 ml, 2.84 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with hexanes and 1 N HCl and allowed to stir for 1 hour. The resulting solid was collected by suction filtration, washing with water and hexanes to yield Intermediate I-136D (0.176 g, 0.727 mmol, 66.5% yield): 1H NMR (400 MHz, MeOH4) δ 8.53 (d, J=2.9 Hz, 1H), 7.68 (dd, J=8.4, 2.6 Hz, 1H), 7.49-7.37 (m, 2H). LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 241.9 (M+H)+.
    • Intermediate I-136E: 8-bromo-6-fluoro-3-methoxyquinoline
  • Figure US20190292176A1-20190926-C00352
  • Intermediate I-136D (0.095 g, 0.341 mmol), K2CO3 (0.141 g, 1.023 mmol), and methyl iodide (0.043 ml, 0.682 mmol) were dissolved in acetone (3.41 ml) and heated to 50° C. in a sealed tube overnight. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate I-136E (0.060 g, 0.234 mmol, 68.7% yield). 1H NMR (400 MHz, CDCl3) δ 8.76 (dd, J=2.8, 0.6 Hz, 1H), 7.72 (dd, J=8.0, 2.8 Hz, 1H), 7.37 (dd, J=8.8, 2.6 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 4.00 (s, 3H). LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 255.8 (M+H)+.
    • Intermediate I-136
  • Intermediate I-136E (0.087 g, 0.340 mmol), BISPIN (0.173 g, 0.679 mmol), potassium acetate (0.083 g, 0.849 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.022 g, 0.027 mmol) were stored on HIVAC for 15 minutes then were dissolved in 1,4-dioxane (3 ml) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate I-136 (0.103 g, 0.170 mmol, 50%). This material was dissolved in DMF to make a stock solution of 10 mg per mL and used without further purification. LC-MS: method H, RT=1.10 min, MS (ESI) m/z: 221.9 (M+H)+. See the mass of the boronic acid in the LC/MS.
    • Intermediate I-137 (2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00353
    • Intermediate I-137A: (2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00354
  • To a solution of Intermediate I-133 (0.100 g, 0.361 mmol) in THF (5 mL) at room temperature was added 15% phosgene solution in toluene (1.274 mL, 1.807 mmol) and the mixture was stirred at room temperature overnight. Solvent was completely removed to give Intermediate I-137A (0.125 g, 0.369 mmol, 102% yield) as a yellow solid. LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 338.9 (M+H)+.
    • Intermediate I-137
  • 2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-amine (0.199 g, 0.737 mmol) and pyridine (0.298 mL, 3.69 mmol) were dissolved in DCM (2 mL) To this solution was added Intermediate I-137A (0.125 g, 0.369 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure to yield Intermediate I-137 (0.130 g, 0.227 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ 8.48 (br. s., 2H), 7.76 (d, J=9.7 Hz, 1H), 5.45 (dd, J=6.6, 2.9 Hz, 1H), 5.12 (dd, J=6.6, 2.9 Hz, 1H), 4.33 (t, J=5.5 Hz, 2H), 3.90 (t, J=5.4 Hz, 2H), 1.34 (d, J=6.6 Hz, 6H), 0.81 (s, 9H), 0.00 (s, 6H). LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 572.1 (M+H)+.
    • Intermediate I-138 (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00355
    • Intermediate I-138A: 2-amino-7-methylthiazolo[5,4-b]pyridin-5-ol, 2hydrobromide
  • Figure US20190292176A1-20190926-C00356
  • Intermediate I-16B (0.500 g, 2.56 mmol) was dissolved in HBr in acetic acid (1.738 mL, 15.37 mmol, 33% by wt.), and the reaction mixture was stirred at 130° C. for 3h. The reaction mixture was concentrated under reduced pressure to yield Intermediate I-138A (0.636, 1.854 mmol, 72.4% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J=0.9 Hz, 1H), 2.48 (d, J=0.7 Hz, 3H). LC-MS: method H, RT=0.46 min, MS (ESI) m/z: 182.1 (M+H)+.
    • Intermediate I-138B: (R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-7-methylthiazolo[5,4-b]pyridin-2-amine
  • Figure US20190292176A1-20190926-C00357
  • Intermediate I-138A (0.500 g, 1.458 mmol) was dissolved in DMF (14.58 ml) and Cs2CO3 (2.85 g, 8.75 mmol) was added followed by (R)-tert-Butyl((1-iodopropan-2-yl)oxy)diphenylsilane (0.619 g, 1.458 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then heated to 40° C. and allow to stir overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on ISCO using 40 g column eluting with 0-100% EtOAc in hexanes to yield Intermediate I-138B (0.324 g, 0.678 mmol, 46.5% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.69 (ddd, J=8.0, 4.1, 1.5 Hz, 4H), 7.42-7.28 (m, 6H), 6.32 (d, J=0.7 Hz, 1H), 4.97 (s, 2H), 4.26-4.18 (m, 2H), 4.16-4.09 (m, 5H), 2.45 (d, J=0.7 Hz, 3H), 1.15 (d, J=6.2 Hz, 3H), 1.06 (s, 9H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 478.3 (M+H)+.
    • Intermediate I-138C (R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-2-chloro-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00358
  • Copper(II) chloride (0.155 g, 1.153 mmol) and t-butyl nitrite (0.137 ml, 1.153 mmol) were dissolved in MeCN (2.71 ml) and allowed to stir 10 minutes. Intermediate I-138B (0.324 g, 0.678 mmol) was dissolved in MeCN (4.07 ml) and the copper solution was added. The reaction mixture was stirred for 2.5h at 60° C. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using a 24 g column with 0-100% gradient of EtOAc in hexanes to yield Intermediate I-138C (0.222 g, 0.447 mmol, 65.8% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.71-7.64 (m, 4H), 7.44-7.28 (m, 6H), 6.42 (s, 1H), 4.34-4.09 (m, 3H), 2.56 (d, J=0.7 Hz, 3H), 1.18 (d, J=5.9 Hz, 3H), 1.06 (s, 9H). LC-MS: method H, RT=1.71 min, MS (ESI) m/z: 497.2 (M+H)+.
    • Intermediate I-138D (R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00359
  • Intermediate I-9 (0.052 g, 0.173 mmol) and Intermediate I-138C (0.086 g, 0.173 mmol) were dissolved in DMF (1.730 ml). PdCl2(dppf)-CH2Cl2 adduct (8.48 mg, 10.38 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and purified on ISCO using 0-100% EtOAc in hexanes on a 24 g column to yield Intermediate I-138D (0.055 g, 0.087 mmol, 50.1% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 7.71-7.69 (m, 4H), 7.41-7.30 (m, 7H), 6.47 (d, J=0.9 Hz, 1H), 4.40-4.24 (m, 4H), 4.12 (s, 3H), 2.74 (d, J=0.9 Hz, 3H), 2.66 (s, 3H), 1.19 (d, J=5.9 Hz, 3H), 1.08 (s, 9H). LC-MS: method H, RT=1.15 min, Compound does not ionize.
    • Intermediate I-138E (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-ol
  • Figure US20190292176A1-20190926-C00360
  • Intermediate I-138D (0.055 g, 0.087 mmol) was dissolved in THF (0.866 ml) and TBAF (0.104 ml, 0.104 mmol) was added. The reaction mixture was allowed to stir at room temperature for 1h and concentrated under reduced pressure. Purified on ISCO using 0-100% EtOAc in hexanes gradient on a 12 g column to yield Intermediate I-138E (0.027 g, 0.068 mmol, 79% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.75 (s, 1H), 6.75 (d, J=0.9 Hz, 1H), 4.56-4.19 (m, 4H), 4.12 (s, 3H), 3.49 (d, J=5.5 Hz, 1H), 2.95 (s, 1H), 2.80 (d, J=0.9 Hz, 3H), 2.66 (s, 3H), 1.31 (d, J=6.2 Hz, 3H). LC-MS: method H, RT=1.26 min, MS (ESI) m/z: 397.2 (M+H)+.
    • Intermediate I-138
  • To a solution of Intermediate I-138E (0.027 g, 0.068 mmol) in THF (3 mL) at room temperature was added 15% phosgene solution in toluene (0.240 mL, 0.341 mmol) and the mixture was stirred at room temperature for 1 h. Solvent was completely removed and the sample was under vacuum overnight to give Intermediate I-138 (0.030 g, 0.065 mmol, 96% yield) as a yellow solid. Used without any purification. LC-MS: method H, RT=1.43 min, MS (ESI) m/z: 459.1 (M+H)+.
    • Intermediate I-139 (R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00361
    • Intermediate I-139A (2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00362
  • To a solution of Intermediate I-131 (0.030 g, 0.114 mmol) in THF (3 mL) at room temperature was added 15% phosgene solution in toluene (0.403 mL, 0.571 mmol), and the mixture was stirred at room temperature overnight. Solvent was completely removed to give Intermediate I-139A (0.035 g, 0.108 mmol, 95% yield) as a yellow solid. Used without further purification in the next step. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 325.0 (M+H)+.
    • Intermediate I-139
  • 2-Methylpyrimidin-5-amine (0.023 g, 0.215 mmol) and pyridine (0.083 mL, 1.032 mmol) were dissolved in DCM (2 mL) To this solution was added Intermediate I-139A (0.035 g, 0.108 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1h. The reaction mixture was concentrated under reduced pressure to yield Intermediate I-139 (0.038 g, 0.096 mmol, 89%). LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 398.0 (M+H)+.
    • Intermediate I-140 (3-Methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00363
    • Intermediate I-140A: 8-Bromo-3-methoxyquinoline-6-carbaldehyde
  • Figure US20190292176A1-20190926-C00364
  • A mixture of Intermediate I-125 (0.050 g, 0.198 mmol) and selenium dioxide (0.132 g, 1.190 mmol) in dioxane (3.0 mL) was heated in a microwave at 180° C. for 9 hours. The insoluble material was removed by filtration and washed with EtOAc. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% EtOAc in hexane using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate I-140A (0.051 g, 0.163 mmol, 82% yield) as a white solid. Contains 15% starting material. Will be used without further purification. LC-MS: method H, RT=0.83 min, MS (ESI) m/z: 267.9 (M+H)+.
    • Intermediate I-140B: (8-Bromo-3-methoxyquinolin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00365
  • Intermediate I-140A (0.0502 g, 0.189 mmol) was dissolved in THF (1.887 ml) and sodium borohydride (7.14 mg, 0.189 mmol) was added in one portion. The reaction mixture was allowed to stir at room temperature for 3h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with water, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate I-140B (0.048 g, 0.179 mmol, 95% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J=2.9 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=2.9 Hz, 1H), 4.89 (d, J=5.1 Hz, 2H), 4.00 (s, 3H), 1.91 (s, 1H). LC-MS: method H, RT=0.69 min, MS (ESI) m/z: 269.9 (M+H)+.
    • Intermediate I-140
  • Intermediate I-140B (0.0524 g, 0.195 mmol), BISPIN (0.099 g, 0.391 mmol), potassium acetate (0.048 g, 0.489 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.013 g, 0.016 mmol) were stored on HIVAC for 15 minutes then were dissolved in 1,4-dioxane (3 ml) (sure sealed bottle) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes (fixed hold time off). The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in dioxanes to provide a 10 mg/mL stock solution of the above boronic ester. Used without further purification. See mass of boronic acid in the LC/MS LC-MS: method H, RT=0.50 min, MS (ESI) m/z: 234.0 (M+H)+.
    • Intermediate I-141 Methyl 5-(((((2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C00366
    • Intermediate I-141A: (2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00367
  • To a solution of Intermediate I-133 (0.058 g, 0.210 mmol) in THF (5 mL) at room temperature was added 15% phosgene in toluene (0.739 mL, 1.048 mmol) and the mixture was stirred at room temperature overnight. The solvent was completely removed to give Intermediate I-141A (0.071 g, 0.209 mmol, 100% yield) as a yellow solid. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 339.1 (M+H)+.
    • Intermediate I-141
  • Methyl 5-aminopyrimidine-2-carboxylate (0.065 g, 0.425 mmol) and pyridine (0.172 mL, 2.123 mmol) were dissolved in DCM (2 mL). To this solution was added Intermediate I-141A (0.072 g, 0.212 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1h. The reaction mixture was concentrated under reduced pressure. Purified on ISCO using 0-100% EtOAc in hexanes to yield Intermediate I-141 (0.066 g, 0.145 mmol, 68.2% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 2H), 7.87 (d, J=9.7 Hz, 1H), 6.94 (s, 1H), 5.56 (dd, J=6.5, 2.8 Hz, 1H), 5.38-5.17 (m, 1H), 4.09 (s, 3H), 1.47 (d, J=6.4 Hz, 6H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 456.0 (M+H)+.
    • Intermediate I-142 (R)-methyl 5-((((1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy) carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C00368
    • Intermediate I-142A: (R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00369
  • To a solution of Intermediate I-131 (0.058 g, 0.210 mmol) in THF (5 mL) at room temperature was added 15% phosgene in toluene (0.739 mL, 1.048 mmol) and the mixture was stirred at room temperature overnight. The solvent was completely removed to give Intermediate I-142A (0.072 g, 0.221 mmol, 100% yield) as a yellow solid. LC-MS: method H, RT=1.17 min, MS (ESI) m/z: 325.1 (M+H)+.
    • Intermediate I-142
  • Methyl 5-aminopyrimidine-2-carboxylate (0.068 g, 0.443 mmol) and pyridine (0.179 mL, 2.214 mmol) were dissolved in DCM (2 mL). To this solution was added Intermediate I-142A (0.072 g, 0.221 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure. Purified on ISCO using 0-100% EtOAc in hexanes to yield I-142 (0.87 g, 0.197 mmol, 89% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 2H), 7.89 (d, J=9.9 Hz, 1H), 6.98 (s, 1H), 5.42 (d, J=3.3 Hz, 1H), 4.72 (dd, J=11.9, 3.1 Hz, 1H), 4.48 (dd, J=11.9, 6.6 Hz, 1H), 4.09 (s, 3H), 1.51 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.88 min, MS (ESI) m/z: 442.0 (M+H)+.
    • Intermediate I-143 (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C00370
    • Intermediate I-143A: (2R,3S)-3-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-ol
  • Figure US20190292176A1-20190926-C00371
  • To a solution of Intermediate I-44 (0.200 g, 0.708 mmol) in THF (2.83 ml) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (0.140 g, 0.920 mmol) followed by potassium carbonate (0.147 g, 1.062 mmol). The reaction vial was sealed and heated to 65° C. overnight. The crude mixture was cooled to 0° C. and concentrated sulfuric acid (0.113 ml, 2.124 mmol) was added followed by water (0.064 ml, 3.54 mmol). The reaction mixture was allowed to thaw to room temperature, and stirred for 20 min. The reaction mixture was quenched with 20 mL 1.5 M K2HPO4, extracted with 100 mL EtOAc, washed with brine, dried over MgSO4, filtered and concentrated to afford a beige solid that was dry loaded onto celite and purified by ISCO (40 g, 0-50% DCM/EtOAc) to afford Intermediate I-143A (0.145 g, 0.409 mmol, 57.8% yield) as an off white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=7.0 Hz, 1H), 4.38 (dd, J=6.3, 3.4 Hz, 1H), 4.16-4.03 (m, 1H), 2.01 (d, J=4.8 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.82 min, MS (ESI) m/z: 353.9 (M+H)+.
    • Intermediate I-143B: (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C00372
  • Intermediate I-121 (149 mg, 0.467 mmol), Intermediate I-143A (145 mg, 0.467 mmol) and PdCl2(dppf) (20.52 mg, 0.028 mmol) were dissolved in dioxane (8.523 mL) and Na2CO3 (2.104 mL, 4.21 mmol, 2 M) and heated to 100° C. in an oil bath for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using 0-100% EtOAc in DCM on a 24 g column to yield Intermediate I-143B (0.022 g, 0.047 mmol, 10.07% yield): LC-MS: method H, RT=1.40 min, MS (ESI) m/z: 466.8 (M+H)+.
    • Intermediate I-143
  • To a solution of Intermediate I-143B (0.022 g, 0.047 mmol) in THF (5 mL) at room temperature was added 15% phosgene in toluene (0.166 mL, 0.235 mmol) and the mixture was stirred at room temperature overnight. Solvent was completely removed to give Intermediate I-143 (0.025 g, 0.047 mmol, 100% yield) as a yellow solid. LC-MS: method H, RT=1.41 min, MS (ESI) m/z: 530.8 (M+H)+.
    • Intermediate I-144 2-ethoxy-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00373
    • Intermediate I-144A: 5-bromo-2-ethoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00374
  • Intermediate I-1G (372 mg, 1.287 mmol) was suspended in EtOH (10 mL) and was mixed with 21% sodium ethoxide in ethanol (2 mL, 5.36 mmol). Mixture was stirred at 40° C. for 1 hour. The solvent was removed on rotavapor and residue was dissolved in 20 mL of EtOAc and 15 mL of water. The layers were separated and the aqueous layer was extracted with EtOAc (10 mL×2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Crude product was loaded on ISCO (24 g column, 0-50% EtOAC/Hexane gradient) to yield Intermediate I-144A (292 mg, 1.093 mmol, 85% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 4.50 (q, J=7.0 Hz, 2H), 2.50 (s, 3H), 1.42 (t, J=7.0 Hz, 3H) LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 269.1 (M+H)+.
    • Intermediate I-144
  • In a sealed tube, Intermediate I-144A (290 mg, 1.086 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (551 mg, 2.171 mmol), potassium acetate (213 mg, 2.171 mmol) were mixed in 1,4-dioxane (5 mL). After degassing with bubbling N2 for 10 minutes, Pd(dppf)Cl2CH2Cl2 adduct (44.3 mg, 0.054 mmol) was added. The vial was sealed and was heated at 120° C. for 60 minutes. The reaction mixture was cooled room temperature and loaded on celite. Purified on ISCO (40 g column, 0-50% EtOAc/Hexane in 18 minutes) to yield I-144 (0.311 g, 0.990 mmol, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.91 (s, 1H), 7.68 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.26 (br. s., 3H), 1.41 (t, J=7.0 Hz, 3H), 1.34 (s, 12H). LC-MS: method H, RT=0.94 min, MS (ESI) m/z: 233.0 (M+H)+. See mass of boronic acid.
    • Example 1 5-(benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00375
  • A mixture of Intermediate I-1G (40 mg, 0.138 mmol), benzofuran-2-ylboronic acid (28.0 mg, 0.173 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.78 mg, 8.30 μmol) in toluene (1.8 mL) and EtOH (0.600 mL) was degassed with argon for 2.0 min. To this solution was added sodium carbonate (2M, 0.121 mL, 0.242 mmol). The mixture was heated in a microwave reactor at 100° C. for 30 min. The reaction mixture was diluted with EtOAc/water. The organic layer was collected, dried over sodium sulfate. The crude residue was dissolved in DMSO/acetonitrile (6 mL/6 mL), purified using a preparative HPLC (method A, 70-100% B in 10 min, flow rate of 40 mL/min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 1 (28 mg, 0.085 mmol, 61.4% yield) as yellow lyophilate. 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.13 (d, J=0.8 Hz, 1H), 7.85 (t, JHF=71.85 Hz, 1H), 7.79 (dd, J=7.7, 0.6 Hz, 1H), 7.75 (dd, J=1.8, 1.0 Hz, 1H), 7.68 (dd, J=8.3, 0.8 Hz, 1H), 7.41 (ddd, J=8.3, 7.2, 1.1 Hz, 1H), 7.34-7.30 (m, 1H), 2.66 (s, 3H); 19F NMR (471 MHz, DMSO-d6) δ −88.42 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.32 min, MS (ESI) m/z: 327.1 (M+H)+. Analytical HPLC (low pH, 254 nM): Sunfire, RT=12.62 min, 100% purity; XBridge, RT=8.29 min, 99% purity.
    • Example 2 2-(difluoromethoxy)-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00376
    • Intermediate 2A: (5-methoxybenzofuran-2-yl)boronic acid
  • Figure US20190292176A1-20190926-C00377
  • To 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (1.190 mL, 1.903 mmol) dropwise. The solution became slightly yellow. The reaction mixture was stirred at −78° C. for 20 min, followed by addition of triisopropyl borate (0.737 mL, 3.17 mmol). After 30 min stirring at −78° C., the cooling bath was removed and the stirring was continued at room temperature for 1.5 h. The reaction mixture was diluted with EtOAc, quenched with 3.0 mL of 1.0 N HCl. After stirring at room temperature for 25 min, the organic layer was collected, washed with brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform/a drop of MeOH and charged to a 4 g silica gel cartridge which was eluted with hexanes for 2 min., then a 10 min gradient from 0% to 60%. The desired fractions were combined, concentrated and lyophilized to give Intermediate 2A (170 mg, 0.886 mmol, 69.8% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) δ 7.41 (d, J=9.1 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.9, 2.6 Hz, 1H), 3.84 (s, 3H); LC-MS: method A, RT=1.45 min, MS (ESI) m/z: 149.0 (M-B(OH)2)+.
    • Example 2
  • A mixture of Intermediate I-1G (22 mg, 0.076 mmol), Intermediate 2A (18.26 mg, 0.095 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (4.97 mg, 6.09 μmol) in toluene (1.5 mL) and EtOH (0.5 mL) was degassed with argon for 2.0 min. To this solution was added sodium carbonate (2M, 0.067 mL, 0.133 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 min, then diluted with EtOAc/water. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude residue was dissolved in DMSO/MeOH (6 mL/4 mL), purified using a preparative HPLC (method A, 70-100% B in 10 min, flow rate of 40 mL/min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 2 (15 mg, 0.042 mmol, 54.8% yield) as yellow lyophilate. 1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.21 (d, J=1.4 Hz, 1H), 8.05 (s, 1H), 7.88 (t, JHF=71.53 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 6.98 (dd, J=8.9, 2.6 Hz, 1H), 3.82 (s, 3H), 2.63 (s, 3H); 19F NMR (471 MHz, DMSO-d6) δ −87.80 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.27 min, MS (ESI) m/z: 357.0 (M+H)+. Analytical HPLC (low pH, 254 nM): Sunfire, RT=12.92 min, 99% purity; XBridge, RT=9.70 min, 99% purity.
    • Example 3 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]oxazole
  • Figure US20190292176A1-20190926-C00378
    • Intermediate 3A: 2-iodobenzo[d]oxazole
  • Figure US20190292176A1-20190926-C00379
  • To magnesium bromide (52 mg, 0.282 mmol) in THF (0.5 mL) cooled at −10° C. was added 1.6 N n-BuLi in hexanes (0.530 mL, 0.847 mmol) dropwise. The reaction mixture was stirred between −10° C. and 0° C. for 1.0 h. Benzo[d]oxazole (101 mg, 0.847 mmol) in THF (0.5 mL) was added, and the brown mixture was stirred at room temperature for 2.0 h. Iodine (79 mg, 0.311 mmol) in THF (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, quenched with 10% Na2S2O3. The organic layer was washed with water, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 3 min., then a 15 min gradient from 0% to 30%. The desired fractions were combined and concentrated to give Intermediate 3A (47 mg, 0.192 mmol, 67.9% yield) as a solid. 1H NMR (400 MHz, chloroform-d) δ 7.67-7.60 (m, 1H), 7.50-7.44 (m, 1H), 7.28-7.20 (m, 2H); LC-MS: method A, RT=1.73 min, MS (ESI) m/z: 246.0 (M+H)+.
    • Example 3
  • To Intermediate I-1 (31 mg, 0.092 mmol), Intermediate 3A (29.4 mg, 0.120 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.03 mg, 7.38 μmol) was added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.101 mL, 0.203 mmol). The reaction mixture was heated in a microwave reactor at 110° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude residue was purified using a preparative HPLC (method A, 40-100% B in 10 min, flow rate of 40 mL/min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 3 (27 mg, 0.082 mmol, 89% yield) as a white lyophilate. 1H NMR (500 MHz, acetonitrile-d3) 8.74 (br. s., 1H), 8.32 (d, J=1.9 Hz, 1H), 7.93 (br. s., 1H), 7.89-7.85 (m, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.71 (t, JHF=71.53 Hz, 1H), 7.53-7.45 (m, 2H), 2.69 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −90.12 (s, 2F); LC-MS: Method A, 40 to 100% B. RT=1.81 min, MS (ESI) m/z: 328.0 (M+H)+. Analytical HPLC (low pH, 254 nM): Sunfire, RT=9.41 min, 99% purity; XBridge, RT=7.19 min, 99% purity.
    • Example 4 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00380
  • To a microwave reaction tube was charged dichlorobis(chloro-di-tert-butylphosphine)palladium (1.118 mg, 2.076 μmol), Cu(Xantphos)I (6.39 mg, 8.30 μmol), cesium carbonate (85 mg, 0.259 mmol), benzo[d]thiazole (0.017 mL, 0.156 mmol) and Intermediate I-1G (30 mg, 0.104 mmol). Toluene (1.0 mL) was added and the reaction mixture was sealed and heated at 100° C. The mixture was diluted with EtOAc/water, the organic layer was collected, dried over sodium sulfate. The crude residue was purified using a preparative HPLC (method A, 60-100% B in 10 min, flow rate of 40 mL/min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 4 (2.2 mg, 6.34 μmol, 6.11% yield) as a white lyophilate. 1H NMR (500 MHz, acetonitrile-d3) δ 8.84 (d, J=1.7 Hz, 1H), 8.78 (s, 1H), 8.15-8.11 (m, 2H), 7.87 (dd, J=1.8, 1.0 Hz, 1H), 7.72 (t, JHF=71.82 Hz, 1H), 7.59 (ddd, J=8.2, 7.1, 1.2 Hz, 1H), 7.50 (td, J=7.6, 1.1 Hz, 1H), 2.72 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −90.06 (s, 2F); LC-MS: Method H, 50 to 100% B. RT=1.93 min, MS (ESI) m/z: 344.2 (M+H)+. Analytical HPLC (low pH, 254 nM): Sunfire, RT=12.49 min, 100% purity; XBridge, RT=9.38 min, 99% purity.
    • Example 5 2-(difluoromethoxy)-5-(1H-indol-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00381
    • Intermediate 5A: tert-butyl 2-(tributylstannyl)-1H-indole-1-carboxylate
  • Figure US20190292176A1-20190926-C00382
  • To diisopropylamine (0.984 mL, 6.90 mmol) in THF (12 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (4.32 mL, 6.90 mmol). The reaction mixture was stirred at −78° C. for 0.5 h. Next, tert-butyl 1H-indole-1-carboxylate (0.935 mL, 4.60 mmol) was added, and the reaction mixture was stirred at −78° C. for 0.5 h. Tributyltin chloride (1.489 mL, 5.52 mmol) was added, and the reaction mixture was stirred at −78° C. for 0.5 h, then at room temperature for 1.5 h. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g silica gel cartridge which was eluted with hexanes for 3 min., then a 18 min gradient from 0% to 30%. The desired fractions were combined and concentrated to give Intermediate 5A (2.1 g, 4.15 mmol, 90% yield) as clear oil. 1H NMR (500 MHz, chloroform-d) δ 7.98-7.94 (m, 1H), 7.54-7.50 (m, 1H), 7.26-7.15 (m, 2H), 6.74-6.69 (m, 1H), 1.71 (s, 9H), 1.58-1.49 (m, 7H), 1.33 (sxt, J=7.3 Hz, 6H), 1.11-1.06 (m, 5H), 0.89 (t, J=7.4 Hz, 9H); LC-MS: Method A, 60 to 100% B. RT=1.86 min, MS (ESI) m/z: not observed.
    • Example 5
  • A solution of Intermediate 5A (65.7 mg, 0.130 mmol) and Intermediate I-1G (30 mg, 0.104 mmol) in toluene (1.2 mL) was degassed with argon for 3 min. Tetrakis(triphenylphosphine)palladium(O) (6.00 mg, 5.19 μmol) was added. The reaction mixture was sealed and heated in a microwave reactor at 125° C. for 30 min. HPLC and LCMS indicated only 15% conversion. Then another portion of Intermediate 5A (65.7 mg, 0.130 mmol) and tetrakis(triphenylphosphine)palladium(O) (6.00 mg, 5.19 μmol) were added, and the reaction mixture was heated at 125° C. for another 1.0 h. Toluene was removed under vacuum. 4.0 N HCl in dioxane (2.076 mL, 8.30 mmol) was added and the reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuum. The crude residue was purified using a preparative HPLC (method A, 50-100% B in 10 min, flow rate of 40 mL/min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 5 (5.0 mg, 0.014 mmol, 13.92% yield) as yellow lyophilate. 1H NMR (500 MHz, acetonitrile-d3) δ 8.72 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 7.71 (t, JHF=71.82 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H), 7.61 (dd, J=8.3, 0.8 Hz, 1H), 7.30-7.28 (m, 1H), 7.23 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.12 (td, J=7.5, 1.0 Hz, 1H), 2.65 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −90.04 (s, 2F); LC-MS: Method H, 0 to 100% B. RT=1.88 min, MS (ESI) m/z: 326.3 (M+H)+. Analytical HPLC (method A): Sunfire, RT=11.54 min, 99% purity; XBridge, RT=9.21 min, 90% purity.
    • Example 6 2-(difluoromethoxy)-5-(4,5-dimethoxybenzofuran-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00383
    • Intermediate 6A: 5-(hydroxymethylene)-6,7-dihydrobenzofuran-4(5H)-one
  • Figure US20190292176A1-20190926-C00384
  • To sodium hydride (1.175 g, 29.4 mmol) and potassium hydride (0.098 g, 0.734 mmol) in THF (25 mL) at 0° C. was added ethyl formate (2.99 mL, 36.7 mmol), followed by addition of 6,7-dihydrobenzofuran-4(5H)-one (1.0 g, 7.34 mmol) in THF (5.0 mL) dropwise. The reaction mixture was stirred at room temperature for 1.0 h and heated at 50° C. for 1.5 h. HPLC and LCMS indicated a completion of reaction. The mixture was diluted with EtOAc, cooled to 0° C., quenched with 3.0 mL MeOH/water, pH was adjusted to 7 with 1.0 N HCl. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 6A (1.36 g, 8.28 mmol, 113% yield) was obtained as yellow liquid. It was used for the next step without further purification. 1H NMR indicated a mixture of the keto and enol form in a ratio of 1:7. 1H NMR of the enol form: (500 MHz, chloroform-d) δ 7.39-7.36 (m, 1H), 7.31-7.26 (m, 1H), 6.74 (d, J=2.2 Hz, 1H), 2.93-2.87 (m, 2H), 2.68 (td, J=7.0, 0.8 Hz, 2H); LC-MS: method A, RT=1.19 and 1.35 min, MS (ESI) m/z: 165.0 (M+H)+.
    • Intermediate 6B: 4-hydroxybenzofuran-5-carbaldehyde
  • Figure US20190292176A1-20190926-C00385
  • To a suspension of DDQ (2.074 g, 9.14 mmol) in dioxane (6.0 mL) was added Intermediate 6A (1.2 g, 7.31 mmol) in dioxane (7.0 mL) dropwise. The reaction mixture was stirred at room temperature for 2.0 h. TLC indicated a completion of the reaction. It was diluted with EtOAc, stirred for 15 min. The precipitate was filtered and the filtrate was concentrated. The crude was triturated with chloroform and the precipitate was removed by filtration. The filtrate was concentrated, dissolved in a small amount of chloroform and charged to a 80 g silica gel cartridge which was eluted with hexanes for 3 min., then a 15 min gradient from 0% to 40%. The desired fractions were combined and concentrated to give Intermediate 6B (0.66 g, 4.07 mmol, 55.7% yield) as a slightly brown solid. 1H NMR (500 MHz, chloroform-d) δ 12.01 (s, 1H), 9.94 (s, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.7, 1.0 Hz, 1H), 7.03 (dd, J=2.2, 0.8 Hz, 1H); LC-MS: method A, RT=1.65 min, MS (ESI) m/z: 163.0 (M+H)+.
    • Intermediate 6C: 4-methoxybenzofuran-5-carbaldehyde
  • Figure US20190292176A1-20190926-C00386
  • To Intermediate 6B (0.66 g, 4.07 mmol) in DMF (6.0 mL) was added potassium carbonate (1.547 g, 11.19 mmol), followed by iodomethane (0.445 mL, 7.12 mmol). The mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with EtOAc/water. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 6C (0.68 g, 3.86 mmol, 95% yield) was obtained as a white solid. It was used for the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 10.51 (d, J=0.8 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.28-7.24 (m, 1H), 7.08 (dd, J=2.2, 0.8 Hz, 1H), 4.29 (s, 3H); LC-MS: method A, RT=1.62 min, MS (ESI) m/z: 177.0 (M+H)+.
    • Intermediate 6D: 4-methoxybenzofuran-5-yl formate
  • Figure US20190292176A1-20190926-C00387
  • To a stirred solution of Intermediate 6C (0.31 g, 1.760 mmol) in dichloromethane (4.0 mL) was added mCPBA (0.557 g, 2.420 mmol). Trifluoroacetic acid (0.136 mL, 1.760 mmol) in dichloromethane (2.0 mL) was added. The reaction mixture was stirred at room temperature for 2.0 h. Sodium thiosulfite (10%, 1.0 mL) was added to quench the reaction. Solvent was removed under vacuum. The residue was partitioned between EtOAc/saturated sodium bicarbonate. The organic layer was collected, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, Intermediate 6D (0.34 g, 1.769 mmol, 101% yield) was obtained as brown oil that was used for next step without further purification. LC-MS: method A, RT=1.53 min, MS (ESI) m/z: 215.0 (M+Na)+.
    • Intermediate 6E: 4-methoxybenzofuran-5-ol
  • Figure US20190292176A1-20190926-C00388
  • To Intermediate 6D (0.34 g, 1.769 mmol) in MeOH (5.0 mL) was added potassium carbonate (0.428 g, 3.10 mmol). The mixture was allowed to stir at room temperature for 20 min. MeOH was removed under vacuum. The residue was partitioned between EtOAc/water. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 2 min., then a 15 min gradient from 0% to 40%. The desired fractions were combined and concentrated to give Intermediate 6E (0.22 g, 1.340 mmol, 76% yield) as viscous oil. 1H NMR (500 MHz, chloroform-d) δ 7.57 (d, J=2.2 Hz, 1H), 7.13 (dd, J=8.7, 1.0 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.88 (dd, J=2.2, 0.8 Hz, 1H), 4.13 (s, 3H); LC-MS: method A, RT=1.40 min, MS (ESI) m/z: 187.0 (M+Na)+.
    • Intermediate 6F: 4-methoxy-5-(methoxymethoxy)benzofuran
  • Figure US20190292176A1-20190926-C00389
  • To Intermediate 6E (0.21 g, 1.279 mmol) in DMF (4.0 mL) at 0° C. was added sodium hydride (0.070 g, 1.759 mmol, 60% in mineral). The reaction mixture was stirred at 0° C. for 5 min, and at room temperature for 10 min. The mixture turned to deep blue color. Chloromethyl methyl ether (0.136 mL, 1.791 mmol) was added slowly, and the reaction mixture was stirred at room temperature for 30 min. HPLC and TLC indicated a completion of the reaction. The mixture was diluted with EtOAc, washed with water, brine. The organic layer was dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 3 min., then a 12 min gradient from 0% to 30%. The desired fractions were combined and concentrated to give Intermediate 6F (0.24 g, 1.153 mmol, 90% yield). 1H NMR (500 MHz, chloroform-d) δ 7.56 (d, J=2.2 Hz, 1H), 7.18-7.13 (m, 2H), 6.91 (dd, J=2.2, 0.6 Hz, 1H), 5.21 (s, 2H), 4.10 (s, 3H), 3.59 (s, 3H); LC-MS: method A, RT=1.70 min, MS (ESI) m/z: 231.0 (M+H)+.
    • Intermediate 6G: (4-methoxy-5-(methoxymethoxy)benzofuran-2-yl)boronic acid
  • Figure US20190292176A1-20190926-C00390
  • To Intermediate 6F (0.236 g, 1.133 mmol) in THF (4.0 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (1.240 mL, 1.984 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 min, followed by addition of triisopropyl borate (0.790 mL, 3.40 mmol). The reaction mixture was stirred for 30 min, and the cooling bath was removed to allow warm up to room temperature for 1.0 h. TLC and HPLC indicated a completion of the reaction. The reaction mixture was diluted with EtOAc and quenched with 4.0 mL of 0.5 N HCl. After stirring at room temperature for 10 min, the organic layer was collected, washed with brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 4 g silica gel cartridge which was eluted with 5% for 2 min., then a 5 min gradient from 5% to 85%. The desired fractions were combined, concentrated and lyophilized to give Intermediate 6G (0.23 g, 0.913 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.39 (s, 1H), 7.06 (s, 2H), 5.06 (s, 2H), 4.72 (br. s., 1H), 3.98 (s, 3H), 3.46 (s, 3H); LC-MS: method A, RT=1.42 min, MS (ESI) m/z: 177.0.
    • Intermediate 6H 2-(difluoromethoxy)-5-(4-methoxy-5-(methoxymethoxy)benzofuran-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00391
  • A mixture of Intermediate I-1G (30 mg, 0.104 mmol), Intermediate 6G (32.7 mg, 0.130 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.93 mg, 7.26 μmol) in toluene (1.8 mL) and EtOH (0.600 mL) was degassed with argon for 2.0 min. To this solution was added sodium carbonate (2M, 0.104 mL, 0.208 mmol). The mixture was heated in a microwave reactor at 100° C. for 30 min, at which time HPLC and LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc/water. The organic layer was collected, dried over sodium sulfate. The crude residue was dissolved in DMSO/acetonitrile (2 mL/3 mL), purified using a preparative HPLC (method A, 50-100% B in 10 min; RT=9.5 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 6H (26 mg, 0.060 mmol, 57.8% yield) as yellow lyophilate. 1H NMR (500 MHz, acetonitrile-d3) δ 8.75 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.25 (d, J=0.8 Hz, 1H), 7.72 (dd, J=1.9, 1.1 Hz, 1H), 7.71 (t, JHF=71.80 Hz, 1H), 7.29-7.25 (m, 1H), 7.22-7.19 (m, 1H), 5.20 (s, 2H), 4.14 (s, 3H), 3.55 (s, 3H), 2.67 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −90.01 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.19 min, MS (ESI) m/z: 417.1 (M+H)+. Analytical HPLC (method A): Sunfire, RT=12.38 min, 99% purity; XBridge, RT=9.66 min, 94% purity.
    • Intermediate 6I 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzofuran-5-ol
  • Figure US20190292176A1-20190926-C00392
  • To Intermediate 6H (16 mg, 0.038 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 6.0 N HCl (0.640 mL, 3.84 mmol). The reaction mixture was stirred at 60° C. for 1.0 h. HPLC indicated a completion of the reaction. It was diluted with EtOAc, washed with water, brine. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, Intermediate 6I (13 mg, 0.035 mmol, 91% yield) was obtained as a brown solid that was used for next step without further purification. 1H NMR (500 MHz, acetonitrile-d3) δ 8.72 (s, 1H), 8.21 (d, J=5.0 Hz, 2H), 7.69 (t, JHF=71.53 Hz, 1H), 7.68 (br. s., 1H), 7.18 (d, J=8.5 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.53 (br. s., 1H), 4.14 (s, 3H), 2.65 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −89.92 (br. s., 2F); LC-MS: method A, RT=1.86 min, MS (ESI) m/z: 373.0 (M+H)+.
    • Example 6
  • To a stirred solution of Intermediate 6I (13 mg, 0.035 mmol) and cesium carbonate (28.4 mg, 0.087 mmol) in DMF (0.8 mL) at room temperature was added methyl iodide (3.82 μl, 0.061 mmol) in acetonitrile (0.03 mL). The reaction mixture was stirred at room temperature for 1.0 h. HPLC and LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc, quenched with 0.2 N HCl (2.0 mL). The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude was purified using a preparative HPLC (method A, 60-100% B in 10 min; RT=8.5 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 6 (9.5 mg, 0.024 mmol, 68.3% yield) as yellow lyophilate. 1H NMR (500 MHz, acetonitrile-d3) δ 8.74 (s, 1H), 8.24 (d, J=1.7 Hz, 1H), 8.19 (s, 1H), 7.71 (t, JHF=71.80 Hz, 1H), 7.70 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 4.09 (s, 3H), 3.91 (s, 3H), 2.66 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −90.01 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.15 min, MS (ESI) m/z: 387.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=12.88 min, 100% purity; XBridge, RT=10.21 min, 96% purity.
    • Example 7 6-(benzyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00393
  • To a stirred solution of Intermediate I-4D (10 mg, 0.028 mmol) and cesium carbonate (22.67 mg, 0.070 mmol) in DMF (0.6 mL) at room temperature was added benzyl bromide (5.79 μl, 0.049 mmol) in acetonitrile (0.03 mL). The reaction mixture was stirred at room temperature for 3 h. HPLC and LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc, quenched with 0.2 N HCl (2.0 mL). The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude was purified via preparative LC/MS (method D), 55-95% B over 10 minutes. Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 7 (12.1 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.73 (d, J=1.4 Hz, 1H), 8.05-8.02 (m, 1H), 7.90 (d, J=5.8 Hz, 1H), 7.89 (t, JHF=71.53 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.53 (d, J=7.4 Hz, 2H), 7.43 (t, J=7.4 Hz, 2H), 7.39-7.35 (m, 1H), 7.26 (dd, J=8.8, 2.5 Hz, 1H), 5.23 (s, 2H), 2.67 (s, 3H); LC-MS: Method A, 0 to 100% B. RT=3.33 min, MS (ESI) m/z: 450.0 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 8 4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00394
    • Intermediate 8A: 4-chloro-2-iodobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00395
  • To a suspension of 4-chlorobenzo[d]thiazol-2-amine (0.66 g, 3.57 mmol) and p-TSA monohydrate (2.040 g, 10.72 mmol) in acetonitrile (16 mL) at 10° C. (cooled with ice water) was added dropwise a solution of sodium nitrite (0.493 g, 7.15 mmol) and potassium iodide (1.483 g, 8.94 mmol) in water (4 mL) over a period of 25 min. The reaction mixture was stirred at 10° C. for 10 min, and allowed to warm up to room temperature and stirred over the weekend. To the reaction mixture was added sodium bicarbonate (pH to 9.0), water and EtOAc. The organic layer was collected, washed with water, saturated Na2S2O3, water, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform/toluene/MeOH and charged to a 40 silica gel cartridge which was eluted with hexanes for 3 min., then a 18 min gradient from 0% to 30%. The desired fractions were combined and concentrated to give Intermediate 8A (0.571 g, 1.932 mmol, 54.1% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.77 (dd, J=8.1, 1.0 Hz, 1H), 7.49 (dd, J=7.8, 1.0 Hz, 1H), 7.38-7.33 (m, 1H); LC-MS: method A, RT=1.94 min, MS (ESI) m/z: 296.0 and 298.0 (M+H)+.
    • Example 8
  • To Intermediate I-1 (16 mg, 0.048 mmol), Intermediate 8A (20 mg, 0.067 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.0 mg, 3.67 μmol) was added toluene (1.2 mL) and EtOH (0.4 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.052 mL, 0.105 mmol). The reaction mixture was heated in a microwave reactor at 110° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude material was purified via preparative LC/MS (method D, 55-90% B over 10 minutes). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield the Example 8 (4.2 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.79 (d, J=1.4 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.90 (t, JHF=71.53 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 2.71 (s, 3H); LC-MS: Method H, 0 to 100% B. RT=3.66 min, MS (ESI) m/z: 378.0 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 9 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazolo[4,5-b]pyridine
  • Figure US20190292176A1-20190926-C00396
    • Intermediate 9A: 2-chlorothiazolo[4,5-b]pyridine
  • Figure US20190292176A1-20190926-C00397
  • To a slurry of thiazolo[4,5-b]pyridine-2-thiol (343 mg, 2.039 mmol) in dichloromethane (0.5 mL) was added sulfuryl chloride (3.32 mL, 40.8 mmol). The suspension was stirred at 50° C. for 2.0 h, and at room temperature overnight. To the yellow suspension was added ice water, stirred at room temperature for 15 min to decompose the excess sulfuryl chloride. EtOAc and 4.0 N NaOH were added to adjust the pH to 10-12. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with 5% for 3 min., then a 12 min gradient from 5% to 60%. The desired fractions were combined and concentrated to give Intermediate 9A (265 mg, 1.553 mmol, 76% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 8.76 (dd, J=5.0, 1.7 Hz, 1H), 8.19 (dd, J=8.0, 1.7 Hz, 1H), 7.39 (dd, J=8.0, 4.7 Hz, 1H); LC-MS: method A, RT=1.22 min, MS (ESI) m/z: 171 and 173 (M+H)+.
    • Example 9
  • To Intermediate I-1 (17 mg, 0.051 mmol), Intermediate 9A (11.22 mg, 0.066 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.30 mg, 4.05 μmol) was added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.056 mL, 0.111 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The mixture was stirred at room temperature for 15 min. The organic layer was collected. After evaporation of solvent, the crude material was purified via preparative LC/MS (method D, 40-90% B over 10 minutes) to yield the Example 9 (11.2 mg). 1H NMR (500 MHz, methanol-d4) δ 8.93 (d, J=1.7 Hz, 1H), 8.73 (s, 1H), 8.72 (dd, J=4.7, 1.4 Hz, 1H), 8.47 (dd, J=8.0, 1.4 Hz, 1H), 7.89 (s, 1H), 7.71 (t, JHF=71.53 Hz, 1H), 7.61 (s, 1H), 7.44 (dd, J=8.0, 4.7 Hz, 1H), 2.71 (s, 3H); LC-MS: Method H, 0 to 100% B. RT=2.59 min, MS (ESI) m/z: 345.0 (M+H)+. Analytical HPLC purity (method B): 95%.
    • Example 10 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00398
  • To Intermediate I-1 (25 mg, 0.074 mmol), Intermediate I-3 (24 mg, 0.093 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (4.86 mg, 5.95 μmol) was added toluene (1.2 mL) and EtOH (0.4 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.082 mL, 0.164 mmol). The reaction mixture was heated in a microwave reactor at 110° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. EtOAc/brine was added to the mixture. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude was dissolved in DMF (3.5 mL) and was purified via preparative LC/MS (method D, 60-100% B over 10 minutes) to yield Example 10 (15 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.73 (s, 1H), 7.89 (s, 1H), 7.87 (t, JHF=71.89 Hz, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.02 (s, 1H), 3.86 (s, 3H), 2.75 (s, 3H), 2.68 (s, 3H); LC-MS: method A, RT=2.66 min, MS (ESI) m/z: 388.0 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 11 tert-butyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
  • Figure US20190292176A1-20190926-C00399
    • Intermediate 11A: tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
  • Figure US20190292176A1-20190926-C00400
  • tert-Butyl nitrite (0.181 mL, 1.371 mmol) was added to copper (II) bromide (297 mg, 1.332 mmol) in dry acetonitrile (3.0 mL) under argon. The reaction mixture was stirred at room temperature for 10 min. A suspension of tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (200 mg, 0.783 mmol) in dry acetonitrile (4.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.0 h. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 2 min., then a 12 min gradient from 0% to 50%. The desired fractions were combined, concentrated and lyophilized to give Intermediate 11A (85 mg, 0.266 mmol, 34.0% yield) as a white solid. 1H NMR (500 MHz, acetonitrile-d3) δ 4.56 (t, J=1.8 Hz, 2H), 3.70 (t, J=5.8 Hz, 2H), 2.81-2.76 (m, 2H), 1.47 (s, 9H); LC-MS: method A, RT=1.86 min, MS (ESI) m/z: 319.0 and 321.0 (M+H)+.
    • Example 11
  • To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 11A (34.2 mg, 0.107 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added toluene (2.1 mL) and EtOH (0.7 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.098 mL, 0.196 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude product was purified via a prep LC/MS (method D) to give Example 11 (23.4 mg, 0.052 mmol, 57.9% yield): 1H NMR (500 MHz, methanol-d4) δ 8.66 (s, 1H), 8.49 (d, J=1.7 Hz, 1H), 7.76 (d, J=0.8 Hz, 1H), 7.69 (t, JHF=71.80 Hz, 1H), 4.76 (s, 2H), 3.83 (t, J=5.8 Hz, 2H), 2.99 (t, J=5.6 Hz, 2H), 2.65 (s, 3H), 1.51 (s, 9H); LC-MS: method A, RT=2.51 min, MS (ESI) m/z: 449.0 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 12 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00401
    • Intermediate 12A: N-((5-methoxy-2-methylphenyl)carbamothioyl)benzamide
  • Figure US20190292176A1-20190926-C00402
  • To a solution of 5-methoxy-2-methylaniline (1.47 g, 10.72 mmol) in acetone was added dropwise benzoyl isothiocyanate (1.924 g, 11.79 mmol). The reaction mixture was stirred at room temperature for 30 min. HPLC and LCMS indicated a completion of the reaction. Acetone was removed under vacuum. The crude was triturated with EtOAc/hexanes (1:4). The precipitate was collected by filtration, dried under vacuum to give Intermediate 12A (3.1 g, 10.32 mmol, 96% yield) as a green solid. 1H NMR (500 MHz, chloroform-d) δ 12.33 (br. s., 1H), 9.14 (br. s., 1H), 7.96-7.92 (m, 2H), 7.71-7.67 (m, 1H), 7.61-7.56 (m, 3H), 7.21 (d, J=8.5 Hz, 1H), 6.83 (dd, J=8.4, 2.6 Hz, 1H), 3.84 (s, 3H), 2.33 (s, 3H); LC-MS: method A, RT=2.11 min, MS (ESI) m/z: 301(M+H)+.
    • Intermediate 12B: 1-(5-methoxy-2-methylphenyl)thiourea
  • Figure US20190292176A1-20190926-C00403
  • To a solution of Intermediate 12A (3.1 g, 10.32 mmol) in THF (20 mL) and MeOH (10 mL) heated at 70° C. was added 4.0 N NaOH (7.74 mL, 31.0 mmol). The reaction mixture was stirred at 70° C. for 2.0 h. HPLC and TLC indicated a completion of the reaction. The mixture was then left stirring at room temperature overnight. THF and MeOH were removed under vacuum. The crude product was then suspended in water. The precipitate was collected by filtration, washed with water and dried in the air under vacuum and then dried under high vacuum to give Intermediate 12B (1.6 g, 8.15 mmol, 79% yield) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.76 (dd, J=8.3, 2.8 Hz, 1H), 3.31 (s, 3H), 2.11 (s, 3H); LC-MS: method A, RT=1.16 min, MS (ESI) m/z: 197.0 (M+H)+.
    • Intermediate 12C: 7-methoxy-4-methylbenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00404
  • To a suspension of Intermediate 12B (1.43 g, 7.29 mmol) in AcOH (20 mL) at room temperature was added benzyltrimethylammonium tribromide (2.84 g, 7.29 mmol) in acetonitrile (15 mL) dropwise (15 min). The reaction mixture was stirred at room temperature overnight. HPLC and LCMS indicated a completion of the reaction. Most of the solvent was removed under vacuum. The mixture was diluted with EtOAc, and the pH was adjusted to 8 with 1.0 N NaOH. The insoluble material was removed by filtration. The organic layer of the filtrate was collected, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 12C (1.42 g, 7.31 mmol, 100% yield) was obtained as a solid. 1H NMR and HPLC indicated >90% purity. It was used for the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 7.09 (dd, J=8.1, 0.7 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 3.93 (s, 3H), 2.51 (s, 3H); LC-MS: method A, RT=1.28 min, MS (ESI) m/z: 195.0 (M+H)+.
    • Intermediate 12D: 2-bromo-7-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00405
  • Tert-butyl nitrite (0.225 mL, 1.699 mmol) was added to a solution of copper (II) bromide (354 mg, 1.586 mmol) in acetonitrile (5.0 mL). The reaction mixture was stirred at room temperature for 10 min, followed by addition of Intermediate 12C (220 mg, 1.133 mmol) in acetonitrile (3.0 mL). The reaction mixture was stirred at room temperature 1.0 h. HPLC and LCMS indicated a complete conversion of starting material to the desired mono-bromo and undesired di-bromo product. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g silica gel cartridge which was eluted with hexanes for 2 min., then a 18 min gradient from 0% to 20%. TLC indicated the two products were not separated by ISCO column. The crude residue was then purified using a preparative HPLC (method A, 50-100% B in 10 min., RT=7.0 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 12D (120 mg, 0.465 mmol, 41.0% yield). 1H NMR (500 MHz, chloroform-d) δ 7.22 (dd, J=8.0, 0.8 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 3.97 (s, 3H), 2.65 (d, J=0.8 Hz, 3H); LC-MS: method A, RT=2.17 min, MS (ESI) m/z: 258.0 and 260.0 (M+H)+.
    • Example 12
  • To Intermediate I-1 (20 mg, 0.059 mmol), Intermediate 12D (19.97 mg, 0.077 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.89 mg, 4.76 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.074 mL, 0.149 mmol). The reaction mixture was heated in a microwave reactor at 125° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude was dissolved in DMF (4.0 mL) and purified via preparative LC/MS (method D, 60-100% B over 25 minutes). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 12 (2.5 mg). 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.81 (d, J=1.9 Hz, 1H), 7.94 (s, 1H), 7.90 (t, JHF=71.53 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 3.99 (s, 3H), 2.73 (s, 3H), 2.70 (s, 3H); LC-MS: method A, RT=2.77 min, MS (ESI) m/z: 388.0 (M+H)+.
    • Example 13 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-difluoro-7-methoxybenzo[d]thiazol
  • Figure US20190292176A1-20190926-C00406
    • Intermediate 13A: 4,6-difluoro-7-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00407
  • To 2,4-difluoro-5-methoxyaniline (270 mg, 1.697 mmol) in acetonitrile (6 mL) was added ammonium thiocyanate (194 mg, 2.55 mmol). The reaction mixture was stirred at room temperature for 10 min. Then benzyltrimethylammonium tribromide (662 mg, 1.697 mmol) in acetonitrile (3.0 mL) was added dropwise (10 min). The mixture was then stirred at room temperature overnight. HPLC and LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc/saturated sodium bicarbonate. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform/MeOH, and charged to a 12 g silica gel cartridge which was eluted with 5% for 3 min., then a 12 min gradient from 5% to 75%. The desired fractions were combined and concentrated to give Intermediate 13A (240 mg, 1.110 mmol, 65.4% yield) as a pale solid. 1H NMR (500 MHz, methanol-d4) δ 6.98 (dd, J=12.1, 10.5 Hz, 1H), 3.99 (d, J=1.7 Hz, 3H); 19F NMR (471 MHz, methanol-d4) δ −132.46 (s, 1F), −139.29 (s, 1F); LC-MS: method A, RT=1.54 min, MS (ESI) m/z: 217.0 (M+H)+.
    • Intermediate 13B: 2-chloro-4,6-difluoro-7-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00408
  • To a solution of copper (II) chloride (82 mg, 0.611 mmol) in acetonitrile (6.0 mL) at 40° C. was added tert-butyl nitrite (0.087 mL, 0.661 mmol), followed by Intermediate 13A (110 mg, 0.509 mmol) as a solid. The reaction mixture was stirred at 40° C. for 1.0 h, and left stirring at room temperature overnight. It was diluted with EtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine. After evaporation of solvent, Intermediate 13B (12 mg, 0.051 mmol, 10.01% yield) was obtained as yellow solid. 1H NMR (500 MHz, chloroform-d) δ 7.07 (dd, J=12.1, 9.6 Hz, 1H), 4.10 (d, J=2.2 Hz, 3H); 19F NMR (471 MHz, chloroform-d) δ −125.09 (s, 1F), −130.33 (s, 1F); LC-MS: method A, RT=2.01 min, MS (ESI) m/z: 236.0 and 238.0 (M+H)+.
    • Example 13
  • To Intermediate I-1 (12 mg, 0.036 mmol), Intermediate 13B (11.36 mg, 0.048 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (2.332 mg, 2.86 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.045 mL, 0.089 mmol). The reaction mixture was heated in a microwave reactor at 125° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude residue was purified using a preparative HPLC (method A, 70-100% B in 10 min; RT=9.0 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 13 (2.0 mg, 4.84 μmol, 13.55% yield). 1H NMR (500 MHz, acetonitrile-d3) δ 8.84 (d, J=1.7 Hz, 1H), 8.82 (s, 1H), 7.91 (dd, J=1.9, 0.8 Hz, 1H), 7.73 (t, JHF=71.80 Hz, 1H), 7.27 (dd, J=12.0, 10.3 Hz, 1H), 4.15 (d, J=1.7 Hz, 3H), 2.73 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −89.97 (s, 2F), −127.74 (s, 1F), −133.31 (s, 1F); LC-MS: Method A, 50 to 100% B. RT=2.30 min, MS (ESI) m/z: 410.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=13.23 min, 99% purity; XBridge, RT=8.56 min, 99% purity.
    • Example 14 tert-butyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl) carbamate
  • Figure US20190292176A1-20190926-C00409
    • Intermediate 14A: methyl 2-bromobenzo[d]thiazole-7-carboxylate
  • Figure US20190292176A1-20190926-C00410
  • Tert-butyl nitrite (1.111 mL, 8.40 mmol) was added to copper (II) bromide (1.770 g, 7.92 mmol) in dry acetonitrile (15 mL) under argon. The reaction mixture was stirred at room temperature for 10 min. A suspension of methyl 2-aminobenzo[d]thiazole-7-carboxylate (1.0 g, 4.80 mmol) in dry acetonitrile (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 h, then at 50° C. for 45 min. HPLC and LCMS indicated a completion of the reaction. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, Intermediate 14A (1.2 g, 4.41 mmol, 92% yield) was obtained as a brown solid. It was used for next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 8.19 (dd, J=8.0, 1.1 Hz, 1H), 8.13 (dd, J=7.7, 1.1 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 4.05 (s, 3H); LC-MS: method A, RT=2.02 min, MS (ESI) m/z: 272.0 274.0 (M+H)+.
    • Intermediate 14B: 2-bromobenzo[d]thiazole-7-carboxylic acid
  • Figure US20190292176A1-20190926-C00411
  • To a solution of Intermediate 14A (0.64 g, 2.352 mmol) in THF (12 mL) was added lithium hydroxide monohydrate (0.296 g, 7.06 mmol) dissolved in water (4.0 mL). The reaction mixture was stirred at room temperature for 2.5 h. HPLC indicated a completion of the reaction. The mixture was diluted with EtOAc, quenched with 0.5N HCl (20 mL). The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 14B (0.60 g, 2.325 mmol, 99% yield) was obtained as a yellow solid. It was used for next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (dd, J=8.3, 1.1 Hz, 1H), 8.12 (dd, J=7.7, 1.1 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H); LC-MS: method A, RT=1.76 min, MS (ESI) m/z: 258.0 and 260.0 (M+H)+.
    • Intermediate 14C: tert-butyl (2-bromobenzo[d]thiazol-7-yl)carbamate
  • Figure US20190292176A1-20190926-C00412
  • To a suspension of Intermediate 14B (80 mg, 0.310 mmol) in THF (2.0 mL) was added TEA (0.065 mL, 0.465 mmol). The mixture turned to a clear solution. To this solution was added trimethylsilyl azide (0.045 mL, 0.341 mmol) and T3P 50% wt in EtOAc (0.203 mL, 0.341 mmol). The reaction mixture was stirred at room temperature for 5 min, then tert-butanol (0.039 mL, 0.403 mmol) was added. The mixture was heated at 80° C. for 2.0 h. Another 2.0 equivalents of triethylamine and 3 equivalents of t-BuOH were added, and the mixture was heated at 80° C. for 8.0 h. The reaction mixture was diluted with EtOAc, washed with 0.5 N HCl, brine. The organic layer was dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 2 min., then a 15 min gradient from 0% to 30%. The desired fractions were combined and concentrated to give Intermediate 14C (36 mg, 0.109 mmol, 35.3% yield): a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.79 (dd, J=7.8, 1.2 Hz, 1H), 7.51-7.43 (m, 2H), 6.48 (br. s., 1H), 1.58 (s, 9H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z: 329.0 and 331.0 (M+H)+.
    • Example 14
  • To Intermediate I-1 (28 mg, 0.083 mmol), Intermediate 14C (32.9 mg, 0.100 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.44 mg, 6.66 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.104 mL, 0.208 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 35 min. The mixture was diluted with EtOAc, washed with brine. The organic layer was dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 4 g silica gel cartridge which was eluted with hexanes for 2 min., then a 10 min gradient from 0% to 30%. The desired fractions were combined and concentrated to give 20 mg of the crude product. This crude product was further purified by prep HPLC. The crude residue was purified using a preparative HPLC (method A, 60-100% B in 10 min; RT=8.5 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 14 (11 mg, 28% yield). 1H NMR (500 MHz, chloroform-d) δ 8.78 (d, J=1.7 Hz, 1H), 8.72 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.88 (dd, J=1.8, 1.0 Hz, 1H), 7.69 (t, JHF=71.53 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 2.71 (s, 3H), 1.62 (s, 9H); LC-MS: Method A, 50 to 100% B. RT=2.00 min, MS (ESI) m/z: 459.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=11.9 min, 100% purity; XBridge, RT=7.46 min, 97% purity.
    • Example 15 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(thiazol-4-ylmethoxy)benzo[d]thiazo
  • Figure US20190292176A1-20190926-C00413
    • Intermediate 15A: 2-bromo-3-methoxyaniline
  • Figure US20190292176A1-20190926-C00414
  • To a suspension of 2-bromo-1-methoxy-3-nitrobenzene (3.90 g, 16.81 mmol) and iron powder (2.82 g, 50.4 mmol) in EtOH (50 mL) was added concentrated HCl (3.08 mL, 37.0 mmol). The mixture was heated at 85° C. for 2.0 h. HPLC indicated a completion of the reaction. After cooled to room temperature, the solvent was removed under vacuum. The residue was suspended in EtOAc and saturated sodium bicarbonate. The insoluble material was removed by filtration through a pad of wet celite. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 15A (3.25 g, 16.09 mmol, 96% yield) was obtained as brown oil. It was used for the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 7.08 (t, J=8.1 Hz, 1H), 6.45 (dd, J=8.0, 1.4 Hz, 1H), 6.34 (dd, J=8.3, 1.1 Hz, 1H), 3.89 (s, 2H); LC-MS: method A, RT=1.21 min, MS (ESI) m/z: 202.0 and 204.0 (M+H)+.
    • Intermediate 15B: 7-methoxybenzo[d]thiazole-2-thiol
  • Figure US20190292176A1-20190926-C00415
  • A solution of Intermediate 15A (3.25 g, 16.09 mmol) and potassium O-ethyl carbonodithioate (6.45 g, 40.2 mmol) in DMF (20 mL) was heated at 135° C. under argon for 6.0 h. HPLC and LCMS indicated a completion of the reaction. The mixture was cooled to room temperature, diluted with 20 mL water, followed by addition of 30 mL 1.0 N HCl. The precipitate formed was collected by filtration, washed with water, dried under vacuum and then chased with toluene (3×) to yield Intermediate 15B (3.1 g, 15.71 mmol, 98% yield) as a brown solid. It was used for the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 13.77 (br. s., 1H), 7.38 (t, J=8.1 Hz, 1H), 6.94 (t, J=8.1 Hz, 2H), 3.91 (s, 3H); LC-MS: method A, RT=1.63 min, MS (ESI) m/z: 198.0 (M+H)+.
    • Intermediate 15C: 7-methoxy-2-(methylthio)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00416
  • To a solution of Intermediate 15B (2.01 g, 10.19 mmol) in DMF (40 mL) at room temperature was added potassium carbonate (3.52 g, 25.5 mmol). After stirring at room temperature for 10 min, iodomethane (0.796 mL, 12.74 mmol) was added. The reaction mixture was stirred at room temperature for 20 min, at which time HPLC indicated a completion of the reaction. It was diluted with EtOAc, washed with water, brine and dried over sodium sulfate. After evaporation of solvent, Intermediate 15C (2.2 g, 10.41 mmol, 102% yield) was obtained as a brown solid. It was used for the next step without purification. 1H NMR (500 MHz, chloroform-d) δ 7.53 (dd, J=8.0, 0.8 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H), 6.79 (dd, J=8.0, 0.6 Hz, 1H), 3.99 (s, 3H), 2.82 (s, 3H); LC-MS: method A, RT=2.00 min, MS (ESI) m/z: 212.0 (M+H)+.
    • Intermediate 15D: 7-methoxy-2-(methylsulfonyl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00417
  • To a solution of Intermediate 15C (2.2 g, 10.41 mmol) dissolved in MeOH (100 mL) was added dropwise a solution of OXONE (19.20 g, 31.2 mmol) suspended in water (100 mL). The reaction mixture was stirred at room temperature over the weekend. HPLC and TLC indicated a completion of the reaction. The reaction was quenched by addition of dimethyl sulfide (4.62 mL, 62.5 mmol). After stirring at room temperature for 45 min, methanol was removed under vacuum. The mixture was diluted with EtOAc/water. The insoluble material was removed by filtration. The filtrate was collected. The organic layer was washed with water (2×), saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, Intermediate 15D (2.5 g, 10.28 mmol, 99% yield) was obtained as a pale solid. 1H NMR (500 MHz, chloroform-d) δ 7.83 (dd, J=8.3, 0.8 Hz, 1H), 7.59 (t, J=8.1 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.42 (s, 3H); LC-MS: method A, RT=1.55 min, MS (ESI) m/z: 243.9 (M+H)+.
    • Intermediate 15E: 2-hydrazinyl-7-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00418
  • To a suspension of Intermediate 15D (2.5 g, 10.28 mmol) in EtOH (15 mL) was added hydrazine monohydrate (15.55 mL, 308 mmol). The mixture was sonicated for 2 min, heated in oil bath at 100° C. for 1.0 h. HPLC and LCMS indicated a completion of the reaction. Solvent was removed under vacuum. The crude was redissolved in MeOH, and MeOH was removed under vacuum. To the crude was then added ice-cold water (6.0 mL). The precipitate formed was collected by filtration, washed with water, dried over air for 30 min and then at high vacuum over night to give Intermediate 15E (1.67 g, 8.55 mmol, 83% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.97 (dd, J=8.0, 0.8 Hz, 1H), 6.64 (dd, J=8.3, 0.6 Hz, 1H), 5.01 (s, 2H), 3.32 (s, 3H); LC-MS: method A, 0 to 100% B. RT=1.15 min, MS (ESI) m/z: 196.0 (M+H)+.
    • Intermediate 15F: 2-chloro-7-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00419
  • To Intermediate 15E (1.6 g, 8.19 mmol) suspended in dichloromethane (8.0 mL) in a round-bottom flask was added thionyl chloride (8.37 mL, 115 mmol) slowly. The reaction mixture was heated in a pre-heated oil bath at 55° C. for 30 min. HPLC indicated a completion of the reaction. Thionyl chloride was removed under vacuum, chased with EtOAc once to give a yellow solid. The solid was dissolved in EtOAc, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 15F (1.6 g, 8.01 mmol, 98% yield) was obtained as yellow solid. It was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.53-7.48 (m, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 3.91 (s, 3H); LC-MS: method A, RT=1.98 min, MS (ESI) m/z: 199.9 201.9 (M+H)+.
    • Intermediate 15G: 2-chlorobenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00420
  • Aluminum chloride (2.67 g, 20.03 mmol) was added to a solution of Intermediate 15F (1.6 g, 8.01 mmol) in toluene (40 mL). The mixture was heated at 85° C. for 1.5 h. HPLC indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (30 mL) and EtOAc (50 mL), and stirred at room temperature for 30 min. The organic layer was collected, washed with water, saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was triturated with EtOAc/hexanes (1:3). The precipitate was collected to give Intermediate 15G (1.3 g). The filtrate was concentrated, dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with 5% for 2 min., then a 12 min gradient from 5% to 50%. The desired fractions were combined and concentrated to give additional product (96 mg). LC-MS: method A, RT=1.66 min, MS (ESI) m/z: 186.0 and 188.0 (M+H)+.
    • Intermediate 15H: 7-((tert-butyldimethylsilyl)oxy)-2-chlorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00421
  • To a stirred solution of Intermediate 15G (1.39 g, 7.49 mmol) in DMF (20 mL) was added TBDMS-Cl (1.467 g, 9.73 mmol) and imidazole (0.892 g, 13.10 mmol). The reaction mixture was left stirring at room temperature for 1.0 h. The mixture was partitioned between EtOAc/water. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g silica gel cartridge which was eluted with hexanes for 3 min., then a Intermediate 15 min gradient from 0% to 15%. The desired fractions were combined and concentrated to give Intermediate 15H (2.14 g, 7.14 mmol, 95% yield) as brown oil. 1H NMR (500 MHz, chloroform-d) δ 7.60 (dd, J=8.3, 0.8 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 6.85 (dd, J=8.0, 0.8 Hz, 1H), 1.07 (s, 9H), 0.29 (s, 6H); LC-MS: Method A, 50 to 100% B. RT=2.38 min, MS (ESI) m/z: 300.0 and 302.0 (M+H)+.
    • Intermediate 15I 7-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00422
  • To Intermediate I-1 (1.05 g, 3.12 mmol), Intermediate 15H (1.077 g, 3.59 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.128 g, 0.156 mmol) was added toluene (9 mL), EtOH (3 mL) and sodium carbonate (2M, 3.12 mL, 6.25 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 135° C. for 70 min. HPLC indicated completion of reaction. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of toluene/chloroform and charged to a 80 g silica gel cartridge which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 75%. The desired fractions were combined and concentrated to give Intermediate 15I (0.98 g, 2.069 mmol, 66.2% yield) as a bright yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.81 (d, J=1.9 Hz, 1H), 8.76 (s, 1H), 7.83-7.80 (m, 2H), 7.68 (t, JHF=71.80 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.86 (dd, J=7.8, 0.7 Hz, 1H), 2.71 (s, 3H), 1.13 (s, 9H), 0.35 (s, 6H); 19F NMR (471 MHz, chloroform-d) δ −89.74 (s, 2F); LC-MS: Method A, 80 to 100% B. RT=2.41 min, MS (ESI) m/z: 474.0 (M+H)+.
    • Intermediate 15J: 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00423
  • To a solution of Intermediate 15I (1.96 g, 4.14 mmol) in THF (15 mL) at room temperature was added acetic acid (0.521 mL, 9.10 mmol), followed by addition of 1.0 N TBAF in THF (4.97 mL, 4.97 mmol) dropwise. The reaction mixture was stirred at room temperature for 20 min, at which time HPLC and LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc, washed with water, saturated sodium bicarbonate (2×), brine, and dried over sodium sulfate. After evaporation of the solvent, the crude product was triturated with EtOAc/hexanes (1:4). The precipitate was collected by filtration to give Intermediate 15J (1.40 g, 3.893 mmol, 94.0% yield). The filtrate was further concentrated and purified with a 12 g ISCO column eluting with 5%-50% EtOAc in hexanes over 12 min. to give additional product (60 mg). 1H NMR (500 MHz, methanol-d4) δ 8.78 (s, 1H), 8.72 (d, J=1.9 Hz, 1H), 7.87 (s, 1H), 7.79 (t, JHF=71.80 Hz, 1H), 7.60 (dd, J=8.3, 0.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 6.84 (dd, J=7.7, 0.6 Hz, 1H), 2.70 (s, 3H); 19F NMR (471 MHz, methanol-d4) δ −91.07 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=1.68 min, MS (ESI) m/z: 360.0 (M+H)+.
    • Example 15
  • A solution of 4-hydroxymethyl thiazole (24.03 mg, 0.209 mmol) and DIAD (0.041 mL, 0.209 mmol) in THF (1.0 mL) was added dropwise to a mixture of Intermediate 15J (25 mg, 0.070 mmol) and triphenylphosphine (36.5 mg, 0.139 mmol) in THF (0.5 mL) heated at 65° C. At the end of addition, HPLC and LCMS indicated a complete conversion of starting material to the product. Solvent was removed under vacuum and the crude was dissolved in DMSO/acetonitrile (2 mL/1 mL), filtered and purified by prep HPLC (method A, 65-100% B in 10 min; RT=7.2 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 15 (10 mg, 0.022 mmol, 31.2% yield) as yellow lyophilate. 1H NMR (500 MHz, chloroform-d) δ 8.94 (d, J=2.2 Hz, 1H), 8.85 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 7.86-7.82 (m, 2H), 7.69 (t, JHF=71.53 Hz, 1H), 7.59-7.56 (m, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 5.57 (d, J=0.6 Hz, 2H), 2.71 (s, 3H); 19F NMR (471 MHz, chloroform-d) δ −89.74 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=1.94 min, MS (ESI) m/z: 457.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=11.07 min, 99% purity; XBridge, RT=7.14 min, 99% purity.
    • Example 16 tetrahydrofuran-3-yl (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00424
  • To a stirred solution of THF-3-ol (8.21 mg, 0.093 mmol) in dichloromethane (0.6 mL) was added 20% phosgene in toluene (0.078 mL, 0.149 mmol). The reaction mixture was stirred at room temperature for 1.5 h. Solvent was removed under vacuum. The chloroformate obtained was dissolved in dichloromethane (0.5 mL) and added to a solution of Intermediate I-4 (15 mg, 0.037 mmol) and TEA (0.026 mL, 0.186 mmol) in dichloromethane (0.6 mL). The reaction mixture was stirred at room temperature for 30 min. Solvent was removed under vacuum. The crude was dissolved in acetonitrile/DMSO (1 mL/0.5 mL) and was purified by prep HPLC (method A, 60-100% B in 10 min; RT=6 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 16 (3.0 mg, 5.69 μmol, 15.27% yield). 1H NMR (500 MHz, chloroform-d) δ 8.76 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.84 (dd, J=1.9, 0.8 Hz, 1H), 7.68 (t, JHF=71.53 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.17 (dd, J=9.1, 2.5 Hz, 1H), 5.35-5.24 (m, 2H), 4.18 (t, J=5.0 Hz, 2H), 3.99-3.86 (m, 3H), 3.69 (q, J=5.0 Hz, 2H), 2.71 (s, 3H), 2.20 (dd, J=14.2, 6.2 Hz, 1H), 2.11-2.04 (m, 1H); 19F NMR (471 MHz, chloroform-d) δ −89.77 (s, 2F); LC-MS: method A, RT=2.31 min, MS (ESI) m/z: 517.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=8.80 min, 98% purity; XBridge, RT=5.64 min, 98% purity.
    • Example 17 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-phenoxyethoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00425
  • A solution of 2-phenoxyethanol (20.76 mg, 0.150 mmol) and DIAD (0.029 mL, 0.150 mmol) in THF (1.0 mL) was added dropwise to a mixture of Intermediate 15J (18 mg, 0.050 mmol) and triphenylphosphine (26.3 mg, 0.100 mmol) in THF (0.5 mL) heated at 65° C. At the end of addition, HPLC and LCMS indicated a complete conversion of starting material to the product. Solvent was removed under vacuum and the crude was dissolved in DMSO/acetonitrile (1 mL/1 mL), filtered and purified by prep HPLC (method A, 80-100% B in 10 min; RT=8 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 17 (13 mg, 0.026 mmol, 52.5% yield) as yellow lyophilate. 1H NMR (500 MHz, methanol-d4) δ 8.66 (d, J=1.7 Hz, 1H), 8.62 (s, 1H), 7.73 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.57 (t, JHF=71.80 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H), 7.24 (t, J=8.0 Hz, 2H), 6.95-6.89 (m, 3H), 6.85 (d, J=8.0 Hz, 1H), 4.51-4.47 (m, 2H), 4.41-4.36 (m, 2H), 2.59 (s, 3H); 19F NMR (471 MHz, methanol-d4) δ −93.93 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.35 min, MS (ESI) m/z: 480.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=5.27 min, 97% purity; XBridge, RT=2.99 min, 97% purity.
    • Example 18 7-(2-(benzyloxy)ethoxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00426
  • A solution of 2-(benzyloxy)ethanol (22.87 mg, 0.150 mmol) and DIAD (0.029 mL, 0.150 mmol) in THF (1.0 mL) was added dropwise to a mixture of Intermediate 15J (18 mg, 0.050 mmol) and triphenylphosphine (26.3 mg, 0.100 mmol) in THF (0.5 mL) heated at 65° C. At the end of addition, HPLC and LCMS indicated a complete conversion of starting material to the product. Solvent was removed under vacuum and the crude was dissolved in DMSO/acetonitrile (1 mL/1 mL), filtered and purified by prep HPLC (method A, 65-100% B in 10 min; RT=7.2 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 18 (5.0 mg, 9.83 μmol, 19.62% yield) as yellow lyophilate. 1H NMR (500 MHz, chloroform-d) δ 8.87 (d, J=1.9 Hz, 1H), 8.74 (s, 1H), 7.84 (dd, J=2.2, 1.1 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.69 (t, JHF=71.80 Hz, 1H), 7.50-7.45 (m, 3H), 7.44-7.39 (m, 2H), 7.36-7.32 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.75 (s, 2H), 4.47-4.42 (m, 2H), 4.03-3.98 (m, 2H), 2.72 (s, 3H); 19F NMR (471 MHz, chloroform-d) δ −89.74 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.33 min, MS (ESI) m/z: 494.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=5.58 min, 96% purity; XBridge, RT=3.01 min, 98% purity.
    • Example 19 (Tetrahydrofuran-2-yl)methyl (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00427
  • To a solution of (THF-2-yl)methanol (0.194 mL, 1.997 mmol) in dichloromethane (2.0 mL) was added phosgene, 20% in toluene (3.15 mL, 5.99 mmol). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum to give the chloroformate (0.32 g, 1.944 mmol, 97% yield) as a colorless liquid that was used for the next step without further purification.
  • To a solution of Intermediate I-4 (15 mg, 0.037 mmol) in dichloromethane (0.5 mL) was added DIEA (0.052 mL, 0.298 mmol). After stirring at room temperature for 5 min, the chloroformate obtained above (18.40 mg, 0.112 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. HPLC and LCMS indicated a completion of the reaction. Solvent was removed under vacuum. The crude was dissolved in acetonitrile/DMSO (1 mL/1.0 mL) and was purified by prep HPLC (method A, 60-100% B in 10 min; RT=6.5 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 19 (14 mg, 0.026 mmol, 68.7% yield) as yellow lyophilate. 1H NMR (500 MHz, chloroform-d) δ 8.73 (d, J=1.9 Hz, 1H), 8.67 (s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.82 (dd, J=1.9, 1.1 Hz, 1H), 7.67 (t, JHF=71.80 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 7.16 (dd, J=8.9, 2.3 Hz, 1H), 5.40 (br. s., 1H), 4.25 (dd, J=11.3, 3.0 Hz, 1H), 4.19-4.15 (m, 3H), 4.03 (dd, J=11.1, 7.6 Hz, 1H), 3.96-3.90 (m, 1H), 3.88-3.82 (m, 1H), 3.69 (q, J=5.4 Hz, 2H), 2.69 (s, 3H), 2.07-2.00 (m, 1H), 1.99-1.91 (m, 2H); 19F NMR (471 MHz, chloroform-d) δ −89.77 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=1.88 min, MS (ESI) m/z: 531.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=4.06 min, 97% purity; XBridge, RT=3.02 min, 97% purity.
    • Example 20 tetrahydro-2H-pyran-4-yl (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00428
  • To a solution of tetrahydro-2H-pyran-4-ol (0.196 mL, 2.056 mmol) and in dichloromethane (2.0 mL) was added phosgene, 20% in toluene (3.25 mL, 6.17 mmol). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum to give the chloroformate (0.33 g, 2.005 mmol, 98% yield) as a colorless liquid that was used for the next step without further purification.
  • To a solution of Intermediate I-4 (15 mg, 0.037 mmol) in dichloromethane (0.5 mL) was added DIEA (0.052 mL, 0.298 mmol). After stirring at room temperature for 5 min, the chloroformate (18.40 mg, 0.112 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. HPLC and LCMS indicated a completion of the reaction. Solvent was removed under vacuum. The crude was dissolved in acetonitrile/DMSO (1 mL/1.0 mL) and was purified by prep HPLC (method A, 60-100% B in 10 min; RT=6.5 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 20 (4.0 mg, 7.39 μmol, 19.82% yield) as yellow lyophilate. 1H NMR (500 MHz, chloroform-d) δ 8.78 (d, J=1.7 Hz, 1H), 8.71 (s, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.67 (t, JHF=71.80 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.19 (dd, J=8.8, 2.5 Hz, 1H), 5.24 (br. s., 1H), 4.91 (br. s., 1H), 4.19 (t, J=5.1 Hz, 3H), 3.99-3.93 (m, 4H), 3.70 (q, J=5.3 Hz, 3H), 3.58 (t, J=9.5 Hz, 3H), 2.71 (s, 3H), 1.98 (d, J=10.7 Hz, 2H), 1.76-1.68 (m, 2H); 19F NMR (471 MHz, chloroform-d) δ −89.78 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=1.86 min, MS (ESI) m/z: 531.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=4.09 min, 97% purity; XBridge, RT=3.04 min, 98% purity.
    • Example 21 tetrahydro-2H-pyran-4-yl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-7-yl)carbamate
  • Figure US20190292176A1-20190926-C00429
    • Intermediate 21A 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-amine
  • Figure US20190292176A1-20190926-C00430
  • To a suspension of Example 14 (90 mg, 0.196 mmol) in ethyl acetate (1.0 mL) and MeOH (1.0 mL) was added 4.0 N HCl in dioxane (2.454 mL, 9.82 mmol). The reaction mixture was stirred at room temperature overnight. After evaporation of solvent, the crude residue was purified using a preparative HPLC (method A, 50-100% B in 10 min; RT=6 min). The desired fractions were placed in a SpeedVac overnight to remove solvent. TFA was removed by redissolving in EtOAc and washing with saturated sodium bicarbonate. After evaporation of solvent and lyophilization, Intermediate 21A (47 mg, 0.125 mmol, 63.5% yield) was obtained as yellow lyophilate. 1H NMR (500 MHz, chloroform-d) δ 8.84 (s, 1H), 8.70 (s, 1H), 7.81 (s, 1H), 7.66 (t, JHF=71.80 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 2.69 (s, 3H); LC-MS: Method A, 40 to 100% B. RT=1.60 min, MS (ESI) m/z: 359.0 (M+H)+. Analytical HPLC (method A): Sunfire, RT=5.54 min, 95% purity; XBridge, RT=4.54 min, 95% purity.
    • Example 21
  • To a solution of Intermediate 21A (15 mg, 0.042 mmol) in THF (0.8 mL) was added TEA (0.035 mL, 0.251 mmol). After stirring at room temperature for 2 min, the chloroformate prepared in Example 20 (20.67 mg, 0.126 mmol) was added. The reaction mixture was stirred at 50° C. for 1.0 h. HPLC and LCMS indicated a completion of the reaction. The reaction mixture was quenched with 1.0 N HCl (0.25 mL). Solvent was removed under vacuum. The crude was purified via preparative LC/MS (method D, 40-75% B over 10 minutes). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 21 (8 mg). 1H NMR (500 MHz, methanol-d4) δ 8.72 (s, 2H), 7.92 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.71 (t, JHF=71.53 Hz, 1H), 7.58-7.53 (m, 1H), 7.53-7.48 (m, 1H), 5.01 (dt, J=8.4, 4.3 Hz, 1H), 4.25 (s, 2H), 3.98 (br. s., 2H), 3.66-3.59 (m, 1H), 2.69 (s, 3H), 2.08 (dd, J=9.1, 4.1 Hz, 1H), 1.83 (ddt, J=13.2, 8.8, 4.3 Hz, 1H); LC-MS: method A, RT=2.18 min, MS (ESI) m/z: 487.2 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 22 (Tetrahydrofuran-2-yl)methyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)carbamate
  • Figure US20190292176A1-20190926-C00431
  • To a solution of Intermediate 21A (15 mg, 0.042 mmol) in THF (0.5 mL) was added TEA (0.035 mL, 0.251 mmol). After stirring at room temperature for 2 min, the chloroformate prepared in Example 19 (15.16 mg, 0.092 mmol) was added. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was quenched with 1.0 N HCl (0.25 mL). Solvent was removed under vacuum. The crude was purified via preparative LC/MS (method D, 40-75% B over 13 minutes). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 22 (9 mg). 1H NMR (500 MHz, methanol-d4) δ 8.73 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.71 (t, JHF=71.53 Hz, 1H), 7.57 (d, J=10.7 Hz, 1H), 7.53-7.48 (m, 1H), 4.31 (dd, J=11.3, 3.3 Hz, 1H), 4.28-4.22 (m, 1H), 4.17-4.11 (m, 1H), 3.94 (br. s., 1H), 3.86 (d, J=7.2 Hz, 1H), 2.69 (s, 3H), 2.10 (dd, J=12.1, 5.8 Hz, 1H), 1.98 (d, J=7.2 Hz, 2H), 1.78-1.69 (m, 1H); LC-MS: method A, RT=2.18 min, MS (ESI) m/z: 487.3 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 23 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methoxythiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00432
    • Intermediate 23A: 5-methoxythiazolo[5,4-b]pyridin-2-amine
  • Figure US20190292176A1-20190926-C00433
  • To 6-methoxypyridin-3-amine (636 mg, 5.12 mmol) in acetonitrile (14 mL) was added ammonium thiocyanate (585 mg, 7.68 mmol). The reaction mixture was stirred at room temperature for 10 min. Then benzyltrimethylammonium tribromide (1998 mg, 5.12 mmol) in acetonitrile (5.0 mL) was added dropwise (10 min). The mixture was then stirred at room temperature overnight. HPLC and LCMS indicated a single major peak with the desired mass. The mixture was diluted with EtOAc/saturated sodium bicarbonate. The organic layer was collected, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 23A (900 mg, 4.97 mmol, 97% yield) was obtained as a brown solid. 1H NMR indicated >90% purity. It was used for the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 7.61 (d, J=8.5 Hz, 1H), 7.41 (s, 2H), 6.69 (d, J=8.5 Hz, 1H), 3.83 (s, 3H); LC-MS: method A, RT=1.08 min, MS (ESI) m/z: 181.9 (M+H)+.
    • Intermediate 23B: 2-bromo-5-methoxythiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00434
  • Tert-butyl nitrite (0.175 mL, 1.324 mmol) was added to copper (II) bromide (266 mg, 1.192 mmol) in dry acetonitrile (5 mL) under argon. The reaction mixture was stirred at room temperature for 10 min. Intermediate 23A (160 mg, 0.883 mmol) was added. The reaction mixture was stirred at room temperature for 4.0 h. HPLC and LCMS indicated a completion of the reaction. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 0.5N HCl. After stirring at room temperature for 10 min, some insoluble impurity was removed by filtration through a pad of wet celite. The organic layer of the filtrate was collected, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The crude product was purified by flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexane over 15 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 23B (194 mg, 0.792 mmol, 90% yield) as yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.08 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 4.02 (s, 3H); LC-MS: method A, RT=1.92 min, MS (ESI) m/z: 244.8 and 246.8 (M+H)+.
    • Example 23
  • To Intermediate I-1 (25 mg, 0.074 mmol), Intermediate 23B (22.79 mg, 0.093 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.04 mg, 3.72 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.082 mL, 0.164 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. After cooled to room temperature, it was diluted with EtOAc, washed with saturated sodium bicarbonate, brine. The organic layer was dried over sodium sulfate, concentrated and purified via preparative LC/MS (method D, 50-90% B over 10 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 23 (8.0 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.71 (s, 1H), 8.40 (d, J=8.8 Hz, 1H), 7.93 (s, 1H), 7.89 (t, JHF=71.25 Hz, 1H), 7.06 (d, J=9.1 Hz, 1H), 4.01 (s, 3H), 2.68 (s, 3H); LC-MS: method A, RT=2.39 min, MS (ESI) m/z: 375.0 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 24 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxythiazolo[4,5-c]pyridine
  • Figure US20190292176A1-20190926-C00435
    • Intermediate 24A: 7-methoxythiazolo[4,5-c]pyridine-2-thiol
  • Figure US20190292176A1-20190926-C00436
  • A solution of 4-chloro-5-methoxypyridin-3-amine (0.25 g, 1.576 mmol) and potassium O-ethyl carbonodithioate (0.695 g, 4.34 mmol) in DMF (2) was heated at 135° C. under argon for 3.0 h. HPLC and LCMS indicated a completion of the reaction. The mixture was cooled to room temperature, diluted with 2.0 mL water, followed by addition of 10 mL 1.0 N HCl. The precipitated formed was stirred at room temperature for 15 min, then collected by filtration, washed with water, dried under vacuum and then lyophilized to give Intermediate 24A (0.27 g, 1.362 mmol, 86% yield) as a brown solid. It was used for the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.23 (s, 1H), 4.02 (s, 3H); LC-MS: method A, RT=1.20 min, MS (ESI) m/z: 198.9 (M+H)+.
    • Intermediate 24B: 2-chloro-7-methoxythiazolo[4,5-c]pyridine
  • Figure US20190292176A1-20190926-C00437
  • To a slurry of Intermediate 24A (60 mg, 0.303 mmol) in dichloromethane (0.3 mL) was added sulfuryl chloride (0.492 mL, 6.05 mmol). The suspension was stirred at room temperature overnight. To the yellow suspension was added ice/water, stirred at room temperature for 15 min to decompose the excess sulfuryl chloride (exothermic!). EtOAc and 4.0 N NaOH were added to adjust the pH to 10-12. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 4 g silica gel cartridge which was eluted with 5% EtOAc in hexanes for 2 min., then a 10 min gradient from 5% to 60%. The desired fractions were combined and concentrated to give Intermediate 24B (40 mg, 0.199 mmol, 65.9% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 8.95 (s, 1H), 8.24 (s, 1H), 4.11 (s, 3H); LC-MS: method A, RT=1.21 min, MS (ESI) m/z: 200.9 and 202.9 (M+H)+.
    • Example 24
  • To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 24B (22.38 mg, 0.112 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.64 mg, 4.46 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.098 mL, 0.196 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. After cooled to room temperature, it was diluted with EtOAc, washed with saturated sodium bicarbonate, brine. The organic layer was dried over sodium sulfate, concentrated and purified via preparative LC/MS (method D, 35-80% B over 10 minutes, then a
  • After a five-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 24 (4.1 mg). 1H NMR (400 MHz, acetonitrile-d3) δ 9.23 (s, 1H), 8.91 (s, 1H), 8.86 (s, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.73 (t, JHF=71.50 Hz, 1H), 4.24 (s, 3H); 19F NMR (376 MHz, acetonitrile-d3) δ −77.11 (br. s., 3F, TFA), −90.66 (s, 2F); LC-MS: method A, RT=1.95 min, MS (ESI) m/z: 374.9 (M+H)+. Analytical HPLC purity (method B): 91%.
    • Example 25 tert-butyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)carbamate
  • Figure US20190292176A1-20190926-C00438
    • Intermediate 25A: 4,5,6,7-tetrahydrobenzofuran-4-ol
  • Figure US20190292176A1-20190926-C00439
  • To a solution of 6,7-dihydrobenzofuran-4(5H)-one (4.94 g, 36.3 mmol) in MeOH (110 mL) at 0° C. was added NaBH4 (1.579 g, 41.7 mmol) in 3 portions. The reaction mixture was stirred at 0° C. for 2.0 h. TLC indicated a completion of the reaction. MeOH was removed under reduced pressure. To the residue was added EtOAc, water. The pH was adjusted to 7 with saturated ammonium chloride/0.5 N HCl. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 25A (4.96 g, 35.9 mmol, 99% yield) was obtained as a clear oil. 1H NMR (500 MHz, chloroform-d) δ 7.29-7.26 (d, J=1.77 Hz, 1H), 6.41 (d, J=1.77 Hz, 1H), 4.77-4.71 (m, 1H), 2.69-2.61 (m, 1H), 2.59-2.50 (m, 1H), 2.04-1.89 (m, 2H), 1.87-1.75 (m, 2H), 1.64 (br. s., 1H); LC-MS: method A, RT=1.24 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 25B: tert-butyldimethyl((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)silane
  • Figure US20190292176A1-20190926-C00440
  • To a solution of Intermediate 25A (4.96 g, 35.9 mmol) in DMF (60 mL) was added imidazole (3.67 g, 53.8 mmol) and TBDMS-Cl (6.76 g, 44.9 mmol). The reaction mixture was stirred at room temperature for 1.5 h. TLC and HPLC indicated a completion of the reaction. The reaction mixture was diluted with EtOAc and quenched with water. The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated in vacuum. The crude product was purified by flash chromatography (loading in chloroform, 0% to 10% EtOAc in hexane over 20 min using a 120 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 25B (8.34 g, 33.0 mmol, 92% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ 7.27-7.25 (m, 1H), 6.33 (d, J=1.9 Hz, 1H), 4.79-4.75 (m, 1H), 2.68-2.61 (m, 1H), 2.57-2.50 (m, 1H), 2.10-2.02 (m, 1H), 1.95-1.89 (m, 1H), 1.81-1.68 (m, 2H), 0.95 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H); LC-MS: Method A, 40 to 100% B. RT=2.30 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 25C: tert-butyl((2-iodo-4,5,6,7-tetrahydrobenzofuran-4-yl)oxy) dimethylsilane
  • Figure US20190292176A1-20190926-C00441
  • To Intermediate 25B (300 mg, 1.188 mmol) in THF (4.0 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (1.114 mL, 1.783 mmol). The mixture was warmed up to 0° C. with an ice bath and stirred for 20 min. The mixture was cooled to −78° C. with dry ice/acetone bath, and iodine (362 mg, 1.426 mmol) in 1 ml THF was added slowly, The reaction mixture was stirred at −78° C. for 10 min, then at 0° C. for 30 min. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with 10% Na2S2O3, brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 25C (414 mg, 0.996 mmol, 84% yield) was obtained as a brown oil. 1H NMR indicated >90% purity. It was used for next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 6.47 (s, 1H), 4.74-4.70 (m, 1H), 2.71-2.65 (m, 1H), 2.61-2.54 (m, 1H), 2.06-1.99 (m, 1H), 1.92-1.86 (m, 1H), 1.77-1.64 (m, 2H), 0.95 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H); LC-MS: Method A, 80 to 100% B. RT=1.76 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 25D 5-(4-((tert-butyldimethylsilyl)oxy)-4,5,6,7-tetrahydrobenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00442
  • To Intermediate 25C (410 mg, 1.084 mmol) and Intermediate I-1 (335 mg, 0.997 mmol) was added toluene (3 mL) and EtOH (1 mL). The reaction mixture was stirred at room temperature until solids are dissolved then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (35.4 mg, 0.043 mmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (2M, 1.084 mL, 2.167 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then put in microwave reactor at 130° C. for 30 min. To the reaction mixture was added EtOAc/water, stirred at room temperature for 10 min. The insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 15% EtOAc in hexane over 15 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 25D (320 mg, 0.591 mmol, 54.5% yield): LC-MS: Method A, 80 to 100% B. RT=2.74 min, MS (ESI) m/z: 461.22 (M+H)+.
    • Intermediate 25E 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofuran-4-ol
  • Figure US20190292176A1-20190926-C00443
  • To a solution of Intermediate 25D (320 mg, 0.695 mmol) in THF (2.0 mL) at room temperature was added 1.0 N TBAF in THF (0.834 mL, 0.834 mmol). The reaction mixture was stirred at room temperature for 4.0 h. HPLC indicated a completion of reaction. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexane over 12 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 25E (80 mg, 0.226 mmol, 32.6% yield). 1H NMR (500 MHz, methanol-d4) δ 8.57 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.67 (t, JHF=71.28 Hz, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 4.78 (t, J=4.7 Hz, 1H), 2.81-2.74 (m, 1H), 2.72-2.64 (m, 1H), 2.59 (s, 3H), 2.14-2.07 (m, 1H), 2.02-1.95 (m, 1H), 1.91-1.77 (m, 2H); LC-MS: method A, RT=2.13 min, MS (ESI) m/z: 347.3 (M+H)+.
    • Intermediate 25F: tert-butyl N-[(tert-butoxy)carbonyl]-N-{2-[2-(difluoromethoxy)-7-methylquinoxalin-5-yl]-4,5,6,7-tetrahydro-1-benzofuran-4-yl}carbamate
  • Figure US20190292176A1-20190926-C00444
  • A solution of Intermediate 25E (74 mg, 0.214 mmol) and DIAD (0.091 mL, 0.470 mmol) in THF (2.0 mL) was added dropwise to a mixture of di-tert-butyl iminodicarboxylate (81 mg, 0.374 mmol) and triphenylphosphine (112 mg, 0.427 mmol) in THF (1.0 mL) heated at 50° C. At the end of addition, HPLC and LCMS indicated a complete conversion of starting material to the product. After evaporation of solvent, the crude product was purified by flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexanes over 18 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 25F (12 mg, 0.022 mmol, 10.29% yield) as yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.58 (s, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.65 (t, JHF=71.80 Hz, 1H), 7.56 (s, 1H), 7.52 (dd, J=1.8, 1.0 Hz, 1H), 5.41-5.35 (m, 1H), 2.77-2.73 (m, 2H), 2.60 (s, 3H), 2.20-2.11 (m, 4H), 1.47-1.44 (s, 18H); LC-MS: Method A, 50 to 100% B. RT=2.47 min, MS (ESI) m/z: 446.2 (M-Boc)+.
    • Example 25
  • To Intermediate 25F (12 mg, 0.022 mmol) was added dichloromethane (1.0 mL) containing TFA (3.39 μl, 0.044 mmol). The solution was aged at room temperature overnight. Solvent was removed under vacuum. The crude material was purified via preparative LC/MS (method D, 55-95% B over 10 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 25 (5.3 mg). 1H NMR (500 MHz, methanol-d4) δ 8.56 (s, 1H), 7.96 (s, 1H), 7.66 (t, JHF=72.80 Hz, 1H), 7.56-7.52 (m, 2H), 4.70 (br. s., 1H), 2.75-2.68 (m, 2H), 2.58 (s, 3H), 2.03 (d, J=9.4 Hz, 2H), 1.94-1.87 (m, 1H), 1.74 (dd, J=10.2, 6.3 Hz, 1H); LC-MS: method A, RT=2.59 min, MS (ESI) m/z: 468.3 (M+Na)+. Analytical HPLC purity (method B): 100%.
    • Example 26 4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00445
    • Intermediate 26A: 2-chloro-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00446
  • To a solution of copper (II) chloride (1.661 g, 12.35 mmol) in acetonitrile (8 mL) at 40° C. was added tert-butyl nitrite (1.769 mL, 13.38 mmol), followed by Intermediate I-3A (2 g, 10.30 mmol) as a solid. The mixture was stirring at 40° C. for 2.0 h. HPLC and LCMS indicated a complete conversion of starting material. The mixture was diluted with EtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine. After evaporation of solvent, Intermediate 26A (2.4 g, 11.23 mmol, 99% yield) was obtained as a brown solid. 1H NMR indicated >95% purity. 1H NMR (500 MHz, chloroform-d) δ 7.07 (d, J=2.5 Hz, 1H), 6.93-6.77 (m, 1H), 3.85 (s, 3H), 2.66 (s, 3H); LC-MS: method B, 0 to 100% B), retention time: 2.08 min, [M+1]+=213.9
    • Intermediate 26B: 2-chloro-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00447
  • Aluminum chloride (4.49 g, 33.7 mmol) was added to a solution of Intermediate 26A (2.4 g, 11.23 mmol) in toluene (50 mL). The mixture was heated at 110° C. for 1.5 h. TLC indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water (3×), saturated sodium bicarbonate (3×), water (3×) and air-dried for 1.0 h under vacuum. It was further dried under high vacuum overnight to give Intermediate 26B as a brown solid (1.9 g). 1H NMR (400 MHz, methanol-d4) δ 7.06 (d, J=2.3 Hz, 1H), 6.82 (s, 1H), 2.57 (s, 3H). LC-MS: Method A, 50 to 100% B. RT=1.72 min, MS (ESI) m/z: 200.0 and 202.0 (M+H)+.
    • Intermediate 26C: 6-((tert-butyldimethylsilyl)oxy)-2-chloro-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00448
  • To a stirred solution of Intermediate 26B (2.2 g, 11.02 mmol) in DMF (50 mL) was added TBDMS-Cl (2.325 g, 15.43 mmol) and imidazole (1.313 g, 19.28 mmol). The reaction mixture was left stirring at room temperature for 1.0 h. HPLC and TLC indicated a completion of the reaction. The mixture was partitioned between EtOAc/water. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 120 g ISCO column which was eluted with hexanes for 3 min., then a 30 min gradient from 0% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 26C (1.57 g, 5.00 mmol, 45.4% yield) as an orange solid. 1H NMR (400 MHz, chloroform-d) δ 7.09-6.94 (m, 1H), 6.81 (dd, J=2.5, 0.8 Hz, 1H), 2.64 (s, 3H), 1.01 (s, 9H), 0.23 (s, 6H). LC-MS: Method A, 50 to 100% B. RT=2.72 min, MS (ESI) m/z: 314.0 and 316.0.0 (M+H)+.
    • Intermediate 26D 6-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00449
  • To Intermediate I-1 (310 mg, 0.922 mmol), Intermediate 26C (333 mg, 1.061 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (37.7 mg, 0.046 mmol) was added toluene (3 mL), EtOH (1 mL) and sodium carbonate (2M, 0.922 mL, 1.844 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 135° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 75% EtOAc in hexanes. The desired fractions were combined and concentrated to yield Intermediate 26D (450 mg, 0.923 mmol, 100% yield) as a bright yellow solid. LC-MS: Method A, 50 to 100% B. RT=2.72 min, MS (ESI) m/z: 488.0 (M+H)+.
  • Intermediate 26E:
    • 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00450
  • To a solution of Intermediate 26D (450 mg, 0.923 mmol) in THF (5 mL) at room temperature was added acetic acid (0.116 mL, 2.030 mmol), followed by addition of 1.0 N TBAF in THF (1.107 mL, 1.107 mmol) dropwise. The reaction mixture was stirred at room temperature for 30 min. LCMS indicated a completion of reaction. The mixture was diluted with EtOAc, washed with water, saturated sodium bicarbonate (2×), brine, and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified with a 12 g ISCO column eluting from 5% EtOAc to 50% EtOAc in hexanes to give Intermediate 26E (290 mg, 0.777 mmol, 84% yield). 1H NMR (500 MHz, acetonitrile-d3) δ 8.81 (d, J=1.9 Hz, 1H), 8.74 (s, 1H), 7.80 (dd, J=1.8, 1.0 Hz, 1H), 7.89-7.51 (m, 1H), 7.28 (d, J=1.9 Hz, 1H), 6.88 (dd, J=2.5, 0.8 Hz, 1H), 2.76 (s, 3H), 2.69 (s, 3H). LC-MS: Method A, 50 to 100% B. RT=1.44 min, MS (ESI) m/z: 373.9 (M+H)+.
    • Intermediate 26F 2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethanamine hydrochloride
  • Figure US20190292176A1-20190926-C00451
  • A solution of DIAD (0.391 mL, 2.009 mmol) was added to a mixture of Intermediate 26E (250 mg, 0.670 mmol). Tert-butyl (2-hydroxyethyl)carbamate (108 mg, 0.670 mmol) and triphenylphosphine (351 mg, 1.339 mmol) in toluene (5 mL) was added dropwise. The reaction mixture was heated 110° C. for 30 min. The mixture was concentrated and dissolved in 1 ml of DCM and purified by 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was concentrated. The sample was redissolved in 5 ml of DCM and 4N HCl/dioxane (8.37 mL, 33.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Solvent was removed under vacuum to give Intermediate 26F (250 mg, 0.552 mmol, 82% yield) as a solid. 1H NMR (400 MHz, chloroform-d) δ 8.65 (d, J=1.8 Hz, 1H), 8.52 (s, 1H), 7.62 (d, J=0.8 Hz, 1H), 7.54 (t, JHF=72 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 6.86 (d, J=1.5 Hz, 1H), 5.02-4.95 (m, 2H), 3.98 (t, J=5.1 Hz, 2H), 2.72 (s, 4H), 2.58 (s, 4H); LC-MS: Method A, 50 to 100% B. RT=2.12 min, MS (ESI) m/z: 416.9 (M+H)+.
    • Example 26
  • To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of 4-fluorobenzene-1-sulfonyl chloride (7.73 mg, 0.040 mmol) in 0.2 ml of DCM. The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was dissolved in 1 ml of MeOH and sodium methoxide (0.199 mL, 0.099 mmol) was added. The reaction mixture was stirred at room temperature for 1h. The crude material was purified via preparative LC/MS (method C, 45-85% B over 20 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 26 (7.0 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.58 (s, 1H), 7.91 (dd, J=8.3, 5.5 Hz, 2H), 7.81 (s, 1H), 7.46-7.41 (m, 3H), 6.86 (s, 1H), 4.09 (s, 3H), 4.06 (t, J=5.2 Hz, 2H), 3.23 (t, J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H); LC-MS: method A, RT=2.360 min, MS (ESI) m/z: 539.2 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 27 N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00452
    • Intermediate 27A: tert-butyl (2-(3-chloro-4-nitrophenoxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00453
  • To a solution of tert-butyl (2-hydroxyethyl)carbamate (918 mg, 5.70 mmol) in THF (8 mL) was added 0.5 M potassium bis(trimethylsilyl)amide in toluene (12.53 mL, 6.27 mmol). The reaction mixture was stirred at room temperature for 20 min. 2-Chloro-4-fluoro-1-nitrobenzene (500 mg, 2.85 mmol) was added and the reaction mixture was stirred at room temperature for 0.5 h, then at 55° C. for 1.5 h. The mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 45% EtOAc in hexane over 15 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 27A (425 mg, 1.342 mmol, 47.1% yield) as yellow liquid. 1H NMR (500 MHz, chloroform-d) δ 8.04-8.00 (d, J=9.1 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 6.90 (dd, 2.5 Hz, 1H), 4.14-4.10 (m, 2H), 3.58 (q, J=5.3 Hz, 2H), 1.50 (s, 9H); LC-MS: method A, RT=1.97 min, MS (ESI) m/z: 261.1 and 263.1 (M-t-Bu)+.
    • Intermediate 27B: tert-butyl (2-(4-amino-3-chlorophenoxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00454
  • To a solution of Intermediate 27A (0.42 g, 1.326 mmol) in MeOH (10 mL) was added ammonium chloride (1.135 g, 21.22 mmol) and zinc dust (0.694 g, 10.61 mmol). The reaction mixture was stirred at room temperature for 30 min. HPLC and LCMS indicated a completion of the reaction. MeOH was removed under vacuum. The residue was diluted with EtOAc/saturated sodium bicarbonate and stirred at room temperature for 10 min. The mixture was filtered to remove insoluble material. The filtrate was collected, organic layer was washed with brine, dried over sodium sulfate, concentrated to give Intermediate 27B (380 mg, 1.325 mmol, 100% yield) as oil. 1H NMR (500 MHz, chloroform-d) δ 6.87 (d, J=2.5 Hz, 1H), 6.75-6.68 (m, 2H), 4.98 (br. s., 1H), 3.95 (t, J=5.2 Hz, 2H), 3.51 (t, J=5.0 Hz, 2H), 1.48 (s, 9H); LC-MS: method A, RT=1.47 min, MS (ESI) m/z: 187.1 and 189.1 (M-Boc)+.
    • Intermediate 27C: tert-butyl(2-((2-amino-4-chlorobenzo[d]thiazol-6-yl)oxy)ethyl) carbamate
  • Figure US20190292176A1-20190926-C00455
  • To Intermediate 27B (465 mg, 1.622 mmol) in acetonitrile (5.0 mL) was added ammonium thiocyanate (216 mg, 2.84 mmol). The reaction mixture was stirred at room temperature for 10 min. Benzyltrimethylammonium tribromide (854 mg, 2.189 mmol) in acetonitrile (2.0 mL) was added dropwise (5 min). The reaction mixture was stirred at room temperature for 30 min. HPLC and LCMS indicated ca 30% starting material present. Then another portion of ammonium thiocyanate (211 mg, 2.77 mmol) and benzyltrimethylammonium tribromide (415 mg, 1.06 mmol) were added. The reaction mixture was left stirring at room temperature overnight. Acetonitrile was removed under vacuum. The mixture was diluted with EtOAc, THF/saturated sodium bicarbonate. The insoluble material was removed by filtration. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate and concentrated to give Intermediate 27C (460 mg, 1.204 mmol, 74.3% yield) as yellow solid that was used for the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 7.59 (s, 2H), 7.30 (d, J=2.5 Hz, 1H), 7.01-6.96 (m, 1H), 6.92 (d, J=2.5 Hz, 1H), 3.95 (t, J=5.8 Hz, 2H), 3.27 (q, J=5.5 Hz, 2H), 1.39 (s, 9H); LC-MS: method A, RT=1.67 min, MS (ESI) m/z: 344.1 (M+H)+.
    • Intermediate 27D: tert-butyl (2((2-bromo-4-chlorobenzo[d]thiazol-6-yl)oxy)ethyl) carbamate
  • Figure US20190292176A1-20190926-C00456
  • Tert-butyl nitrite (0.249 mL, 1.885 mmol) was added to copper (II) bromide (421 mg, 1.885 mmol) in acetonitrile (6 mL) under argon. The reaction mixture was stirred at room temperature for 10 min. Intermediate 27C (405 mg, 1.178 mmol) suspended in acetonitrile (6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 min. HPLC and LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc, quenched with 0.5N HCl. After stirring at room temperature for 10 min, the organic layer of the filtrate was collected, washed with 0.5 N HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 35% EtOAc in hexane over 18 min using a 24 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 27D (411 mg, 1.008 mmol, 86% yield) as a semi solid which was lyophilized to a solid. 1H NMR (500 MHz, chloroform-d) δ 7.18 (d, J=2.2 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 4.98 (br. s., 1H), 4.09 (t, J=5.1 Hz, 2H), 3.58 (q, J=5.0 Hz, 2H), 1.48 (s, 9H); LC-MS: method A, RT=1.72 min, MS (ESI) m/z: 407.0 and 409.0 (M+H)+.
    • Intermediate 27E: tert-butyl (2-((4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) ethyl)carbamate
  • Figure US20190292176A1-20190926-C00457
  • To Intermediate 27D (358 mg, 0.878 mmol) and Intermediate I-1 (295 mg, 0.878 mmol) was added toluene (6 mL) and EtOH (2 mL). The reaction mixture was stirred at room temperature until solids are dissolved then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (35.9 mg, 0.044 mmol) was added. The flask was degassed and flushed with argon. Sodium carbonate (2M, 0.878 mL, 1.756 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then put in microwave reactor at 120° C. for 35 min. HPLC and TLC indicated a completion of the reaction. To the reaction mixture was added EtOAc/water, stirred at room temperature for 10 min. The insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 35% EtOAc in hexanes over 15 min using a 24 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 27E (421 mg, 0.784 mmol, 89% yield) as yellow solid. 1H NMR (400 MHz, acetonitrile-d3) δ 8.77 (d, J=1.5 Hz, 1H), 8.72 (s, 1H), 7.82 (dd, J=1.9, 1.0 Hz, 1H), 7.71 (t, JHF=71.53 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 4.12 (t, J=5.5 Hz, 2H), 3.49 (q, J=5.6 Hz, 2H), 2.71 (s, 3H), 1.45 (s, 9H); 19F NMR (376 MHz, acetonitrile-d3) δ −90.04 (s, 2F); LC-MS: Method A, 40 to 100% B. RT=2.44 min, MS (ESI) m/z: 537.2 (M+H)+.
    • Intermediate 27F: tert-butyl (2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00458
  • To Intermediate 27E (400 mg, 0.745 mmol) in DMF (5.0 mL) was added 0.5 N NaOMe in MeOH (3.28 mL, 1.639 mmol). The reaction mixture was stirred at room temperature for 40 min, diluted with THF (3.0 mL) and EtOAc (10 mL) and quenched with 1.0 N HCl (1.862 mL, 1.862 mmol). THF (50 mL) was added followed with brine. The mixture turned to a clean solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give Intermediate 27F (370 mg, 0.739 mmol, 99% yield) as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.29 (d, J=2.5 Hz, 1H), 4.10 (t, J=5.78 Hz, 2H), 4.09 (s, 3H), 3.38-3.34 (m, 2H), 2.65 (s, 3H), 1.40 (s, 9H); LC-MS: Method A, 40 to 100% B. RT=2.44 min, MS (ESI) m/z: 501.2 and 503.2 (M+H)+.
    • Intermediate 27G 2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanamin e hydrochloride
  • Figure US20190292176A1-20190926-C00459
  • To Intermediate 27F (0.32 g, 0.639 mmol) was added 4.0 N HCl in dioxane (15.97 mL, 63.9 mmol), followed by MeOH (8.0 mL). The reaction mixture was stirred at 45° C. for 15 min, and then at room temperature for 30 min. HPLC indicated a completion of reaction. Solvent was removed under vacuum. The crude was partitioned between EtOAc/saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and lyophilized to give Intermediate 27G (50 mg, 0.114 mmol, 17.90% yield). 1H NMR (400 MHz, methanol-d4) δ 8.19 (d, J=1.8 Hz, 1H), 8.05 (s, 1H), 7.31 (s, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 4.27 (t, J=5.0 Hz, 2H), 3.94 (s, 3H), 3.44 (t, J=5.0 Hz, 2H), 2.44 (s, 3H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z: 401.1 and 403.1 (M+H)+.
    • Example 27
  • To Intermediate 27G (24 mg, 0.055 mmol) in DMF (0.8 mL) was added DIEA (0.058 mL, 0.329 mmol). After stirring at room temperature for 2 min, benzenesulfonyl chloride (10.61 μl, 0.082 mmol) was added and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was quenched with MeOH (1.0 mL). The crude material was purified via preparative LC/MS (method C, 40-85% B over 20 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 27 (6.4 mg, 22% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.57 (d, J=1.7 Hz, 1H), 7.87-7.85 (m, 1H), 7.85-7.83 (m, 2H), 7.64-7.58 (m, 4H), 7.15 (d, J=2.2 Hz, 1H), 4.11-4.07 (m, 5H), 3.22 (br. s., 2H), 2.65 (s, 3H); LC-MS: method A, RT=2.55 min, MS (ESI) m/z: 541.0 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 28 N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00460
  • To Intermediate 27G (30 mg, 0.069 mmol) in DMF (0.8 mL) was added DIEA (0.060 mL, 0.343 mmol). After stirring at room temperature for 4 min, 4-fluorobenzenesulfonyl chloride (14.68 mg, 0.075 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with MeOH (1.0 mL) and purified via preparative LC/MS (method C, 45-85% B over 20 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 28 (8.9 mg, 22% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.57 (d, J=1.7 Hz, 1H), 7.97-7.89 (m, 3H), 7.84 (s, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.45-7.40 (m, 2H), 7.14 (d, J=2.2 Hz, 1H), 4.11-4.07 (m, 5H), 3.24 (t, J=5.2 Hz, 2H), 2.65 (s, 3H); LC-MS: method A, RT=2.50 min, MS (ESI) m/z: 559.0 and 561.0 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 29 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00461
  • To Intermediate I-2 (41 mg, 0.177 mmol), Intermediate I-5 (79 mg, 0.177 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.21 mg, 8.83 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.177 mL, 0.353 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate, concentrated. The crude residue was dissolved in DMSO/MeOH (3.5 mL each), purified using a preparative HPLC (method A, 65-100% B in 10 min; then 100% B in 2 min, RT=7.2 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 29 (59 mg, 0.106 mmol, 59.8% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 9.05 (s, 1H), 8.88 (s, 1H), 7.98-7.89 (m, 3H), 7.26 (td, J=8.7, 1.8 Hz, 3H), 6.85 (s, 1H), 5.95 (br. s., 1H), 4.82 (s, 2H), 4.07 (t, J=4.6 Hz, 2H), 3.56 (s, 3H), 3.39-3.31 (m, 2H), 2.80 (s, 3H), 2.72 (s, 3H); 19F NMR (471 MHz, acetonitrile-d3) δ −107.47 (s, 1F); LC-MS: method A, RT=2.32 min, MS (ESI) m/z: 553.1 (M+H)+. Analytical HPLC (method A): Sunfire, RT=10.81 min, 99% purity; XBridge, RT=6.64 min, 99% purity.
    • Example 30 N-(2-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00462
    • Intermediate 30A N-(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00463
  • To Intermediate I-1 (40 mg, 0.119 mmol), Intermediate I-5 (48.2 mg, 0.108 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.07 mg, 8.65 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.119 mL, 0.238 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate, concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 75% EtOAc in hexane over 20 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 30A (50 mg, 0.087 mmol, 80% yield) as yellow solid. LC-MS: method A, RT=2.71 min, MS (ESI) m/z: 575.1 (M+H)+.
    • Example 30
  • To Intermediate 30A (14 mg, 0.024 mmol) dissolved in EtOH (0.5 mL) and THF (0.4 mL) was added sodium ethoxide in ethanol (0.027 mL, 0.073 mmol) (21% by weight). The reaction mixture was stirred at room temperature for 15 min., another portion of sodium ethoxide in ethanol (0.027 mL, 0.073 mmol) was added. The mixture was left stirring at room temperature overnight. LCMS indicated a completion of the reaction. Solvent was removed and the residue was dissolved in DMSO/MEOH (1:1) and purified via preparative LC/MS (method D, 65-100% B over 10 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 30 (11.3 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 7.91 (dd, J=8.5, 5.5 Hz, 2H), 7.78 (s, 1H), 7.46-7.41 (m, 3H), 6.86 (s, 1H), 4.54 (q, J=7.1 Hz, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.23 (t, J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H), 1.45 (t, J=7.2 Hz, 3H); LC-MS: method A, RT=2.48 min, MS (ESI) m/z: 553.3 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 31 N-(2-((2-(2-ethyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00464
    • Intermediate 31A: tert-butyl (2-bromo-4-methyl-6-nitrophenyl)(2-oxobutyl)carbamate
  • Figure US20190292176A1-20190926-C00465
  • To Intermediate I-1B (1.28 g, 3.87 mmol) in DMF (15 mL) at room temperature was added Cs2CO3 (2.204 g, 6.76 mmol). The brown solution was stirred at room temperature for 5 min, followed by addition of 1-bromobutan-2-one (0.592 mL, 5.80 mmol) in acetonitrile (0.4 mL). The brown solution turned yellow. The reaction mixture was stirred at room temperature for 15 min. TLC indicated a completion of the reaction The mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 40% EtOAc in hexane over 10 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 31A (1.5 g, 3.74 mmol, 97% yield) as yellow liquid. 1H NMR (400 MHz, chloroform-d) indicated presence of two rotamers. δ 7.73-7.67 (m, 2H), 4.51-4.05 (m, 2H), 2.57-2.49 (m, 2H), 2.47 and 2.42 (s, 3H), 1.53 and 1.37 (s, 9H), 1.18 and 1.13 (t, J=7.26 Hz, 3H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z: 310.0 and 303.0 (M-Boc)+.
    • Intermediate 31B: 5-bromo-2-ethyl-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00466
  • To Intermediate 31A (1.55 g, 3.86 mmol) in ethyl acetate (8 mL) was added 4.0 N HCl in dioxane (11.59 mL, 46.4 mmol) and the reaction mixture was stirred at room temperature for 45 min. HPLC indicated a completion of the reaction. Solvent was removed under vacuum to give the deprotected intermediate as yellow oil. The deprotected intermediate was dissolved in THF (20 mL). Tin (II) chloride dihydrate (2.88 g, 12.75 mmol) was added, followed by concentrated HCl (0.476 mL, 5.79 mmol). The mixture was placed and stirred in oil bath pre-heated at 45° C. for 1.0 h. HPLC and LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc/water and neutralized with saturated sodium bicarbonate. The reaction mixture was stirred at room temperature for 15 min, the precipitate was removed by a separatory funnel. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give Intermediate 31B (0.93 g, 3.70 mmol, 96% yield) as a light yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.70 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.72 (dd, J=1.8, 0.9 Hz, 1H), 2.99 (q, J=7.7 Hz, 2H), 2.50 (s, 3H), 1.36 (t, J=7.6 Hz, 3H); LC-MS: method A, RT=1.93 min, MS (ESI) m/z: 251.1 and 253.1 (M+H)+.
    • Intermediate 31C: (2-ethyl-7-methylquinoxalin-5-yl)boronic acid
  • Figure US20190292176A1-20190926-C00467
  • A mixture of Intermediate 31B (129 mg, 0.514 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (261 mg, 1.027 mmol), potassium acetate (101 mg, 1.027 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (16.78 mg, 0.021 mmol) in dioxane (3.0 mL) was degassed by bubbling argon for 10 min. The reaction vial was sealed and heated in microwave reactor at 130° C. for 30 min. LCMS indicated complete conversion of starting material. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine and dried over sodium sulfate.
  • The crude residue was dissolved in MeOH/DMSO (1:1) and purified using a preparative HPLC (method A, 20-100% B in 10 min; then 100% B in 2 min; RT=3.5 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 31C (50 mg, 0.231 mmol, 45.1% yield) as a solid. 1H NMR in CDCl3 suggested presence of isomeric forms. HPLC and LCMS indicated a single peak. LC-MS: method A, RT=1.86 min, MS (ESI) m/z: 217.0 (M+H)+.
    • Example 31
  • To Intermediate 31C (8.73 mg, 0.040 mmol), Intermediate I-5 (18 mg, 0.040 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (2.64 mg, 3.23 μmol) was added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.040 mL, 0.081 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate, concentrated. The crude product was purified via preparative LC/MS (method D, 60-100% B over 10 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 31 (15.2 mg). 1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.75 (s, 1H), 8.04 (br. s., 1H), 7.99 (s, 1H), 7.91 (dd, J=8.7, 5.4 Hz, 2H), 7.47-7.41 (m, 3H), 6.87 (s, 1H), 4.06 (t, J=5.1 Hz, 2H), 3.23 (t, J=5.1 Hz, 2H), 3.09 (q, J=7.7 Hz, 2H), 2.74 (s, 3H), 2.68 (s, 3H), 1.40 (t, J=7.6 Hz, 3H); LC-MS: method A, RT=2.59 min, MS (ESI) m/z: 537.3 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 32 methyl 5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00468
    • Intermediate 32A: (2-(methoxycarbonyl)-7-methylquinoxalin-5-yl)boronic acid
  • Figure US20190292176A1-20190926-C00469
  • A mixture of methyl 5-bromo-7-methylquinoxaline-2-carboxylate (103 mg, 0.366 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (205 mg, 0.806 mmol), potassium acetate (90 mg, 0.916 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (11.97 mg, 0.015 mmol) in dioxane (3.0 mL) was degassed by bubbling argon for 10 min. The reaction vial was sealed and heated in microwave reactor at 130° C. for 30 min. LCMS indicated complete conversion of starting material. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine and dried over sodium sulfate. The crude residue was dissolved in MeOH/DMSO (1:1) and purified using a preparative HPLC (method A, 30-100% B in 10 min; then 100% B in 2 min; RT=3.5 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 32A (46 mg, 0.187 mmol, 51.0% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 9.43 (s, 1H), 8.30 (br. s., 1H), 8.07 (br. s., 1H), 4.11 (s, 3H), 2.64 (s, 3H); LC-MS: method A, RT=1.64 min, MS (ESI) m/z: 247.1 boronic acid (M+H)+.
    • Intermediate 32B 5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylic acid
  • Figure US20190292176A1-20190926-C00470
  • To Intermediate 32A (24 mg, 0.098 mmol), Intermediate I-5 (43.4 mg, 0.098 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.98 mg, 4.88 μmol) was added toluene (1.5 mL) and MeOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.098 mL, 0.195 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. LCMS indicated a completion of the reaction to the acid. The mixture was diluted with EtOAc/THF (40 Ml/20 mL), acidified with 0.5 N HCl. The organic layer was washed with brine, dried over sodium sulfate and concentrated, purified via preparative LC/MS (method D, 15-55% B over 20 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Intermediate 32B (38.5 mg). 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.91 (s, 1H), 8.16 (br. s., 1H), 8.05 (t, J=5.2 Hz, 1H), 7.98-7.89 (m, 3H), 7.48-7.41 (m, 2H), 6.87 (d, J=1.1 Hz, 1H), 4.07 (t, J=5.2 Hz, 2H), 3.25-3.21 (m, 2H), 2.74 (s, 3H), 2.73 (s, 3H); LC-MS: method A, RT=2.04 min, MS (ESI) m/z: 553.2 (M+H)+.
    • Example 32
  • To a suspension of Intermediate 32B (28 mg, 0.051 mmol) in CH2Cl2 (2.0 mL) and MeOH (0.5 mL) at room temperature was added (diazomethyl)trimethylsilane 2.0 M in diethyl ether (0.076 mL, 0.152 mmol). The suspension turned clear. The reaction mixture was stirred at room temperature for 1.0 h. HPLC and LCMS indicated a completion of the reaction. Solvent was removed under vacuum. The crude was purified via preparative LC/MS (method D, 50-90% B over 10 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 32 (16.4 mg). 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.92 (d, J=1.1 Hz, 1H), 8.18 (s, 1H), 7.92 (dd, J=8.5, 5.2 Hz, 2H), 7.48-7.45 (m, 2H), 7.45-7.42 (m, 2H), 6.87 (s, 1H), 4.07 (t, J=5.4 Hz, 2H), 4.04 (s, 3H), 3.24 (br. s., 2H), 2.74 (s, 3H), 2.73 (s, 3H); LC-MS: method A, RT=2.28 min, MS (ESI) m/z: 567.2 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 33 N-(2-((2-(2-cyclopropoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00471
    • Intermediate 33A: cyclopropanol
  • Figure US20190292176A1-20190926-C00472
  • To a solution of cyclopropylboronic acid (0.65 g, 7.57 mmol) in 10% NaOH (5.0 mL) at 0° C. was added a solution of 30% hydrogen peroxide (21.44 mL, 189 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was diluted with diethyl ether, quenched with saturated NaHSO3 (15 mL) at 0° C. After stirring for 15 min, the organic layer was collected, washed with brine, dried over sodium sulfate and concentrated at 0° C. to give Intermediate 33A (0.16 g, 2.75 mmol, 36.4% yield) as colorless liquid. It was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 3.62-3.41 (m, 1H), 0.69-0.40 (m, 4H).
    • Example 33
  • To 60% sodium hydride (15.66 mg, 0.392 mmol) was added Intermediate 33A (37.9 mg, 0.653 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 15 min. A solution of Intermediate 30A (15 mg, 0.026 mmol) in DMF (1.0 mL) was added. The reaction mixture was stirred at room temperature for 25 min. LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc, quenched with 0.5 N HCl. The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated. The crude was dissolved in DMF/acetonitrile (1:1, 2.2 mL) and purified via preparative LC/MS (method D, 60-100% B over 10 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 33 (8.6 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.59 (s, 1H), 7.90 (dd, J=8.5, 5.2 Hz, 2H), 7.83 (s, 1H), 7.45-7.40 (m, 3H), 6.85 (s, 1H), 4.53-4.49 (m, 1H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H), 0.93-0.88 (m, 2H), 0.87-0.82 (m, 2H); LC-MS: method A, RT=2.67 min, MS (ESI) m/z: 565.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 34 4-fluoro-N-(2-((2-(2-(fluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00473
    • Intermediate 34A: methyl 2-((5-bromo-7-methylquinoxalin-2-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00474
  • To sodium hydride, 60% (411 mg, 10.27 mmol) in DMF (15 mL) cooled with a water bath was added methyl 2-hydroxyacetate (0.959 mL, 12.45 mmol). The reaction mixture was stirred for 20 min. A solution of Intermediate I-1G (900 mg, 3.11 mmol) in DMF (5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. HPLC indicated a completion of the reaction. The reaction mixture was diluted with EtOAc, quenched with 0.5 N HCl. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexane over 12 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 34A (811 mg, 2.61 mmol, 84% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.51 (s, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.44 (dd, 0.9 Hz, 1H), 4.97 (s, 2H), 3.71 (s, 3H), 2.41 (s, 3H); LC-MS: method A, RT=1.97 min, MS (ESI) m/z: 311.0 and 313.0 (M+H)+.
    • Intermediate 34B: 2-((5-bromo-7-methylquinoxalin-2-yl)oxy)acetic acid
  • Figure US20190292176A1-20190926-C00475
  • To Intermediate 34A (811 mg, 2.61 mmol) dissolved in THF (16 mL) at room temperature was added 1.0 N NaOH (4.56 mL, 4.56 mmol). The reaction mixture was stirred at room temperature for 15 min. HPLC and LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc/water, quenched with 1.0 N HCl (4.95 mL, 4.95 mmol). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated to give Intermediate 34B (730 mg, 2.457 mmol, 94% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.58 (dd, J=1.5, 0.9 Hz, 1H), 5.12 (s, 2H), 2.53 (s, 3H); LC-MS: method A, RT=1.81 min, MS (ESI) m/z: 297.0 and 299.0 (M+H)+.
    • Intermediate 34C: 5-bromo-2-(fluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00476
  • To a suspension of Intermediate 34B (400 mg, 1.346 mmol) in dichloromethane (30 mL) at room temperature was added xenon difluoride (251 mg, 1.481 mmol). The reaction mixture was stirred at room temperature for 4.0 h, followed by addition of another portion of xenon difluoride (251 mg, 1.481 mmol). The reaction mixture was left stirring at room temperature overnight. The suspension turned to a clear solution at this point. A third portion of xenon difluoride (387 mg, 2.289 mmol) was added and the reaction mixture was stirred at room temperature for 4.0 h. The reaction was quenched by addition of saturated sodium bicarbonate, extracted with dichloromethane, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexane over 15 min using a 24 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 34C (55 mg, 0.203 mmol, 15.07% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.60 (s, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.68 (dd, J=1.7, 1.0 Hz, 1H), 6.28 and 6.16 (d, JHF=51.28 Hz, 2H), 2.56 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ −157.89 (s, 1F); LC-MS: method A, RT=1.97 min, MS (ESI) m/z: 271.0 and 273.0 (M+H)+.
    • Intermediate 34D: (2-(fluoromethoxy)-7-methylquinoxalin-5-yl)boronic acid
  • Figure US20190292176A1-20190926-C00477
  • A mixture of Intermediate 34C (48 mg, 0.177 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (71.9 mg, 0.283 mmol), potassium acetate (34.8 mg, 0.354 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.78 mg, 7.08 μmol) in dioxane (2.0 mL) was degassed by bubbling argon for 5 min. The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. HPLC and LCMS indicated complete conversion of starting material. The mixture was diluted with EtOAc, washed with brine. The organic layer was dried over sodium sulfate. The crude residue was purified using a preparative HPLC (method A, 30-100% B in 10 min; then 100% B in 2 min). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 34D (20 mg, 0.085 mmol, 47.9% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 8.48 (s, 1H), 8.02 (br. s., 1H), 7.75 (br. s., 1H), 6.24 and 6.14 (d, JHF=51.50 Hz, 1H), 2.56 (s, 3H); NMR (376 MHz, methanol-d4) δ −158.05 (br. s., 1F); LC-MS: method A, RT=1.87 min, MS (ESI) m/z: 237.0 (M+H)+.
    • Example 34
  • To Intermediate 34D (9.54 mg, 0.040 mmol), Intermediate I-5 (18 mg, 0.040 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (2.64 mg, 3.23 μmol) was added toluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.040 mL, 0.081 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. To the reaction mixture was added EtOAc/water. The organic layer was collected, dried over sodium sulfate, concentrated. The crude product was purified via preparative LC/MS (method G, 60-100% B over 20 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 34 (19.9 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.68 (s, 1H), 7.98-7.87 (m, 3H), 7.48-7.41 (m, 3H), 6.87 (s, 1H), 6.37 and 6.23 (d, JHF=51.44 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 3.24 (t, J=5.1 Hz, 2H), 2.74 (s, 3H), 2.67 (s, 3H); LC-MS: method A, RT=2.52 min, MS (ESI) m/z: 557.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 35 2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-6-((2-phenyl-1H-imidazol-5-yl)methoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00478
    • Intermediate 35A: 5-(chloromethyl)-2-phenyl-1H-imidazole hydrochloride
  • Figure US20190292176A1-20190926-C00479
  • To (2-phenyl-1H-imidazol-5-yl)methanol (0.216 g, 1.240 mmol) at room temperature was added thionyl chloride (0.453 ml, 6.20 mmol). The reaction mixture was stirred at room temperature for 10 min, and then at 65° C. for 2.0 h. The reaction mixture was diluted with chloroform (5.0 mL) and the resulting solution was evaporated. Additional co-evaporation with chloroform gave Intermediate 35A (0.28 g, 1.222 mmol, 99% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.15 (m, 2H), 7.83 (s, 1H), 7.67-7.62 (m, 3H), 4.93 (s, 2H).
    • Intermediate 35B: 2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00480
  • To Intermediate 26D (561 mg, 1.150 mmol) dissolved in THF (4.0 mL) at room temperature was added 5.4 M sodium methoxide in MeOH (0.746 mL, 4.03 mmol). The reaction mixture turned deep red. The reaction mixture was stirred at room temperature for 20 min. HPLC and LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl (2.88 mL, 2.88 mmol). The organic layer was washed with brine, dried and concentrated to give Intermediate 35B (300 mg, 0.889 mmol, 77% yield) as yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.47 (d, J=1.5 Hz, 1H), 8.43 (s, 1H), 7.63 (s, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 3.73 (s, 3H), 2.69 (s, 3H), 2.55 (s, 3H); LC-MS: Method A, 50 to 100% B. RT=2.45 min, MS (ESI) m/z: 338.1 (M+H)+.
    • Example 35
  • To a stirred solution of Intermediate 35B (25 mg, 0.074 mmol) and cesium carbonate (97 mg, 0.296 mmol) in DMF (0.8 mL) at room temperature was added a solution of Intermediate 35A (37.3 mg, 0.163 mmol) in DMF (0.8 mL) dropwise. The reaction mixture was stirred at room temperature for 0.5 h, then another portion of Intermediate 35A (37.3 mg, 0.163 mmol) in DMF (0.8 mL) was added. The reaction mixture was stirred at room temperature for 1.0 h, diluted with EtOAc, quenched with ammonium chloride. The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated. The crude material was purified via preparative LC/MS (method D, 50-90% B over 20 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 35 (6.1 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.75 (br. s., 1H), 8.61 (br. s., 1H), 8.02 (d, J=6.9 Hz, 2H), 7.84 (br. s., 2H), 7.74 (br. s., 1H), 7.61 (d, J=7.4 Hz, 3H), 7.12 (br. s., 1H), 5.26 (br. s., 2H), 4.09 (br. s., 3H), 2.77 (br. s., 3H), 2.66 (br. s., 3H); LC-MS: method A, RT=2.54 min, MS (ESI) m/z: 494.2 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 36 N-benzyl-2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetamide
  • Figure US20190292176A1-20190926-C00481
    • Intermediate 36A: methyl 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00482
  • To a suspension of Intermediate 35B (240 mg, 0.711 mmol) in DMF (10 mL) was added THF (2.0 mL) and cesium carbonate (695 mg, 2.134 mmol). The solution turned from yellow to brown. Methyl bromoacetate (0.328 mL, 3.56 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 min, then at 50° C. for 2.0 h. HPLC and LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc/THF and water. The product could not dissolve at this stage. The organic suspension was separated from aqueous solution, concentrated to remove solvent and water. The crude was triturated with a mixture of acetonitrile and water. The solid was collected by filtration, washed with acetonitrile and dried to give Intermediate 36A (280 mg, 0.684 mmol, 96% yield) as yellow solid. 1H NMR was not taken due to very poor solubility in DMSO-d6. LC-MS: method A, RT=1.17 min, MS (ESI) m/z: 410.0 (M+H)+.
    • Intermediate 36B 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetic acid
  • Figure US20190292176A1-20190926-C00483
  • To a suspension of Intermediate 36A (44 mg, 0.107 mmol) in THF (2.0 mL) and MeOH (0.5 mL) at room temperature was added 1.0 N NaOH (0.537 mL, 0.537 mmol). The suspension was stirred at room temperature for 2.0 h with occasional sonicating (3×) for 1 min. HPLC and LCMS indicated a complete of reaction. To the reaction mixture was added 1.0 N HCl (0.537 mL, 0.537 mmol), followed by addition of EtOAc/water. The organic layer was washed with brine and dried over sodium sulfate and concentrated. The crude was lyophilized to give Intermediate 36B (42 mg, 0.102 mmol, 95% yield) as a light yellow lyophilate. 1H NMR (500 MHz, methanol-d4) δ 8.57 (d, J=1.9 Hz, 1H), 8.52 (s, 1H), 7.73 (dd, J=1.9, 0.8 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 6.98 (dd, J=2.5, 0.8 Hz, 1H), 4.68 (s, 2H), 4.11 (s, 3H), 2.80 (s, 3H), 2.64 (s, 3H); LC-MS: method A, RT=1.06 min, MS (ESI) m/z: 396.0 (M+H)+. Analytical HPLC purity (method B): 96%.
    • Example 36
  • To a suspension of Intermediate 36B (12.5 mg, 0.032 mmol) and phenylmethanamine (0.014 mL, 0.126 mmol) in DMF (1.0 mL) was added DIEA (0.044 mL, 0.253 mmol), followed by T3P 50% wt in EtOAc (0.075 mL, 0.126 mmol). The reaction mixture was stirred at room temperature for 1.0 h. HPLC and LCMS indicated a completion of the reaction. The reaction was quenched by addition of 0.1% TFA in MeOH/water. The crude material was purified via preparative LC/MS (method D, 60-100% B over 15 minutes, then a 10-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 36 (9.8 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.72 (t, J=6.2 Hz, 1H), 8.62 (d, J=1.7 Hz, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.33-7.22 (m, 5H), 7.11 (d, J=1.7 Hz, 1H), 4.67 (s, 2H), 4.39 (d, J=6.1 Hz, 2H), 4.10 (s, 3H), 2.77 (s, 3H), 2.66 (s, 3H); LC-MS: method A, RT=2.55 min, MS (ESI) m/z: 485.2 (M+H)+. Analytical HPLC purity (method B): 95%.
    • Example 37 5-(7-chlorobenzofuran-2-yl)-2-methoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00484
    • Intermediate 37A: 7-chloro-2-iodobenzofuran
  • Figure US20190292176A1-20190926-C00485
  • To diisopropylamine (0.280 mL, 1.966 mmol) in THF (4.0 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (1.229 mL, 1.966 mmol). The reaction mixture was stirred at −78° C. for 0.5 h. 7-Chlorobenzofuran (200 mg, 1.311 mmol) in THF (1.0 mL) was added, The reaction mixture was stirred at −78° C. for 0.5 h. Iodine (665 mg, 2.62 mmol) in THF (1.0 mL) was added dropwise until the brown color persisted (ca 1.3 eq.) The reaction mixture was stirred at −78° C. for 0.5 h, then at room temperature for 0.5 h. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride (5.0 mL) and 10% Na2S2O3 (5.0 mL). After stirring at room temperature for 10 min, the organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product Intermediate 37A (360 mg, 1.189 mmol, 91% yield) was obtained as a slightly brown oil. It was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.40 (dd, J=7.7, 1.3 Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.11 (m, 1H), 6.99 (s, 1H). LC-MS: method H, 2 to 98% B. RT=1.07 min, MS (ESI) m/z: MW not observed (M+H)+.
    • Intermediate 37B: 5-(7-chlorobenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00486
  • To Intermediate I-1 (45.6 mg, 0.180 mmol), Intermediate 37A (50.0 mg, 0.180 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.87 mg, 7.18 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 0.157 mL, 0.314 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. The crude reaction mixture was diluted with EtOAc/water. The insoluble material was removed by filtration. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give Intermediate 37B (64 mg, 0.177 mmol, 99% yield) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.24 (d, J=1.9 Hz, 1H), 8.20 (s, 1H), 7.90 (t, JHF=71.53 Hz, 1H), 7.83-7.81 (m, 1H), 7.79 (dd, J=7.8, 1.0 Hz, 1H), 7.51 (dd, J=7.8, 1.0 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 2.67 (s, 3H); LC-MS: method H, RT=2.70 min, MS (ESI) m/z: 361.0 (M+H)+.
    • Example 37
  • To Intermediate 37B (35 mg, 0.097 mmol) dissolved in THF (1.5 mL) and MeOH (1.5 mL) at room temperature was added 4.3 M sodium methoxide in MeOH (0.090 mL, 0.388 mmol). The reaction mixture was stirred at room temperature for 1.0 h. LCMS indicated ca 60% conversion. Then another portion of 4.3 M sodium methoxide in MeOH (0.090 mL, 0.388 mmol) was added and the reaction was continued at room temperature for 2.0 h. LCMS indicated a completion of the reaction. Methanol was removed under vacuum. The reaction mixture was diluted with EtOAc, quenched with 0.5 N HCl (2.0 mL). The organic layer was washed with saturated sodium bicarbonate, brine, dried and concentrated. The crude material was purified via preparative LC/MS (method D, 65-100% B over 20 minutes, then a 8-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 37 (16.0 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.17 (s, 1H), 8.10 (d, J=1.7 Hz, 1H), 7.77 (dd, J=7.8, 1.0 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.49 (dd, J=7.8, 1.0 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 4.09 (s, 3H), 2.64 (s, 3H); LC-MS: method H. RT=2.76 min, MS (ESI) m/z: 325.1 and 327.1 (M+H)+. Analytical HPLC purity (method B): 95%.
    • Example 38 2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate
  • Figure US20190292176A1-20190926-C00487
    • Intermediate 38A: 2-chloro-1-(2,2-diethoxyethoxy)-4-methoxybenzene
  • Figure US20190292176A1-20190926-C00488
  • To a suspension of sodium hydride (60%) (0.189 g, 4.73 mmol) in DMF (5.0 mL) was added 2-chloro-4-methoxyphenol (0.5 g, 3.15 mmol) dissolved in DMF (3.0 mL) at room temperature. After hydrogen evolution was ceased (20 min at 40° C. oil bath), 2-bromo-1,1-diethoxyethane (0.593 mL, 3.94 mmol) was added. The reaction mixture was heated at 160° C. for 18 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc/water. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give Intermediate 38A (0.95 g, 3.46 mmol, 110% yield) as a light yellow oil. It was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 6.93 (d, J=3.1 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.73 (dd, J=8.9, 3.0 Hz, 1H), 4.84 (t, J=5.2 Hz, 1H), 4.00 (d, J=5.3 Hz, 2H), 3.83-3.76 (m, 2H), 3.75 (s, 3H), 3.71-3.64 (m, 2H), 1.27-1.22 (t, J=7.04 Hz, 6H). LC-MS: method H, 2 to 98% B. RT=1.02 min, MS (ESI) m/z: 297.0 (M+Na)+.
    • Intermediate 38B: 7-chloro-5-methoxybenzofuran
  • Figure US20190292176A1-20190926-C00489
  • A mixture of Amberlyst-15 (1.2 g, 2.91 mmol) in chlorobenzene (100 mL) was heated at reflux (oil bath temperature 165° C.) to remove water by azeotropic distillation. Distillate was removed until the volume remaining in the flask was about 80 mL. To this mixture was then added dropwise over 1.0 h a solution of Intermediate 38A (0.8 g, 2.91 mmol) in chlorobenzene (9.0 mL). The reaction mixture was stirred at reflux with constant water removal for another 2.0 h. After cooled to room temperature, the Amberlyst-15 was removed by filtration. The filtrated was concentrated under vacuum, and loaded directly to ISCO column for purification. The crude product was purified by flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexane over 15 min using a 24 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 38B (0.32 g, 1.752 mmol, 60.2% yield) as a light yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=2.2 Hz, 1H), 6.97-6.93 (m, 2H), 6.73 (d, J=2.2 Hz, 1H), 3.83 (s, 3H); LC-MS: method H, 2 to 98% B. RT=0.94 min, MS (ESI) m/z: 183.0 (M+H)+.
    • Intermediate 38C: 7-chlorobenzofuran-5-ol
  • Figure US20190292176A1-20190926-C00490
  • To Intermediate 38B (0.32 g, 1.752 mmol) and tetrabutylammonium iodide (0.680 g, 1.840 mmol) in dichloromethane (4 mL) at −78° C. was added 1.0 M boron trichloride in heptane (4.12 ml, 4.12 mmol) dropwise. The reaction mixture was stirred at −78° C. for 45 min. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 3.0 h. HPLC and TLC indicated a completion of the reaction. The mixture was poured into saturated sodium bicarbonate and ice, stirred for 20 min, extracted with EtOAc. The organic layer was collected, washed with 10% Na2S2O3, water, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 1 min., then a 15 min gradient from 0% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 38C (0.29 g, 1.720 mmol, 98% yield) as a slightly brown solid. 1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=2.0 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H).
    • Intermediate 38D: tert-butyl((7-chlorobenzofuran-5-yl)oxy)dimethylsilane
  • Figure US20190292176A1-20190926-C00491
  • To a stirred solution of Intermediate 38C (0.30 g, 1.780 mmol) in DMF (4.0 mL) was added TBDMS-Cl (0.402 g, 2.67 mmol) and imidazole (0.218 g, 3.20 mmol). The reaction mixture was stirred at room temperature for 1.5 h. HPLC and TLC indicated a completion of the reaction. The mixture was partitioned between EtOAc/water. The organic layer was washed with water, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 3 min., then a 15 min gradient from 0% to 15%. The desired fractions were combined and concentrated to give Intermediate 38D (0.4 g, 1.414 mmol, 79% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=2.2 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 1.01 (s, 9H), 0.22 (s, 6H); LC-MS: method H, 2 to 98% B. RT=0.96 min, MS (ESI) m/z: MS not observed (M+H)+.
    • Intermediate 38E: tert-butyl((7-chloro-2-iodobenzofuran-5-yl)oxy)dimethylsilane
  • Figure US20190292176A1-20190926-C00492
  • To diisopropylamine (0.302 mL, 2.121 mmol) in THF (4.0 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (1.326 mL, 2.121 mmol). The reaction mixture was stirred at −78° C. for 20 min. Intermediate 38D (0.4 g, 1.414 mmol) in THF (1.0 mL) was added dropwise, The reaction mixture was stirred at −78° C. for 0.5 h. Iodine (0.610 g, 2.404 mmol) in THF (1.0 mL) was added dropwise until the brown color persisted (ca 1.2 eq), and the reaction mixture was stirred at −78° C. for 0.5 h, then at room temperature for 0.5 h. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride (5.0 mL) and 10% Na2S2O3 (5.0 mL). After stirring at room temperature for 10 min, the organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 38E (0.51 g, 1.148 mmol, 81% yield) was obtained as a slightly brown oil. It was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 6.89 (s, 1H), 6.84 (d, J=2.2 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 1.00 (s, 9H), 0.21 (s, 6H). LC-MS: method H, 2 to 98% B. RT=1.36 min, MS (ESI) m/z: no desired MS observed (M+H)+.
    • Intermediate 38F 5-(5-((tert-butyldimethylsilyl)oxy)-7-chlorobenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00493
  • To Intermediate I-1 (0.311 g, 1.223 mmol), Intermediate 38E (0.5 g, 1.223 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.040 g, 0.049 mmol) was added toluene (4.5 mL) and EtOH (1.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (2M, 1.070 mL, 2.141 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. HPLC and LCMS indicated a completion of the reaction. The crude reaction mixture was directly loaded on an ISCO column for purification. The crude product was purified by flash chromatography (loading in chloroform, 0% to 25% EtOAc in hexane over 15 min using a 24 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 38F (0.36 g, 0.733 mmol, 59.9% yield) as an yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.02 (s, 1H), 7.66 (dd, J=1.8, 0.9 Hz, 1H), 7.65 (t, JHF=71.75 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 2.66 (s, 3H), 1.02 (s, 9H), 0.23 (s, 6H); 19F NMR (376 MHz, chloroform-d) δ −89.72 (s, 1F); LC-MS: method H, 2 to 98% B. RT=1.51 min, MS (ESI) m/z: 491.1 and 493.1 (M+H)+.
    • Intermediate 38G: 7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol
  • Figure US20190292176A1-20190926-C00494
  • To Intermediate 38F (0.36 g, 0.733 mmol) dissolved in THF (3.0 mL) and MeOH (3.0 mL) at room temperature was added 4.3 M sodium methoxide in MeOH (0.767 mL, 3.30 mmol). The reaction mixture was stirred at room temperature for 4.0 h. HPLC and LCMS indicated a completion of the reaction. The reaction mixture was quenched with 1.0 N HCl (2.93 mL, 2.93 mmol), diluted with EtOAc. The organic layer was washed with brine, dried and concentrated to give Intermediate 38G (0.26 g, 0.687 mmol, 94% yield) as yellow solid. This was used for the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 8.43 (s, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.90 (s, 1H), 7.57 (d, J=0.9 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 6.84-6.80 (m, 1H), 4.05 (s, 3H), 2.56 (s, 3H); LC-MS: method H, 2 to 98% B. RT=1.14 min, MS (ESI) m/z: 341.0 and 343.0 (M+H)+.
    • Intermediate 38H 2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00495
  • To a suspension of Intermediate 38G (145 mg, 0.426 mmol) in DMF (3.0 mL) and THF (2.0 mL) was added cesium carbonate (277 mg, 0.851 mmol). The reaction mixture was stirred at room temperature for 20 min. Then 2-bromoethyl acetate (0.063 mL, 0.574 mmol) in THF (0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, then at 65° C. for 1.5 h. HPLC and LCMS indicated completion of reaction. After cooled to room temperature, the reaction mixture was diluted with EtOAc and water, extracted with EtOAc (6×). The combined organic layer was washed with brine and dried with sodium sulfate and concentrated to give yellow solid as the acetate. The crude acetate was suspended in a mixture of THF (3.0 mL) and MeOH (0.8 mL). To this suspension was added 1.0 N NaOH (0.851 mL, 0.851 mmol). The reaction mixture was stirred at room temperature for 30 min. The suspension turned to a clear brown solution. HPLC and LCMS indicated a clean conversion of the ester to acid. The reaction was quenched with 1.0 N HCl (0.638 mL, 0.638 mmol) diluted in 1.0 mL of water, extracted with EtOAc, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 10% to 60% EtOAc in hexane over 10 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 38H (110 mg, 0.286 mmol, 67.2% yield) as a lightly yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.07 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.70 (dd, J=1.8, 0.9 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 4.90 (t, J=5.5 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 2H), 3.78-3.74 (m, 2H), 2.61 (s, 3H); LC-MS: method H, 2 to 98% B. RT=1.14 min, MS (ESI) m/z: 385.0 and 387.0 (M+H).
    • Intermediate 38I 2-{[7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-1-benzofuran-5-yl]oxy}ethyl chloroformate
  • Figure US20190292176A1-20190926-C00496
  • To a solution Intermediate 38H (100 mg, 0.260 mmol) in THF (3.0 mL) at room temperature was added 15% phosgene in toluene (0.733 mL, 1.039 mmol). The reaction mixture was left stirring at room temperature overnight. HPLC and LCMS indicated the reaction was complete. Solvent was completely removed under high vacuum to give Intermediate 38I (116 mg, 0.259 mmol, 100% yield) as a slightly yellow solid. It was used for the next step without purification. LC-MS: method H, 2 to 98% B. RT=1.30 min, MS (ESI) m/z: 447.1 (M+H)+.
    • Example 38
  • To a solution of 2-methylpyridin-4-amine (19.34 mg, 0.179 mmol) in DCM (0.8 mL) was added DIEA (0.062 mL, 0.358 mmol), followed by addition of Intermediate 38I (16 mg, 0.036 mmol) in THF (0.8 mL). The reaction mixture was stirred at room temperature for 1.0 h. HPLC and LCMS indicated a completion of reaction. The reaction was quenched by addition of a small amount of MeOH/water/0.1% TFA. Solvent was removed under vacuum. The crude material was purified via preparative LC/MS (method D, 50-90% B over 18 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 38 (10 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.37 (br. s., 1H), 8.68 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 7.39-7.32 (m, 3H), 7.16 (d, J=1.9 Hz, 1H), 4.51 (d, J=4.4 Hz, 2H), 4.34 (d, J=3.9 Hz, 2H), 4.07 (s, 3H), 2.62 (s, 3H), 2.42 (s, 3H); LC-MS: method H, RT=2.16 min, MS (ESI) m/z: 519.2 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 39 N-(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00497
    • Intermediate 39A: tert-butyl (2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzofuran-5-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00498
  • A solution of tert-butyl (2-hydroxyethyl)carbamate (85 mg, 0.528 mmol) and DIAD (0.123 mL, 0.634 mmol) in THF (1.0 mL) was added dropwise to a mixture of Intermediate 38G (72 mg, 0.211 mmol) and triphenylphosphine (163 mg, 0.623 mmol) in THF (2.0 mL) heated at 70° C. The reaction mixture was stirred at 70° C. for 15 min, at which time HPLC and LCMS indicated a completion of the reaction. Solvent was removed under vacuum. The crude product was purified by flash chromatography (loading in chloroform, 5% to 45% EtOAc in hexane over 15 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 39A (80 mg, 0.152 mmol, 72.0% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.05 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 4.03-4.00 (m, 2H), 3.34 (t, J=5.6 Hz, 2H), 2.60 (s, 3H), 1.40 (s, 9H); LC-MS: method H, 2 to 98% B. RT=1.29 min, MS (ESI) m/z: 484.1(M+H)+.
    • Intermediate 39B 2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethanamine
  • Figure US20190292176A1-20190926-C00499
  • To Intermediate 39A (80 mg, 0.165 mmol) in DCM (2 mL) was added 2,6-lutidine (0.077 mL, 0.661 mmol) followed by TMS-OTf (0.119 mL, 0.661 mmol). The reaction mixture was stirred at room temperature for 1h. The mixture was diluted with EtOAc and NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine and concentrated. The residual was treated with 1.0 ml of MeOH, stirred at room temperature for 15 min, and concentrated to give Intermediate 39B (60 mg) as yellow solid. the crude sample was used for next step without purification.
    • Example 39
  • To a suspension of Intermediate 39B (18 mg, 0.047 mmol) in DMF (1.0 mL) and THF (1.0 mL) was added DIEA (0.066 mL, 0.375 mmol), followed by benzenesulfonyl chloride (8.27 μl, 0.064 mmol). The reaction mixture was stirred at room temperature for 2.0 h. Solvent was removed and the crude was purified via preparative LC/MS (method D, 55-95% B over 10 minutes, then a 7-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield 39 (22.8 mg). 1H NMR (500 MHz, chloroform-d) δ 8.51 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.65 (s, 1H), 7.62-7.57 (m, 1H), 7.55-7.50 (m, 2H), 6.91 (d, J=1.9 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 4.99 (t, J=6.1 Hz, 1H), 4.12 (s, 3H), 4.03 (t, J=5.1 Hz, 2H), 3.42 (q, J=5.5 Hz, 2H), 2.63 (s, 3H); LC-MS: method H, RT=2.66 min, MS (ESI) m/z: 524.2 (M+H)+. Analytical HPLC purity (method B):100%.
    • Example 40 5-(benzo[b]thiophen-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00500
  • To a solution of benzo[b]thiophen-2-yltributylstannane (35.1 mg, 0.083 mmol) and Intermediate I-1G (20 mg, 0.069 mmol) in 1,4-dioxane (1 mL) was added Pd(Ph3P)4 (9.59 mg, 8.30 μmol). The mixture was heated at 150° C. for 1 h in a microwave reactor. LCMS indicated a completion of the reaction. The mixture was diluted with acetonitrile and filtered. The filtrate was concentrated and purified by a preparative HPLC (method A, 65-100% B in 8 min.). The desired fractions were collected, dried and lyophilized to give 40 (18 mg, 0.050 mmol, 72.2% yield). 1H NMR (400 MHz, chloroform-d) δ 8.66 (s, 1H), 8.07 (s, 1H), 8.00-7.46 (m, 5H), 7.45-7.32 (m, 2H), 2.64 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.43 (s, 2F). LC-MS: method B, RT=2.55 min, MS (ESI) m/z: 343.0 (M+H)+. Analytical HPLC purity (method A): 99%.
    • Example 41 2-(difluoromethoxy)-5-(7-methoxybenzofuran-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00501
  • To (7-methoxybenzofuran-2-yl)boronic acid (13.28 mg, 0.069 mmol) and Intermediate I-1G was added toluene (0.75 mL) and EtOH (0.25 mL). The reaction mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.78 mg, 8.30 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate 2M (0.069 mL, 0.138 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 140° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified by 12 g ISCO column eluted with 0-70% EtOAc in hexane for 15 min. The desired fraction was collected, dried and purified by preparative HPLC (method A, 30-100% B in 10 min.) to give Example 41 (8 mg, 0.022 mmol, 31.5% yield). 1H NMR (400 MHz, chloroform-d) δ 8.66 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.10 (s, 1H), 7.91-7.47 (m, 2H), 7.29 (s, 1H), 7.23-7.17 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 4.10 (s, 3H), 2.65 (s, 3H). 19F NMR (376 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method B, RT=2.53 min, MS (ESI) m/z: 357.0 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 42 2-(difluoromethoxy)-5-(4-methoxybenzofuran-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00502
    • Intermediate 42A: (benzofuran-4-yloxy)(tert-butyl)dimethylsilane
  • Figure US20190292176A1-20190926-C00503
  • To a solution of benzofuran-4-ol (200 mg, 1.491 mmol) in DMF (5 mL) was added TBDMS-Cl (337 mg, 2.237 mmol) and imidazole (203 mg, 2.98 mmol). The mixture was stirred at room temperature for 2 h. LCMS indicated a completion of the reaction. The mixture was diluted by EtOAc and water, extracted with EtOAc, the combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-50% EtOAc/Hex, the desired fraction was collected to give Intermediate 42A (270 mg, 1.087 mmol, 72.9% yield). 1H NMR (400 MHz, chloroform-d) δ 7.53 (d, J=2.3 Hz, 1H), 7.18-7.10 (m, 2H), 6.79 (d, J=1.8 Hz, 1H), 6.72-6.60 (m, 1H), 1.06 (s, 10H), 0.31-0.18 (m, 6H). LC-MS: method B, RT=2.55 min, MS (ESI) m/z: 249 (M+H)+.
    • Intermediate 42B: 4-(tert-butyldimethylsilyloxy)benzofuran-2-ylboronic acid
  • Figure US20190292176A1-20190926-C00504
  • To a solution of Intermediate 42A (270 mg, 1.087 mmol) in THF (4 mL) was added n-BuLi (0.815 mL, 1.304 mmol) at −78° C. After 30 min stirring, trimethyl borate (0.243 mL, 2.174 mmol) was added, and the reaction mixture was slowly warmed up to room temperature over 1h. HCl (5.43 mL, 5.43 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was diluted with EtOAc and water, extracted with EtOAc and the combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-70% EtOAc/Hex. The desired fraction was collected to give Intermediate 42B (190 mg, 0.650 mmol, 59.8% yield). LC-MS: method C, RT=2.35 min, MS (ESI) m/z: 293 (M+H)+.
    • Intermediate 42C 5-(4-(tert-butyldimethylsilyloxy)benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00505
  • To Intermediate I-1 (50 mg, 0.173 mmol) and Intermediate 42B (60.7 mg, 0.208 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The reaction mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (16.95 mg, 0.021 mmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.173 mL, 2M, 0.346 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. LCMS indicated a completion of the reaction. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×), the combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction was collected to give Intermediate 42C (79 mg, 0.173 mmol, 100% yield). 1H NMR (400 MHz, chloroform-d) δ 8.66 (s, 1H), 8.23 (d, J=1.8 Hz, 1H), 8.09 (s, 1H), 7.88-7.47 (m, 2H), 7.23-7.18 (m, 2H), 6.69 (dd, J=6.3, 2.3 Hz, 1H), 2.65 (s, 3H), 1.12-1.09 (m, 9H), 0.29 (s, 6H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.43 (s, 2F). LC-MS: method C, RT=2.68 min.
    • Intermediate 42D: 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-4-ol
  • Figure US20190292176A1-20190926-C00506
  • To a solution of Intermediate 42C (76 mg, 0.166 mmol) in MeOH (1 mL) and THF was added HCl (0.277 mL, 12M, 3.33 mmol). The mixture was stirred at room temperature for 1h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and saturated NaHCO3, extracted with EtOAc, the combined organic layer was washed with brine, dried with MgSO4 and concentrated. Intermediate 42D (50 mg, 0.142 mmol, 85% yield) was obtained and used for next step without purification. 1H NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.87-7.47 (m, 2H), 7.23-7.18 (m, 2H), 6.72-6.65 (m, 1H), 2.66 (s, 3H). 19F NMR (376 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method B, RT=4.44 min, MS (ESI) m/z: 343.1 (M+H)+.
    • Example 42
  • To a solution of Intermediate 42D (10 mg, 0.029 mmol) in acetonitrile (1 mL) was added Cs2CO3 (28.6 mg, 0.088 mmol) and MeI (1.827 μl, 0.029 mmol). The mixture was stirred at 45° C. for 1 h. The mixture was diluted with 1 ml of DMSO and 1 ml of acetonitrile, filtered and purified with a preparative HPLC (method A, 65-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 42 (5.6 mg, 0.015 mmol, 52.7% yield). 1H NMR (chloroform-d, 400 MHz): δ=8.65 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.46-7.86 (m, 2H), 7.28-7.32 (m, 1H), 7.19-7.23 (m, 1H), 6.71 (d, J=7.8 Hz, 1H), 4.02 (s, 3H), 2.65 ppm (s, 3H). 19F NMR (chloroform-d, 400 MHz) −90.12 (s, 2F). LC-MS: method B, RT=4.56 min, MS (ESI) m/z: 357.1 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 43 5-(4-(benzyloxy)benzofuran-2-yl)-2-methoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00507
  • To a solution of Intermediate 42D (10 mg, 0.029 mmol) in acetonitrile (1 mL) was added Cs2CO3 (28.6 mg, 0.088 mmol) and benzyl bromide (3.47 μl, 0.029 mmol). The mixture was stirred at 45° C. for 1 h. The mixture was diluted with 1.0 ml of MeOH and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The mixture was purified with preparative HPLC (method A, 65-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give 43 (2.5 mg, 5.86 μmol, 20.07% yield). 1H NMR (chloroform-d, 400 MHz): δ=8.53 (s, 1H), 8.19 (s, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.62 (s, 1H), 7.49-7.57 (m, 2H), 7.40-7.47 (m, 2H), 7.33-7.39 (m, 1H), 7.21-7.25 (m, 2H), 6.72-6.80 (m, 1H), 5.28 (s, 2H), 4.12 (s, 3H), 2.63 ppm (s, 3H). LC-MS: method C, RT=3.25 min, MS (ESI) m/z: 397.1 (M+H)+. Analytical HPLC purity (method A): 93.0%.
    • Example 44 5-(5-(benzyloxy)benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00508
    • Intermediate 44A: benzofuran-5-ol
  • Figure US20190292176A1-20190926-C00509
  • To an ice-cooled solution of 5-methoxybenzofuran (0.71 g, 4.79 mmol) in dichloromethane (8.0 mL) was added 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol). The mixture was stirred at 0° C. for 1.0 h. HPLC indicated ca 30-40% starting material still remaining. Then another portion of 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol) was added and the mixture was stirred from 0° C. to room temperature over an hour. HPLC indicated a complete conversion of starting material. The mixture was poured into ice water, stirred for 15 min, extracted with dichloromethane. The organic layer was dried over sodium sulfate. After evaporation of solvent, Intermediate 44A (0.33 g, 2.460 mmol, 51.3% yield) was obtained as slightly brown oil. It was used for the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 7.60 (d, J=2.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.82 (dd, J=8.8, 2.8 Hz, 1H), 6.69-6.67 (m, 1H), 4.78 (s, 1H); LC-MS: Method A, 50 to 100% B. RT=2.32 min, MS (ESI) m/z: no (M+H)+.
    • Intermediate 44B: (benzofuran-5-yloxy)(tert-butyl)dimethylsilane
  • Figure US20190292176A1-20190926-C00510
  • To a stirred solution of Intermediate 44A (0.33 g, 2.460 mmol) in DMF (8.0 mL) was added TBDMS-Cl (0.519 g, 3.44 mmol) and imidazole (0.285 g, 4.18 mmol). The reaction mixture was left stirring at room temperature for 2.0 h. The mixture was partitioned between EtOAc/water. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 24 g silica gel cartridge which was eluted with hexanes for 3 min., then a 15 min gradient from 0% to 20% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 44B (0.48 g, 1.932 mmol, 79% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ 7.60 (d, J=1.9 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.83 (dd, J=8.7, 2.3 Hz, 1H), 6.70-6.69 (m, 1H), 1.03 (s, 9H), 0.23 (s, 6H); LC-MS: Method A, 50 to 100% B. RT=2.19 min, MS (ESI) m/z: 249 (M+H)+.
    • Intermediate 44C: 5-(tert-butyldimethylsilyloxy)benzofuran-2-ylboronic acid
  • Figure US20190292176A1-20190926-C00511
  • To Intermediate 44B (0.48 g, 1.932 mmol) in THF (7.0 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (1.993 mL, 3.19 mmol) dropwise. The solution turned to brown. The mixture was stirred at −78° C. for 10 min, followed by addition of triisopropyl borate (1.346 mL, 5.80 mmol). The mixture was stirred for 20 min, and the cooling bath was removed to allow warm up to room temperature over 0.5 h. It was diluted with EtOAc, quenched with 20 mL of 0.5 N HCl. After stirring at room temperature for 10 min, the organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 3 min., then a 12 min gradient from 0% to 60% EtOAc in hexanes. The desired fractions were combined, concentrated and lyophilized to give Intermediate 44C (0.416 g, 1.424 mmol, 73.7% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) δ 7.39 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.88 (dd, J=8.8, 2.5 Hz, 1H), 1.03 (s, 9H), 0.22 (s, 6H); LC-MS: Method A, 0 to 100% B. RT=2.30 min, MS (ESI) m/z: 293.1 (M+H)+.
    • Intermediate 44D: 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-ol
  • Figure US20190292176A1-20190926-C00512
  • A mixture of Intermediate I-1G (324 mg, 1.122 mmol), Intermediate 44C (410 mg, 1.403 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (36.7 mg, 0.045 mmol) in toluene (6 mL) and EtOH (2.000 mL) was degassed with argon for 2.0 min. To this solution was added sodium carbonate (2.0 M, 0.982 mL, 1.964 mmol). The mixture was then heated in an oil bath at 85° C. overnight. The crude reaction mixture was diluted with EtOAc/water. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude product was obtained as brown oil that solidified when treated with MeOH. It was used for the next step without further purification.
  • To the crude product obtained above (0.55 g, 1.205 mmol) in MeOH (4.0 mL) and THF (4.00 mL) was added 12 N HCl (1.004 mL, 12.05 mmol). The mixture was stirred at room temperature for 30 min. TLC indicated ca 40% starting material remaining. Another portion of 12 N HCl (1.004 mL, 12.05 mmol) was added. The reaction was continued at room temperature for 1.5 h. TLC indicated a clean reaction. Methanol was removed under vacuum, the crude was diluted with EtOAc, washed with water and brine. The organic layer was collected, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform/THF and charged to a 12 g silica gel cartridge which was eluted with hexanes for 3 min., then a 10 min gradient from 0% to 60% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 44D (0.423 g, 1.236 mmol, 103% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.90 (s, 1H), 8.21 (d, J=1.7 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.89 (t, JHF=71.53 Hz, 1H), 7.75 (dd, J=1.9, 1.1 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.84 (dd, J=8.8, 2.5 Hz, 1H), 2.63 (s, 3H); 19F NMR (471 MHz, DMSO-d6) δ −87.80 (s, 2F); LC-MS: Method A, 0 to 100% B. RT=2.30 min, MS (ESI) m/z: 343.0 (M+H)+.
    • Example 44
  • To a solution of Intermediate 44D (20 mg, 0.058 mmol) in acetonitrile (1 mL) was added Cs2CO3 (57.1 mg, 0.175 mmol) and (bromomethyl)benzene (100 mg, 0.584 mmol). The mixture was stirred at 45° C. for 1 h. The mixture was diluted with 1 ml of DMSO and 1 ml of acetonitrile and filtered. The filtrate was purified with a preparative HPLC (method A, 65-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 44 (17 mg, 0.037 mmol, 63.9% yield). 1H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.66-7.34 (m, 8H), 7.20 (d, J=2.2 Hz, 1H), 7.07-7.02 (m, 1H), 5.14 (s, 2H), 2.64 (s, 3H). 19F NMR (chloroform-d, 400 MHz):) −90.12 (s, 2F). LC-MS: method C, RT=2.84 min, MS (ESI) m/z: 433.0 (M+H)+. Analytical HPLC purity (method A): 100%.
    • Example 45 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00513
  • To 2-bromoimidazo[1,2-a]pyridine (17.58 mg, 0.089 mmol) and Intermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The reaction mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.059 mL, 2M, 0.119 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 30-100% B in 10 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 45 (6.5 mg, 0.019 mmol, 32.1% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.90 (br. s., 1H), 8.71 (br. s., 1H), 8.58 (d, J=6.8 Hz, 1H), 8.43 (s, 1H), 8.03 (br. s., 1H), 7.50 (s, 2H), 7.31 (t, J=6.8 Hz, 1H), 2.63 (s, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.60 (br. s., 2F). LC-MS: method C, RT=1.66 min, MS (ESI) m/z: 327.0 (M+H)+. Analytical HPLC purity (method A): 99%.
    • Example 46 Methyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00514
    • Intermediate 46A: tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00515
  • To a solution of triphenylphosphine (53.6 mg, 0.205 mmol) in THF (1.0 mL) at 0° C., was added DIAD (0.040 mL, 0.205 mmol) dropwise. The mixture was stirred at 0° C. for 10 min. A solution of Intermediate 44D (35 mg, 0.102 mmol) and tert-butyl (2-hydroxyethyl)carbamate (33.0 mg, 0.205 mmol) in THF (1.0 mL) was added dropwise. The mixture was stirred at 0° C. to room temperature for 30 min, then heated up to 55° C. overnight. After evaporation of solvent, the crude was dissolved in DMSO/acetonitrile (1.5 mL/1.5 mL) and purified using a preparative HPLC (method A, 30-100% B in 10 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 46A (18 mg, 0.037 mmol, 36.3% yield) as a yellow lyophilate. 1H NMR (chloroform-d, 400 MHz): δ=8.65 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.40-7.91 (m, 3H), 7.13 (d, J=2.5 Hz, 1H), 6.90-7.03 (m, 1H), 5.05 (br. s., 1H), 4.02-4.20 (m, 2H), 3.59 (br. s., 2H), 2.66 (s, 3H), 1.48 ppm (s, 9H). 19F NMR (chloroform-d, 376 MHz): δ=−90.15 ppm (s, 2F). LC-MS: method B, RT=2.58 min, MS (ESI) m/z: 486.1 (M+H)+.
    • Intermediate 46B 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00516
  • To a solution of Intermediate 46A (13 mg, 0.027 mmol) in DCM (2 mL) was added TFA (0.206 mL, 2.68 mmol) and the mixture was stirred at room temperature overnight. Solvent was removed. The residual was purified with a preparative HPLC (method A, 30-100% B in 10 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 46B (8 mg, 0.020 mmol, 75% yield). 1H NMR (acetonitrile-d3, 400 MHz): δ=8.71 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.49-7.89 (m, 3H), 7.27 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H), 4.27 (t, J=4.8 Hz, 2H), 3.40 (t, J=4.9 Hz, 2H), 2.65 ppm (s, 3H). 19F NMR (acetonitrile-d3, 376 MHz): δ=−76.15 (br. s., 3F), −90.48 ppm (s, 2F). LC-MS: method C, RT=2.02 min, MS (ESI) m/z: 386.0 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 46
  • To a suspension of Intermediate 46B (6.5 mg, 0.013 mmol) in DCM (1 mL) was added Et3N (9.07 μl, 0.065 mmol) followed by methyl chloroformate (2.016 μl, 0.026 mmol). The mixture was stirred at room temperature for 1 h. Solvent was removed and the residual was purified with a preparative HPLC (method A, 50-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 46 (4.0 mg, 8.75 μmol, 67.2% yield). 1H NMR (acetonitrile-d3, 400 MHz): δ=8.71 (s, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.04 (s, 1H), 7.44-7.91 (m, 3H), 7.23 (d, J=2.5 Hz, 1H), 6.98 (dd, J=8.8, 2.5 Hz, 1H), 4.08 (t, J=5.6 Hz, 2H), 3.61 (s, 3H), 3.50 (q, J=5.7 Hz, 2H), 2.64 ppm (s, 3H). 19F NMR (acetonitrile-d3, 376 MHz): δ=−90.47 ppm (s, 2F). LC-MS: method C, RT=2.42 min, MS (ESI) m/z: 444.1 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 47 5-(1H-benzo[d]imidazol-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00517
  • To 2-chloro-1H-benzo[d]imidazole (10.89 mg, 0.071 mmol) and Intermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.045 mL, 2M, 0.089 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min, then at 140° C. for 20 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 20-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 47 (10 mg, 0.030 mmol, 50.5% yield). 1H NMR (acetonitrile-d3, 400 MHz): δ=8.85 (d, J=1.5 Hz, 1H), 8.79 (br. s., 1H), 7.46-7.93 (m, 6H), 2.66 ppm (s, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.69 (s, 2F). LC-MS: method C, RT=1.71 min, MS (ESI) m/z: 327.1 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 48 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00518
  • To 2-chloro-6-methoxybenzo[d]thiazole (14.26 mg, 0.071 mmol) and Intermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.045 mL, 2M, 0.089 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 65-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 48 (12.5 mg, 0.033 mmol, 55.1% yield). 1H NMR (acetonitrile-d3, 400 MHz): δ=8.70-8.83 (m, 2H), 7.95-8.04 (m, 1H), 7.48-7.90 (m, 3H), 7.12-7.21 (m, 1H), 3.90 (s, 3H), 2.69 ppm (s, 3H). 19F NMR (acetonitrile-d3, 400 MHz):) −90.12 (s, 2F). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 374.0 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 49 tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy) acetate
  • Figure US20190292176A1-20190926-C00519
  • To a solution of Intermediate 44D (20 mg, 0.058 mmol) in DMF (1 mL) was added Cs2CO3 (57.1 mg, 0.175 mmol) and tert-butyl 2-bromoacetate (57.0 mg, 0.292 mmol). The mixture was stirred at 100° C. for 2 h. The mixture was diluted with 1 ml of DMSO and 1 ml of acetonitrile, filtered. The filtrate was purified with a preparative HPLC (method A, 65-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 49 (20 mg, 0.043 mmol, 73.5% yield). 1H NMR (chloroform-d, 400 MHz): δ=8.64 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.02 (s, 1H), 7.42-7.86 (m, 3H), 7.12 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.8, 2.5 Hz, 1H), 4.59 (s, 2H), 2.65 (s, 3H), 1.50-1.56 ppm (m, 9H). 19F NMR (chloroform-d, 376 MHz): δ=−90.15 ppm (s, 2F). LC-MS: method C, RT=2.61 min, MS (ESI) m/z: 457.1 (M+H)+. Analytical HPLC purity (method A): 100%.
    • Example 50 2-(difluoromethoxy)-5-(5-methoxy-1H-benzo[d]imidazol-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00520
  • To 2-chloro-5-methoxy-1H-benzo[d]imidazole (13.04 mg, 0.071 mmol) and Intermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The reaction mixture was stirred at room temperature until solids are dissolved, then [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.059 mL, 2M, 0.119 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 140° C. for 30 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 30-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 50 (6 mg, 0.016 mmol, 27.5% yield). 1H NMR (acetonitrile-d3, 400 MHz): δ=8.77 (br. s., 2H), 7.70 (s, 3H), 7.27-7.39 (m, 1H), 7.05-7.18 (m, 1H), 3.90 (s, 3H), 2.65 ppm (s, 3H). 19F NMR (acetonitrile-d3, 376 MHz): δ=−76.64 (br. s., 3F), −90.69 ppm (s, 2F). LC-MS: method C, RT=1.78 min, MS (ESI) m/z: 357.0 (M+H)+. Analytical HPLC purity (method A): 98%
    • Example 51 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00521
    • Intermediate 51A: 2-bromo-4-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00522
  • To a suspension of 4-methoxybenzo[d]thiazol-2-amine (2.5 g, 13.87 mmol) and p-TSA monohydrate (7.92 g, 41.6 mmol) in acetonitrile (80 mL) at 10° C. (cooled with ice water) was added dropwise a solution of sodium nitrite (1.914 g, 27.7 mmol) and potassium bromide (4.13 g, 34.7 mmol) in water (5 ml) over a period of 25 min. The reaction mixture was stirred at 10° C. for 10 min, and allowed to warm up to room temperature and stirred for 2.0 h. HPLC indicated a completion of reaction. To the reaction mixture was added sodium bicarbonate (pH to 9.0), water and EtOAc. The organic layer was collected, washed with water, saturated Na2S2O3, water, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 120 g silica gel cartridge which was eluted with hexanes for 4 min., then an 18 min gradient from 0% to 40% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 51A (2.51 g, 10.28 mmol, 74.1% yield) as a slightly yellow solid. 1H NMR (500 MHz, chloroform-d) δ 7.40-7.37 (m, 2H), 6.92 (dd, J=6.3, 2.5 Hz, 1H), 4.06 (s, 3H); LC-MS: method A, RT=1.79 min, MS (ESI) m/z: 244.0 and 246.0 (M+H)+.
    • Example 51
  • To Intermediate 51A (10 mg, 0.041 mmol) and Intermediate I-1 (20.66 mg, 0.061 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (4.01 mg, 4.92 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.031 mL, 2M, 0.061 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. LCMS indicated a completion of the reaction. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 50-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 51 (2.5 mg, 6.43 μmol, 15.69% yield). 1H NMR (400 MHz, chloroform-d) δ 8.93 (d, J=1.65 Hz, 1H), 8.71 (s, 1H), 7.80 (s, 1H), 7.58 (d, J=8.25 Hz, 1H), 7.47-7.86 (m, 1H), 7.39 (t, J=7.97 Hz, 1H), 6.96 (d, J=7.70 Hz, 1H), 4.13 (s, 3H), 2.68 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −89.62 (s, 2F). LC-MS: method C, RT=2.45 min, MS (ESI) m/z: 374.0 (M+H)+. Analytical HPLC purity (method A): 97%.
    • Example 52 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00523
    • Intermediate 52A: 2-bromo-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00524
  • To a white suspension of 4-methylbenzo[d]thiazol-2-amine (0.5 g, 3.04 mmol) and p-TSA monohydrate (1.737 g, 9.13 mmol) in acetonitrile (20 mL) at 10° C. (cooled with ice water) was added dropwise a solution of sodium nitrite (0.420 g, 6.09 mmol) and potassium bromide (0.906 g, 7.61 mmol) in water (5 mL) over a period of 25 min. The reaction mixture was stirred at 10° C. for 10 min, and allowed to warm up to room temperature and stirred for 1.0 h. To the reaction mixture was added sodium bicarbonate (pH to 9.0), water and EtOAc. The organic layer was collected, washed with water, saturated Na2S2O3, water, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column which was eluted with hexanes for 2 min., then a 20 min gradient from 0% to 40% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 52A (640 mg, 2.81 mmol, 92% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 7.62 (td, J=0.69, 7.71 Hz, 1H), 7.21-7.34 (m, 3H), 2.71 (s, 3H). LC-MS: method C, RT=2.11 min, MS (ESI) m/z: 227.0 and 229.0 (M+H)+.
    • Example 52
  • To Intermediate 52A (17 mg, 0.074 mmol) and Intermediate I-1 (30 mg, 0.089 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.29 mg, 8.92 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.056 mL, 2M, 0.112 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 65-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 52 (11.5 mg, 0.031 mmol, 41.5% yield). 1H NMR (400 MHz, chloroform-d) δ 8.86 (d, J=1.52 Hz, 1H), 8.71 (s, 1H), 7.47-7.90 (m, 3H), 7.30-7.36 (m, 2H), 2.90 (s, 3H), 2.72 (s, 3H). 19F NMR (400 MHz, chloroform-d) δ −90.12 (s, 2F). LC-MS: method C, RT=2.68 min, MS (ESI) m/z: 358.0 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 53 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00525
    • Intermediate 53A: 2-bromo-4-fluorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00526
  • To a suspension of 4-fluorobenzo[d]thiazol-2-amine (0.52 g, 3.09 mmol) and p-TSA monohydrate (1.764 g, 9.28 mmol) in acetonitrile (20 mL) at 10° C. (cooled with ice water) was added dropwise a solution of sodium nitrite (0.427 g, 6.18 mmol) and potassium bromide (0.920 g, 7.73 mmol) in water (5 mL) over a period of 25 min. The reaction mixture was stirred at 10° C. for 10 min, and allowed to warm up to room temperature and stirred for 1.0 h. To the reaction mixture was added sodium bicarbonate (pH to 9.0), water and EtOAc. The organic layer was collected, washed with water, saturated Na2S2O3, water, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column which was eluted with hexanes for 2 min., then a 20 min gradient from 0% to 40% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 53A (640 mg, 2.76 mmol, 89% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 7.59 (dd, J=0.76, 8.08 Hz, 1H), 7.40 (dt, J=4.55, 8.08 Hz, 1H), 7.20 (ddd, J=1.01, 8.08, 10.11 Hz, 1H). LC-MS: method C, RT=1.84 min, MS (ESI) m/z: 231.9 and 233.9 (M+H)+.
    • Example 53
  • To Intermediate 53A (17.26 mg, 0.074 mmol) and Intermediate I-1 (30 mg, 0.089 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.29 mg, 8.92 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.056 mL, 2M, 0.112 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 53 (15.0 mg, 0.039 mmol, 53.0% yield). 1H NMR (400 MHz, chloroform-d) δ 8.92 (d, J=1.77 Hz, 1H), 8.71 (s, 1H), 7.84 (dd, J=0.88, 1.89 Hz, 1H), 7.76 (dd, J=0.88, 7.96 Hz, 1H), 7.48-7.87 (m, 1H), 7.39 (dt, J=4.67, 8.02 Hz, 1H), 7.23 (ddd, J=1.01, 7.96, 10.48 Hz, 1H), 2.71 (s, 3H). 19F NMR (400 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 362.0 (M+H)+. Analytical HPLC purity (method A): 96%.
    • Example 54 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)-N-methylethanamine
  • Figure US20190292176A1-20190926-C00527
    • Intermediate 54A: tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethyl(methyl)carbamate
  • Figure US20190292176A1-20190926-C00528
  • A solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (41.0 mg, 0.234 mmol) and DIAD (0.057 mL, 0.292 mmol) in THF (1.0 mL) was added to a mixture of Intermediate 44D (20 mg, 0.058 mmol) and triphenylphosphine (30.7 mg, 0.117 mmol) in THF (2 mL) at 80° C. using a syringe pump over 4 h. The mixture was stirred at 80° C. for 1 h. Solvent was removed, the residual was dissolved in 1 ml of DMF. The crude material was purified via preparative LC/MS (method D, 65-85% B over 10 min., then an 8-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Intermediate 54A (14.8 mg, 0.028 mmol, 47.2% yield). 1H NMR (500 MHz, methanol-d4) δ 8.61 (s, 1H), 8.18 (d, J=1.38 Hz, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.49-7.83 (m, 1H), 7.42 (d, J=8.80 Hz, 1H), 7.11 (d, J=2.48 Hz, 1H), 6.92 (dd, J=2.48, 8.80 Hz, 1H), 4.15 (t, J=5.50 Hz, 2H), 3.63 (t, J=5.23 Hz, 2H), 2.99 (s, 3H), 2.61 (s, 3H), 1.45 (s, 9H). LC-MS: method C, RT=2.69 min, MS (ESI) m/z: 500.2 (M+H)+.
    • Example 54
  • To a solution of Intermediate 54A (9 mg, 0.018 mmol) in DCM (1 mL) was added TFA (1 ml). The mixture was stirred at room temperature for 1h. Solvent was removed and the crude sample was purified with preparative HPLC (method A, 30-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 54 (7 mg, 0.013 mmol, 74.9% yield). 1H NMR (400 MHz, methanol-d4) δ 8.68 (s, 1H), 8.23 (d, J=1.77 Hz, 1H), 8.06 (s, 1H), 7.70 (s, 1H), 7.56-7.97 (m, 1H), 7.52 (d, J=8.84 Hz, 1H), 7.29 (d, J=2.53 Hz, 1H), 7.07 (dd, J=2.65, 8.97 Hz, 1H), 4.28-4.38 (m, 2H), 3.45-3.58 (m, 2H), 2.83 (s, 3H), 2.64 (s, 3H). 19F NMR (376 MHz, methanol-d3) δ −76.92 (br. s., 3F), −95.23-88.19 (m, 2F). LC-MS: method C, RT=2.02 min, MS (ESI) m/z: 400.0 (M+H)+. Analytical HPLC purity (method A): 99%
    • Example 55 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00529
    • Intermediate 55A: 2,7-dibromo-4,6-dimethoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00530
  • To a mixture of 4,6-dimethoxybenzo[d]thiazol-2-amine (0.5 g, 2.378 mmol) and p-TSA monohydrate (1.357 g, 7.13 mmol) in acetonitrile (20 mL) at 10° C. (cooled with ice water) was added dropwise a solution of sodium nitrite (0.328 g, 4.76 mmol) and potassium bromide (0.707 g, 5.95 mmol) in water (5 mL) over a period of 25 min. The reaction mixture was stirred at 10° C. for 10 min, and allowed to warm up to room temperature and stirred for 1.0 h. The mixture was turned to a clear brown solution. To the reaction mixture was added sodium bicarbonate (pH to 9.0), water and EtOAc. The organic layer was collected, washed with water, saturated Na2S2O3, water, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column which was eluted with hexanes for 2 min., then a 20 min gradient from 0% to 40% EtOAc in hexanes. The desired fraction was collected and concentrated to Intermediate 55A (110 mg, 13% yield). 1H NMR (400 MHz, chloroform-d) δ 6.60 (s, 1H), 4.06 (s, 3H), 3.98 (s, 3H). LC-MS: method C, RT=2.18 min, MS (ESI) m/z: 351 353 and 355 (M+H)+.
    • Intermediate 55B 7-bromo-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00531
  • To Intermediate 55A (26 mg, 0.074 mmol) and Intermediate I-1 (30 mg, 0.088 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (4.81 mg, 5.89 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.055 mL, 2M, 0.110 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 100° C. for 2h. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 70-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 55B (8 mg, 0.016 mmol, 22.07% yield). 1H NMR (400 MHz, chloroform-d) δ 8.85 (d, J=1.77 Hz, 1H), 8.73 (s, 1H), 7.79 (dd, J=0.88, 1.90 Hz, 1H), 7.47-7.89 (m, 1H), 6.68 (s, 1H), 4.15 (s, 3H), 4.04 (s, 3H), 2.67 (s, 3H). 19F NMR (400 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method C, RT=2.56 min, MS (ESI) m/z: 481.9 and 484.0 (M+H)+.
    • Example 55
  • To a solution of Intermediate 55B (6 mg, 0.012 mmol) in ethyl acetate (5 ml) was added Pd/C (5 mg) and TEA (10.40 μl, 0.075 mmol) and the mixture was stirred under a hydrogen balloon at 50° C. for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated. The crude material was purified via preparative LC/MS (method D, 45-90% B over 10 min., then a 10-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to Example 55 (0.2 mg, 0.496 μmol, 3.99% yield). 1H NMR (500 MHz, methanol-d4) δ 8.76 (d, J=1.65 Hz, 1H), 8.67 (s, 1H), 7.77 (d, J=0.83 Hz, 1H), 7.48-7.85 (m, 1H), 7.03 (s, 1H), 6.59 (d, J=2.20 Hz, 1H), 4.05 (s, 3H), 3.89 (s, 3H). LC-MS: method C, RT=2.46 min, MS (ESI) m/z: 404 (M+H)+. Analytical HPLC purity (method A): 100%.
    • Example 56 2-methoxy-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00532
    • Intermediate 56A: 5-methoxybenzofuran-2-ylboronic acid
  • Figure US20190292176A1-20190926-C00533
  • To 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (1.190 mL, 1.903 mmol) dropwise. The solution turned to slightly yellow. The mixture was stirred at −78° C. for 20 min, followed by addition of triisopropyl borate (0.737 mL, 3.17 mmol). The mixture was stirred for 30 min, and the cooling bath was removed to allow warm up to room temperature over 1.5 h. It was diluted with EtOAc, quenched with 3.0 mL of 1.0 N HCl. After stirring at room temperature for 25 min, the organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform with a drop of MeOH, and charged to a 4 g silica gel cartridge which was eluted with hexanes for 2 min., then a 10 min gradient from 0% to 60% EtOAc in hexanes. The desired fractions were combined, concentrated and lyophilized to give Intermediate 56A (170 mg, 0.886 mmol, 69.8% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) δ 7.41 (d, J=9.1 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.9, 2.6 Hz, 1H), 3.84 (s, 3H); LC-MS: method A, RT=1.45 min, MS (ESI) m/z: 149.0 (M-B(OH)2)+.
    • Example 56
  • To Intermediate I-9A (20 mg, 0.079 mmol) and Intermediate 56A (20.48 mg, 0.107 mmol) was added toluene (0.75 mL) and EtOH (0.250 mL). The reaction mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.16 mg, 6.32 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.079 mL, 2M, 0.158 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude material was purified via preparative LC/MS (method D, 55-90% B over 10 min., then a 10-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 56 (13.7 mg, 0.043 mmol, 54.1% yield). 1H NMR (500 MHz, methanol-d4) δ 8.47 (s, 1H), 8.06 (d, J=1.93 Hz, 1H), 7.94 (d, J=0.83 Hz, 1H), 7.56-7.65 (m, 2H), 7.41 (d, J=9.08 Hz, 1H), 7.11 (d, J=2.48 Hz, 1H), 6.90 (dd, J=2.48, 8.80 Hz, 1H), 4.09 (s, 3H), 3.85 (s, 3H), 2.59 (s, 3H). LC-MS: method C, RT=2.63 min, MS (ESI) m/z: 321 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 58 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00534
  • To Intermediate 15F (15 mg, 0.075 mmol) and Intermediate I-1 (30.3 mg, 0.090 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.36 mg, 9.02 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.056 mL, 2M, 0.113 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 30 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 65-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 58 (10.5 mg, 0.028 mmol, 37.1% yield). 1H NMR (400 MHz, chloroform-d) δ 8.84 (d, J=1.52 Hz, 1H), 8.72 (s, 1H), 7.81-7.83 (m, 1H), 7.79 (dd, J=0.63, 8.21 Hz, 1H), 7.45-7.87 (m, 2H), 6.88 (d, J=7.83 Hz, 1H), 4.07 (s, 3H), 2.70 (s, 3H). 19F NMR (400 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 374.0 (M+H)+. Analytical HPLC purity (method A): 99%.
    • Example 59 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluoro-6-methoxy benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00535
    • Intermediate 59A: 4-fluoro-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00536
  • To 2-fluoro-4-methoxyaniline (636 mg, 4.51 mmol) in acetonitrile (14 mL) was added ammonium thiocyanate (515 mg, 6.76 mmol). The mixture was stirred at room temperature for 10 min. Then it was cooled with tape water, and benzyltrimethylammonium tribromide (1757 mg, 4.51 mmol) in acetonitrile (5.0 mL) was added dropwise (10 min). The mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc/saturated sodium bicarbonate. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform/a small amount of MeOH and charged to a 40 g silica gel cartridge which was eluted with 5% EtOAc in hexanes for 3 min., then a 12 min gradient from 5% to 75% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 59A (0.65 g, 3.28 mmol, 72.8% yield) as a pale solid. 1H NMR (500 MHz, DMSO-d6) δ 6.84 (d, J=1.7 Hz, 1H), 6.75 (br. s., 2H), 6.55 (dd, J=12.1, 2.2 Hz, 1H), 3.74-3.72 (m, 3H); 19F NMR (471 MHz, DMSO-d6) δ −124.96 (s, 1F); LC-MS: method A, RT=1.17 min, MS (ESI) m/z: 199.0 (M+H).
    • Intermediate 59B: 2-bromo-4-fluoro-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00537
  • To a suspension of Intermediate 59A (0.32 g, 1.614 mmol) in acetonitrile (15 mL) was added p-TSA monohydrate (0.983 g, 5.17 mmol). The salt formed was stirred at room temperature for 15 min, and at 10° C. (cooled with ice water) for 5 min, followed by dropwise addition of a solution of sodium nitrite (0.223 g, 3.23 mmol) and potassium bromide (0.480 g, 4.04 mmol) in water (5 mL) over a period of 2 min. The reaction mixture was stirred at from 10° C. to room temperature overnight. The reaction was quenched with saturated sodium bicarbonate. The insoluble material was removed by filtration. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 2 min., then a 15 min gradient from 0% to 30% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 59B (0.15 g, 0.572 mmol, 35.5% yield) as a pale yellow solid. 1H NMR (500 MHz, chloroform-d) δ 7.07 (dd, J=2.2, 0.8 Hz, 1H), 6.84 (dd, J=11.6, 2.2 Hz, 1H), 3.89 (s, 3H); 19F NMR (471 MHz, chloroform-d) δ −119.63 (s, 1F); LC-MS: method A, RT=1.87 min, MS (ESI) m/z: 262.0 and 264.0 (M+H)+.
    • Example 59
  • To Intermediate 59B (15 mg, 0.057 mmol) and Intermediate I-1 (23.08 mg, 0.069 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.61 mg, 6.87 μmol) was added. The flask was degassed and flushed with argon. Finally sodium carbonate (0.043 mL, 2M, 0.086 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 40 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 60-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 59 (8.5 mg, 0.022 mmol, 37.9% yield). 1H NMR (400 MHz, chloroform-d) δ 8.86 (d, J=1.52 Hz, 1H), 8.70 (s, 1H), 7.81 (d, J=0.76 Hz, 1H), 7.45-7.97 (m, 1H), 7.22 (d, J=2.27 Hz, 1H), 6.88 (dd, J=2.15, 11.75 Hz, 1H), 3.92 (s, 3H), 2.69 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.22 (s, 2F), −121.48 (br. s., 1F). LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 391.9 (M+H)+. Analytical HPLC purity (method A): 100%.
    • Example 60 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00538
  • To 2-chloro-5-fluorobenzo[d]thiazole (15 mg, 0.080 mmol) and Intermediate I-1 (32.2 mg, 0.096 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was stirred at room temperature until solids are dissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.83 mg, 9.59 μmol) was added. The flask was degassed and flushed with Ar. Finally sodium carbonate (2M, 0.12 mL, 0.24 mmol) was added dropwise. The reaction vessel was sealed and bubbled with argon for 5 min, then placed in microwave reactor at 120° C. for 40 min. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude material was purified via preparative LC/MS (method D, 60-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 60 (18.8 mg, 0.052 mmol, 65.1% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.75 (d, J=1.65 Hz, 1H), 8.15 (dd, J=4.81, 8.94 Hz, 1H), 8.09 (dd, J=2.48, 8.53 Hz, 1H), 7.93 (s, 1H), 7.73-8.04 (m, 1H), 7.44 (dt, J=2.75, 9.08 Hz, 1H), 2.67 (s, 3H). LC-MS: method C, a=2.54 min, MS (ESI) m/z: 361.9 (M+H)+. Analytical HPLC purity (method A): 100%.
    • Example 61 Methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole-7-carboxylate
  • Figure US20190292176A1-20190926-C00539
    • Intermediate 61A: methyl 2-bromobenzo[d]thiazole-7-carboxylate
  • Figure US20190292176A1-20190926-C00540
  • tert-Butyl nitrite (1.111 mL, 8.40 mmol) was added to copper (II) bromide (1.770 g, 7.92 mmol) in dry acetonitrile (15 mL) under argon. The mixture was stirred at room temperature for 10 min. A suspension of methyl 2-aminobenzo[d]thiazole-7-carboxylate (1.0 g, 4.80 mmol) in dry acetonitrile (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was heated at 50° C. for 45 min. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, Intermediate 61A (1.2 g, 4.41 mmol, 92% yield) was obtained as brown solid. It was used for next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 8.19 (dd, J=8.0, 1.1 Hz, 1H), 8.13 (dd, J=7.7, 1.1 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 4.05 (s, 3H); LC-MS: method A, RT=2.02 min, MS (ESI) m/z: 272.0 274.0 (M+H)+.
    • Example 61
  • To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 61A (31.6 mg, 0.116 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.098 mL, 2M, 0.196 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. To the reaction mixture was added EtOAc/water. The organic layers were collected, dried over sodium sulfate. After evaporation of solvent, the crude product was purified via preparative LC/MS (method D, 55-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 61 (2.9 mg, 7.08 μmol, 7.93%). 1H NMR (500 MHz, Methanol-d4) δ 8.73 (s, 1H), 8.71 (d, J=1.65 Hz, 1H), 8.30 (dd, J=0.83, 7.98 Hz, 1H), 8.15 (dd, J=0.83, 7.43 Hz, 1H), 7.84 (s, 1H), 7.61 (t, J=7.70 Hz, 1H), 7.52-7.82 (m, 1H), 4.05 (s, 3H), 2.68 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 402.10 (M+H)+. Analytical HPLC purity (method B): 98%
    • Example 62 Methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
  • Figure US20190292176A1-20190926-C00541
    • Intermediate 62A 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine
  • Figure US20190292176A1-20190926-C00542
  • To Example 11 (19 mg, 0.042 mmol) was added 4.0 N HCl in dioxane (1059 μl, 4.24 mmol). The mixture was aged at room temperature for 2.0 h. Solvent was removed and the product was lyophilized overnight to give Intermediate 62A (14 mg, 0.034 mmol, 81% yield). 1H NMR (500 MHz, methanol-d4) δ 8.65 (s, 1H), 8.61 (s, 1H), 7.82 (s, 1H), 7.65 (t, JHF=71.53 Hz, 1H), 4.56 (br. s., 2H), 3.77-3.73 (m, 2H), 3.72-3.68 (m, 2H), 2.66 (s, 3H); 19F NMR (471 MHz, methanol-d4) δ −90.23 (s, 2F); LC-MS: method A, RT=1.70 min, MS (ESI) m/z: 349.0 (M+H)+.
    • Example 62
  • To a solution of Intermediate 62A (9 mg, 0.026 mmol) and DIEA (0.023 mL, 0.129 mmol) in DCM (1 mL) was added a solution of methyl chloroformate (4.00 μl, 0.052 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1.0 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude was purified with a preparative HPLC (method A, 60-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 62 (8 mg, 0.018 mmol, 68.6% yield). 1H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.55 (s, 1H), 7.74 (s, 1H), 7.40-7.97 (m, 1H), 4.82 (br. s., 2H), 3.88 (br. s., 2H), 3.79 (s, 3H), 3.05 (br. s., 2H), 2.64 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.20 (s, 2F). LC-MS: method C, RT=2.43 min, MS (ESI) m/z: 406.9 (M+H)+. Analytical HPLC purity (method A): 92%.
    • Example 63 N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide
  • Figure US20190292176A1-20190926-C00543
  • To a solution of Intermediate I-4 (12 mg, 0.027 mmol) and DIEA (23.88 μl, 0.137 mmol) in DCM (2 ml) was added a solution of benzenesulfonyl chloride (9.66 mg, 0.055 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 63 (10 mg, 0.018 mmol, 64.7% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.90-8.58 (m, 2H), 7.95 (d, J=8.8 Hz, 1H), 7.90-7.50 (m, 7H), 7.05 (dd, J=8.8, 2.5 Hz, 1H), 5.97 (br. s., 1H), 4.06 (t, J=5.3 Hz, 2H), 3.33 (q, J=5.6 Hz, 2H), 2.68 (s, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.50 (s, 2F). LC-MS: method C, RT=2.39 min, MS (ESI) m/z: 543.0 (M+H)+. Analytical HPLC purity (method A): 96%.
    • Example 64 (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methanol
  • Figure US20190292176A1-20190926-C00544
    • Intermediate 64A: (2-bromobenzo[d]thiazol-7-yl)methanol
  • Figure US20190292176A1-20190926-C00545
  • To a solution of Intermediate 61A (0.53 g, 1.948 mmol) in THF (10 mL) at 0° C. was added 1.0 M Super-H in THF (4.28 mL, 4.28 mmol) dropwise. The mixture was stirred at 0° C. for 1.0 h. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride at 0° C., and then with a few drops of 1.0 N HCl. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and was purified with 40 g ISCO column eluted with hexanes for 3 min, then an 18 min gradient from 0 to 100% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 64A (380 mg, 1.557 mmol, 80% yield) as a light yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 7.80 (d, J=8.08 Hz, 1H), 7.44 (t, J=7.71 Hz, 1H), 7.31 (d, J=7.33 Hz, 1H), 4.83 (s, 2H). LC-MS: method C, RT=1.58 min, MS (ESI) m/z: 243 and 245 (M+H)+.
    • Example 64
  • To Intermediate I-1 (106 mg, 0.315 mmol), Intermediate 64A (100 mg, 0.410 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (20.59 mg, 0.025 mmol) was added toluene (7.5 mL) and EtOH (2.500 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.315 mL, 2M, 0.630 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified 12 g ISCO column eluted with 0-100% EtOAc in hexanes for 15 min., followed by a preparative HPLC (method A, 30-100% B in 8 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 64 (88 mg, 0.261 mmol, 83% yield). 1H NMR (500 MHz, methanol-d4) δ 8.76 (s, 1H), 8.02 (d, J=8.25 Hz, 1H), 7.88 (dd, J=1.10, 1.93 Hz, 1H), 7.62-7.94 (m, 1H), 7.50-7.58 (m, 1H), 7.43 (dd, J=0.96, 7.29 Hz, 1H), 4.94 (s, 2H), 2.69 (s, 3H). 19F NMR (376 MHz, methanol-d4) δ −91.06 (s, 2F). LC-MS: method C, RT=2.24 min, MS (ESI) m/z: 373.9 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 65 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(methoxymethyl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00546
  • To a suspension of Example 64 (18 mg, 0.048 mmol) in THF (1 mL) was added NaH (3.86 mg, 0.096 mmol) and the mixture was stirred at room temperature for 30 min Then Met (0.090 mL, 1.446 mmol) was added. The mixture was heated up to 50° C. for 2 h. The mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude was purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 65 (2 mg, 5.06 μmol, 10.49% yield). 1H NMR (400 MHz, chloroform-d) δ 8.82 (d, J=2.02 Hz, 1H), 8.75 (s, 1H), 8.13 (d, J=8.08 Hz, 1H), 7.84 (s, 1H), 7.48-7.88 (m, 2H), 7.39 (d, J=7.33 Hz, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.70 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.20 (s, 2F). LC-MS: method C, RT=2.45 min, MS (ESI) m/z: 387.9 (M+H)+. Analytical HPLC purity (method A): 99%.
    • Example 66 N-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00547
    • Intermediate 66A: tert-butyl N-[(2-bromo-1,3-benzothiazol-7-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate
  • Figure US20190292176A1-20190926-C00548
  • A solution of DIAD (0.134 mL, 0.688 mmol) in THF (2 mL) was added to a solution of di-tert-butyl iminodicarboxylate (150 mg, 0.688 mmol), Intermediate 64A (56 mg, 0.229 mmol) and triphenylphosphine (181 mg, 0.688 mmol) in THF (2 mL). The mixture was stirred at room temperature for 1 h, diluted with DCM and saturated NaHCO3, extracted with DCM, the combined organic layer was washed with brine, dried MgSO4 and concentrated. The crude sample was purified with 40 g ISCO column eluted with 0-100% DCM/Hex for 20 min, the desired fraction was collected to give Intermediate 66A (55 mg, 0.124 mmol, 54.1% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ 7.90 (d, J=7.98 Hz, 1H), 7.45 (t, J=7.84 Hz, 1H), 7.30 (dd, J=0.83, 7.43 Hz, 1H), 4.98 (s, 2H), 1.41-1.46 (m, 18H). LC-MS: method C, RT=2.37 min, MS (ESI) m/z: 908.9 [2M+23]+.
    • Intermediate 66B: tert-butyl N-[(tert-butoxy)carbonyl]-N-({2-[2-(difluoromethoxy)-7-methylquinoxalin-5-yl]-1,3-benzothiazol-7-yl}methyl)carbamate
  • Figure US20190292176A1-20190926-C00549
  • To Intermediate I-1 (37.9 mg, 0.113 mmol), Intermediate 66A (50 mg, 0.113 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.37 mg, 9.02 μmol) was added toluene (7.5 mL) and EtOH (2.500 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.113 mL, 2M, 0.226 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 70-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 66B (21 mg, 0.035 mmol, 30.9% yield). 1H NMR (500 MHz, methanol-d4) δ 8.76 (s, 1H), 8.02 (d, J=8.25 Hz, 1H), 7.88 (dd, J=1.10, 1.93 Hz, 1H), 7.62-7.94 (m, 1H), 7.50-7.58 (m, 1H), 7.43 (dd, J=0.96, 7.29 Hz, 1H), 4.94 (s, 2H), 2.69 (s, 3H). 19F NMR (376 MHz, methanol-d) δ −90.20 (s, 2F). LC-MS: method C, RT=2.62 min, MS (ESI) m/z: 573.2 (M+H)+.
    • Intermediate 66C: tert-butyl (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl) benzo[d]thiazol-7-yl)methylcarbamate
  • Figure US20190292176A1-20190926-C00550
  • To a solution of Intermediate 66B (17 mg, 0.030 mmol) in DCM (1 mL) was added TFA (0.023 mL, 0.297 mmol). The mixture was stirred at room temperature for 15 min, diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with NaHCO3 and brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 70-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 66C (13 mg, 0.027 mmol, 92% yield). 1H NMR (400 MHz, chloroform-d) δ 8.83 (d, J=1.8 Hz, 1H), 8.70 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.84 (d, J=1.0 Hz, 1H), 7.87-7.48 (m, 3H), 7.37 (d, J=6.8 Hz, 1H), 2.70 (s, 3H), 1.52 (s, 9H). 19F NMR (376 MHz, chloroform-d) δ −90.20 (s, 2F). LC-MS: method C, RT=2.44 min, MS (ESI) m/z: 472.9 (M+H)+.
    • Intermediate 66D (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methanamine
  • Figure US20190292176A1-20190926-C00551
  • To a solution of Intermediate 66C (11 mg, 0.022 mmol, 94% yield) in DCM was added TFA (359 μl, 4.66 mmol) and the mixture was stirred at room temperature for 15 min. The crude was purified with a preparative HPLC (method A, 30-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 66D (11 mg, 0.022 mmol, 94% yield). 1H NMR (400 MHz, methanol-d4) δ 8.80 (d, J=1.8 Hz, 1H), 8.71 (s, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.92-7.59 (m, 3H), 7.52-7.44 (m, 1H), 4.44 (s, 2H), 2.70 (s, 3H). 19F NMR (376 MHz, methanol-d4) δ −78.07 (s, 3F), −92.13 (s, 2F). LC-MS: method C, RT=1.91 min, MS (ESI) m/z: 372.9 (M+H)+.
    • Example 66
  • To a solution of Intermediate 66D (8 mg, 0.016 mmol) and DIEA (0.014 mL, 0.082 mmol) in DCM (1 mL) was added a solution of benzenesulfonyl chloride (5.81 mg, 0.033 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1.0 h. Solvent was removed, the residual was purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 66 (3 mg, 5.21 μmol, 31.7% yield). 1H NMR (400 MHz, chloroform-d) δ 8.76 (d, J=1.8 Hz, 1H), 8.73 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.92-7.84 (m, 3H), 7.70-7.30 (m, 6H), 4.93 (d, J=5.8 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H), 2.70 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.22 (s, 2F). LC-MS: method C, RT=2.30 min, MS (ESI) m/z: 513.1 (M+H)+. Analytical HPLC purity (method A): 90%
    • Example 67 N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy) ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00552
    • Intermediate 67A: 2-bromo-4-fluorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00553
  • Aluminum chloride (308 mg, 2.308 mmol) was added to a solution of Intermediate 59B (220 mg, 0.839 mmol) in toluene (4 mL). The mixture was heated at 85° C. for 1.5 h. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (10 mL) and EtOAc (10 mL), and stirred at room temperature for 30 min. The organic layer was collected, washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 5 min., then an 18 min gradient from 0% to 40% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 67A (45 mg, 0.181 mmol, 21.61% yield) as brown solid. 1H NMR (400 MHz, methanol-d4) δ 6.98 (dd, J=2.3, 0.8 Hz, 1H), 6.71 (dd, J=11.9, 2.3 Hz, 1H). LC-MS: method C, RT=1.72 min, MS (ESI) m/z: 247 and 249 (M+H)+.
    • Intermediate 67B: tert-butyl 2-(2-bromo-4-fluorobenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00554
  • A solution of DIAD (0.088 mL, 0.453 mmol) and tert-butyl (2-hydroxyethyl) carbamate (0.070 mL, 0.453 mmol) in THF (1 mL) was added to a solution of Intermediate 67A (45 mg, 0.181 mmol) and triphenylphosphine (71.4 mg, 0.272 mmol) in THF (2 mL) at 80° C. using syringe pump over 2 h. The mixture was concentrated and redissolved in 1 ml of DCM and was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min, the desired fraction was collected to give Intermediate 67B (30 mg, 0.077 mmol, 42.3% yield). 1H NMR (400 MHz, chloroform-d) δ 7.05 (d, J=1.8 Hz, 1H), 6.82 (dd, J=11.4, 2.3 Hz, 1H), 5.13-4.95 (m, 1H), 4.07 (t, J=5.1 Hz, 2H), 3.62-3.48 (m, 2H), 1.48-1.42 (m, 9H). LC-MS: method C, RT=2.14 min, MS (ESI) m/z: 391 and 393 (M+H)+.
    • Intermediate 67C: tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00555
  • To Intermediate I-1 (23 mg, 0.068 mmol), Intermediate 67B (29.4 mg, 0.075 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (4.47 mg, 5.47 μmol) was added toluene (0.75 mL) and EtOH (0.250 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.068 mL, 2M, 0.137 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 min. To the reaction mixture was added EtOAc/water. The organic layers were collected, dried over sodium sulfate. The crude residue was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction was concentrated and further purified with a preparative HPLC (method A, 70-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 67C (30 mg, 0.054 mmol, 79% yield). 1H NMR (400 MHz, chloroform-d) δ 8.85 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.95-7.41 (m, 1H), 7.21 (d, J=2.0 Hz, 1H), 6.88 (dd, J=11.6, 2.3 Hz, 1H), 4.13 (t, J=5.1 Hz, 2H), 3.60 (br. s., 2H), 2.69 (s, 3H), 1.48 (s, 9H). 19F NMR (376 MHz, chloroform-d) δ −90.55 (s, 2F), −123.30 (br. s., 1F). LC-MS: method C, RT=2.47 min, MS (ESI) m/z: 521.2 (M+H)+.
    • Intermediate 67D 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00556
  • To a solution of Intermediate 67C (25 mg, 0.048 mmol) in DCM (1 mL) was added TFA (0.920 mL, 11.94 mmol). The mixture was stirred at room temperature for 1 h. Solvent was removed, the residual was purified with a preparative HPLC (method A, 30-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 67D (22 mg, 0.040 mmol, 84% yield). 1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 7.87 (d, J=1.0 Hz, 1H), 8.00-7.55 (m, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.04 (dd, J=11.9, 2.3 Hz, 1H), 4.43-4.30 (m, 2H), 3.52-3.41 (m, 2H), 2.69 (s, 3H). 19F NMR (376 MHz, methanol-d4) δ −77.57 (br. s., 3F), −84.34-98.20 (s 2F), −123.30 (br. s., 1F). LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 421.2 (M+H)+.
    • Example 67
  • To a solution of Intermediate 67D (15 mg, 0.028 mmol) and DIEA (49.0 μl, 0.281 mmol) in DCM was added a solution of benzenesulfonyl chloride (7.20 μl, 0.056 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1.0 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 67 (4 mg, 6.64 μmol, 23.64% yield). 1H NMR (400 MHz, chloroform-d) δ 8.86 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.98-7.90 (m, 2H), 7.81 (s, 1H), 7.64-7.50 (m, 3H), 7.87-7.43 (m, 1H), 7.10 (d, J=2.3 Hz, 1H), 6.77 (dd, J=11.5, 2.1 Hz, 1H), 4.96 (t, J=5.9 Hz, 1H), 4.10 (t, J=5.1 Hz, 2H), 3.47 (q, J=5.3 Hz, 2H), 2.69 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.22 (s, 2F), −120.80 (br. s., 1F). LC-MS: method C, RT=2.40 min, MS (ESI) m/z: 560.9 (M+H)+. Analytical HPLC purity (method A): 95%.
    • Example 68 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00557
  • To Intermediate I-1 (20 mg, 0.059 mmol), 2-chloro-5-methylbenzo[d]thiazole (14.21 mg, 0.077 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.89 mg, 4.76 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.065 mL, 2M, 0.131 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 min. To the reaction mixture was added EtOAc/water. The organic layers were collected, dried over sodium sulfate. After evaporation of solvent, the crude was purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 68 (11 mg, 0.030 mmol, 50.7% yield). 1H NMR (400 MHz, chloroform-d) δ 8.81 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.82 (dd, J=1.9, 0.9 Hz, 1H), 7.85-7.48 (m, 1H), 7.28 (br. s., 1H), 2.70 (s, 3H), 2.56 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.20 (s, 2F). LC-MS: method C, RT=2.57 min, MS (ESI) m/z: 357.9 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 69 Methyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00558
    • Intermediate 69A: 2-chlorobenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00559
  • Aluminum chloride (184 mg, 1.377 mmol) was added to a solution of 2-chloro-7-methoxybenzo[d]thiazole (100 mg, 0.501 mmol) in toluene (2 mL). The mixture was heated at 85° C. for 1.5 h. HPLC indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL) and EtOAc (50 mL), and stirred at room temperature for 30 min. The organic layer was collected, washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g silica gel cartridge which was eluted with hexanes for 5 min., then a 10 min gradient from 0% to 40% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 69A (85 mg, 0.458 mmol, 91% yield) as brown solid. 1H NMR (400 MHz, methanol-d4) δ 7.47-7.36 (m, 1H), 7.35-7.24 (m, 1H), 6.82 (d, J=8.1 Hz, 1H). LC-MS: method C, RT=1.72 min, MS (ESI) m/z: 185.8 (M+H)+.
    • Intermediate 69B: tert-butyl 2-(2-chlorobenzo[d]thiazol-7-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00560
  • A solution of DIAD (0.223 mL, 1.145 mmol) and tert-butyl (2-hydroxyethyl) carbamate (0.177 mL, 1.145 mmol) in THF (1 mL) was added to a solution of Intermediate 69A (85 mg, 0.458 mmol) and triphenylphosphine (180 mg, 0.687 mmol) in THF (2 mL) at 80° C. using syringe pump over 3 h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and saturated NaHCO3, extracted with EtOAc, the combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min, the desired fraction was collected to give Intermediate 69B (125 mg, 0.380 mmol, 83% yield). 1H NMR (400 MHz, chloroform-d) δ 7.58 (dd, J=8.2, 0.6 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 4.21 (t, J=5.2 Hz, 2H), 3.60 (q, J=5.3 Hz, 2H), 1.51-1.44 (m, 9H). LC-MS: method C, RT=2.17 min, MS (ESI) m/z: 329. (M+H)+.
    • Intermediate 69C: tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00561
  • To Intermediate I-1 (29 mg, 0.086 mmol), Intermediate 69B (32.6 mg, 0.099 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.64 mg, 6.90 μmol) was added toluene (0.75 mL) and EtOH (0.250 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.086 mL, 2M, 0.173 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 min. To the reaction was added EtOAc/water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-50% EtOAc in hexane for 15 min. The desired fraction was collected and concentrated to give Intermediate 69C (35 mg, 0.068 mmol, 79% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.79 (s, 1H), 8.77 (d, J=1.8 Hz, 1H), 7.80 (dd, J=1.9, 0.9 Hz, 1H), 7.67-7.62 (m, 1H), 7.97-7.56 (m, 1H), 7.41 (t, J=8.1 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 4.25 (t, J=5.7 Hz, 2H), 3.53 (q, J=5.8 Hz, 2H), 2.66 (d, J=13.6 Hz, 1H), 2.63 (s, 3H), 1.33 (s, 9H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.55 (s, 2F). LC-MS: method C, RT=2.49 min, MS (ESI) m/z: 503.0 (M+H)+.
    • Intermediate 69D 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00562
  • To a solution of Intermediate 69C (30 mg, 0.060 mmol) in DCM (1 mL) was added TFA (0.920 mL, 11.94 mmol). The mixture was stirred at room temperature for 1 h. Solvent was removed, the residual was purified with a preparative HPLC (method A, 30-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 69D (30 mg, 0.058 mmol, 96% yield). 1H NMR (400 MHz, methanol-d4) δ 8.79 (d, J=1.8 Hz, 1H), 8.73 (s, 1H), 7.90 (d, J=0.8 Hz, 1H), 7.79 (s, 1H), 7.99-7.60 (m, 1H), 7.53 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.56-4.42 (m, 2H), 3.52 (t, J=4.9 Hz, 2H), 2.70 (s, 3H). 19F NMR (376 MHz, methanol-d4) δ −77.64 (br. s., 3F), −91.57 (br. s., 2F). LC-MS: method C, RT=1.96 min, MS (ESI) m/z: 402.9 (M+H)+.
    • Example 69
  • To a solution of Intermediate 69D (10 mg, 0.019 mmol) and DIEA (0.017 mL, 0.097 mmol) in DCM (1 mL) was added a solution of methyl chloroformate (3.00 μl, 0.039 mmol) in DCM. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and water, and then extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 60-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 69 (5.5 mg, 0.011 mmol, 58.6% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.84-8.81 (m, 1H), 8.79 (s, 1H), 7.90-7.46 (m, 5H), 6.99 (d, J=7.8 Hz, 1H), 4.29 (t, J=5.4 Hz, 2H), 3.65-3.56 (m, 6H), 2.70 (s, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ −86.49-95.62 (m, 2F). LC-MS: method C, RT=2.36 min, MS (ESI) m/z: 461.0 (M+H)+. Analytical HPLC purity (method A): 95%.
    • Example 70 Methyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00563
    • Intermediate 70A: 2-chloro-7-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00564
  • To a solution of copper (II) chloride (1.030 g, 7.66 mmol) in acetonitrile (60 mL) at 40° C. was added tert-butyl nitrite (1.097 mL, 8.30 mmol), followed by Intermediate 12C (1.24 g, 6.38 mmol) as a solid. The mixture was stirred at 40° C. for 1.0 h, diluted with EtOAc, washed with 1.0 N HCl, water and brine. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g silica gel cartridge which was eluted with 5% dichloromethane in hexanes for 2 min., then a 12 min gradient from 5% to 50% dichloromethane in hexanes. The desired fractions were combined and concentrated to give Intermediate 70A (1.2 g, 5.62 mmol, 88% yield) as a slightly yellow solid.
    • Intermediate 70B: 2-chloro-4-methylbenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00565
  • Aluminum chloride (369 mg, 2.77 mmol) was added to a solution of Intermediate 70A (215 mg, 1.006 mmol) in toluene (4 mL). The mixture was heated at 85° C. for 1.5 h. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL) and EtOAc (50 mL), and stirred at room temperature for 30 min. The organic layer was collected, washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g silica gel cartridge which was eluted with hexanes for 5 min., then an 18 min gradient from 0% to 40% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 70B (105 mg, 0.526 mmol, 52.3% yield) as brown solid. 1H NMR (400 MHz, Methanol-d4) δ 6.98 (dd, J=2.3, 0.8 Hz, 1H), 6.71 (dd, J=11.9, 2.3 Hz, 1H). LC-MS: method C, RT=2.20 min, MS (ESI) m/z: 547.2 (M+H)+. LC-MS: method C, RT=1.87 min, MS (ESI) m/z: 199.8 (M+H)+.
    • Intermediate 70C: tert-butyl 2-(2-chloro-4-methylbenzo[d]thiazol-7-yloxy) ethylcarbamate
  • Figure US20190292176A1-20190926-C00566
  • A solution of DIAD (0.243 mL, 1.252 mmol) and Intermediate 70B (100 mg, 0.501 mmol) in THF (1 mL) was added to a solution of tert-butyl (2-hydroxyethyl) carbamate (0.194 mL, 1.252 mmol) and triphenylphosphine (197 mg, 0.751 mmol) in THF (2 mL) at 80° C. using a syringe pump for 2 h. The mixture was diluted with dichloromethane and saturated NaHCO3, extracted with dichloromethane, the combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with 40 g ISCO column eluted with 0-100% EtOAc in hexanes for 20 min, the desired fraction was collected to give Intermediate 70C (170 mg, 0.496 mmol, 99% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.2, 0.9 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 5.09-4.94 (m, 1H), 4.23-4.14 (m, 2H), 3.57 (q, J=5.1 Hz, 2H), 2.60 (d, J=0.5 Hz, 3H), 1.55-1.42 (m, 9H). LC-MS: method C, RT=2.26 min, MS (ESI) m/z: 342.9 (M+H)+.
    • Intermediate 70D: tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00567
  • To Intermediate I-1 (33.9 mg, 0.101 mmol), Intermediate 70C (45 mg, 0.131 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.60 mg, 8.08 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.111 mL, 2M, 0.222 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 min. To the reaction mixture was added EtOAc/water. The organic layers were collected, dried over sodium sulfate. After evaporation of solvent, the crude product was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction was collected to give Intermediate 70D (46 mg, 0.087 mmol, 86% yield) was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.87 (d, J=1.5 Hz, 1H), 8.74 (s, 1H), 7.81 (dd, 1.0 Hz, 1H), 7.94-7.46 (m, 1H), 7.23 (dd, J=8.0, 0.9 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 4.25 (t, J=4.9 Hz, 2H), 3.67 (d, J=4.8 Hz, 2H), 2.81 (s, 3H), 2.71 (s, 3H), 1.48 (s, 9H). 19F NMR (376 MHz, chloroform-d) δ −90.17 (s, 2F). LC-MS: method C, RT=2.63 min, MS (ESI) m/z: 517.0 (M+H)+.
    • Intermediate 70E 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00568
  • To a solution of Intermediate 70D (40 mg, 0.077 mmol) in DCM (1 mL) was added TFA (0.597 mL, 7.74 mmol). The mixture was stirred at room temperature for 1 h. Solvent was removed, the residual was purified with a preparative HPLC (method A, 30-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to Intermediate 70E (35 mg, 0.065 mmol, 84% yield). 1H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 1H), 8.71 (s, 1H), 7.87 (s, 1H), 8.01-7.54 (m, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 4.45 (t, J=4.9 Hz, 2H), 3.48 (t, J=4.9 Hz, 2H), 2.78 (s, 3H), 2.71 (s, 3H). 19F NMR (376 MHz, Methanol-d4) δ −78.76 (br. s., 3F), −92.71 (s, 2F). LC-MS: method C, RT=2.10 min, MS (ESI) m/z: 416.9 (M+H)+.
    • Example 70
  • To a solution of Intermediate 70E (10 mg, 0.019 mmol) and DIEA (0.016 mL, 0.094 mmol) in DCM (1 mL) was added a solution of methyl chloroformate (2.92 μl, 0.038 mmol) in DCM. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude was purified with a preparative HPLC (method A, 60-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 70 (5.5 mg, 0.019 mmol, 59% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.80 (d, J=1.8 Hz, 1H), 7.93 (s, 1H), 8.11-7.68 (m, 1H), 7.42 (br. s., 1H), 7.30 (d, J=7.8 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 4.22 (t, J=5.6 Hz, 2H), 3.50-3.38 (m, 5H), 2.71 (s, 3H), 2.69 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ −88.27 (s, 2F). LC-MS: method C, RT=2.49 min, MS (ESI) m/z: 475.0 (M+H)+. Analytical HPLC purity (method A): 96%.
    • Example 71 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(thiazol-4-ylmethoxy) benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00569
    • Intermediate 71A: 2-chlorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00570
  • Aluminum chloride (6.01 g, 45.1 mmol) was added to a solution of 2-chloro-6-methoxybenzo[d]thiazole (3 g, 15.03 mmol) in toluene (80 mL). The mixture was heated at 110° C. for 1.5 h. TLC indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water (3×), saturated sodium bicarbonate (3×), water (3×) and air-dried for 1.0 h under vacuum. It was further dried under high vacuum overnight to give Intermediate 71A (2.6 g, 14.01 mmol, 93% yield) as a pale gray solid. The crude sample was used for the next step without further purification. 1H NMR (400 MHz, Methanol-d4) δ 7.70 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 7.00 (dd, J=8.8, 1.5 Hz, 1H). LC-MS: method C, RT=1.65 min, MS (ESI) m/z: 185.8 (M+H)+.
    • Intermediate 71B: 6-(tert-butyldimethylsilyloxy)-2-chlorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00571
  • To a stirred solution of Intermediate 71A (2.6 g, 14.01 mmol) in DMF (50 mL) was added TBDMS-Cl (2.96 g, 19.61 mmol) and imidazole (1.669 g, 24.51 mmol). The reaction mixture was left stirring at room temperature for 1.0 h. The mixture was diluted with EtOAc/water and extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 120 g ISCO column which was eluted with hexanes for 3 min., then a 30 min gradient from 0% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 71B (3 g, 10.00 mmol, 71.4% yield) as clear orange oil. 1H NMR (400 MHz, chloroform-d) δ 7.80 (s, 1H), 7.21 (s, 1H), 7.03-6.94 (m, 1H), 1.01 (s, 9H), 0.24 (s, 6H). LC-MS: method C, RT=2.57 min, MS (ESI) m/z: 300 (M+H)+.
    • Intermediate 71C 6-(tert-butyldimethylsilyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00572
  • To Intermediate I-1 (1 g, 3.94 mmol), Intermediate 71B (1.358 g, 4.53 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.161 g, 0.197 mmol) was added toluene (9 mL), EtOH (3 mL) and sodium carbonate (3.94 mL, 2 M, 7.87 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 135° C. for 30 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of toluene/chloroform and charged to a 120 g silica gel cartridge which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 75% dichloromethane in hexanes (flow rate 65 mL/min). The desired fractions were combined and concentrated to give Intermediate 71C (1.6 g, 2.70 mmol, 68.6% yield) as a bright yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 8.03-7.98 (m, 1H), 7.81-7.78 (m, 1H), 7.86-7.49 (m, 1H), 7.40 (d, J=2.5 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H), 2.69 (s, 3H), 1.04 (s, 9H), 0.27 (s, 6H). LC-MS: method C, gradient time 1 min, RT=2.30 min, MS (ESI) m/z: 473.9 (M+H)+.
    • Intermediate 71D: 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00573
  • To a solution of Intermediate 71C (1.75 g, 3.70 mmol) in THF (15 mL) at room temperature was added acetic acid (0.465 mL, 8.13 mmol), followed by addition of 1.0 N TBAF in THF (4.43 mL, 4.43 mmol) dropwise. The mixture was stirred at room temperature for 20 min. The mixture was diluted with EtOAc, washed with water, saturated sodium bicarbonate (2×), brine, and dried over sodium sulfate. After evaporation of the solvent, the crude product was triturated with EtOAc in hexanes (1:4). The precipitate was collected by filtration to give Intermediate 71D (1 g, 2.78 mmol, 75% yield) as a yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 7.96 (s, 1H), 7.93-7.53 (m, 3H), 7.34 (d, J=2.3 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H), 2.67 (s, 3H). LC-MS: method C, gradient time 1 min, RT=1.45 min, MS (ESI) m/z: 359.9 (M+H)+.
    • Example 71
  • A solution of DIAD (0.019 mL, 0.100 mmol) in toluene (0.5 mL) was added to a mixture of Intermediate 71D (12 mg, 0.033 mmol), thiazol-4-ylmethanol (11.54 mg, 0.100 mmol) and triphenylphosphine (17.52 mg, 0.067 mmol) in toluene (2 mL) at 110° C. on 5 portions (0.4 ml each for 30 min). The mixture turned to a clear solution and was stirred at 110° C. for 30 min. The mixture was concentrated and purified with a preparative HPLC (method A, 70-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 71 (5 mg, 9.86 μmol, 29.5% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.95 (d, J=2.0 Hz, 1H), 8.78-8.73 (m, 2H), 7.99 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.89-7.48 (m, 1H), 7.24 (dd, J=9.1, 2.5 Hz, 1H), 5.35 (s, 2H), 2.68 (s, 3H). NMR (376 MHz, acetonitrile-d3) δ −90.50 (s, 2F). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 456.9 (M+H)+. Analytical HPLC purity (method A): 90%.
    • Example 72 N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00574
  • To a solution of Example 63 (6.9 mg, 0.013 mmol) in THF (0.5 mL) was added sodium methoxide (0.076 mL, 0.038 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a preparative HPLC (method A, 60-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 72 (4 mg, 7.11 μmol, 55.9% yield). 1H NMR (400 MHz, chloroform-d) δ 8.61 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.95-7.89 (m, 2H), 7.78 (dd, J=1.9, 0.9 Hz, 1H), 7.61-7.56 (m, 1H), 7.55-7.49 (m, 2H), 7.30 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H), 5.00 (t, J=5.9 Hz, 1H), 4.14 (s, 3H), 4.10 (t, J=5.1 Hz, 2H), 3.47 (q, J=5.7 Hz, 2H), 2.66 (s, 3H). LC-MS: method C, RT=2.37 min, MS (ESI) m/z: 507.0 (M+H)+. Analytical HPLC purity (method A): 95%.
    • Example 73 N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00575
  • To a solution of Intermediate 26F (28 mg, 0.054 mmol) in DCM (1 mL) was added DIEA (0.095 ml, 0.542 mmol) and benzenesulfonyl chloride (19.15 mg, 0.108 mmol). The mixture was stirred at room temperature for 1 hour. Solvent was removed under vacuum and the residual was purified with a preparative HPLC (method A, 70-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to Example 73 (15 mg, 0.025 mmol, 46.2% yield). 1H NMR (400 MHz, chloroform-d) δ 8.74 (d, J=1.8 Hz, 1H), 8.68 (s, 1H), 8.00-7.89 (m, 2H), 7.87-7.44 (m, 5H), 7.15 (d, J=2.3 Hz, 1H), 6.93-6.85 (m, 1H), 4.10 (t, J=5.1 Hz, 2H), 3.46 (t, J=5.1 Hz, 2H), 2.82 (s, 3H), 2.70 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −90.22 (s, 2F). LC-MS: method C, RT=2.46 min, MS (ESI) m/z: 557.0 (M+H)+. Analytical HPLC purity (method A): 96%.
    • Example 74 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00576
  • A solution of DIAD (0.041 mL, 0.209 mmol) in toluene (0.5 mL) was added to a mixture of Intermediate 15J (25 mg, 0.070 mmol), 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (20.34 mg, 0.139 mmol) and triphenylphosphine (36.5 mg, 0.139 mmol) in toluene (2 mL) at 110° C. on 5 portion of 0.4 ml each for 30 min. The mixture turned to a clean solution and was stirred at 110° C. for 30 min. The mixture was concentrated and the residual was dissolved in 1 ml of DCM and treated with 12N HCl (0.290 mL, 3.48 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 74 (11.5 mg, 0.027 mmol, 38.5% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.81 (d, J=2.0 Hz, 1H), 8.78 (s, 1H), 7.84 (dd, J=1.9, 0.9 Hz, 1H), 7.90-7.46 (m, 3H), 6.99 (d, J=7.8 Hz, 1H), 4.33-4.25 (m, 2H), 3.99-3.92 (m, 2H), 2.69 (s, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.50 (s, 2F). LC-MS: method C, RT=2.33 min, MS (ESI) m/z: 403.9 (M+H)+. Analytical HPLC purity (method A): 94%
    • Example 75 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00577
  • A solution of DIAD (0.016 mL, 0.083 mmol) in toluene (0.5 mL) was added to a mixture of Intermediate 15J (10 mg, 0.028 mmol), 2-methoxyethanol (4.24 mg, 0.056 mmol) and triphenylphosphine (14.60 mg, 0.056 mmol) in toluene (2 mL) at 110° C. on 5 portion of 0.4 ml each for 30 min. The mixture turned to a clean solution and was stirred at 110° C. for 30 min. The mixture was concentrated and redissolved in 1 ml of DMF and was purified with a preparative HPLC (method A, 60-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 75 (10 mg, 0.023 mmol, 82% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.81 (d, J=2.0 Hz, 1H), 8.79 (s, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.90-7.43 (m, 3H), 6.99 (d, J=7.8 Hz, 1H), 4.44-4.25 (m, 2H), 3.87-3.80 (m, 2H), 3.44 (s, 3H), 2.69 (s, 3H)19F NMR (376 MHz, acetonitrile-d3) δ −90.22 (s, 2F). LC-MS: method C, RT=2.46 min, MS (ESI) m/z: 418.0 (M+H)+. Analytical HPLC purity (method A): 99%.
    • Example 76 benzyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ylcarbamate
  • Figure US20190292176A1-20190926-C00578
  • To a solution of Intermediate 21A (15 mg, 0.042 mmol) in DCM (1 mL) was added DIEA (0.044 mL, 0.251 mmol). After stirring at room temperature for 2 min, benzyl carbonochloridate (0.013 mL, 0.092 mmol) was added. The mixture was heated up to 60° C. for 2 h. The mixture was concentrated and redissolved in 1 ml of DMF and was purified with a preparative HPLC (method A, 50-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 76 (5 mg, 9.95 μmol, 23.77% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.80 (d, J=1.8 Hz, 1H), 8.73 (s, 1H), 7.89 (dd, J=8.1, 0.8 Hz, 1H), 7.83 (s, 1H), 7.75 (br. s., 1H), 7.60 (d, J=7.8 Hz, 1H), 7.86-7.51 (m, 1H), 7.48-7.44 (m, 2H), 7.43-7.33 (m, 3H), 5.25 (s, 2H), 2.68 (s, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.22 (s, 2F). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 492.9 (M+H)+. Analytical HPLC purity (method A): 98%.
    • Example 77 2-(2-methoxy-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00579
    • Intermediate 77A 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00580
  • A solution of DIAD (0.016 mL, 0.083 mmol) in toluene (0.5 mL) was added to a mixture of Intermediate 71D (10 mg, 0.028 mmol), 2-methoxyethanol (4.24 mg, 0.056 mmol) and triphenylphosphine (14.60 mg, 0.056 mmol) in toluene (2 mL) at 110° C. on 5 portion of 0.4 ml each for 30 min and then was stirred at 110° C. for 30 min. The mixture was concentrated and redissolved in 1 ml of DMF and was purified with a preparative HPLC (method A, 60-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 77A (10 mg, 0.023 mmol, 82% yield). 1H NMR (400 MHz, acetonitrile-d3) δ 8.75 (d, J=1.8 Hz, 1H), 8.74 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.88-7.50 (m, 1H), 7.16 (dd, J=8.8, 2.5 Hz, 1H), 4.27-4.08 (m, 2H), 3.82-3.67 (m, 2H), 3.40 (s, 3H), 2.68 (s, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ −90.22 (s, 2F). LC-MS: method C, RT=2.47 min, MS (ESI) m/z: 418.1 (M+H)+. Analytical HPLC purity (method A): 95%.
    • Example 77
  • To a solution of Intermediate 77A (5 mg, 0.012 mmol) in THF (0.5 mL) was added sodium methoxide (0.072 mL, 0.036 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched by 1 drop of water and concentrated. The residual was purified via preparative LC/MS (method C, 50-90% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to Example 77 (3.0 mg, 7.79 μmol, 65.0% yield). 1H NMR (500 MHz, methanol-d4) δ 8.51 (s, 1H), 8.47 (d, J=1.9 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.47 (s, 1H), 7.15 (dd, J=8.8, 2.5 Hz, 1H), 4.24-4.18 (m, 2H), 4.11 (s, 3H), 3.85-3.78 (m, 2H), 2.63 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 382.15 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 78 2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00581
  • To a solution of Example 75 (8.5 mg, 0.020 mmol) in THF (0.5 mL) was added sodium methoxide (0.122 mL, 0.061 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched by 1 drop of water solvent was removed, the residual was purified via preparative LC/MS (method C, 50-90% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to Example 78 (6.6 mg, 0.017 mmol, 85% yield). 1H NMR (500 MHz, methanol-d4) δ 8.55 (s, 1H), 8.53 (d, J=1.9 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.1 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 4.41-4.32 (m, 2H), 4.11 (s, 3H), 3.88 (dd, J=5.4, 3.7 Hz, 2H), 3.50 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 382.15 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 79 N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl) benzenesulfonamide
  • Figure US20190292176A1-20190926-C00582
    • Intermediate 79A N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-2,2,2-trifluoro-N-(phenylsulfonyl)acetamide
  • Figure US20190292176A1-20190926-C00583
  • To a solution of Intermediate 26F (28 mg, 0.054 mmol) in DCM (1 ml) was added TFA (0.418 ml, 5.42 mmol) and the mixture was stirred at room temperature for 1 hour. Solvent was removed and the sample was under vacuum overnight. The residual was dissolved in DCM (1 ml) then DIEA (0.095 ml, 0.542 mmol) and benzenesulfonyl chloride (19.15 mg, 0.108 mmol) was added. The mixture was stirred at room temperature for 1 hour. Solvent was removed under vacuum and the residual was purified with a preparative HPLC (method A, 70-100% B in 6 min.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Intermediate 79A (8 mg, 0.012 mmol, 22.62% yield). LC-MS: method C, RT=2.68 min, MS (ESI) m/z: 653 (M+H)+.
    • Example 79
  • To a solution of Intermediate 79A (8 mg, 0.012 mmol) in THF (0.5 mL) was added sodium methoxide (0.074 mL, 0.037 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched by 1 drop of water and concentrated. The residual was diluted with 1 ml of DMF and was purified via preparative LC/MS (method C, 55-90% B over 20 min., then a 10-min hold at 90% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to Example 79 (3.9 mg, 7.49 μmol, 61.1% yield). 1H NMR (500 MHz, methanol-d4) δ 8.55 (d, J=1.7 Hz, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.87-7.85 (m, 1H), 7.73 (s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.51-7.46 (m, 2H), 7.13 (d, J=2.2 Hz, 1H), 6.80 (d, J=1.7 Hz, 1H), 4.10 (s, 3H), 4.03 (t, J=5.5 Hz, 2H), 3.34 (t, J=5.5 Hz, 2H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.48 min, MS (ESI) m/z: 521.0 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 80 Methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ylcarbamate
  • Figure US20190292176A1-20190926-C00584
  • To a solution of Intermediate 21A (6 mg, 0.017 mmol) in DCM (1 mL) was added DIEA (0.058 mL, 0.335 mmol). After stirring at room temperature for 2 min, methyl chloroformate (18.99 mg, 0.201 mmol) was added to the solution and the mixture was stirred at 60° C. for 3h. Solvent was removed, the residual was dissolved in 1 ml of DMF and purified via preparative LC/MS (method C, 35-70% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford Example 80 (3.6 mg, 8.30 μmol, 49.6% yield). 1H NMR (500 MHz, methanol-d4) δ 8.72-8.68 (m, 2H), 7.88 (d, J=8.8 Hz, 1H), 7.84-7.52 (m, 3H), 7.51-7.45 (m, 1H), 3.82 (s, 3H), 2.67 (s, 3H). LC-MS: method C, RT=2.24 min, MS (ESI) m/z: 416.9 (M+H)+. Analytical HPLC purity (method B): 96%
    • Example 81 N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00585
  • To a solution of Intermediate 26F (10 mg, 0.022 mmol) and DIEA (0.039 mL, 0.221 mmol) in DCM (1 mL) was added a solution of 4-fluorobenzene-1-sulfonyl chloride (8.59 mg, 0.044 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1 h. Solvent was removed under vacuum and the residual was purified via preparative LC/MS (method C, 45-85% B over 10 min., then a 7-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to Example 81 (4.4 mg, 7.66 μmol, 34.7% yield). 1H NMR (500 MHz, methanol-d4) δ 8.71 (d, J=1.9 Hz, 1H), 8.67 (s, 1H), 7.93-7.88 (m, 2H), 7.78 (dd, 1.0 Hz, 1H), 7.83-7.51 (m, 1H), 7.23-7.12 (m, 3H), 6.80 (dd, J=2.5, 0.8 Hz, 1H), 4.05 (t, J=5.5 Hz, 2H), 3.35 (t, J=5.5 Hz, 2H), 2.76 (s, 3H), 2.67 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 575.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 82 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)-N-phenylacetamide
  • Figure US20190292176A1-20190926-C00586
    • Intermediate 82A: tert-butyl 2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C00587
  • To a solution of Intermediate 15J (20 mg, 0.056 mmol) in DMF (1 mL) was added butyl 2-bromoacetate (0.041 mL, 0.278 mmol) and NaH (4.45 mg, 0.111 mmol). The mixture was stirred at room temperature for 30 min, diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-50% EtOAc in hexanes for 15 min. The desired fraction was collected to give Intermediate 82A (25 mg, 0.053 mmol, 95% yield) as a yellow solid. 1H NMR (500 MHz, Methanol-d4) δ 8.71 (s, 2H), 7.87-7.66 (m, 3H), 7.44 (t, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 4.78 (s, 2H), 2.68 (s, 3H), 1.48 (s, 9H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 474 (M+H)+.
    • Intermediate 82B 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)acetic acid
  • Figure US20190292176A1-20190926-C00588
  • To a solution of Intermediate 82A (16 mg, 0.034 mmol) in DCM (1 mL) was added TFA (0.260 mL, 3.38 mmol). The mixture was stirred at room temperature overnight, Solvent was removed, the residual was dissolved in 1 ml of DMF and was purified via preparative LC/MS (method D: 10-45% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Intermediate 82B (14 mg, 0.034 mmol, 99% yield). LC-MS: method C, RT=2.25 min, MS (ESI) m/z: 418(M+H)+.
    • Example 82
  • To a solution of Intermediate 82B (6.5 mg, 0.016 mmol) in CH2Cl2 (1 mL) was added DIEA (27.2 μL, 0.156 mmol) and 1-propanephosphonic acid cyclic anhydride, (T3P) (180 μL, 50 wt % solution in ethyl acetate, 0.047 mmol) was added aniline (5.80, 0.062 mmol). The reaction mixture was stirred at room temperature for 2h. Solvent was removed, the residual was dissolved in 1 ml of DMF and was purified via preparative LC/MS (method C, 50-90% B over 10 min., then a 7-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford Example 82 (5.0 mg, 10.15 μmol, 65.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.23 (s, 1H), 7.99 (d, J=1.7 Hz, 1H), 7.36-6.91 (m, 2H), 6.82 (d, J=7.7 Hz, 2H), 6.71 (t, J=8.0 Hz, 1H), 6.52 (t, J=8.0 Hz, 2H), 6.27 (s, 1H), 6.20 (d, J=7.7 Hz, 1H), 1.87 (s, 3H), 1.73-1.57 (m, 3H). LC-MS: method C, RT=2.46 min, MS (ESI) m/z: 493.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 83 N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-4-(trifluoromethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00589
  • To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058 mL, 0.331 mmol) in DCM (1 mL) was added a solution of 4-(trifluoromethyl)benzene-1-sulfonyl chloride (12.15 mg, 0.050 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1 h. Solvent was removed, the residual was purified via preparative LC/MS (method C, 55-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 83 (6.2 mg, 9.93 μmol, 30.0% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.97-7.84 (m, 1H), 7.51-7.41 (m, 1H), 7.26-7.22 (m, 2H), 7.17-7.12 (m, 2H), 7.21-6.91 (m, 2H), 6.69-6.46 (m, 1H), 6.02-5.83 (m, 1H), 3.26-3.18 (m, 2H), 2.50 (s, 2H), 1.89 (s, 3H), 1.86 (s, 3H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 625.1 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 84 N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-2,4-difluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00590
  • To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of 2,4-difluorobenzene-1-sulfonyl chloride (10.56 mg, 0.050 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1 h. Solvent was removed, the residual was purified via preparative LC/MS (method C: 0-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 84 (7.8 mg, 0.013 mmol, 39.7% yield). 1H NMR (500 MHz, Methanol-d4) δ 8.72 (s, 1H), 8.69 (s, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.79 (s, 1H), 7.84-7.52 (m, 1H), 7.15 (s, 1H), 7.01 (s, 1H), 6.96-6.88 (m, 1H), 6.75 (s, 1H), 4.07-4.03 (m, 2H), 3.73 (s, 3H), 3.46 (t, J=5.4 Hz, 2H). LC-MS: method C, RT=2.45 min, MS (ESI) m/z: 593.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 85 N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-3,4-difluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00591
  • To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of 3,4-difluorobenzene-1-sulfonyl chloride (10.56 mg, 0.050 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 2 h. Solvent was removed, the residual was purified via preparative LC/MS (method C: 0-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 85 (2.3 mg, 3.88 μmol, 11.72% yield). 1H NMR (500 MHz, Methanol-d4) δ 8.75-8.71 (m, 1H), 8.69-8.66 (m, 1H), 7.85-7.51 (m, 4H), 7.35-7.26 (m, 1H), 7.20-7.14 (m, 1H), 6.82-6.77 (m, 1H), 4.07 (t, J=5.4 Hz, 2H), 3.38 (t, J=5.5 Hz, 2H), 2.77 (s, 3H), 2.68 (s, 3H). LC-MS: method C, RT=2.51 min, MS (ESI) m/z: 593.1 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 86 4-chloro N (2 (2 (2 (difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00592
  • To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of 4-chlorobenzene-1-sulfonyl chloride (10.49 mg, 0.050 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed and the sample was purified via preparative LC/MS (method C, 60-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to Example 86 (4.9 mg, 8.29 μmol, 25.03% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.82-8.64 (m, 1H), 8.08-7.61 (m, 7H), 7.48-7.37 (m, 1H), 6.84-6.78 (m, 1H), 4.09-4.00 (m, 2H), 3.25-3.22 (m, 2H), 2.73 (s, 3H), 2.68 (s, 3H). LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 591.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 87 N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-methylbenzenesulfonamide
  • Figure US20190292176A1-20190926-C00593
    • Intermediate 87A N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy) ethyl)-4-methylbenzenesulfonamide
  • Figure US20190292176A1-20190926-C00594
  • To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058 mL, 0.331 mmol) in DMF (1 mL) was added a solution of 4-methylbenzene-1-sulfonyl chloride (9.47 mg, 0.050 mmol) in 0.2 ml of DCM. The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed, the residual was purified via preparative LC/MS (method C, 55-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Intermediate 87A (5.5 mg, 9.64 μmol, 29% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.72 (d, J=1.7 Hz, 1H), 8.04-7.74 (m, 2H), 7.72 (d, J=8.3 Hz, 2H), 7.44 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 6.88 (d, J=1.4 Hz, 1H), 4.04 (t, J=5.4 Hz, 2H), 3.17 (t, J=5.4 Hz, 2H), 2.73 (s, 3H), 2.67 (s, 3H), 2.36 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 571.2 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 87
  • To a solution of Intermediate 87A (3.32 mg, 5.82 μmol) in DMF (0.5 mL) was added sodium methoxide in MeOH (0.035 mL, 0.5M, 0.017 mmol). The mixture was stirred at room temperature for 2 h. LCMS indicated completion of the reaction. The reaction was quenched by water and was purified via preparative LC/MS (method C, 55-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 87 (2.7 mg, 5.05 μmol, 87% yield). 1H NMR (500 MHz, Methanol-d4) δ 8.55 (d, J=1.9 Hz, 1H), 8.51 (s, 1H), 7.74 (d, J=8.3 Hz, 3H), 7.27 (d, J=8.3 Hz, 2H), 7.10 (d, J=2.5 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 4.22 (br. s., 2H), 4.10 (s, 3H), 4.01 (t, J=5.5 Hz, 2H), 3.35-3.33 (m, 2H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.55 min, MS (ESI) m/z: 535.3 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 89 4-fluoro N (2 (2 (2 (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00595
    • Intermediate 89A: 2-chloro-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00596
  • To a solution of copper (II) chloride (1.661 g, 12.35 mmol) in acetonitrile (8 mL) at 40° C. was added tert-butyl nitrite (1.769 mL, 13.38 mmol), followed by Intermediate I-3A (2.2 g, 11.33 mmol) as a solid. The mixture was stirring at 40° C. for 2.0 h. HPLC and LCMS indicated a complete conversion of starting material. The mixture was diluted with EtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine. After evaporation of solvent, Intermediate 89A (2.4 g, 11.23 mmol, 99% yield) was obtained as brown solid. 1H NMR (500 MHz, chloroform-d) δ 7.07 (d, J=2.5 Hz, 1H), 6.93-6.77 (m, 1H), 3.85 (s, 3H), 2.66 (s, 3H). LC-MS: method C, RT=2.08 min, MS (ESI) m/z: 213.9 (M+H)+.
    • Intermediate 89B: 2-chloro-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00597
  • Aluminum chloride (4.49 g, 33.7 mmol) was added to a solution of Intermediate 89A (2.4 g, 11.23 mmol) in toluene (50 mL). The mixture was heated at 110° C. for 1.5 h. TLC indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water (3×), saturated sodium bicarbonate (3×), water (3×) and air-dried for 1.0 h under vacuum. It was further dried under high vacuum overnight to give Intermediate 89B as brown solid (2.2 g, 11.02 mmol, 98% yield).
    • Intermediate 89C: (6-(tert-butyldimethylsilyloxy)-2-chloro-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00598
  • To a stirred solution of Intermediate 89B (2.2 g, 11.02 mmol) in DMF (50 mL) was added TBDMS-Cl (2.325 g, 15.43 mmol) and imidazole (1.313 g, 19.28 mmol). The reaction mixture was left stirring at room temperature for 1.0 h. HPLC and TLC indicated a clean reaction. The mixture was partitioned between EtOAc/water. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 120 g ISCO column which was eluted with hexanes for 3 min., then a 30 min gradient from 0% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 89C (1.57 g, 5.00 mmol, 45.4% yield) as a clear orange solid. 1H NMR (400 MHz, chloroform-d) δ 7.09-6.94 (m, 1H), 6.81 (dd, J=2.5, 0.8 Hz, 1H), 2.64 (s, 3H), 1.01 (s, 9H), 0.23 (s, 6H). LC-MS: method C, RT=2.74 min, MS (ESI) m/z: 314 (M+H)+.
    • Intermediate 89D 6-(tert-butyldimethylsilyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00599
  • To Intermediate I-2 (28 mg, 0.121 mmol), Intermediate 89C (37.9 mg, 0.121 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (4.93 mg, 6.03 μmol) was added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.121 mL, 2M, 0.241 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 135° C. for 40 min. LCMS indicated a clean reaction. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 75% dichloromethane in hexanes The desired fractions were combined and concentrated to give Intermediate 89D (48 mg, 0.103 mmol, 85% yield). LC-MS: method C, gradient time 1 min, RT=2.53 min, MS (ESI) m/z: 466.2 (M+H)+.
    • Intermediate 89E 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00600
  • To a solution of Intermediate 89D (48 mg, 0.103 mmol) in THF (5 mL) at room temperature was added acetic acid (0.013 mL, 0.227 mmol) followed by addition of 1.0 N TBAF in THF (0.124 mL, 0.124 mmol) dropwise. The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of reaction. The mixture was diluted with EtOAc, washed with water, saturated sodium bicarbonate (2×), brine, and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified with a 12 g ISCO column eluting with 0% to 80% EtOAc in hexanes for 15 min. The desired fraction was collected to give Intermediate 89E (36 mg, 0.102 mmol, 99% yield). 1H NMR (500 MHz, chloroform-d) δ 9.08 (s, 1H), 8.93-8.77 (m, 1H), 7.94 (s, 1H), 7.23 (d, J=2.2 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.85 (s, 2H), 3.58 (s, 3H), 2.83 (s, 3H), 2.71 (s, 3H). LC-MS: method C, RT=2.21 min, MS (ESI) (m/z) 352 [M+H]+
    • Intermediate 89F: tert-butyl 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00601
  • A solution of DIAD (0.055 mL, 0.282 mmol) in 1 ml of toluene was added dropwise to a mixture of Intermediate 89E (33 mg, 0.094 mmol), tert-butyl (2-hydroxyethyl)carbamate (18.16 mg, 0.113 mmol) and triphenylphosphine (49.3 mg, 0.188 mmol) in toluene (1 mL) at 110° C. LCMS indicated a completion of the reaction. The mixture was concentrated and purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 89F (45 mg, 0.091 mmol, 97% yield). 1H NMR (500 MHz, methanol-d4) δ 9.05 (s, 1H), 8.79 (d, J=1.7 Hz, 1H), 7.90 (s, 1H), 7.28 (d, J=2.5 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 4.81 (s, 2H), 4.09 (t, J=5.5 Hz, 2H), 3.56 (s, 3H), 3.50 (t, J=5.4 Hz, 2H), 2.78 (s, 3H), 2.69 (s, 3H), 1.44 (s, 9H). LC-MS: method C, RT=2.49 min, MS (ESI) (m/z) 495.1 [M+H]+.
    • Intermediate 89G 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00602
  • To a solution of Intermediate 89F (40 mg, 0.081 mmol) in DCM (1 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed. The crude sample was diluted with EtOAc and water, extracted with EtOAc, the combined organic layer was washed with saturated NaHCO3 and brine, dried with MgSO4 and concentrated to give Intermediate 89G (30 mg, 0.076 mmol, 94% yield). 1H NMR (500 MHz, Methanol-d4) δ 9.05 (s, 1H), 8.81 (d, J=1.7 Hz, 1H), 7.91 (s, 1H), 7.29 (d, J=2.5 Hz, 1H), 6.95 (d, J=1.4 Hz, 1H), 4.80 (s, 2H), 4.26 (t, J=5.1 Hz, 2H), 3.54 (s, 3H), 3.35 (t, J=5.0 Hz, 2H), 2.79 (s, 3H), 2.68 (s, 3H). LC-MS: method C, RT=1.91 min, MS (ESI) m/z: 395 (M+H)+.
    • Example 89
  • To a solution of Intermediate 89G (15 mg, 0.038 mmol) and 4-fluorobenzene-1-sulfonyl chloride (8.88 mg, 0.046 mmol) in DMF (1 mL) was added DIEA (0.066 mL, 0.380 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed, the residual was dissolved purified via preparative LC/MS (method D, 50-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 89 (0.9 mg, 1.629 μmol, 4.28% yield). 1H NMR (500 MHz, Methanol-d4) δ 9.06 (s, 1H), 8.80 (d, J=1.9 Hz, 1H), 7.95-7.85 (m, 3H), 7.24-7.15 (m, 3H), 6.81 (dd, J=2.2, 0.8 Hz, 1H), 4.82 (s, 2H), 4.06 (t, J=5.5 Hz, 2H), 3.57 (s, 3H), 3.35 (t, J=5.5 Hz, 2H), 2.77 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 553.2 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 90 4-fluoro N (2 (2 (2 methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00603
    • Intermediate 90A: tert-butyl 2-(4-nitro-3-(trifluoromethyl)phenoxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00604
  • DIAD (0.798 mL, 4.10 mmol) was added to a mixture of 4-nitro-3-(trifluoromethyl)phenol (0.34 g, 1.642 mmol) in THF (1.0 mL). Next, tert-butyl (2-hydroxyethyl)carbamate (0.529 g, 3.28 mmol) and triphenylphosphine (0.861 g, 3.28 mmol) in THF (10 mL) were added to the above mixture using syringe pump in 3 h. The reaction mixture was stirred at room temperature overnight. LCMS indicated a completion of the reaction. The mixture was concentrated and purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 90A (1.1 g, 1.570 mmol, 96% yield) as brown oil. 1H NMR (400 MHz, chloroform-d) δ 8.01 (d, J=9.0 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.13 (dd, J=9.0, 2.6 Hz, 1H), 4.18-4.13 (m, 2H), 3.58 (q, J=5.4 Hz, 2H), 1.45 (s, 9H). LC-MS: method C, RT=2.07 min, MS (ESI) m/z: 251 [M+1-Boc]+.
    • Intermediate 90B: tert-butyl 2-(4-amino-3-(trifluoromethyl)phenoxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00605
  • To a solution of Intermediate 90A (574 mg, 1.64 mmol) in ethyl acetate (10 mL) under argon was added 10% Pd/C (100 mg, 1.640 mmol). The mixture was stirred under an atmosphere of hydrogen (balloon) at room temperature for 3.0 h. HPLC and TLC indicated a completion of reaction. Pd/C was removed by filtration. The filtrate was concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-100% EtOAc for 20 min. The desired fraction was collected and concentrated to give Intermediate 90B (670 mg, 1.569 mmol, 96% yield) as dark oil. 1H NMR (500 MHz, chloroform-d) δ 6.98 (d, J=2.8 Hz, 1H), 6.91 (dd, J=8.7, 2.9 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.36 (br. s., 1H), 3.96 (t, J=5.1 Hz, 2H), 3.91 (br. s., 2H), 3.50 (d, J=5.0 Hz, 2H), 1.62 (s, 3H). LC-MS: method C, RT=1.83 min, MS (ESI) m/z: 221 (M+H-Boc)+.
    • Intermediate 90C: tert-butyl 2-(2-amino-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy) ethylcarbamate
  • Figure US20190292176A1-20190926-C00606
  • To a solution of Intermediate 90B (180 mg, 0.562 mmol) in acetonitrile (5 mL) was added ammonium thiocyanate (128 mg, 1.686 mmol). The mixture was stirred at room temperature for 10 min. Benzyltrimethylammonium tribromide (219 mg, 0.562 mmol) in acetonitrile (2 mL) was added dropwise (5 min). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-100% EtOAc in hexanes for 15 min. The desired fraction was collected to give Intermediate 90C (100 mg, 0.265 mmol, 47.2% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) δ 7.48 (d, J=2.2 Hz, 1H), 7.14 (d, J=2.5 Hz, 1H), 4.05 (t, J=5.6 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 1.44 (s, 9H). 19F NMR (471 MHz, methanol-d4) δ −63.25 (s, 3F). LC-MS: method C, RT=1.85 min, MS (ESI) m/z: 378 (M+H)+.
    • Intermediate 90D: tert-butyl (2((2-bromo-4-(trifluoromethyl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00607
  • tert-Butyl nitrite (0.061 mL, 0.464 mmol) was added to copper (II) bromide (101 mg, 0.450 mmol) in dry acetonitrile (2 mL) under argon. The mixture was stirred at room temperature for 10 min. A suspension of Intermediate 90C (100 mg, 0.265 mmol) in dry acetonitrile (2 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. LCMS indicated a completion of the reaction. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, the crude sample was purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 90D (92 mg, 0.208 mmol, 79% yield) as a white solid. LC-MS: method C, RT=2.20 min, MS (ESI) m/z: 547.2 (M+H)+.
    • Intermediate 90E: tert-butyl 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00608
  • To Intermediate I-1 (15.24 mg, 0.045 mmol), and Intermediate 90D (20 mg, 0.045 mmol) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (1.851 mg, 2.266 μmol) was added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.045 mL, 2M, 0.091 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 135° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 75% dichloromethane in hexanes. The desired fractions were combined and concentrated to give Intermediate 90E (25.9 mg, 0.045 mmol, 100% yield) as a bright yellow solid. LC-MS: method C, gradient time 1 min, RT=1.67 min, MS (ESI) m/z: 571 (M+H)+.
    • Intermediate 90F: tert-butyl 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00609
  • To a solution of Intermediate 90E (25.7 mg, 0.045 mmol) in THF (1 mL) was added sodium methoxide (0.090 mL, 0.5M, 0.045 mmol) and the mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The mixture was diluted with DCM and water, extracted with DCM and the combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 90F (10 mg, 0.019 mmol, 41.6% yield) as a white solid. 1H NMR (500 MHz, Methanol-d4) δ 8.63 (s, 1H), 8.51 (s, 1H), 7.75 (s, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.39 (s, 1H), 4.14 (t, J=5.5 Hz, 2H), 4.11 (s, 3H), 3.52 (t, J=5.4 Hz, 2H), 2.64 (s, 3H), 1.44 (s, 9H). LC-MS: method C, R=2.66 min, MS (ESI) m/z: 535 (M+H)+.
    • Intermediate 90G: 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl) benzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00610
  • To a solution of Intermediate 90F (7 mg, 0.013 mmol) in DCM (1 mL) was added TFA (0.020 mL, 0.262 mmol). The mixture was stirred at room temperature for 5 h. Solvent was removed and Intermediate 90G was used for next step without purification. LC-MS: method C, RT=2.15 min, MS (ESI) m/z: 435 (M+H)+.
    • Example 90
  • To a solution of Intermediate 90G (5.65 mg, 0.013 mmol) and 4-fluorobenzene-1-sulfonyl chloride (3.04 mg, 0.016 mmol) in DMF (1 mL) was added DIEA (0.023 mL, 0.130 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed, the residual was purified via preparative LC/MS (method D, 55-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 90 (4.4 mg, 7.43 μmol, 57.1% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.13-7.03 (m, 3H), 6.59-6.54 (m, 2H), 6.42 (d, J=2.2 Hz, 1H), 3.30 (t, J=5.2 Hz, 2H), 3.26 (s, 3H), 2.45 (br. s., 2H), 1.82 (s, 3H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 593.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 91 N-(2-(2-(2-cyclopropyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00611
    • Intermediate 91A: tert-butyl (2-bromo-4-methyl-6-nitrophenyl)(2-cyclopropyl-2-oxoethyl)carbamate
  • Figure US20190292176A1-20190926-C00612
  • To Intermediate I-1B (400 mg, 1.208 mmol) in DMF (5 mL) at room temperature was added Cs2CO3 (1181 mg, 3.62 mmol). The brown solution was stirred at room temperature for 5 min, followed by addition of 2-bromo-1-cyclopropylethanone (438 mg, 2.416 mmol) in acetonitrile (0.4 mL). The mixture was stirred at room temperature for 2 h. TLC and LCMS indicated a clean reaction. The mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-100% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 91A (490 mg, 1.186 mmol, 98% yield) as yellow oil. LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 356 and 358 [M+1-tBu]+.
    • Intermediate 91B: 5-bromo-2-cyclopropyl-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00613
  • To Intermediate 91A (490 mg, 1.186 mmol) in DCM (4 mL) was added 4.0 N HCl in dioxane (3.56 mL, 14.23 mmol) and the mixture was stirred at room temperature for 1 h. TLC indicated a completion of the reaction. Solvent was removed to give the deprotected intermediate as yellow oil. The deprotected intermediate was dissolved in THF (4 mL). Tin(II) chloride dihydrate (883 mg, 3.91 mmol) was added followed by concentrated HCl (0.146 mL, 1.779 mmol). The mixture was placed and stirred in an oil bath pre-heated at 45° C. for 1.0 h. TLC and LCMS indicated a clean reaction. The reaction mixture was diluted with EtOAc/water and neutralized with saturated sodium bicarbonate. The mixture was stirred at room temperature for 15 min and extracted with EtOAc (5×). The precipitate (tin hydroxide) was removed by a separatory funnel. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-60% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 91B (310 mg, 1.178 mmol, 99% yield) as a light yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.76 (s, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.69 (dd, J=1.8, 0.9 Hz, 1H), 2.54 (s, 3H), 2.34-2.23 (m, 1H), 1.30-1.25 (m, 2H), 1.24-1.16 (m, 2H). LC-MS: method C, RT=2.07 min, MS (ESI) m/z: 263 and 265. (M+H)+.
    • Intermediate 91C 2-cyclopropyl-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00614
  • A mixture of Intermediate 91B (30 mg, 0.114 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (50.7 mg, 0.200 mmol), potassium acetate (22.38 mg, 0.228 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (2.79 mg, 3.42 μmol) in dioxane (2 mL) was degassed with argon for 10 min. The reaction vial was heated in microwave reactor at 120° C. for 30 min. LCMS indicated complete conversion of starting material and a clean reaction. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude sample of Intermediate 91C was obtained and used for the next step without purification. LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 229 (M+H)+ (boronic acid).
    • Example 91
  • To Intermediate 91C (34.8 mg, 0.112 mmol), Intermediate I-5 (20 mg, 0.045 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (1.834 mg, 2.246 μmol) was added toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.045 mL, 2M, 0.090 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was purified via preparative LC/MS (method D, 60-100% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 91 (6.8 mg, 0.012 mmol, 27.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.67 (s, 1H), 8.03 (br. s., 1H), 7.95-7.81 (m, 3H), 7.48-7.37 (m, 3H), 6.85 (s, 1H), 4.05 (t, J=5.0 Hz, 2H), 3.22 (br. s., 2H), 2.72 (s, 3H), 2.64 (s, 3H), 1.29-1.13 (m, 5H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 549.2 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 92 Benzyl 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00615
    • Intermediate 92A: tert-butyl 2-(3-methyl-4-nitrophenoxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00616
  • A solution of DIAD (7.77 mL, 40.0 mmol) in 2 ml of toluene was added to a mixture of 3-methyl-4-nitrophenol (3.4 g, 22.20 mmol), tert-butyl (2-hydroxyethyl) carbamate (4.29 g, 26.6 mmol) and triphenylphosphine (6.99 g, 26.6 mmol) in toluene (50 mL) at 110° C. using syringe pump in 2 h. The reaction mixture was stirred at 110° C. for additional 30 min, then at room temperature overnight. The mixture was diluted with EtOAc and water, extracted with EtOAc, the combined organic layer was washed with NaHCO3 and brine, dried with Na2SO4 and concentrated. The crude sample was purified with a 120 g ISCO column eluted with 0-70% EtOAc in hexanes for 40 min. The desired fraction was collected and concentrated to give Intermediate 92A (3.3 g, 11.14 mmol, 50.2% yield). 1H NMR (500 MHz, chloroform-d) δ 8.08 (d, J=8.8 Hz, 1H), 6.84-6.77 (m, 2H), 4.97 (br. s., 1H), 4.09 (t, J=5.1 Hz, 2H), 3.56 (q, J=5.0 Hz, 2H), 2.63 (s, 3H), 1.46 (s, 9H). LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 197 (M+H-Boc)+.
    • Intermediate 92B: tert-butyl 2-(4-amino-3-methylphenoxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00617
  • To a solution of Intermediate 92A (3.5 g, 11.81 mmol) in ethyl acetate (10 mL) under argon was added 10% Pd/C (200 mg, 23.62 mmol). The mixture was stirred under an atmosphere of hydrogen (balloon) at room temperature overnight. Pd/C was removed by filtration. The filtrate was concentrated. The crude sample was purified with a 120 g ISCO column eluted with 0-100% EtOAc in hexanes for 45 min. The desire fraction was collected to give Intermediate 92B (2.5 g, 9.39 mmol, 79% yield) as a pink solid. 1H NMR (500 MHz, chloroform-d) δ 6.67 (s, 1H), 6.62 (d, J=1.7 Hz, 2H), 5.00 (br. s., 1H), 3.95 (t, J=5.1 Hz, 2H), 3.49 (d, J=5.0 Hz, 2H), 3.37 (br. s., 2H), 2.16 (d, J=0.6 Hz, 3H), 1.46 (s, 9H). LC-MS: method C, RT=1.34 min, MS (ESI) m/z: 167 [M+1-Boc]+.
    • Intermediate 92C: tert-butyl 2-(2-amino-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00618
  • To a solution of Intermediate 92B (2.5 g, 9.39 mmol) in acetonitrile (20 mL) was added ammonium thiocyanate (1.072 g, 14.08 mmol). The mixture was stirred at room temperature for 10 min. Benzyltrimethylammonium tribromide (3.66 g, 9.39 mmol) in acetonitrile (10 mL) was added dropwise (5 min). The mixture was stirred at room temperature overnight. LCMS indicated a clean reaction. The mixture was diluted with EtOAc/saturated sodium bicarbonate. The insoluble material was removed by filtration. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the product was precipitated out from methanol, collected by filtration, washed with acetonitrile to give Intermediate 92C (2.8 g, 8.66 mmol, 92% yield) as a slightly yellow solid. 1H NMR (500 MHz, chloroform-d) δ 6.97 (d, J=2.2 Hz, 1H), 6.75 (d, J=1.9 Hz, 1H), 5.05 (s, 2H), 4.02 (t, J=5.0 Hz, 2H), 3.53 (d, J=4.7 Hz, 2H), 2.53 (s, 3H), 1.46 (s, 9H). LC-MS: method C, RT=2.57 min, MS (ESI) m/z: 324 (M+H)+.
    • Intermediate 92D: tert-butyl 2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00619
  • To a stirred solution of Intermediate 92C (2.8 g, 8.66 mmol) and copper (II) chloride (1.029 g, 10.39 mmol) in acetonitrile (30 mL) was added tert-butyl nitrite (1.487 mL, 11.26 mmol). The mixture was stirred at room temperature for 2 h. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, the crude dark oil was purified with a 120 g ISCO column eluted with 0-70% EtOAc in hexanes for 40 min. The desired fraction was collected and concentrated to give Intermediate 92D (1.75 g, 5.10 mmol, 59.0% yield) as an off-white solid. 1H NMR (500 MHz, chloroform-d) δ 7.05 (d, J=2.5 Hz, 1H), 6.89 (dd, J=2.5, 0.8 Hz, 1H), 5.00 (br. s., 1H), 4.05 (t, J=5.1 Hz, 2H), 3.56 (d, J=5.0 Hz, 2H), 2.65 (s, 3H), 1.46 (s, 9H). LC-MS: method C, RT=2.21 min, MS (ESI) m/z: 343 (M+H)+.
    • Intermediate 92E: 2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00620
  • To a solution of Intermediate 92D (100 mg, 0.292 mmol) in DCM (1.5 mL) was added TFA (1.124 mL, 14.58 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The mixture was concentrated and the residual was diluted with EtOAc and saturated NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 92E (70 mg, 0.288 mmol, 99% yield) as an off-white solid. 1H NMR (400 MHz, Methanol-d4) δ 7.29 (d, J=2.4 Hz, 1H), 7.06-6.84 (m, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.28 (br. s., 2H), 2.58 (s, 3H). LC-MS: method C, RT=1.43 min, MS (ESI) m/z: 243 (M+H)+.
    • Intermediate 92F: benzyl 2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00621
  • To a stirred solution of Intermediate 92E (70 mg, 0.288 mmol) in THF (1 mL) at room temperature was added sodium bicarbonate (1.154 mL, 2M, 2.307 mmol). CBz-Cl (0.049 mL, 0.346 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h, LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-60% EtOAc in hexanes for 15 min. The desired product was collected and concentrated to give Intermediate 92F (100 mg, 0.265 mmol, 92% yield). 1H NMR (400 MHz, chloroform-d) δ 7.38-7.35 (m, 5H), 7.04 (d, J=2.2 Hz, 1H), 6.87 (d, J=1.3 Hz, 1H), 5.25 (br. s., 1H), 5.12 (s, 2H), 4.72 (s, 1H), 4.07 (t, J=5.1 Hz, 2H), 3.64 (q, J=5.3 Hz, 2H), 2.65 (s, 3H). LC-MS: method C, RT=2.22 min, MS (ESI) m/z: 377 (M+H)+.
    • Example 92
  • To Intermediate I-2 (30 mg, 0.129 mmol), Intermediate 92F (58.5 mg, 0.155 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.28 mg, 6.46 μmol) was added toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.129 mL, 2M, 0.259 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 100% EtOAc in hexanes The desired fractions were combined and concentrated. The sample was further purified via preparative LC/MS (method D, 50-90% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 92 (42 mg, 0.079 mmol, 61.5% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.80 (s, 1H), 8.01 (s, 1H), 7.60-7.48 (m, 2H), 7.36 (d, J=4.4 Hz, 4H), 7.33-7.28 (m, 1H), 7.00 (br. s., 1H), 5.05 (s, 2H), 4.80 (s, 2H), 4.10 (t, J=5.5 Hz, 2H), 3.48-3.41 (m, 5H), 2.74 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 529.2 (M+H)+.
    • Example 93 4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00622
    • Intermediate 93A: 2-chloro-4-methoxy-1-nitrobenzene
  • Figure US20190292176A1-20190926-C00623
  • To a solution of 2-chloro-4-fluoro-1-nitrobenzene (220 mg, 1.253 mmol) in THF (2 mL) was added sodium methoxide (7.52 mL, 0.5, 3.76 mmol). The mixture was stirred at room temperature for 1.0 h. LCMS indicated a completion of the reaction The mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified with flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexanes over 12 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to give Intermediate 93A (230 mg, 1.226 mmol, 98% yield) as a yellow liquid. 1H NMR (400 MHz, chloroform-d) δ 8.02 (d, J=9.2 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.89 (dd, J=9.2, 2.6 Hz, 1H), 3.90 (s, 3H). LC-MS: method C, RT=1.80 min, MS (ESI) m/z: 188 (M+H)+.
    • Intermediate 93B: 2-chloro-4-methoxyaniline
  • Figure US20190292176A1-20190926-C00624
  • To a solution of Intermediate 93A (230 mg, 1.226 mmol) in MeOH (6.0 mL) was added ammonium chloride (1312 mg, 24.52 mmol) and zinc dust (802 mg, 12.26 mmol). The mixture was stirred at room temperature for 1 h. MeOH was removed under vacuum. The residue was diluted with EtOAc/saturated sodium bicarbonate and stirred at room temperature for 10 min. The mixture was filtered to remove insoluble material. The filtrate was collected, organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude sample was purified with a 12 g ISCO column eluted with 0-100% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 93B (193 mg, 1.225 mmol, 100% yield) as oil. 1H NMR (400 MHz, chloroform-d) δ 6.86 (t, J=2.5 Hz, 1H), 6.76-6.64 (m, 2H), 3.74 (d, J=3.1 Hz, 3H). LC-MS: method C, RT=0.8 min, MS (ESI) m/z: 158 (M+H)+.
    • Intermediate 93C: 4-chloro-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00625
  • To a solution of Intermediate 93B (190 mg, 1.206 mmol) in acetonitrile (5.0 mL) was added ammonium thiocyanate (161 mg, 2.110 mmol). The mixture was stirred at room temperature for 10 min. Benzyltrimethylammonium tribromide (635 mg, 1.628 mmol) in acetonitrile (2.0 mL) was added dropwise (5 min). The mixture was stirred at room temperature overnight. Acetonitrile was removed under vacuum. The mixture was diluted with EtOAc, THF/saturated sodium bicarbonate. The insoluble material was removed by filtration. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate and concentrated to give Intermediate 93C (250 mg, 1.165 mmol, 97% yield) as a yellow solid that was used for the next step without further purification. 1H NMR (400 MHz, methanol-d4) δ 7.16 (d, J=2.4 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 3.79 (s, 3H). LC-MS: method C, RT=1.38 min, MS (ESI) m/z: 215 (M+H)+.
    • Intermediate 93D: 2-bromo-4-chloro-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00626
  • To a solution of copper (II) bromide (0.21 g, 1.51 mmol) in acetonitrile (8 mL) at 40° C. was added tert-butyl nitrite (0.200 mL, 1.514 mmol) followed by Intermediate 93C (250 mg, 1.165 mmol) as a solid. The mixture was stirring at 40° C. for 2.0 h. HPLC and LCMS indicated a complete conversion of starting material. The mixture was diluted with EtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine. After evaporation of solvent, Intermediate 93D (215 mg, 0.772 mmol, 66.3% yield) was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 7.17 (d, J=2.4 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 3.87 (s, 3H). LC-MS: method C, RT=2.08 min, MS (ESI) m/z: 279.9 (M+H)+.
    • Example 93
  • To Intermediate I-2 (11 mg, 0.047 mmol), Intermediate 93D (15.85 mg, 0.057 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (1.936 mg, 2.370 μmol) was added toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.047 mL, 2M, 0.095 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 40 min. LCMS indicated a clean reaction. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was purified via preparative LC/MS (method D, 45-85% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 93 (3.3 mg, 8.47 μmol, 17.86% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.07 (s, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 4.82 (s, 2H), 3.89 (s, 3H), 3.47 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 386.1 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 94 5-(5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00627
  • To Intermediate I-2E (5 mg, 0.019 mmol), (5-methoxybenzofuran-2-yl)boronic acid (4.31 mg, 0.022 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.764 mg, 0.936 μmol) was added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.019 mL, 2M, 0.037 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was purified via preparative LC/MS (method D; 50-90% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 94 (5.1 mg, 0.014 mmol, 75.0% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.28 (d, J=1.7 Hz, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.61-7.58 (m, 1H), 7.31 (d, J=2.5 Hz, 1H), 6.98-6.96 (m, 1H), 4.80 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.47 (s, 3H). LC-MS: method C, RT=2.36 min, MS (ESI) m/z: 335.10 (M+H)+. Analytical HPLC purity (method B): 92%.
    • Example 95 N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00628
    • Intermediate 95A: tert-butyl 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00629
  • To Intermediate I-2 (40 mg, 0.172 mmol), Intermediate 92D (59.1 mg, 0.172 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.04 mg, 8.62 μmol) was added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.172 mL, 2M, 0.345 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 40 min. LCMS indicated a clean reaction. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 100% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 95A (80 mg, 0.162 mmol, 94% yield). 1H NMR (400 MHz, chloroform-d) δ 9.06 (d, J=3.5 Hz, 1H), 8.85 (d, J=3.3 Hz, 1H), 7.92 (br. s., 1H), 7.23 (t, J=2.6 Hz, 1H), 6.93 (br. s., 1H), 5.07 (br. s., 1H), 4.83 (d, J=2.4 Hz, 2H), 4.12-4.05 (m, 2H), 3.60-3.53 (m, 5H), 2.83 (s, 3H), 2.70 (d, J=2.0 Hz, 3H), 1.48 (s, 9H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 495 (M+H)+.
    • Intermediate 95B 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00630
  • To a solution of Intermediate 95A (18 mg, 0.036 mmol) in DCM (1 mL) was added 2,6-lutidine (16.95 μl, 0.146 mmol) followed by TMS-OTf (13.15 μl, 0.073 mmol) at room temperature. The mixture was stirred at room temperature overnight. Another portion of TMS-OTf (13.15 μl, 0.073 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 95B (14.2 mg, 0.036 mmol, 98% yield). The sample was used for next step without further purification. 1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 1H), 8.82 (d, J=1.8 Hz, 1H), 7.93 (s, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.99 (dd, J=2.4, 0.9 Hz, 1H), 4.82-4.81 (m, 2H), 4.15 (t, J=5.2 Hz, 2H), 3.15 (t, J=5.1 Hz, 2H), 2.79 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=1.43 min, MS (ESI) m/z: 243 (M+H)+.
    • Example 95
  • To a solution of Intermediate 95B (14.20 mg, 0.036 mmol) in DMF (1 mL) was added DIEA (0.063 mL, 0.360 mmol) and benzenesulfonyl chloride (5.57 μl, 0.043 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 0.2 ml of MeOH. Solvent was removed, the residual was purified via preparative LC/MS (method D, 50-90% B over 12 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 95 (3.3 mg, 6.05 μmol, 16.80% yield). 1H NMR (500 MHz, methanol-d4) δ 9.06 (s, 1H), 8.80 (d, J=1.5 Hz, 1H), 7.97-7.84 (m, 3H), 7.55 (d, J=7.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.15 (d, J=2.0 Hz, 1H), 6.81 (d, J=1.5 Hz, 1H), 4.82 (s, 2H), 4.04 (t, J=5.4 Hz, 2H), 3.57 (s, 3H), 3.35 (t, J=5.7 Hz, 2H), 2.76 (s, 3H), 2.69 (s, 3H). LC-MS: method C, RT=2.43 min, MS (ESI) m/z: 535.15 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 96 2-fluoro N (2 (2 (2 (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00631
  • To a solution of Intermediate 95B (8 mg, 0.020 mmol) in DMF (1 mL) was added DIEA (0.035 mL, 0.203 mmol) and 2-fluorobenzene-1-sulfonyl chloride (4.74 mg, 0.024 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed, the residual was purified via preparative LC/MS (method D, 50-90% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 96 (4.2 mg, 7.60 μmol, 37.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.84 (td, J=7.6, 1.7 Hz, 1H), 7.74-7.65 (m, 1H), 7.43-7.34 (m, 3H), 6.76 (d, J=1.4 Hz, 1H), 4.80 (s, 2H), 4.05 (t, J=5.4 Hz, 2H), 3.46 (s, 3H), 3.35-3.33 (m, 2H), 2.74-2.71 (m, 3H), 2.68 (s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 553.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 97 3-fluoro-N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00632
  • To a solution of Intermediate 95B (8 mg, 0.020 mmol) in DMF (1 mL) was added DIEA (0.035 mL, 0.203 mmol) and 3-fluorobenzene-1-sulfonyl chloride (4.74 mg, 0.024 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed, the residual was purified via preparative LC/MS (method D, 50-90% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 97 (4.1 mg, 7.34 μmol, 36.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.80 (d, J=1.9 Hz, 1H), 8.14 (br. s., 1H), 8.02 (s, 1H), 7.73-7.61 (m, 3H), 7.50 (s, 1H), 7.45 (s, 1H), 6.86 (d, J=1.4 Hz, 1H), 4.81 (s, 2H), 4.06 (t, J=5.4 Hz, 2H), 3.47 (s, 3H), 3.26 (d, J=5.0 Hz, 2H), 2.74 (s, 3H), 2.69 (s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 553.1 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 98 N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)methanesulfonamide
  • Figure US20190292176A1-20190926-C00633
    • Intermediate 98A: tert-butyl 2-(3-chloro-4-nitrophenoxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00634
  • To a solution of tert-butyl (2-hydroxyethyl)carbamate (3.67 g, 22.79 mmol) in THF (30 mL) was added 1 N sodium bis(trimethylsilyl)amide in THF (25.06 mL, 25.06 mmol). The mixture was stirred at room temperature for 10 min. 2-Chloro-4-fluoro-1-nitrobenzene (2 g, 11.39 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified with flash chromatography (loading in chloroform, 0% to 45% EtOAc in hexanes over 15 min using a 120 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 98A (3.6 g, 11.37 mmol, 100% yield) as a yellow liquid. 1H NMR (400 MHz, chloroform-d) δ 8.10-7.87 (m, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.88 (dd, J=9.0, 2.6 Hz, 1H), 4.94 (br. s., 1H), 4.11-4.02 (m, 2H), 3.57 (q, J=5.4 Hz, 2H), 1.46 (s, 9H). LC-MS: method C, RT=2.04 min, MS (ESI) m/z: 217 [M+1-Boc]+.
    • Intermediate 98B: tert-butyl 2-(4-amino-3-chlorophenoxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00635
  • To a solution of Intermediate 98A (3.6 g, 11.37 mmol) in MeOH (6.0 mL) was added ammonium chloride (7.30 g, 136 mmol) and zinc dust (4.46 g, 68.2 mmol). The mixture was stirred at room temperature overnight. MeOH was removed. The residue was diluted with EtOAc/saturated sodium bicarbonate and stirred at room temperature for 10 min. The mixture was filtered to remove insoluble material. The filtrate was collected, organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude sample was purified with a 120 g ISCO column eluted with 0-100% EtOAc in hexanes for 40 min. The desired fraction was collected and concentrated to give Intermediate 98B (2.9 g, 10.11 mmol, 89% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ 6.86 (d, J=2.4 Hz, 1H), 6.80-6.65 (m, 2H), 3.94 (t, J=5.2 Hz, 2H), 3.49 (q, J=4.9 Hz, 2H), 1.46 (s, 9H). LC-MS: method C, RT=1.52 min, MS (ESI) m/z: 187 [M+1-B0c]+.
    • Intermediate 98C: tert-butyl 2-(2-amino-4-chlorobenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00636
  • To Intermediate 98B (2.9 g, 10.11 mmol) in acetonitrile (30 mL) was added ammonium thiocyanate (1.347 g, 17.70 mmol). The mixture was stirred at room temperature for 10 min. Benzyltrimethylammonium tribromide (5.32 g, 13.65 mmol) in acetonitrile (2.0 mL) was added dropwise (5 min). The mixture was stirred at room temperature overnight. Acetonitrile was removed. The residual was diluted with EtOAc and saturated sodium bicarbonate, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give Intermediate 98C (2.8 g, 8.14 mmol, 81% yield) as a yellow solid that was used for the next step without further purification. 1H NMR (400 MHz, Methanol-d4) δ 7.02 (d, J=2.4 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 3.97 (t, J=5.4 Hz, 2H), 3.48-3.39 (m, 2H), 1.41 (s, 9H). LC-MS: method C, RT=1.71 min, MS (ESI) m/z: 344 (M+H)+.
    • Intermediate 98D: tert-butyl 2-(2-bromo-4-chlorobenzo[d]thiazol-6-yloxy) ethylcarbamate
  • Figure US20190292176A1-20190926-C00637
  • To a solution of copper (II) bromide (1.402 g, 9.77 mmol) in acetonitrile (30 mL) at 40° C. was added tert-butyl nitrite (1.399 mL, 10.59 mmol) followed by Intermediate 98C (2.8 g, 8.14 mmol) as a solid. The mixture was stirring at 40° C. for 2.0 h and then room temperature overnight. The mixture was diluted with EtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine. After evaporation of solvent, the crude sample was purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 98D (240 mg, 0.589 mmol, 7.23% yield). 1H NMR (400 MHz, chloroform-d) δ 7.15 (d, J=2.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 4.06 (t, J=5.2 Hz, 2H), 3.56 (q, J=5.3 Hz, 2H), 1.46 (s, 9H). LC-MS: method C, RT=2.21 min, MS (ESI) m/z: 406.9 and 408.9 (M+H)+.
    • Intermediate 98E: tert-butyl 2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00638
  • To Intermediate I-2 (40 mg, 0.172 mmol), Intermediate 98D (70.3 mg, 0.172 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.04 mg, 8.62 μmol) was added toluene (1.5 mL), EtOH (0.5 mL) and sodium carbonate (0.172 mL, 2M, 0.345 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 120° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 100% EtOAc in hexanes. The desired fraction was collected and concentrated to give Intermediate 98E (85 mg, 0.165 mmol, 96% yields). 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.06 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.05 (br. s., 1H), 4.81 (s, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.47 (s, 3H), 3.39-3.34 (m, 2H), 2.70 (s, 3H), 1.39 (s, 9H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 515 (M+H)+.
    • Intermediate 98F: 2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00639
  • To a solution of Intermediate 98E (85 mg, 0.165 mmol) in DCM (2 mL) was added 2,6-lutidine (0.058 mL, 0.495 mmol) followed by TMS-OTf (0.135 mL, 0.75 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine and concentrated. The residual was added 1 ml of MeOH and stirred at room temperature for 15 min and concentrated to give Intermediate 98F (65 mg, 0.157 mmol, 95% yield) as a yellow solid. the crude sample was used for next step without purification. 1H NMR (400 MHz, Methanol-d4) δ 9.04 (s, 1H), 8.90-8.82 (m, 1H), 7.92 (s, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.19 (d, J=2.2 Hz, 1H), 4.81 (s, 2H), 4.10 (t, J=5.0 Hz, 2H), 3.56 (s, 3H), 3.10 (br. s., 2H), 2.69 (s, 3H). LC-MS: method C, RT=1.91 min, MS (ESI) m/z: 415 (M+H)+.
    • Example 98
  • To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and methanesulfonyl chloride (4.12 mg, 0.036 mmol). The mixture was stirred at room temperature for 15 min. The reaction was quenched with water, and the solvent was removed. The residual was purified via preparative LC/MS (method D, 55-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 98 (6.2 mg, 0.013 mmol, 41.9% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.33 (s, 1H), 4.81 (s, 2H), 4.18 (t, J=5.5 Hz, 2H), 3.47 (s, 3H), 3.40 (d, J=5.0 Hz, 2H), 2.98 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.10 min, MS (ESI) m/z: 493.10 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 99 N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00640
  • To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and benzenesulfonyl chloride (6.36 mg, 0.036 mmol). The mixture was stirred at room temperature for 15 min. LCMS indicated a completion of the reaction. The reaction was quenched by water and solvent was removed. The residual was purified via preparative LC/MS (method D, 55-100% B over 11 min, then a 4-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 99 (7.0 mg, 0.012 mmol, 41.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.73 (d, J=1.4 Hz, 1H), 8.00 (s, 2H), 7.85 (d, J=7.2 Hz, 2H), 7.69-7.54 (m, 3H), 7.12 (d, J=2.2 Hz, 1H), 4.79 (s, 2H), 4.08 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 3.22 (t, J=5.0 Hz, 2H), 2.67 (s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 555.2 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 100 N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)-2-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00641
  • To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and 2-fluorobenzene-1-sulfonyl chloride (7.01 mg, 0.036 mmol). The mixture was stirred at room temperature for 15 min. LCMS indicated a completion of the reaction. The reaction was quenched by water and solvent was removed. The residual was purified via preparative LC/MS (method D, 55-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 100 (7.6 mg, 0.013 mmol, 44.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.84 (td, J=7.8, 1.5 Hz, 1H), 7.71-7.64 (m, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.45-7.34 (m, 2H), 7.03 (d, J=2.5 Hz, 1H), 4.81 (s, 2H), 4.09 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 3.36 (t, J=5.2 Hz, 2H), 2.69 (s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 573.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 101 N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00642
  • To a solution of Intermediate 98F (14.52 mg, 0.035 mmol) in DMF (1 mL) was added DIEA (0.061 mL, 0.350 mmol) and 4-fluorobenzene-1-sulfonyl chloride (8.17 mg, 0.042 mmol). The mixture was stirred at room temperature For 15 min. LCMS indicated a completion of the reaction. The reaction was quenched by water and solvent was removed. The residual was purified via preparative LC/MS (method D, 55-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 101 (11.3 mg, 0.020 mmol, 56.3% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.78 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.96-7.84 (m, 2H), 7.66 (d, J=2.5 Hz, 1H), 7.47-7.37 (m, 2H), 7.14 (d, J=2.2 Hz, 1H), 4.81 (s, 2H), 4.09 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 3.23 (t, J=5.2 Hz, 2H), 2.70 (s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 573.1 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 102 N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy) ethyl)-3-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00643
  • To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL) was added DIEA (0.052 mL, 0.300 mmol) and 3-fluorobenzene-1-sulfonyl chloride (7.01 mg, 0.036 mmol). The mixture was stirred at room temperature for 15 min. LCMS indicated a completion of the reaction. The reaction was quenched by water and solvent was removed. The residual was purified via preparative LC/MS (method D, 55-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 102 (7.5 mg, 0.013 mmol, 42.8% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.75-7.59 (m, 4H), 7.52-7.42 (m, 1H), 7.13 (d, J=2.5 Hz, 1H), 4.81 (s, 2H), 4.09 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 3.27 (t, J=5.2 Hz, 2H), 2.69 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 573.1 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 103 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carbonitrile
  • Figure US20190292176A1-20190926-C00644
    • Intermediate 103A: 2-bromo-4-methoxy-1-nitrobenzene
  • Figure US20190292176A1-20190926-C00645
  • To a solution of 2-bromo-4-fluoro-1-nitrobenzene (2 g, 9.09 mmol) in THF (30 mL) was added sodium methoxide (1.48 g, 27 mmol). The mixture was stirred at room temperature overnight. Solvent was removed under vacuum and the residual was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified with flash chromatography (loading in chloroform, 0% to 50% EtOAc in hexanes over 40 min using a 120 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 103A (1.7 g, 7.33 mmol, 81% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 8.00 (d, J=9.0 Hz, 1H), 7.23 (d, J=2.6 Hz, 1H), 6.93 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H). LC-MS: method C, RT=1.82 min, MS (ESI) m/z: 231.9 and 233.9 (M+H)+.
    • Intermediate 103B: 2-bromo-4-methoxyaniline
  • Figure US20190292176A1-20190926-C00646
  • To a solution of Intermediate 103A (1.7 g, 7.33 mmol) in MeOH (30 mL) was added ammonium chloride (7.84 g, 147 mmol) and zinc dust (4.79 g, 73.3 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a clean reaction. MeOH was removed. The residue was diluted with EtOAc/saturated sodium bicarbonate and stirred at room temperature for 10 min. The mixture was filtered to remove insoluble material. The filtrate was collected, organic layer was washed with brine, dried over sodium sulfate, concentrated. The crude sample was purified with a 120 g ISCO column eluted with 0-100% EtOAc in hexanes for 40 min. The desired fraction was collected and concentrated to give Intermediate 103B (1.3 g, 6.43 mmol, 88% yield) as oil. 1H NMR (400 MHz, chloroform-d) δ 7.01 (d, J=2.0 Hz, 1H), 6.76-6.70 (m, 2H), 3.79 (br. s., 2H), 3.74 (s, 3H). LC-MS: method C, RT=0.80 min, MS (ESI) m/z: 202 and 204 (M+H)+.
    • Intermediate 103C: 4-bromo-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00647
  • To a mixture of Intermediate 103B (1.3 g, 6.43 mmol) in acetonitrile (15 mL) was added ammonium thiocyanate (0.857 g, 11.26 mmol). The mixture was stirred at room temperature for 10 min. Benzyltrimethylammonium tribromide (3.39 g, 8.69 mmol) in acetonitrile (10 mL) was added dropwise (5 min). The mixture was stirred at room temperature overnight. Acetonitrile was removed. The mixture was diluted with EtOAc, saturated sodium bicarbonate. The insoluble material was removed by filtration. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate and concentrated to give Intermediate 103C (1.5 g, 5.79 mmol, 90% yield) as a yellow solid that was used for the next step without further purification. LC-MS: method C, RT=1.41 min, MS (ESI) m/z: 259 and 261 (M+H)+.
    • Intermediate 103D: tert-butyl N-(4-bromo-6-methoxy-1,3-benzothiazol-2-yl)-N-[(tert-butoxy)carbonyl]carbamate
  • Figure US20190292176A1-20190926-C00648
  • To a solution of Intermediate 103C (1.2 g, 4.63 mmol) in DMF (20 mL) was added DMAP (566 mg, 4.63 mmol) and Boc2O (3032 mg, 13.89 mmol). The mixture was stirred under argon over the weekend. The mixture was partitioned into water (300 mL) and extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified with a 40 g ISCO column eluted with 0-50% EtOAc/hexanes for 40 min. The desired fraction was collected and concentrated to give Intermediate 103D (400 mg, 0.871 mmol, 18.80% yield). LC-MS: method C, RT=2.40 min, MS (ESI) m/z: 302.9 and 304.9 (M+H-Boc)+.
    • Intermediate 103E: 2-amino-6-methoxybenzo[d]thiazole-4-carbonitrile
  • Figure US20190292176A1-20190926-C00649
  • A mixture of Intermediate 103D (100 mg, 0.218 mmol), zinc cyanide (25.6 mg, 0.218 mmol), palladium (II) trifluoroacetate (5.79 mg, 0.017 mmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (13.88 mg, 0.035 mmol) and zinc dust (4.27 mg, 0.065 mmol) in DMA (1.5 mL) was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 100° C. for 20 min. It was diluted with EtOAc/saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction was collected to give di-boc protected intermediate (50 mg, 0.123 mmol, 56.6% yield) as colorless oil. The intermediate was redissolved in 1 ml of DCM and TFA (0.839 mL, 10.88 mmol) was added. The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed and the residual was diluted EtOAc/saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was purified with a 12 g ISCO column eluted with 0-100% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 103E (24 mg, 0.117 mmol, 53.7% yield). 1H NMR (400 MHz, methanol-d4) δ 7.51 (d, J=2.6 Hz, 1H), 7.15 (d, J=2.6 Hz, 1H), 3.83 (s, 3H). LC-MS: method C, RT=1.42 min, MS (ESI) m/z: 206 (M+H)+.
    • Intermediate 103F: 2-bromo-6-methoxybenzo[d]thiazole-4-carbonitrile
  • Figure US20190292176A1-20190926-C00650
  • To a stirred solution of copper (II) bromide (20.13 mg, 0.140 mmol) and Intermediate 103E (24 mg, 0.117 mmol) in acetonitrile (2 mL) was added tert-butyl nitrite (0.020 mL, 0.152 mmol). The mixture was stirred at 20° C. for 4.0 h. TLC and LCMS indicated a clean reaction. Acetonitrile was removed under vacuum, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, the crude was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. Intermediate 103F (15 mg, 0.056 mmol, 47.7% yield) was obtained as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 7.49 (d, J=2.4 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 3.92 (s, 3H). LC-MS: method C, RT=1.79 min, MS (ESI) m/z: 268.9 and 270.9 (M+H)+.
    • Example 103
  • To Intermediate I-2 (9.5 mg, 0.041 mmol), Intermediate 103F (11.02 mg, 0.041 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (1.672 mg, 2.047 μmol) was added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.041 mL, 2M, 0.082 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 120° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was purified via preparative LC/MS (method D, 45-90% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 103 (1.7 mg, 4.34 μmol, 10.59% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.82 (s, 1H), 8.16 (br. s., 1H), 8.09 (s, 1H), 7.75 (br. s., 1H), 4.82 (s, 2H), 3.93 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H). LC-MS: method C, RT=2.31 min, MS (ESI) m/z: 377.1 (M+H)+. Analytical HPLC purity (method B): 96%.
    • Example 104 N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00651
    • Intermediate 104A: tert-butyl 4-bromo-6-methoxybenzo[d]thiazol-2-ylcarbamate
  • Figure US20190292176A1-20190926-C00652
  • To a solution of Intermediate 103D (300 mg, 0.653 mmol) in DCM (3 mL) was added TFA (0.101 mL, 1.306 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and saturated NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 104A (235 mg, 0.654 mmol, 100% yield) as an off white solid which was used for next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.24-7.20 (m, 2H), 3.86 (s, 3H), 1.56 (s, 9H). LC-MS: method C, RT=2.30 min, MS (ESI) m/z: 359 and 360.9 (M+H)+.
    • Intermediate 104B: tert-butyl 4-cyclopropyl-6-methoxybenzo[d]thiazol-2-ylcarbamate
  • Figure US20190292176A1-20190926-C00653
  • A solution of Intermediate 104A (30 mg, 0.084 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.82 mg, 8.35 μmol) in THF (1 mL) was degassed for 2 min. To this solution was added cyclopropylzinc(II) bromide (0.835 mL, 0.5 M in THF, 0.418 mmol). The reaction tube was sealed and heated at 65° C. for 1 h. LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc/water. The organic phase was washed with brine, dried over sodium sulfate. The crude residue was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. Intermediate 104B (26 mg, 0.081 mmol, 97% yield) was obtained as colorless oil. LC-MS: method C, RT=2.33 min, MS (ESI) m/z: 321 (M+H)+.
    • Intermediate 104C: 4-cyclopropyl-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00654
  • To a solution of Intermediate 104B (125 mg, 0.390 mmol) in DCM (1 mL) was added TFA (3.01 mL, 39.0 mmol). The mixture was stirred at room temperature for 1 h. Solvent was removed under vacuum and the residual was diluted with EtOAc and saturated NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 104C (80 mg, 0.363 mmol, 93% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 6.94 (d, J=2.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.19 (br. s., 2H), 3.80 (s, 3H), 2.57-2.43 (m, 1H), 1.14-0.99 (m, 2H), 0.86-0.74 (m, 2H). LC-MS: method C, RT=1.46 min, MS (ESI) m/z: 221 (M+H)+.
    • Intermediate 104D: 2-bromo-4-cyclopropyl-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00655
  • To a stirred solution of copper (II) bromide (188 mg, 1.307 mmol) and Intermediate 104C (240 mg, 1.089 mmol) in acetonitrile (3 mL) was added tert-butyl nitrite (0.187 mL, 1.416 mmol). The mixture was stirred at room temperature overnight. Acetonitrile was removed, the reaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. The organic layer was collected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate, brine, dried over sodium sulfate. After evaporation of solvent, the crude oil was purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 104D (180 mg, 0.633 mmol, 58.1% yield) as yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.03 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 3.83 (s, 3H), 2.73 (s, 1H), 1.20-1.06 (m, 2H), 0.93-0.81 (m, 2H). LC-MS: method C, RT=2.26 min, MS (ESI) m/z: 283.9 and 285.9. (M+H)+.
    • Intermediate 104E: 2-bromo-4-cyclopropylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00656
  • To a solution of Intermediate 104D (150 mg, 0.528 mmol) in DCM (3 mL) was added boron tribromide (1.056 mL, 1.0 M in DCM, 1.056 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, quenched with ice and saturated NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude was purified with a 12 g ISCO column eluted with 0-100% EtOAc in hexanes for 20 min. The desired fraction was collected to give Intermediate 104E (100 mg, 0.37 mmol, 70.2% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 7.02 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H), 2.60 (tt, J=8.5, 5.2 Hz, 1H), 1.14-1.03 (m, 2H), 0.90-0.78 (m, 2H). LC-MS: method C, RT=2.01 min, MS (ESI) m/z: 269.9 and 271.9 (M+H)+.
    • Intermediate 104F: tert-butyl 2-(2-bromo-4-cyclopropylbenzo[d]thiazol-6-yloxy) ethylcarbamate
  • Figure US20190292176A1-20190926-C00657
  • A solution of DIAD (0.108 mL, 0.555 mmol) in toluene (1 ml) was added dropwise to a mixture of Intermediate 104E (50 mg, 0.185 mmol), tert-butyl (2-hydroxyethyl)carbamate (35.8 mg, 0.222 mmol) and triphenylphosphine (97 mg, 0.370 mmol) in toluene (1 mL) at 110° C. The mixture was stirred at 110° C. for 30 min. LCMS indicated a completion of the reaction. The mixture was concentrated and purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 104F (70 mg, 0.169 mmol, 92% yield). 1H NMR (400 MHz, chloroform-d) δ 7.02 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.03 (t, J=5.2 Hz, 2H), 3.55 (q, J=5.2 Hz, 2H), 2.80-2.65 (m, 1H), 1.48-1.42 (m, 9H), 1.16-1.08 (m, 2H), 0.91-0.82 (m, 2H). LC-MS: method C, RT=2.35 min, MS (ESI) m/z: 412.9 and 414.9 (M+H)+.
    • Intermediate 104G: tert-butyl 2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00658
  • To Intermediate I-2 (35 mg, 0.151 mmol), Intermediate 104F (62.3 mg, 0.151 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.16 mg, 2M, 7.54 μmol) was added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.151 mL, 0.302 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 120° C. for 40 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 100% EtOAc in hexanes The desired fractions were combined and concentrated to give Intermediate 104G (70 mg, 0.108 mmol, 71.3% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.82 (s, 1H), 8.02 (s, 1H), 7.49 (br. s., 1H), 7.02 (br. s., 1H), 6.58 (br. s., 1H), 4.81 (s, 2H), 4.04 (br. s., 2H), 3.47 (s, 3H), 3.33 (m., 2H), 3.01-2.88 (m, 1H), 2.69 (s, 3H), 1.39 (s, 9H), 1.17 (d, J=7.4 Hz, 2H), 1.00 (br. s., 2H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 521 (M+H)+.
  • Intermediate 104H:
    • 2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00659
  • To a solution of Intermediate 104G (65 mg, 0.125 mmol) in DCM (1 mL) was added 2,6-lutidine (43.6 μl, 0.375 mmol) followed by TMS-OTf (90 μl, 0.499 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc and NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 104H (52.5 mg, 0.125 mmol, 100% yield). LC-MS: method C, RT=2.01 min, MS (ESI) m/z: 421 (M+H)+.
    • Example 104
  • To a solution of Intermediate 104H (14 mg, 0.033 mmol) in DMF (1 mL) was added DIEA (0.058 mL, 0.333 mmol) and benzenesulfonyl chloride (5.15 μl, 0.040 mmol). The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The reaction was quenched with 0.2 ml of MeOH. Solvent was removed. The residual was purified via preparative LC/MS (method D, 50-90% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 104 (4.8 mg, 8.56 μmol, 25.7% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.80 (s, 1H), 8.01 (s, 1H), 7.95 (br. s., 1H), 7.85 (d, J=7.2 Hz, 2H), 7.68-7.57 (m, 3H), 7.40 (s, 1H), 6.45 (s, 1H), 4.80 (s, 2H), 4.04 (br. s., 2H), 3.47 (s, 3H), 3.19 (br. s., 2H), 2.93 (br. s., 1H), 2.68 (s, 3H), 1.17 (d, J=8.0 Hz, 2H), 0.97 (d, J=3.3 Hz, 2H). LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 561.20 (M+H)+. Analytical HPLC purity (method B): 100%
    • Example 105 N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00660
  • To a solution of Intermediate 104H (16 mg, 0.038 mmol) in DMF (1 mL) was added DIEA (0.066 mL, 0.380 mmol) and 4-fluorobenzene-1-sulfonyl chloride (8.89 mg, 0.046 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The reaction was quenched with 0.2 ml of MeOH. Solvent was removed, the residual was purified via preparative LC/MS (method D, 50-90% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 105 (8.4 mg, 0.015 mmol, 38.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.81 (s, 1H), 8.02 (br. s., 2H), 7.92-7.86 (m, 2H), 7.49-7.37 (m, 3H), 6.44 (s, 1H), 4.81 (s, 2H), 4.04 (br. s., 2H), 3.47 (s, 3H), 3.21 (br. s., 2H), 2.92 (d, J=5.2 Hz, 1H), 2.70-2.66 (m, 3H), 1.17 (d, J=7.4 Hz, 2H), 0.97 (d, J=2.5 Hz, 2H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 579.20 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 106 N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00661
    • Intermediate 106A: 2-chlorobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00662
  • Aluminum chloride (7.01 g, 52.6 mmol) was added to a solution of 2-chloro-6-methoxybenzo[d]thiazole (3.5 g, 17.53 mmol) in toluene (80 mL). The mixture was heated at 110° C. for 1.5 h. TLC indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL), stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water (3×), saturated sodium bicarbonate (3×), water (3×) and air-dried for 1.0 h under vacuum. It was further dried under high vacuum overnight to give Intermediate 106A (2.9 g, 15.62 mmol, 89% yield) as a pale gray solid. The crude sample was used for the next step without purification. 1H NMR (400 MHz, methanol-d4) δ 7.70 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H). LC-MS: method C, RT=1.65 min, MS (ESI) m/z: 185.8 (M+H)+.
    • Intermediate 106B: tert-butyl 2-(2-chlorobenzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00663
  • A solution of DIAD (0.943 mL, 4.85 mmol) in toluene (4 mL) was added dropwise to a mixture of Intermediate 106A (300 mg, 1.616 mmol), tert-butyl (2-hydroxyethyl)carbamate (313 mg, 1.939 mmol) and triphenylphosphine (848 mg, 3.23 mmol) in toluene (10 mL) at 110° C. The mixture turned to a clean solution and was stirred at 110° C. for 30 min. LCMS indicated a completion of the reaction. The mixture was concentrated and purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 106B (620 mg, 1.508 mmol, 93% yield). 1H NMR (400 MHz, chloroform-d) δ 7.83 (d, J=9.0 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.07 (dd, J=8.9, 2.5 Hz, 1H), 5.12-4.94 (m, 2H), 4.11-4.05 (m, 2H), 3.57 (q, J=5.1 Hz, 2H), 1.51-1.42 (m, 9H). LC-MS: method C, RT=2.49 min, MS (ESI) m/z: 329 (M+H)+.
    • Intermediate 106C: tert-butyl 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00664
  • To Intermediate I-2 (35 mg, 0.151 mmol), Intermediate 106B (62.0 mg, 0.151 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.16 mg, 7.54 μmol) was added toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.151 mL, 2M, 0.302 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column which was eluted with hexanes for 3 min., then a 20 min gradient from 0% to 100% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 106C (63 mg, 0.119 mmol, 79% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (br. s., 1H), 8.80 (br. s., 1H), 8.05-7.99 (m, 2H), 7.74 (br. s., 1H), 7.16 (d, J=8.8 Hz, 1H), 7.05 (br. s., 1H), 4.81 (br. s., 2H), 4.08 (br. s., 2H), 3.47 (br. s., 3H), 3.36 (br. s., 2H), 2.68 (br. s., 3H), 1.39 (br. s., 9H). LC-MS: method C, RT=2.40 min, MS (ESI) m/z: 481 (M+H)+.
    • Intermediate 106D 2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanamine
  • Figure US20190292176A1-20190926-C00665
  • To a mixture of Intermediate 106C (60 mg, 0.125 mmol) in DCM (2 ml) was added 2,6-lutidine (43.6 μl, 0.375 mmol) followed by TMS-OTf (90 μl, 0.499 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 106D (45 mg, 0.118 mmol, 95% yield). 1H NMR (400 MHz, chloroform-d) δ 9.09 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.15 (dd, J=9.0, 2.4 Hz, 1H), 4.85 (s, 2H), 4.11 (t, J=4.8 Hz, 2H), 3.58 (s, 3H), 3.17 (br. s., 2H), 2.70 (s, 3H). LC-MS: method C, RT=1.74 min, MS (ESI) m/z: 381 (M+H)+.
    • Example 106
  • To a solution of Intermediate 106D (14 mg, 0.037 mmol) in DMF (1 mL) was added DIEA (0.064 mL, 0.368 mmol) and benzenesulfonyl chloride (5.69 μl, 0.044 mmol). The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The reaction mixture was quenched with 0.2 ml of MeOH. Solvent was removed, the residual was purified via preparative LC/MS (method D, 40-80% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 106 (10.7 mg, 0.021 mmol, 55.9% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.09 (br. s., 1H), 8.79 (br. s., 1H), 8.12-7.94 (m, 3H), 7.85 (d, J=6.9 Hz, 2H), 7.69-7.53 (m, 4H), 7.08 (d, J=8.5 Hz, 1H), 4.81 (br. s., 2H), 4.08 (br. s., 2H), 3.47 (br. s., 3H), 3.22 (br. s., 2H), 2.68 (br. s., 3H). LC-MS: method C, RT=2.25 min, MS (ESI) m/z: 521.15 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 107 4-fluoro N (2 (2 (2 (methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00666
  • To a solution of Intermediate 106D (16 mg, 0.042 mmol) in DMF (1 mL) was added DIEA (0.073 mL, 0.421 mmol) and 4-fluorobenzene-1-sulfonyl chloride (9.82 mg, 0.050 mmol). The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The reaction mixture was quenched with 0.2 ml of MeOH. Solvent was removed, the residual was purified via preparative LC/MS (method D, 40-80% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 107 (16.3 mg, 0.030 mmol, 70.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.09 (br. s., 1H), 8.79 (br. s., 1H), 8.09-7.97 (m, 3H), 7.90 (br. s., 2H), 7.66 (br. s., 1H), 7.42 (t, J=8.4 Hz, 2H), 7.07 (d, J=9.1 Hz, 1H), 4.81 (br. s., 2H), 4.08 (br. s., 2H), 3.47 (m, 3H), 3.23 (br. s., 2H), 2.68 (br. s., 3H). LC-MS: method C, RT=2.25 min, MS (ESI) m/z: 539.15 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 108 4-fluoro N (2 (2 (2 (1 fluoroethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00667
    • Intermediate 108A: 1-(5-bromo-7-methylquinoxalin-2-yl)ethanone
  • Figure US20190292176A1-20190926-C00668
  • To a suspension of methyl 5-bromo-7-methylquinoxaline-2-carboxylate (300 mg, 1.067 mmol) in toluene (5 mL) was added N1,N2-dimethylethane-1,2-diamine (DMEDA) (0.126 mL, 1.174 mmol) and trimethylaluminum (1.601 mL, 3.20 mmol) dropwise under argon at room temperature. The mixture was stirred at room temperature over the weekend. The mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with saturated NaHCO3 and brine, dried with MgSO4 and concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-80% EtOAc in hexanes for 20 min. The desired fraction was collected to give Intermediate 108A (250 mg, 0.943 mmol, 88% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 9.50 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.96 (dd, J=1.7, 1.0 Hz, 1H), 2.85 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=1.99 min, MS (ESI) m/z: 265 and 267 (M+H)+.
    • Intermediate 108B: 2-acetyl-7-methylquinoxalin-5-ylboronic acid
  • Figure US20190292176A1-20190926-C00669
  • A mixture of Intermediate 108A (80 mg, 0.302 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (123 mg, 0.483 mmol), potassium acetate (59.2 mg, 0.604 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (9.86 mg, 0.012 mmol) in dioxane (1 ml) was degassed with argon for 10 min. The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine, dried over sodium sulfate, concentrated to give Intermediate 108B (69.0 mg, 0.3 mmol) which was used for next step without purification. LC-MS: method C, RT=1.94 min, MS (ESI) m/z: 231 (M+H)+ (boronic acid).
    • Intermediate 108C: N-(2-(2-(2-acetyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00670
  • To Intermediate 108B (69.0 mg, 0.3 mmol), Intermediate I-5 (111 mg, 0.250 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (10.21 mg, 0.013 mmol) was added toluene (1.5 mL), EtOH (0.5 mL) and sodium carbonate (0.250 mL, 2M, 0.500 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. To the reaction mixture was added EtOAc/water/brine. The insoluble was removed by filtration with a pad of celite. The organic layers were collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 12 g ISCO column which was eluted with hexanes for 3 min., then a 15 min gradient from 0% to 100% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 108C (20 mg, 0.036 mmol, 14.53% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 9.57 (s, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.08 (dd, J=2.0, 0.9 Hz, 1H), 7.97-7.90 (m, 2H), 7.24-7.16 (m, 3H), 6.85 (d, J=1.5 Hz, 1H), 5.04-4.90 (m, 1H), 4.15-4.09 (m, 2H), 3.48-3.40 (m, 2H), 2.88 (s, 3H), 2.83 (s, 3H), 2.77 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 551 (M+H)+.
    • Intermediate 108D 4-fluoro N (2 (2 (2 (1 hydroxyethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00671
  • To a solution of Intermediate 108C (20 mg, 0.036 mmol) in MeOH (1.5 ml) and THF (0.5 mL) was added CeCl3 (13.53 mg, 0.036 mmol) and NaBH4 (5.50 mg, 0.145 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. TLC and LCMS indicated a completion of the reaction. The reaction mixture was diluted with saturated NH4Cl solution and EtOAc. The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to give Intermediate 108D (20 mg, 0.036 mmol, 100% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.21 (br. s., 1H), 8.78 (br. s., 1H), 8.06 (br. s., 1H), 8.02-7.94 (m, 1H), 7.90 (br. s., 2H), 7.45 (d, J=16.8 Hz, 3H), 6.86 (br. s., 1H), 5.86 (br. s., 1H), 5.03 (br. s., 1H), 4.05 (d, J=3.0 Hz, 2H), 3.21 (d, J=3.0 Hz, 2H), 2.73 (br. s., 3H), 2.68 (br. s., 3H). LC-MS: method C, RT=2.33 min, MS (ESI) m/z: 553 (M+H)+.
    • Example 108
  • To a solution of Intermediate 108D (15 mg, 0.027 mmol) in DCM (1 ml) was added diethylaminosulfur trifluoride (7.17 μl, 0.054 mmol) dropwise at −78° C. The mixture was stirred from −78° C. to room temperature for 30 min. LCMS indicated a completion of the reaction. The reaction was quenched with water, extracted with EtOAc, the combined organic layer was washed with NaHCO3, brine and concentrated. The crude sample was purified via preparative LC/MS (method D, 50-90% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 108 (5.3 mg, 9.46 μmol, 34.9% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.21 (br. s., 1H), 8.83 (br. s., 1H), 8.06 (br. s., 2H), 7.90 (br. s., 2H), 7.44 (d, J=13.5 Hz, 3H), 6.86 (br. s., 1H), 6.19-5.98 (m, 1H), 4.05 (br. s., 2H), 3.22 (br. s., 2H), 2.73 (br. s., 3H), 2.69 (br. s., 3H), 1.85-1.75 (m, 3H). LC-MS: method C, RT=2.70 min, MS (ESI) m/z: 555.10 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 109 N-(2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00672
    • Intermediate 109A: tert-butyl 2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate
  • Figure US20190292176A1-20190926-C00673
  • A mixture of Intermediate 98E (60 mg, 0.116 mmol), zinc cyanide (27.36 mg, 0.232 mmol), palladium (II) trifluoroacetate (6.20 mg, 18.64 μmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (14.86 mg, 0.019 mmol) and zinc dust (4.57 mg, 0.070 mmol) in DMA (2 mL) was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 1 h. The mixture was diluted with EtOAc/saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate. After evaporation of solvent, the crude product was purified with a 40 g ISCO column eluted with 0-100% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 109A (10 mg, 0.020 mmol, 16.98% yield). 1H NMR (400 MHz, chloroform-d) δ 9.09 (s, 1H), 9.04 (d, J=2.0 Hz, 1H), 7.95 (s, 1H), 7.66 (dd, J=4.2, 2.4 Hz, 1H), 7.43 (t, J=2.3 Hz, 1H), 4.86 (s, 2H), 4.19-4.14 (m, 2H), 3.62 (d, J=5.5 Hz, 2H), 3.59 (s, 3H), 2.73 (s, 3H), 1.48 (s, 9H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 506 (M+H)+.
    • Intermediate 109B 6-(2-aminoethoxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carbonitrile
  • Figure US20190292176A1-20190926-C00674
  • To a mixture of Intermediate 109A (10 mg, 0.020 mmol) in DCM (1 mL) was added 2,6-lutidine (6.91 μl, 0.059 mmol) followed by TMS-OTf (14.30 μl, 0.079 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and saturated NaHCO3, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 109B which was used for next step without purification. LC-MS: method C, RT=1.83 min, MS (ESI) m/z: 406 (M+H)+.
    • Example 109
  • To a solution of Intermediate 109B in DMF (1 mL) was added DIEA (0.034 mL, 0.197 mmol) and 4-fluorobenzene-1-sulfonyl chloride (4.61 mg, 0.024 mmol). The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The reaction was quenched with 0.2 ml of MeOH. Solvent was removed, the residual was purified via preparative LC/MS (method D, 45-85% B over 18 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 109 (0.7 mg, 0.621 μmol, 3.15% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.76 (d, J=1.7 Hz, 1H), 8.06 (d, J=2.5 Hz, 1H), 8.03 (d, J=0.5 Hz, 1H), 7.89 (dd, J=8.8, 5.2 Hz, 2H), 7.59 (dd, J=3.2, 2.6 Hz, 1H), 7.41 (t, J=8.8 Hz, 2H), 4.82 (s, 2H), 4.13 (td, J=5.1, 2.5 Hz, 2H), 3.47 (s, 3H), 3.24 (t, J=5.2 Hz, 2H), 2.78 (s, 3H). LC-MS: method C, RT=2.20 min, MS (ESI) m/z: 564.20 (M+H)+. Analytical HPLC purity (method B): 97%.
    • Example 110 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylphenylcarbamate
  • Figure US20190292176A1-20190926-C00675
    • Intermediate 110A 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl acetate
  • Figure US20190292176A1-20190926-C00676
  • To a solution of Intermediate 35B (125 mg, 0.370 mmol) in DMF (4 mL) was added cesium carbonate (362 mg, 1.111 mmol), then 2-bromoethyl acetate (0.049 mL, 0.445 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc, the combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column, eluted with 0-100% EtOAc in hexane for 15 min. The desired fraction was collected and concentrated to give Intermediate 110A (150 mg, 0.354 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.65 (d, J=1.5 Hz, 1H), 8.54 (s, 1H), 7.73 (dd, J=1.8, 0.9 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.95 (dd, J=2.4, 0.9 Hz, 1H), 4.53-4.43 (m, 2H), 4.30-4.21 (m, 2H), 4.12 (s, 3H), 2.19-2.09 (m, 3H). LC-MS: method C, RT=2.58 min, MS (ESI) m/z: 424 (M+H)+.
    • Intermediate 110B 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00677
  • To a suspension of Intermediate 110A (190 mg, 0.449 mmol) in THF (3 mL) and MeOH (1 mL) was added 1 N NaOH (1.346 mL, 1.346 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and 1N HCl, extracted with EtOAc, the combined organic layer was washed with water and brine, dried with MgSO4 and concentrated to Intermediate 110B (155 mg, 0.394 mmol, 88% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.56 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 6.99 (s, 1H), 4.91 (br. s., 1H), 4.07 (m, 5H), 3.76 (d, J=4.1 Hz, 2H), 2.73 (s, 3H), 2.62 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 382 (M+H)+.
    • Intermediate 110C 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C00678
  • To a solution of Intermediate 110B (150 mg, 0.393 mmol) in THF (5 mL) at room temperature was added 15% phosgene in toluene (1.387 mL, 1.966 mmol), and the mixture was stirred at room temperature for 5 h. LCMS indicated the reaction was complete. Solvent was removed and the sample was dried under vacuum overnight to give Intermediate 110C (175 mg, 0.394 mmol, 100% yield) as a yellow solid. It was used for the next step without any purification. LC-MS: method C, RT=2.73 min, MS (ESI) m/z: 444 (M+H)+.
    • Example 110
  • To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) and THF (0.5 mL) was added aniline (14.69 mg, 0.158 mmol), followed by DIEA (0.079 mL, 0.451 mmol). The mixture was stirred at room temperature for 0.5 h. LCMS indicated a completion of reaction. The reaction mixture was quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent) and diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude sample was purified via preparative LC/MS (method D, 70-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 110 (8.6 mg, 0.017 mmol, 37.8% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br. s., 1H), 8.71 (s, 1H), 8.57 (s, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.27 (t, J=7.6 Hz, 2H), 7.03 (s, 1H), 6.99 (t, J=7.4 Hz, 1H), 4.47 (br. s., 2H), 4.33 (br. s., 2H), 4.07 (s, 3H), 2.74 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.80 min, MS (ESI) m/z: 501.20 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 111 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylpyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C00679
  • To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) and THF (0.5 mL) was added pyridin-3-amine (14.84 mg, 0.158 mmol) followed by DIEA (0.079 mL, 0.451 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent). Solvent was removed under vacuum. The crude was purified via preparative LC/MS (method D, 55-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 111 (4.1 mg, 8.17 μmol, 18.14% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.65 (br. s., 1H), 8.58 (s, 1H), 8.22 (d, J=3.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.42-7.29 (m, 1H), 7.03 (s, 1H), 4.50 (br. s., 2H), 4.34 (br. s., 2H), 4.08 (s, 3H), 2.78-2.69 (m, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.09 min, MS (ESI) m/z: 502.10 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 112 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 6-methoxypyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C00680
  • To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) and THF (0.5 mL) was added 6-methoxypyridin-3-amine (19.58 mg, 0.158 mmol) followed by DIEA (0.079 mL, 0.451 mmol). The mixture was stirred at room temperature for 0.5 h. LCMS indicated a completion of reaction. The reaction was quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent). Solvent was removed under vacuum. The crude sample was purified via preparative LC/MS (method D, 70-100% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 112 (8.6 mg, 0.016 mmol, 35.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.77 (br. s., 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.24 (br. s., 1H), 7.81 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.03 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 4.47 (br. s., 2H), 4.33 (br. s., 2H), 4.08 (s, 3H), 3.80 (s, 3H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.52 min, MS (ESI) m/z: 532.25 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 113 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylpyridin-4-ylcarbamate
  • Figure US20190292176A1-20190926-C00681
  • To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) and THF (0.5 mL) was added pyridin-4-amine (14.84 mg, 0.158 mmol) followed by DIEA (0.079 mL, 0.451 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent). The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified via preparative LC/MS (method D, 55-95% B over 15 min., then a 6-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 113 (2.6 mg, 4.98 μmol, 11.05% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.38 (d, J=4.7 Hz, 2H), 7.82 (s, 1H), 7.57 (s, 1H), 7.45 (d, J=5.0 Hz, 2H), 7.04 (s, 1H), 4.51 (br. s., 2H), 4.35 (br. s., 2H), 4.08 (s, 3H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.11 min, MS (ESI) m/z: 502.15 (M+H)+. Analytical HPLC purity (method B): 96%.
    • Example 114 N-(2-(2-(2-((difluoromethoxy)methyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00682
    • Intermediate 114A: methyl 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00683
  • A mixture of methyl 5-bromo-7-methylquinoxaline-2-carboxylate (225 mg, 0.800 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (447 mg, 1.761 mmol), potassium acetate (196 mg, 2.001 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (26.1 mg, 0.032 mmol) in dioxane (3.0 mL) was degassed with argon for 10 min. The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. LCMS indicated a complete conversion of starting material. The mixture was diluted with EtOAc/water, insoluble material was removed by filtration. The filtrate was extracted with EtOAc, washed with brine, dried over sodium sulfate. The crude product was purified with flash chromatography (loading in chloroform, 5% to 75% EtOAc in hexanes over 12 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 114A (225 mg, 0.686 mmol, 86% yield) as brown solid. LC-MS: method C, RT=1.48 min, MS (ESI) m/z: 247 (M+H)+ (boronic acid).
    • Intermediate 114B: ethyl 5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00684
  • To Intermediate 114A (89 mg, 0.271 mmol), Intermediate I-5 (115 mg, 0.258 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (10.54 mg, 0.013 mmol) was added toluene (3 mL), EtOH (1 mL) and sodium carbonate (0.258 mL, 2M, 0.516 mmol). The mixture was degassed with argon for 5 min. The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. The mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 12 g ISCO column eluted with EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 114B (45 mg, 0.039 mmol, 15.01% yield) as a yellow solid [Note: Transesterification with the EtOH solvent occurred under these reaction conditions]. 1H NMR (400 MHz, chloroform-d) δ 9.62 (s, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.84 (s, 1H), 8.17 (dd, J=1.8, 0.9 Hz, 1H), 8.00-7.76 (m, 2H), 7.23-7.07 (m, 2H), 6.84 (dd, J=2.4, 0.9 Hz 1H), 4.63 (q, J=7.3 Hz, 2H), 4.12-4.03 (m, 2H), 3.48-3.39 (m, 2H), 1.93 (s, 3H), 1.59 (s, 3H), 1.54 (t, J=7.2 Hz, 3H). LC-MS: method C, RT=2.44 min, MS (ESI) m/z: 581 (M+H)+.
    • Intermediate 114C 4-fluoro N (2 (2 (2 (hydroxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00685
  • NaBH4 (2.93 mg, 0.077 mmol) and calcium chloride (4.30 mg, 0.039 mmol) was dissolved in THF (2 ml) and the mixture was stirred at room temperature for 1.5 h, followed by addition of a solution of Intermediate 114B (45 mg, 0.039 mmol) in THF (1 mL). The mixture was stirred at room temperature for 1.5 h. LCMS indicated a completion of the reaction. The mixture was diluted with water and EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 114C (20 mg, 0.037 mmol, 96% yield) as a yellow solid. LC-MS: method C, RT=2.23 min, MS (ESI) m/z: 539 (M+H)+.
    • Example 114
  • To a heated suspension of Intermediate 114C (20 mg, 0.037 mmol) and sodium sulfate (1.319 mg, 9.28 μmol) in acetonitrile (2.0 mL) at 65° C. was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (5.76 μl, 0.056 mmol) in acetonitrile (0.5 mL) dropwise over 40 min, The mixture was stirred at 65° C. for 0.5 h. After the mixture was cooled to room temperature, it was diluted with EtOAc and quenched with NaHCO3, extracted with EtOAc. The combined organic layer was washed with NaHCO3 and brine, dried over MgSO4 and concentrated. The crude sample was purified via preparative LC/MS (method D, 40-80% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 114 (0.4 mg, 0.584 μmol, 1.259% yield). LC-MS: method C, RT=2.48 min, MS (ESI) m/z: 589.20 (M+H)+. Analytical HPLC purity (method B): 86%.
    • Example 115 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl 6-methoxypyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C00686
    • Intermediate 115A: 2-(2-chlorobenzo[d]thiazol-6-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00687
  • To a solution of Intermediate I-4A (500 mg, 2.69 mmol) in DMF (10 mL) was added cesium carbonate (1755 mg, 5.39 mmol), then 2-bromoethyl acetate (0.356 mL, 3.23 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight, diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was dissolved in 10 ml of THF followed by addition of NaOH (5.39 mL, 1M, 5.39 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-100% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 115A (550 mg, 2.395 mmol, 89% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ 7.73 (d, J=8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.9, 2.5 Hz, 1H), 4.10-4.04 (m, 2H), 4.01-3.91 (m, 2H). LC-MS: method C, RT=1.64 min, MS (ESI) m/z: 230 (M+H)+.
    • Intermediate 115B 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00688
  • To Intermediate I-1 (512 mg, 1.524 mmol), Intermediate 115A (350 mg, 1.524 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (49.8 mg, 0.061 mmol) was added toluene (3 mL) and EtOH (1). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (1.524 mL, 2M, 3.05 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated. The residual was dissolved in 1 ml DMSO and DCM and was loaded to a 40 g ISCO column eluted with 0-100% EtOAc in hexanes for 20 min. The desired fractions were combined and concentrated to yield Intermediate 115B (550 mg, 1.363 mmol, 89% yield) as a brown-yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=1.8 Hz, 1H), 8.67 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.86-7.46 (m, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.15 (dd, J=9.0, 2.4 Hz, 1H), 4.23-4.16 (m, 2H), 4.04 (d, J=4.6 Hz, 2H), 2.67 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −89.73 (s, 2F). LC-MS: method C, RT=2.31 min, MS (ESI) m/z: 404 (M+H)+.
    • Intermediate 115C 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00689
  • To a solution of Intermediate 115B (550 mg, 1.363 mmol) in THF (10 mL) was added NaOMe in MeOH (4.3 M, 0.936 mL, 4.09 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The reaction was quenched by 1N HCl (12 ml) and extracted with DCM (3×). The combined organic layer was washed with brine, dried with MgSO4 and concentrated to give Intermediate 115C (400 mg, 1.089 mmol, 80% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.63 (d, J=1.5 Hz, 1H), 8.57 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.76 (dd, J=2.0, 0.9 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.16 (dd, J=8.9, 2.5 Hz, 1H), 4.27-4.18 (m, 2H), 4.14 (s, 3H), 4.08-4.01 (m, 2H), 2.66 (s, 3H). LC-MS: method C, RT=2.31 min, MS (ESI) m/z: 368 (M+H)+.
    • Intermediate 115D 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C00690
  • To a suspension of Intermediate 115C (150 mg, 0.408 mmol) in THF (3 mL) at room temperature was added 15% phosgene in toluene (1.440 mL, 2.041 mmol). The mixture was stirred at room temperature overnight. Solvent was removed under vacuum and Intermediate 115D (175 mg, 0.407 mmol, 100% yield) was obtained as a yellow solid. It was used for the next step without any purification. LC-MS: method C, RT=2.56 min, MS (ESI) m/z: 430 (M+H)+.
    • Example 115
  • To a solution of 6-methoxypyridin-3-amine (15.16 mg, 0.122 mmol) in DCM (0.5 mL) was added Intermediate 115D (15 mg, 0.035 mmol) in THF (0.5 mL), followed by DIEA (0.061 mL, 0.349 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent) and concentrated. The residual was purified via preparative LC/MS (method D, 50-100% B over 12 min., then a 7-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 115 (5.0 mg, 9.56 μmol, 27.4% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.73 (s, 1H), 8.57 (d, J=1.4 Hz, 1H), 8.24 (br. s., 1H), 8.01 (d, J=9.1 Hz, 1H), 7.86-7.72 (m, 3H), 7.19 (dd, J=8.8, 2.5 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.54-4.42 (m, 2H), 4.38-4.29 (m, 2H), 4.07 (s, 3H), 3.79 (s, 3H), 2.62 (s, 3H). LC-MS: method C, RT=2.23 min, MS (ESI) m/z: 518.20 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 116 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 5-cyanopyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C00691
  • To a solution of Intermediate 110B in THF (0.5 mL) was added a suspension of (5-cyanopyridin-3-yl)carbamic chloride (21.42 mg, 0.118 mmol) (23.80 mg, 0.131 mmol) in DCM and toluene, followed by DIEA (0.046 ml, 0.262 mmol). The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The mixture was quenched by 10% water/acetonitrile with 01% TFA. Solvent was removed and the crude was purified via preparative LC/MS (method D, 50-85% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 116 (9.0 mg, 0.016 mmol, 61.9% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.51 (br. s., 1H), 8.85 (d, J=2.5 Hz, 1H), 8.72 (s, 1H), 8.65 (d, J=1.7 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 4.57-4.49 (m, 2H), 4.38-4.31 (m, 2H), 4.07 (s, 3H), 2.74 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.52 min, MS (ESI) m/z: 527.15 (M+H)+. Analytical HPLC purity (method B): 95%.
    • Example 117 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C00692
  • To Intermediate 110B (15 mg, 0.039 mmol) in THF (0.5 mL) was added (6-cyanopyridin-3-yl)carbamic chloride (21.42 mg, 0.118 mmol) (21.42 mg, 0.118 mmol) in DCM (1 ml) followed by DIEA (0.069 ml, 0.393 mmol). The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The mixture was quenched by 10% water/acetonitrile with 01% TFA. Solvent was removed, the residual was purified via preparative LC/MS (method D, 55-95% B over 10 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 117 (13.1 mg, 0.025 mmol, 63.3% yield). LC-MS: method C, RT=2.55 min, MS (ESI) m/z: 527.20 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 118 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (3-cyanophenyl)carbamate
  • Figure US20190292176A1-20190926-C00693
  • To a solution of 3-aminobenzonitrile (14.43 mg, 0.122 mmol) in DCM (0.5 mL) was added Intermediate 115D (15 mg, 0.035 mmol) in THF (1 mL) followed by DIEA (0.061 mL, 0.349 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent) and concentrated. The residual was dissolved in DMSO and purified via preparative LC/MS (method D, 60-100% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 118 (2.1 mg, 3.94 μmol, 11.29% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.26 (br. s., 1H), 8.74 (s, 1H), 8.58 (d, J=1.4 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.54-7.48 (m, 1H), 7.48-7.44 (m, 1H), 7.20 (dd, J=8.8, 2.5 Hz, 1H), 4.52 (d, J=4.4 Hz, 2H), 4.37 (d, J=3.9 Hz, 2H), 4.08 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.43 min, MS (ESI) m/z: 512.20 (M+H)+. Analytical HPLC purity (method B): 96%.
    • Example 119 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (2-chloropyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C00694
  • To a solution of Intermediate 110B (15.5 mg, 0.041 mmol) in THF (1 mL) was added (2-chloropyrimidin-5-yl)carbamic chloride (39.0 mg, 0.203 mmol) in DCM (1 ml) followed by DIEA (0.071 ml, 0.406 mmol). The mixture was stirred at room temperature overnight, quenched by a drop of 10% water/acetonitrile with 0.1% TFA. Solvent was removed, the residual was dissolved in DMSO and purified via preparative LC/MS (method C, 55-100% B over 15 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 119 (3.7 mg, 6.61 μmol, 16.28% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 2H), 8.73 (s, 1H), 8.59 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.03 (s, 1H), 4.53 (br. s., 2H), 4.35 (br. s., 2H), 4.07 (s, 3H), 2.74 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 537.15 (M+H)+. Analytical HPLC purity (method B): 96%.
    • Example 120 5-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00695
    • Intermediate 120A: 4-fluoro-2-hydroxy-5-methoxybenzaldehyde
  • Figure US20190292176A1-20190926-C00696
  • To a solution of 3-fluoro-4-methoxyphenol (200 mg, 1.407 mmol) in THF (8 ml) was added magnesium chloride (260 mg, 2.81 mmol), triethylamine (0.981 mL, 7.04 mmol) and paraformaldehyde (211 mg, 7.04 mmol). The reaction mixture was heated to reflux at 80° C. under argon for 3.0 h. TLC and LCMS indicated a complete conversion of starting material. The reaction mixture was cooled to room temperature, diluted with EtOAc, quenched with 1.0 N HCl (8.0 mL)/water and stirred at room temperature for 15 min until the cloudy solution turned to a clear solution. The mixture was passed through a pad of wet celite. The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified with flash chromatography (loading in chloroform, 0% to 30% EtOAc in hexanes over 15 min using a 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 120A (235 mg, 1.381 mmol, 98% yield) as a white solid. 19F NMR (376 MHz, Chloroform-d) δ −117.87 (s, 1F). 1H NMR (400 MHz, chloroform-d) δ 11.09 (d, J=1.8 Hz, 1H), 9.81 (s, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.75 (d, J=11.9 Hz, 1H), 3.91 (s, 3H). LC-MS: method C, RT=1.45 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 120B: ethyl 6-fluoro-5-methoxybenzofuran-2-carboxylate
  • Figure US20190292176A1-20190926-C00697
  • To a mixture of Intermediate 120A (1.7 g, 9.99 mmol) and Cs2CO3 (3.91 g, 11.99 mmol) in acetonitrile (50 mL) was added ethyl bromoacetate (1.266 mL, 10.99 mmol). The mixture was stirred at room temperature over weekend. The mixture was filtered and the filter cake was rinse with EtOAc. The combined filtrate was concentrated to a white solid of ethyl 2-(5-fluoro-2-formyl-4-methoxyphenoxy)acetate. The crude sample was added to a solution of 2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.864 g, 4.00 mmol) in EtOH (10 mL). The mixture was heated at 70° C. for 2 h. TLC and LCMS indicated a completion of the reaction. The mixture was concentrated and the residual was purified with a 120 g ISCO column eluted with 0-100% EtOAc in hexanes for 40 min. The desired fraction was collected and concentrated to give Intermediate 120B (1.6 g, 6.72 mmol, 67.2% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.47 (d, J=0.9 Hz, 1H), 7.35 (dd, J=10.5, 0.8 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H), 4.44 (q, J=7.0 Hz, 2H), 3.95 (s, 3H), 1.43 (t, J=7.2 Hz, 3H). 19F NMR (376 MHz, chloroform-d) δ −130.18 (s, 1F). LC-MS: method C, RT=1.93 min, MS (ESI) m/z: 239.1 (M+H)+.
    • Intermediate 120C: 6-fluoro-5-methoxybenzofuran
  • Figure US20190292176A1-20190926-C00698
  • To a solution of Intermediate 120B (1.6 g, 6.72 mmol) in THF (25 mL) and MeOH (5 mL) was added NaOH (0.806 g, 20.15 mmol) in water (10 mL). The mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The mixture was diluted with EtOAc and 1N HCl (pH<2), extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated to 6-fluoro-5-methoxybenzofuran-2-carboxylic acid as a white solid. LC-MS: method C, RT=1.59 min, MS (ESI) m/z: 211 (M+H)+. The crude acid was redissolved in DMSO (25 mL), then silver carbonate (0.740 g, 1.35 mmol) and AcOH (0.038 mL, 0.672 mmol) was added. The mixture was heated at 120° C. overnight. LCMS indicated a completion of the reaction. The mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and purified with a 120 g ISCO column eluted with 0-50% EtOAc in hexanes for 40 min. The desired fraction was collected and concentrated to give Intermediate 120C (0.97 g, 5.84 mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ 7.71 (d, J=2.2 Hz, 1H), 7.30 (dd, J=10.9, 0.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.79 (dd, J=2.2, 1.1 Hz, 1H). 19F NMR (376 MHz, methanol-d4) δ −138.84 (s, 1F). LC-MS: method C, RT=1.74 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 120D: 6-fluorobenzofuran-5-ol
  • Figure US20190292176A1-20190926-C00699
  • To a mixture of Intermediate 120C (0.73 g, 4.39 mmol) and tetrabutylammonium iodide (1.704 g, 4.61 mmol) in DCM (4 ml) at −78° C. was added boron trichloride in heptane (10.33 ml, 1.0 M, 10.33 mmol) dropwise. The mixture was stirred at −78° C. for 45 min. The cooling bath was removed and the mixture was stirred at room temperature for 3.0 h. HPLC and TLC indicated a clean reaction. The mixture was poured into 1.5M K2HPO4 with ice, stirred for 20 min, extracted with EtOAc. The organic layers were collected, washed with 10% Na2S2O3, water, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g ISCO column eluted with hexanes for 1 min., then a 15 min gradient from 0% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 120D (650 mg, 4.27 mmol, 97% yield) as off-white solid. 19F NMR (376 MHz, chloroform-d) δ −142.05 (s, 1F). 1H NMR (400 MHz, chloroform-d) δ 7.59 (d, J=2.2 Hz, 1H), 7.29-7.26 (d, Hz 1H), 7.17 (d, J=8.6 Hz, 1H), 6.73-6.64 (m, 1H), 5.00 (d, J=4.8 Hz, 1H). LC-MS: method C, RT=1.37 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 120E: tert-butyl(6-fluorobenzofuran-5-yloxy)dimethylsilane
  • Figure US20190292176A1-20190926-C00700
  • To a stirred solution of Intermediate 120D (0.65 g, 4.27 mmol) in DMF (15 mL) was added TBDMS-Cl (0.966 g, 6.41 mmol) and imidazole (0.524 g, 7.69 mmol). The reaction mixture was stirred at room temperature for 1.0 h. TLC and LCMS indicated a clean reaction. The mixture was partitioned between EtOAc/water. The organic layer was washed with water, brine, dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 40 g silica gel cartridge which was eluted with hexanes for 3 min., then 15 min gradient from 0% to 15% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 120E (1 g, 3.75 mmol, 88% yield) as clear oil. 1H NMR (400 MHz, chloroform-d) δ 7.58 (d, J=2.2 Hz, 1H), 7.24 (dd, J=10.0, 0.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.66 (dd, J=2.1, 1.0 Hz, 1H), 1.08-1.00 (m, 9H), 0.26-0.16 (m, 6H). 19F NMR (376 MHz, chloroform-d) δ −133.00 (s, 1F). LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 267 (M+H)+.
    • Intermediate 120F: tert-butyl(6-fluoro-7-(trimethylsilyl)benzofuran-5-yloxy) dimethylsilane
  • Figure US20190292176A1-20190926-C00701
  • To diisopropylamine (0.594 mL, 4.17 mmol) in THF (10 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (2.083 mL, 3.33 mmol). The mixture was stirred at −78° C. for 0.5 h. Then Intermediate 120E (740 mg, 2.78 mmol) in THF (2 mL) was added, the mixture was stirred at −78° C. for 0.5 h. TMS-Cl in DCM (3.61 mL, 3.61 mmol) was added, and the reaction mixture was warmed up to room temperature over 0.5 h. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with Na2CO3, brine, dried over sodium sulfate. After evaporation of solvent, the crude was purified with a 40 g ISCO column eluted with 0-20% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 120F (840 mg, 2.481 mmol, 89% yield) as colorless oil. 19F NMR (376 MHz, chloroform-d) δ −121.09 (s, 1F). 1H NMR (400 MHz, chloroform-d) δ 7.57 (d, J=2.2 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 1.03 (s, 9H), 0.46 (d, J=1.1 Hz, 9H), 0.20 (d, J=1.1 Hz, 6H). LC-MS: method C, RT=2.24 min, MS (ESI) m/z: 339 (M+H)+.
    • Intermediate 120G tert-butyl(6-fluoro-2-iodo-7-(trimethylsilyl)benzofuran-5-yloxy)dimethylsilane
  • Figure US20190292176A1-20190926-C00702
  • To a solution of Intermediate 120F (840 mg, 2.481 mmol) in THF (10 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (2.016 mL, 3.23 mmol). The mixture was stirred at −78° C. for 0.5 h. Then iodine (945 mg, 3.72 mmol) in THF (2 mL) was added, the mixture was stirred at −78° C. for 0.5 h. LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with Na2S2O3 and brine, dried over sodium sulfate. After evaporation of solvent, the crude was purified with a 40 g ISCO column eluted with 0-20% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 120G (880 mg, 1.895 mmol, 76% yield) as colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.00 (d, J=8.6 Hz, 1H), 6.81 (s, 1H), 1.03 (s, 9H), 0.45 (d, J=1.1 Hz, 9H), 0.18 (d, J=1.1 Hz, 6H). 19F NMR (376 MHz, chloroform-d) δ −120.92 (s, 1F). LC-MS: method C, RT=2.57 min, MS (ESI) m/z: 465 (M+H)+.
    • Intermediate 120H: 5-(5-(tert-butyldimethylsilyloxy)-6-fluoro-7-(trimethylsilyl) benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00703
  • To Intermediate I-1 (57.9 mg, 0.172 mmol), Intermediate 120G (80 mg, 0.172 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (7.03 mg, 8.61 μmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, and flushed with argon. To the above mixture was added sodium carbonate (0.172 mL, 2M, 0.344 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The crude reaction mixture was directly loaded onto a 40 g ISCO column, eluted with 0-20% EtOAc in hexanes for 20 min. The desired fractions were combined and concentrated to yield Intermediate 120H (100 mg, 0.128 mmol, 74.3% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.97 (s, 1H), 7.63 (dd, J=1.9, 1.0 Hz, 1H), 7.86-7.47 (m, 1H), 7.17 (d, J=8.6 Hz, 1H), 2.64 (s, 3H), 1.05 (s, 9H), 0.57 (d, J=1.1 Hz, 9H), 0.21 (d, J=0.9 Hz, 6H). 19F NMR (376 MHz, chloroform-d) δ −89.68 (s, 2F). LC-MS: method C, RT=4.63 min, MS (ESI) m/z: 547 (M+H)+.
    • Intermediate 120I 6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(trimethylsilyl)benzofuran-5-ol
  • Figure US20190292176A1-20190926-C00704
  • To solution of Intermediate 120H (100 mg, 0.128 mmol) in THF (3 mL) at room temperature was added sodium methoxide in MeOH (0.095 mL, 4.37M, 0.448 mmol). The reaction mixture was stirred at room temperature for 30 min. TLC and LCMS indicated a completion of the reaction. The reaction mixture was quenched with saturated NH4Cl, diluted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated. The crude was purified with a 12 g ISCO column eluted with 0-50% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 120I (69 mg, 0.122 mmol, 95% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.51 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.97 (s, 1H), 7.62 (dd, J=1.8, 0.9 Hz, 1H), 7.23 (d, J=9.2 Hz, 1H), 4.12 (s, 3H), 0.58 (s, 9H). LC-MS: method C, RT=2.77 min, MS (ESI) m/z: 397 (M+H)+.
    • Intermediate 120J: 6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol
  • Figure US20190292176A1-20190926-C00705
  • To a solution of Intermediate 120I (69 mg, 0.122 mmol) in THF (2 mL) was added AcOH (0.021 mL, 0.365 mmol) followed by TBAF (0.488 mL, 0.488 mmol). The mixture was stirred at room temperature for 3 h. LCMS indicated a completion of the reaction. Solvent was removed and the residual was purified with a 12 g ISCO column eluted with 0-70% EtOAc/hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 120J (30 mg, 0.093 mmol, 76% yield). 1H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 8.42-8.38 (m, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.50 (s, 1H), 7.16 (d, J=10.6 Hz, 1H), 7.12-7.06 (m, 1H), 4.07-3.98 (m, 3H), 2.51 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −137.18 (s, 1F). LC-MS: method C, RT=2.42 min, MS (ESI) m/z: 325 (M+H)+.
    • Example 120
  • To a solution of Intermediate 120J (15 mg, 0.046 mmol) in DMF (1 mL) was added Cs2CO3 (45.2 mg, 0.139 mmol) and Met (0.014 mL, 0.231 mmol). The mixture was stirred at room temperature for 2 h. LCMS indicated a completion of the reaction. The mixture was filtered. The filtrate was purified via preparative LC/MS (method D, 65-100% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 120 (2.6 mg, 7.45 μmol, 16.12% yield). 1H NMR (500 MHz, chloroform-d) δ 8.51 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.33 (d, J=10.5 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.12 (s, 3H), 3.96 (s, 3H), 2.62 (s, 3H). LC-MS: method C, RT=2.59 min, MS (ESI) m/z: 338.9 (M+H)+. Analytical HPLC purity (method B): 97%.
    • Example 121 5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00706
    • Intermediate 121A: 7-chloro-6-fluoro-5-methoxybenzofuran
  • Figure US20190292176A1-20190926-C00707
  • To diisopropylamine (0.270 mL, 1.896 mmol) in THF (5 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (0.948 mL, 1.517 mmol). The mixture was stirred at −78° C. for 0.5 h. Intermediate 120C (210 mg, 1.264 mmol) in THF (1 mL) was added, the mixture was stirred at −78° C. for 0.5 h. Hexachloroethane (449 mg, 1.896 mmol) in THF (1 mL) was added, and the reaction mixture was stirred at −78° C. for 0.5 h. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with Na2SO3, brine, dried over sodium sulfate and concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 121A (240 mg, 1.196 mmol, 95% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.67 (d, J=2.0 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 3.94 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −140.56 (s, 1F). LC-MS: method C, RT=2.01 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 121B: 7-chloro-6-fluoro-2-iodo-5-methoxybenzofuran
  • Figure US20190292176A1-20190926-C00708
  • To a solution of Intermediate 121A (240 mg, 1.196 mmol) in THF (5 mL) at −78° C. was added 1.6 N n-BuLi in hexanes (0.972 mL, 1.555 mmol). The mixture was stirred at −78° C. for 0.5 h. Iodine (456 mg, 1.795 mmol) in THF (2 mL) was added, and the mixture was stirred at −78° C. for 0.5 h. The mixture was warmed up to room temperature and continued stirring for 1 h. The reaction mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with Na2S2O3, brine, dried over sodium sulfate. The crude sample was purified with a 12 g ISCO column eluted with 0-20% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 121B (280 mg, 0.686 mmol, 57.3% yield) as colorless oil. 19F NMR (376 MHz, chloroform-d) δ −140.34 (s, 1F). 1H NMR (400 MHz, chloroform-d) δ 6.96 (d, J=7.3 Hz, 1H), 6.92 (s, 1H), 3.93 (s, 3H). LC-MS: method C, RT=2.24 min, MS (ESI) m/z: No (M+H)+.
    • Example 121
  • To Intermediate I-2 (11.37 mg, 0.049 mmol), Intermediate 121B (20 mg, 0.049 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (2.001 mg, 2.450 μmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, and flushed with argon. To this mixture was added Na2CO3 (0.049 mL, 2M, 0.098 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The crude reaction mixture was directly loaded onto a 12 g ISCO column, eluted with 0-50% EtOAc in hexanes for 20 min. The desired fractions were combined and concentrated. The sample was redissolved in DMSO and further purified via preparative LC/MS (method D, 65-100% B over 15 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 121 (4.7 mg, 0.012 mmol, 24.55% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=7.7 Hz, 1H), 4.79 (s, 2H), 3.93 (s, 3H), 3.46 (s, 3H), 2.66 (s, 3H). LC-MS: method C, RT=2.55 min, MS (ESI) m/z: 387.1 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 122 5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00709
  • To Intermediate I-1 (16.47 mg, 0.049 mmol), Intermediate 121B (20 mg, 0.049 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (2.001 mg, 2.450 μmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.049 mL, 2M, 0.098 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The crude reaction mixture was directly loaded onto a 12 g ISCO column, eluted with 0-20% EtOAc in hexane for 20 min. The desired fractions were combined and concentrated to yield 5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline as a yellow oil. LC-MS: method C, RT=2.81 min, MS (ESI) m/z: 409 (M+H)+. The above sample was dissolved in THF (1 ml) and sodium methoxide (0.036 mL, 4.37M, 0.172 mmol) was added. The mixture was stirred at room temperature for 30 min, quenched with a drop of 10% water/MeOH with 0.1% TFA (HPLC solvent) and concentrated. The crude was redissolved in DMSO and purified via preparative LC/MS (method C, 60-100% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 122 (0.8 mg, 2.146 μmol, 4.38% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 4.09 (s, 3H), 3.95 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.76 min, MS (ESI) m/z: 373.05 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 123 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate
  • Figure US20190292176A1-20190926-C00710
    • Intermediate 123A: 6-fluoro-2-iodobenzofuran-5-ol
  • Figure US20190292176A1-20190926-C00711
  • To a solution of Intermediate 120G (64 mg, 0.138 mmol) in THF (1 mL) was added TBAF (0.413 mL, 0.413 mmol). The mixture was stirred at room temperature for 1 h. Solvent was removed under vacuum and the residual was purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 123A (38 mg, 0.137 mmol, 99% yield) as white solid. 19F NMR (376 MHz, chloroform-d) δ −141.74 (s, 1F). 1H NMR (400 MHz, chloroform-d) δ 7.27-7.23 (m, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.86 (d, J=0.9 Hz, 1H), 5.10-4.99 (m, 1H). LC-MS: method C, RT=1.84 min, MS (ESI) m/z: No (M+H)+.
    • Intermediate 123B: 6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol
  • Figure US20190292176A1-20190926-C00712
  • To Intermediate I-1 (45.9 mg, 0.137 mmol), Intermediate 123A (38 mg, 0.137 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (5.58 mg, 6.83 μmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.137 mL, 2M, 0.273 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The crude reaction mixture was directly loaded onto a 12 g ISCO column, eluted with 0-50% EtOAc in hexanes for 15 min. The desired fractions were combined and concentrated to yield Intermediate 123B (78 mg, 0.130 mmol, 95% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.33 (d, J=10.1 Hz, 1H), 2.65 (s, 3H). 19F NMR (376 MHz, chloroform-d) δ −89.71 (s, 2F), −140.50 (s, 1F). LC-MS: method C, RT=2.37 min, MS (ESI) m/z: 361 (M+H)+.
    • Intermediate 123C 2-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00713
  • To a solution of Intermediate 123B (49.4 mg, 0.137 mmol) in DMF (2 mL) was added Cs2CO3 (134 mg, 0.411 mmol) and 2-bromoethyl acetate (0.031 mL, 0.274 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated. LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 447 (M+H)+. The crude sample was redissolved in THF (1 ml) and sodium methoxide (0.094 mL, 4.37M, 0.411 mmol) was added. The mixture was stirred at room temperature for 30 min, diluted with EtOAc and saturated NH4Cl, extracted with EtOAc. The combined organic layer was washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. The crude sample was dissolved in DMF and load on a 40 g ISCO column, eluted with 0-100% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 123C (50 mg, 0.136 mmol, 99% yield) as a yellow solid. 19F NMR (376 MHz, methanol-d4) δ −136.00 (s, 1F). 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 8.02 (d, J=0.9 Hz, 1H), 7.62 (dd, J=1.8, 0.9 Hz, 1H), 7.38 (dd, J=10.8, 0.9 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.19-4.16 (m, 2H), 4.11 (s, 3H), 3.97-3.92 (m, 2H), 2.61 (s, 3H). LC-MS: method C, RT=2.39 min, MS (ESI) m/z: 369 (M+H)+.
    • Intermediate 123D 2-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C00714
  • To a solution of Intermediate 123C (45 mg, 0.122 mmol) in THF (2 mL) was added 15% phosgene in toluene (0.431 mL, 0.611 mmol), and the mixture was stirred at room temperature overnight. Solvent was removed under vacuum to give Intermediate 123D as a yellow solid. It was used for the next step without any purification. LC-MS: method C, RT=2.63 min, MS (ESI) m/z: 431 (M+H)+.
    • Example 123
  • To a solution of Intermediate 123D (10 mg, 0.023 mmol) in THF (1 mL) was added 2-methylpyridin-4-amine (7.53 mg, 0.070 mmol) in DCM (0.5 mL) followed by DIEA (0.041 mL, 0.232 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The reaction was quenched by addition of a small amount of 10% MeOH/water/0.1% TFA (HPLC solvent). Solvent was removed under vacuum. The residual was dissolved in DMSO and purified via preparative LC/MS (method C, 40-80% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 123 (2.7 mg, 5.37 μmol, 23.15% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.20 (br. s., 1H), 8.67 (s, 1H), 8.50 (d, J=6.6 Hz, 1H), 8.03 (s, 2H), 7.76-7.65 (m, 4H), 7.57 (d, J=8.5 Hz, 1H), 4.60 (br. s., 2H), 4.41 (br. s., 2H), 4.06 (s, 3H), 2.58 (br. s., 6H). LC-MS: method C, RT=1.99 min, MS (ESI) m/z: 503.15 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 124 (8-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00715
  • To Intermediate I-27 (14.22 mg, 0.035 mmol), Intermediate 121B (14.22 mg, 0.035 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (1.423 mg, 1.742 μmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, and flushed with argon. To this mixture was added sodium carbonate (0.035 mL, 2M, 0.070 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The crude reaction mixture was directly loaded onto a 12 g ISCO column and eluted with 0-20% EtOAc in hexanes for 20 min. The desired fractions were combined and concentrated to yield 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxyquinoxaline as an off-white solid. The sample was dissolved in 2 ml of DCM and TFA (0.013 mL, 0.174 mmol) was added. The mixture was stirred at room temperature for 1 h. TLC indicated a small conversion. TBAF (0.070 mL, 0.070 mmol) was added to the mixture and stirred at room temperature overnight. LCMS indicate a completion of the reaction. Solvent was completely removed and the residual was purified via preparative LC/MS (method C, 45-90% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 124 (3.0 mg, 7.33 μmol, 21.04% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.79 (s, 1H), 7.52 (d, J=7.4 Hz, 1H), 5.60 (t, J=5.2 Hz, 1H), 4.80 (d, J=5.5 Hz, 2H), 4.07 (s, 3H), 3.93 (s, 3H). LC-MS: method C, RT=2.20 min, MS (ESI) m/z: 388.90 (M+H)+. Analytical HPLC purity (method B): 95%.
    • Example 125 (8-(6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00716
    • Intermediate 125A 2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-fluorobenzofuran-5-ol
  • Figure US20190292176A1-20190926-C00717
  • To Intermediate I-27 (90 mg, 0.209 mmol), Intermediate 123A (58.1 mg, 0.209 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (8.54 mg, 10.45 μmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.209 mL, 2M, 0.418 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The crude reaction mixture was directly loaded onto a 40 g ISCO column which was eluted with 0-50% EtOAc in hexanes for 20 min. The desired fractions were combined and concentrated to yield Intermediate 125A (105 mg, 0.185 mmol, 88% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.00 (d, J=0.9 Hz, 1H), 7.82-7.77 (m, 1H), 7.31 (dd, J=10.0, 0.8 Hz, 1H), 7.25-7.22 (m, 1H), 5.00 (s, 2H), 4.14 (s, 3H), 1.02 (d, J=5.7 Hz, 9H), 0.19 (s, 6H). LC-MS: method C, RT=2.97 min, MS (ESI) m/z: 455 (M+H)+.
    • Example 125
  • To a solution of Intermediate 125A (14 mg, 0.031 mmol) in DMF (1 mL) was added Cs2CO3 (30.1 mg, 0.092 mmol) and MeI (9.63 μl, 0.154 mmol). The mixture was stirred at room temperature for 2 h. LCMS indicated a completion of the reaction. The mixture was loaded to 12 g ISCO column which was eluted with 0-50% EtOAc in hexanes for 15 min. The desired fraction was combined and concentrated to give 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxyquinoxaline as a light yellow solid. The intermediate was dissolved in THF (2 ml), and TBAF (0.062 mL, 0.062 mmol) was added. The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. Solvent was removed, the residual was purified via preparative LC/MS (method D, 35-75% B over 15 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 125 (3.3 mg, 9.13 μmol, 29.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.70 (d, J=11.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 5.57 (t, J=5.8 Hz, 1H), 4.78 (d, J=5.5 Hz, 2H), 4.08 (s, 3H), 3.90 (s, 3H). LC-MS: method C, RT=1.95 min, MS (ESI) m/z: 355.15 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 126 2-((6-fluoro-2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl (2-methylpyridin-4-yl)carbamate
  • Figure US20190292176A1-20190926-C00718
    • Intermediate 126A 2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-fluorobenzofuran-5-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00719
  • To a solution of Intermediate 125A (90 mg, 0.158 mmol) in DMF (2 mL) was added Cs2CO3 (155 mg, 0.475 mmol) and 2-bromoethyl acetate (0.035 mL, 0.317 mmol). The mixture was stirred at room temperature overnight. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude sample was dissolved in THF (2 ml) and NaOMe (0.109 mL, 4.37M, 0.475 mmol) was added. The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The mixture was diluted with EtOAc and saturate NH4Cl, extracted with EtOAc. The combined organic layer was washed with NaHCO3, brine, dried over MgSO4 and concentrated. The crude sample was dissolved in a small amount of DMF, loaded on a 40 g ISCO column, eluted with 0-100% EtOAc in hexanes for 20 min. The desired fraction was collected and concentrated to give Intermediate 126A (47 mg, 0.075 mmol, 47.6% yield). 1H NMR (400 MHz, chloroform-d) δ 8.53 (s, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.01 (d, J=0.7 Hz, 1H), 7.83-7.76 (m, 1H), 7.32 (dd, J=10.5, 0.8 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 5.00 (s, 2H), 4.23-4.16 (m, 2H), 4.14 (s, 3H), 4.01 (dt, J=8.9, 4.3 Hz, 2H), 1.05-1.01 (m, 9H), 0.19 (s, 6H). LC-MS: method C, RT=2.98 min, MS (ESI) m/z: 499 (M+H)+.
    • Intermediate 126B 2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-fluorobenzofuran-5-yloxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C00720
  • To the solution of Intermediate 126A (47 mg, 0.075 mmol) and DIEA (0.066 ml, 0.377 mmol) in THF (1 mL) was added to 15% phosgene in toluene (0.160 ml, 0.226 mmol). The mixture was stirred at room temperature for 3 h. Solvent was removed under vacuum to give Intermediate 126B as a yellow solid. It was used for the next step without any purification. LC-MS: method C, RT=3.46 min, MS (ESI) m/z: 561 (M+H)+.
    • Example 126
  • To a solution of Intermediate 126B (10 mg, 0.018 mmol) in THF (1 mL) was added 2-methylpyridin-4-amine (5.78 mg, 0.053 mmol) in DCM (0.5 mL) followed by DIEA (0.031 mL, 0.178 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. TBAF (0.071 mL, 0.071 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of a small amount of MeOH/water/0.1% TFA (HPLC solvent). Solvent was removed under vacuum. The residual was dissolved in DMSO and purified via preparative LC/MS (method D, 30-70% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 126 (2.3 mg, 4.26 μmol, 23.89% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.70 (s, 1H), 8.28 (d, J=5.8 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 7.73 (d, J=10.7 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.37 (s, 1H), 7.33 (d, J=5.5 Hz, 1H), 5.57 (s, 1H), 4.78 (d, J=5.0 Hz, 2H), 4.57-4.45 (m, 2H), 4.42-4.32 (m, 2H), 4.07 (s, 3H), 2.41 (s, 3H). LC-MS: method C, RT=1.48 min, MS (ESI) m/z: 519.20 (M+H)+. Analytical HPLC purity (method B): 96%.
    • Example 127 3-methoxy-8-(6-methoxybenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00721
  • To Intermediate I-27 (10.6 mg, 0.025 mmol), 2-bromo-6-methoxybenzo[d]thiazole (6.01 mg, 0.025 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (1.006 mg, 1.231 μmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.025 mL, 2M, 0.049 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 30 min. The crude reaction mixture was directly loaded on a 12 g ISCO column, eluted with 0-50% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to yield 2-(7-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxyquinoxalin-5-yl)-6-methoxybenzo[d]thiazole. LC-MS: method C, RT=3.4 min, MS (ESI) m/z: 468 (M+H)+. The sample was redissolved in THF (1 ml) and TBAF (0.074 mL, 0.074 mmol) was added. The mixture was stirred at room temperature for 30 min. LCMS indicated a completion of the reaction. The mixture was concentrated and purified via preparative LC/MS (method C, 30-70% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 127 (1.4 mg, 3.80 μmol, 15.44% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.72 (s, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.91 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.16 (dd, J=9.0, 2.3 Hz, 1H), 4.82 (d, J=5.5 Hz, 2H), 4.09 (s, 3H). LC-MS: method C, RT=1.82 min, MS (ESI) m/z: 345.10 (M+H)+. Analytical HPLC purity (method B): 100%.
    • Example 128 2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 6-methylpyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C00722
    • Intermediate 128A: 2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00723
  • To a suspension of Intermediate 89B (500 mg, 2.504 mmol) in DMF (10 mL) was added cesium carbonate (1.63 g, 5.01 mmol). Then 2-bromoethyl acetate (0.331 mL, 3.01 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. LCMS indicated a completion of the reaction. NaOH (2.504 mL, 2M, 5.01 mmol) was added to the reaction mixture, followed by MeOH (1 ml). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc, the combined organic layer was washed with brine, dried with MgSO4 and concentrated. The crude sample was purified with a 40 g ISCO column eluted with 0-100% EtOAc in hexane for 20 min. The desired fraction was collected and concentrated to give Intermediate 128A (600 mg, 2.462 mmol, 98% yield). 1H NMR (400 MHz, chloroform-d) δ 7.09 (d, J=2.2 Hz, 1H), 6.97-6.85 (m, 1H), 4.24-4.09 (m, 2H), 4.00 (d, J=3.7 Hz, 2H), 2.66 (s, 3H). LC-MS: method C, RT=1.82 min, MS (ESI) m/z: 244 (M+H)+.
    • Intermediate 128B 2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanol
  • Figure US20190292176A1-20190926-C00724
  • To Intermediate 124E (50 mg, 0.116 mmol), Intermediate 128A (28.3 mg, 0.116 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (4.74 mg, 5.81 μmol) was added toluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushed with argon. To this was added sodium carbonate (0.116 mL, 2M, 0.232 mmol). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. The crude reaction mixture was directly loaded to 12 g ISCO column eluted with 0% to 100% EtOAc in hexanes over 15 min. The desired fractions were combined and concentrated to yield Intermediate 128B (80 mg, 0.109 mmol, 94% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.80 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 7.94-7.90 (m, 1H), 7.27 (s, 1H), 6.96 (dd, J=2.4, 0.9 Hz, 1H), 5.05 (s, 2H), 4.20-4.16 (m, 2H), 4.15 (s, 3H), 4.05-3.98 (m, 2H), 2.82 (s, 3H), 1.04 (s, 9H), 0.21-0.20 (m, 6H). LC-MS: method C, RT=3.07 min, MS (ESI) m/z: 512 (M+H)+.
    • Intermediate 128C 2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C00725
  • To a solution of Intermediate 128B (110 mg, 0.193 mmol) and DIEA (0.169 ml, 0.967 mmol) in THF (2 ml) was added 15% phosgene in toluene (0.409 ml, 0.580 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated to give Intermediate 128C which was used for next step without purification. LC-MS: method C, RT=3.64 min, MS (ESI) m/z: 574 (M+H)+.
    • Intermediate 128D 2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 6-methylpyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C00726
  • To a solution of Intermediate 128C (16.5 mg, 0.029 mmol) in DCM (1 mL) was added 6-methylpyridin-3-amine (9.32 mg, 0.086 mmol) in DCM (0.5 mL) and DIEA (0.050 mL, 0.287 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was loaded to a 12 g ISCO column, eluted with 0-100% EtOAc in hexane for 15 min. The desired fraction was collected and concentrated to give Intermediate 128D (18 mg, 0.028 mmol, 97% yield). 1H NMR (400 MHz, chloroform-d) δ 8.81 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.92-7.90 (m, 1H), 7.85 (br. s., 1H), 7.26 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.97 (dd, J=2.4, 0.9 Hz, 1H), 6.82-6.69 (m, 1H), 5.05 (s, 2H), 4.62-4.54 (m, 2H), 4.34-4.28 (m, 2H), 4.15 (s, 3H), 2.82 (s, 3H), 2.52 (s, 3H), 1.07-1.01 (m, 9H), 0.22-0.18 (m, 6H). LC-MS: method C, RT=2.48 min, MS (ESI) m/z: 646 (M+H)+.
    • Example 128
  • To a solution of Intermediate 128D (18 mg, 0.028 mmol) in DCM (1 mL) was added TBAF (0.139 mL, 0.139 mmol), the mixture was stirred at room temperature for 1 h. Solvent was removed, the residual was dissolved in DMSO and purified via preparative LC/MS (method D, 30-70% B over 20 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 128 (3.0 mg, 5.53 μmol, 19.84% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.73 (s, 1H), 8.71 (br. s., 1H), 8.55 (br. s., 1H), 7.92 (d, J=15.3 Hz, 1H), 7.86 (br. s., 1H), 7.55 (br. s., 1H), 7.32 (br. s., 1H), 7.02 (br. s., 1H), 4.81 (br. s., 2H), 4.48 (br. s., 2H), 4.33 (br. s., 2H), 4.08 (s, 3H), 2.88 (s, 3H), 2.43 (br. s., 3H). LC-MS: method C, RT=1.49 min, MS (ESI) m/z: 532.20 (M+H)+. Analytical HPLC purity (method B): 98%.
    • Example 129 2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 2-methylpyridin-4-ylcarbamate
  • Figure US20190292176A1-20190926-C00727
    • Intermediate 129A 2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl 2-methylpyridin-4-ylcarbamate
  • Figure US20190292176A1-20190926-C00728
  • To a solution of Intermediate 128C (16.5 mg, 0.029 mmol) in DCM (1 mL) was added 2-methylpyridin-4-amine (9.32 mg, 0.086 mmol) in DCM (0.5 mL) and DIEA (0.050 mL, 0.287 mmol). The mixture was stirred at room temperature for 1 h. LCMS indicated a completion of reaction. The reaction mixture was loaded to a 12 g ISCO column, eluted with 0-100% EtOAc in hexanes for 15 min. The desired fraction was collected and concentrated to give Intermediate 129A (17 mg, 0.026 mmol, 92% yield). 1H NMR (400 MHz, chloroform-d) δ 8.81 (d, J=2.0 Hz, 1H), 8.59 (s, 1H), 8.37 (d, J=4.2 Hz, 1H), 7.94-7.90 (m, 1H), 7.29-7.22 (m, 1H), 7.14 (d, J=4.2 Hz, 1H), 6.97 (dd, J=2.4, 0.9 Hz, 1H), 6.87 (br. s., 1H), 5.05 (s, 2H), 4.64-4.56 (m, 2H), 4.35-4.29 (m, 2H), 4.15 (s, 3H), 2.82 (s, 3H), 2.53 (s, 3H), 1.06-1.01 (m, 10H), 0.23-0.18 (m, 6H). LC-MS: method C, RT=2.46 min, MS (ESI) m/z: 646 (M+H)+.
    • Example 129
  • To a solution of Intermediate 129A (17 mg, 0.026 mmol) in DCM (1 mL) was added TBAF (0.132 mL, 0.132 mmol), the mixture was stirred at room temperature for 1 h. Solvent was removed and the residual was dissolved in DMSO and purified via preparative LC/MS (method D, 30-70% B over 25 min., then a 5-min hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 129 (2.9 mg, 5.40 μmol, 20.52% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=9.2 Hz, 2H), 8.25 (br. s., 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.31 (d, J=16.2 Hz, 2H), 7.01 (s, 1H), 4.81 (d, J=4.3 Hz, 2H), 4.50 (br. s., 2H), LC-MS: method C, RT=1.55 min, MS (ESI) m/z: 532.20 (M+H)+. Analytical HPLC purity (method B): 99%.
    • Example 130 5-(benzofuran-2-yl)-2-methoxy-7-methyl-1,6-naphthyridine
  • Figure US20190292176A1-20190926-C00729
    • Intermediate 130A: (E)-2-(2-(dimethylamino)prop-1-en-1-yl)-6-methoxynicotinonitrile
  • Figure US20190292176A1-20190926-C00730
  • 6-methoxy-2-methylnicotinonitrile (200 mg, 1.350 mmol) was dissolved in DMF (1350 μL) and N,N-dimethylacetamide dimethyl acetal (987 μL, 6.75 mmol) and heated to 150° C. for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 130A (177.9 mg, 0.819 mmol, 60.7%) as a yellow solid: LC-MS: Ketone product mass observed, Method H, RT=0.72 min, MS (ESI) m/z: 191.2 (M+H)+.
    • Intermediate 130B: 2-methoxy-7-methyl-1,6-naphthyridin-5-ol
  • Figure US20190292176A1-20190926-C00731
  • Intermediate 130A (178 mg, 0.819 mmol) was dissolved in CHCl3 (6145 μL), AcOH (1024 μL), and HBr (1024 μL) and stirred for 18 hours. The reaction mixture was diluted with 1 N NaOH and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 130B (51.6 mg, 0.271, 33.1%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ 8.34 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.44 (br. s., 1H), 4.02 (d, J=2.8 Hz, 3H), 2.33 (s, 3H); LC-MS: Method H, RT=0.7 min, MS (ESI) m/z: 191.2 (M+H)+.
    • Intermediate 130C: 2-methoxy-7-methyl-1,6-naphthyridin-5-yl trifluoromethanesulfonate
  • Figure US20190292176A1-20190926-C00732
  • Intermediate 130B (0.0516 g, 0.271 mmol), pyridine (0.055 mL, 0.678 mmol), and DIEA (0.104 mL, 0.597 mmol) were dissolved in DCM (13.56 mL). Triflic anhydride (0.092 mL, 0.543 mmol) was added and the reaction mixture stirred for 1.5 hours. The reaction mixture was concentrated in vacuo. 2D TLC was used to determine if the triflate product was unstable to silica gel and there was a slight bit of decomposition observed. Therefore, the reaction mixture was filtered through a pad of silica gel in a fritted funnel with rapid DCM elution and concentrated in vacuo to give Intermediate 130C (77.5 mg, 0.240 mmol, 89%) as a red oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (d, J=9.0 Hz, 1H), 7.52 (s, 1H), 7.00 (d, J=9.0 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H); LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 323.0 (M+H)+.
    • Example 130
  • Intermediate 130C (30 mg, 0.093 mmol) and benzofuran-2-ylboronic acid (22.61 mg, 0.140 mmol) were dissolved in toluene (698 μL) and EtOH (233 μL). PdCl2(dppf)-CH2Cl2 (4.56 mg, 5.59 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 55.9 μL, 0.112 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was purified by preparative HPLC (Method D, 30 to 80% B in 10 minutes) to give Example 130 (9.8 mg, 0.033 mmol, 35.2%): 1H NMR (500 MHz, METHANOL-d4) δ 8.95 (d, J=9.4 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.35-7.29 (m, 1H), 7.02 (d, J=9.4 Hz, 1H), 4.11 (s, 3H), 2.73 (s, 3H); LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 291.2 (M+H)+. Analytical HPLC Method B: 97.2% purity.
    • Example 131 5-(benzofuran-2-yl)-7-methyl-2-vinylquinoxaline
  • Figure US20190292176A1-20190926-C00733
    • Intermediate 131A: 2-(benzyloxy)-5-iodo-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00734
  • Intermediate I-14 (200 mg, 0.699 mmol) was suspended in toluene (4661 μL). Silver oxide (405 mg, 1.748 mmol) then benzyl bromide (83 μL, 0.699 mmol) were added and the reaction mixture was stirred for 1 week. The reaction mixture was filtered to remove the silver salts and concentrated in vacuo. The material was purified by column chromatography (ISCO, 12 g silica gel column, 15 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 131A (78.8 mg, 0.209 mmol, 30%) as an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (s, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.64 (d, J=0.8 Hz, 1H), 7.52 (d, J=6.8 Hz, 2H), 7.45-7.32 (m, 3H), 5.54 (s, 2H), 2.52 (s, 3H); LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 377.0 (M+H)+.
    • Intermediate 131B: 5-(benzofuran-2-yl)-2-(benzyloxy)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00735
  • Intermediate 131A (78.8 mg, 0.209 mmol) and benzofuran-2-ylboronic acid (50.9 mg, 0.314 mmol) were dissolved in toluene (1571 μL) and EtOH (524 μL). PdCl2(dppf)-CH2Cl2 (10.26 mg, 0.013 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 126 μL, 0.251 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 131B (67.7 mg, 0.185 mmol, 88%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.69-7.63 (m, 2H), 7.58-7.53 (m, 3H), 7.45-7.40 (m, 2H), 7.39-7.28 (m, 3H), 5.56 (s, 2H), 2.63 (s, 3H); LC-MS: Method H, compound did not ionize.
    • Intermediate 131C: 5-(benzofuran-2-yl)-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00736
  • Intermediate 131B (67.7 mg, 0.185 mmol) was partially dissolved in MeOH (1848 μL) and EtOAc (1848 μL). Palladium on carbon (19.66 mg, 0.018 mmol) was added. The reaction mixture was purged with hydrogen for 5 minutes and sealed under a hydrogen balloon for 2.5 hours. The reaction mixture was diluted with EtOAc, filtered through a micron filter, and concentrated in vacuo to give Intermediate 131C, which was used directly in the subsequent step: LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 279.1 (M+H)+.
    • Intermediate 131D: 5-(benzofuran-2-yl)-7-methylquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00737
  • Intermediate 131C (51 mg, 0.183 mmol) was suspended in MeOH (533 μL). NaOH (550 μL, 0.550 mmol) then H2O2 (96 μL, 1.100 mmol) were added and the reaction mixture was stirred for 18 hours. More H2O2 (96 μL, 1.100 mmol) was added and the reaction mixture was stirred for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was further washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 131D (34.6 mg, 0.125 mmol, 68.3%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 10.41 (br. s., 1H), 8.40 (s, 1H), 7.98 (d, J=1.0 Hz, 1H), 7.92 (d, J=1.3 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.37-7.32 (m, 2H), 7.00 (s, 1H), 2.57 (s, 3H); LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 277.3 (M+H)+.
    • Intermediate 131E: 5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl trifluoromethanesulfonate
  • Figure US20190292176A1-20190926-C00738
  • Intermediate 131D (26 mg, 0.094 mmol), pyridine (19.03 μL, 0.235 mmol), and DIEA (36.2 μL, 0.207 mmol) were dissolved in DCM (4705 μL). Triflic anhydride (31.8 μL, 0.188 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo. The reaction mixture was filtered through a pad of silica gel in a fritted funnel with rapid DCM elution to give Intermediate 131E (24.8 mg, 0.061 mmol, 64.5%) as an orange solid: LC-MS: Method H, RT=1.28 min, MS (ESI) m/z: 409.0 (M+H)+.
    • Example 131
  • Intermediate 131E (24.8 mg, 0.061 mmol) and vinylboronic acid pinacol ester (21.09 μL, 0.121 mmol) were dissolved in toluene (455 μL) and EtOH (152 μL). PdCl2(dppf)-CH2Cl2 (2.98 mg, 3.64 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 36.4 μL, 0.073 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-75% B in 10 minutes) to give Example 131 (2.6 mg, 0.00874 mmol, 14%): 1H NMR (500 MHz, METHANOL-d4) δ 9.11 (s, 1H), 8.28 (d, J=1.7 Hz, 1H), 8.11 (s, 1H), 7.77 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.27-7.21 (m, 1H), 7.05 (dd, J=17.9, 11.0 Hz, 1H), 6.51 (d, J=17.9 Hz, 1H), 5.85 (d, J=11.3 Hz, 1H), 2.66 (s, 3H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 287.2 (M+H)+. Analytical HPLC Method B: 97.3% purity.
    • Example 132 5-(benzofuran-2-yl)-2-ethyl-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00739
  • Example 131 (1.4 mg, 4.89 μmol) (92793-013-01) was dissolved in MeOH (244 μL). Palladium on carbon (0.520 mg, 0.489 μmol) was added and the reaction mixture was sealed under an atmosphere of hydrogen for 30 minutes. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A, 30 to 100% B in 20 minutes; with a flow rate of 40 mL/min). The desired fractions were concentrated and lyophilized to give Example 132 (0.69 mg, 0.00235 mmol, 48.2% yield) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.87 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.15 (d, J=0.8 Hz, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.60-7.55 (m, 1H), 7.37-7.31 (m, 1H), 7.29-7.23 (m, 1H), 3.12 (q, J=7.7 Hz, 2H), 2.67 (s, 3H), 1.47 (t, J=7.7 Hz, 3H); LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 289.2 (M+H)+. Analytical HPLC Method A: 98.4% purity.
    • Example 133 5-(benzofuran-2-yl)-2-(difluoromethoxy)-8-methylquinoxaline
  • Figure US20190292176A1-20190926-C00740
    • Intermediate 133A: 6-bromo-3-methyl-2-nitroaniline
  • Figure US20190292176A1-20190926-C00741
  • 3-Methyl-2-nitroaniline (250 mg, 1.643 mmol) and NBS (292 mg, 1.643 mmol) were dissolved in AcOH (8216 μL) and heated to 120° C. for 4 hours. The reaction mixture was cooled to ambient temperature and diluted with H2O (50 mL). The material was extracted with EtOAc. The organic layer was washed twice with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 133A (302.8 mg, 1.311 mmol, 80%) as an orange solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.43 (d, J=9.0 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 4.77 (br. s., 2H), 2.47 (s, 3H); LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 231/233 (M+H)+.
    • Intermediate 133B: 3-bromo-6-methylbenzene-1,2-diamine
  • Figure US20190292176A1-20190926-C00742
  • Intermediate 133A (302.8 mg, 1.311 mmol) was dissolved in MeOH (8961 μL) and THF (1120 μL). Ammonium chloride (1402 mg, 26.2 mmol) and zinc (857 mg, 13.11 mmol) were added and the reaction mixture was heated to 40° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was redissolved in EtOAc/saturated Sodium carbonate and allowed to stir vigorously for 15 minutes. The mixture was filtered through a sintered glass funnel. The organic layer was washed twice with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 133B (257.8 mg, 1.282 mmol, 98%): 1H NMR (400 MHz, CHLOROFORM-d) δ 6.91 (d, J=8.2 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 3.53 (br. s., 2H), 3.29 (br. s., 2H), 2.30 (s, 3H); LC-MS: Method H, RT=0.54 min, MS (ESI) m/z: 201/203 (M+H)+.
    • Intermediate 133C: 3-(benzofuran-2-yl)-6-methylbenzene-1,2-diamine
  • Figure US20190292176A1-20190926-C00743
  • Intermediate 133B (257.8 mg, 1.282 mmol) and benzofuran-2-ylboronic acid (311 mg, 1.923 mmol) were dissolved in toluene (9616 μL) and EtOH (3205 μL). PdCl2(dppf)-CH2Cl2 (62.8 mg, 0.077 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 769 μL, 1.539 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 60 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 133C (237.8 mg, 0.998 mmol, 78%) as a brown oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.59-7.55 (m, 1H), 7.52-7.47 (m, 1H), 7.29-7.18 (m, 2H), 7.10 (d, J=8.3 Hz, 1H), 6.73-6.65 (m, 2H), 3.51 (br. s., 4H), 2.36 (s, 3H); LC-MS: Method H, The compound did not ionize.
    • Intermediate 133D: 5-(benzofuran-2-yl)-8-methylquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C00744
  • Intermediate 133C (237.8 mg, 0.998 mmol) was dissolved in EtOH (2697 μL). Ethyl glyoxalate solution (50 wt %, 297 μL, 1.497 mmol) was added and the reaction mixture was heated to 80° C. and allowed to stir overnight. The reaction mixture was cooled to ambient temperature and filtered to collect the solid precipitate, which was washed with EtOH and collected to give Intermediate 133D (63.8 mg, 0.231 mmol, 23.1%) as an off-white solid mixture of regioisomers. The material was used as-is for the subsequent step: LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 277.1 (M+H)+.
    • Example 133
  • Intermediate 133D (30 mg, 0.109 mmol) and K2CO3 (300 mg, 2.172 mmol) were dissolved in DMF (1086 μL) and heated to 100° C. for 5 min. Sodium 2-chloro-2,2-difluoroacetate (66.2 mg, 0.434 mmol) was added and the reaction mixture was heated for 2.5 hours. The reaction mixture was diluted with water and extracted thrice with DCM. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 60 to 90% B in 25 minutes) then repurified by preparative HPLC (Method D, 55-80% B in 15 minutes) to give Example 133 (1.4 mg, 0.00417 mmol, 3.84%): 1H NMR (500 MHz, METHANOL-d4) δ 8.62 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.91-7.59 (m, 3H), 7.36 (t, J=7.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 2.97 (s, 3H); LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 327.1 (M+H)+. Analytical HPLC Method B: 97.3% purity.
    • Example 134 8-(benzofuran-2-yl)-3-methoxy-6-methyl-1,7-naphthyridine\
  • Figure US20190292176A1-20190926-C00745
    • Intermediate 134A: 5-methoxy-3-methylpicolinonitrile
  • Figure US20190292176A1-20190926-C00746
  • 5-Hydroxy-3-methylpicolinonitrile (0.25 g, 1.864 mmol) was suspended in DMF (12.43 mL). Cesium carbonate (1.518 g, 4.66 mmol) then iodomethane (0.146 mL, 2.330 mmol) were added and stirred for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 134A (252.7 mg, 1.706 mmol, 92%) as a light brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J=2.5 Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 3.91 (s, 3H), 2.54 (s, 3H); LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: 149.2 (M+H)+.
    • Intermediate 134B: 5-methoxy-3-(2-oxopropyl)picolinonitrile
  • Figure US20190292176A1-20190926-C00747
  • Intermediate 134A (252.7 mg, 1.706 mmol) was dissolved in DMF (1706 μL) and N,N-dimethylacetamide dimethyl acetal (1247 μL, 8.53 mmol) and heated to 150° C. for 18 hours. More N,N-dimethylacetamide dimethylacetal (0.5 mL) was added and heating continued for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A, 20 to 100% B in 17 minutes) to give Intermediate 134B (81.8 mg, 0.430 mmol, 25.2%) as a brown oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (d, J=2.8 Hz, 1H), 7.11 (d, J=2.8 Hz, 1H), 3.98 (s, 2H), 3.92 (s, 3H), 2.35 (s, 3H); LC-MS: Method H, RT=0.64 min, MS (ESI) m/z: 191.2 (M+H)+.
    • Intermediate 134C: 3-methoxy-6-methyl-1,7-naphthyridin-8-ol
  • Figure US20190292176A1-20190926-C00748
  • Intermediate 134B (81.8 mg, 0.430 mmol) was dissolved in CHCl3 (3226 μL), AcOH (538 μL), and HBr (538 μL) at and stirred overnight. The reaction mixture was diluted with 1 N NaOH and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A, 20 to 100% B in 17 minutes) to give Intermediate 134C (7.6 mg, 0.040 mmol, 9.3%) as a brown solid: 1H NMR (400 MHz, METHANOL-d4) δ 8.34 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.44 (br. s., 1H), 4.02 (d, J=2.8 Hz, 3H), 2.33 (s, 3H); LC-MS: Method H, RT=0.55 min, MS (ESI) m/z: 191.2 (M+H)+.
    • Intermediate 134D: 3-methoxy-6-methyl-1,7-naphthyridin-8-yltrifluoromethanesulfonate
  • Figure US20190292176A1-20190926-C00749
  • Intermediate 134C (10.1 mg, 0.053 mmol), pyridine (21.47 μL, 0.266 mmol), and DIEA (20.40 μL, 0.117 mmol) were dissolved in DCM (2655 μL). Triflic anhydride (35.9 μL, 0.212 mmol) was added and the reaction mixture was stirred for 45 minutes. More triflic anhydride (35.9 μL, 0.212 mmol) was added and stirring continued for 30 minutes. The reaction mixture was filtered through a pad of silica gel in a fritted funnel with rapid DCM elution to give Intermediate 134D (11.8 mg, 0.037 mmol, 69%) as a red oil: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 323.0 (M+H)+.
    • Example 134
  • Intermediate 134D (11.8 mg, 0.037 mmol) and benzofuran-2-ylboronic acid (7.12 mg, 0.044 mmol) were dissolved in DMF (366 μL). PdCl2(dppf)-CH2Cl2 (1.794 mg, 2.197 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 21.97 μL, 0.044 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 0 to 40% B in 10 minutes) to give Example 134 (2.0 mg, 0.00675 mmol, 18.4%): 1H NMR (500 MHz, METHANOL-d4) δ 8.82 (d, J=2.8 Hz, 1H), 8.57 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=2.8 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.37-7.30 (m, 1H), 4.07 (s, 3H), 2.82 (s, 3H); LC-MS: Method H, RT=0.78 min, MS (ESI) m/z: 291.1 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Example 135 5-(benzofuran-2-yl)-2-(furan-3-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00750
    • Intermediate 135A: 5-bromo-7-methylquinoxalin-2-yl trifluoromethanesulfonate
  • Figure US20190292176A1-20190926-C00751
  • Intermediate I-1F (0.2 g, 0.837 mmol), pyridine (0.338 mL, 4.18 mmol), and DIEA (0.321 mL, 1.840 mmol) were dissolved in DCM (41.8 mL). Triflic anhydride (0.565 mL, 3.35 mmol) was added and the reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated in vacuo. The reaction mixture was filtered through a pad of silica gel in a fritted funnel with rapid DCM elution to give Intermediate 135A (137.3 mg, 0.370 mmol, 44.2%) as a red oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.78 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.83 (s, 1H), 2.62 (s, 3H); LC-MS: Method H, RT=1.10 min, The compound did not ionize.
    • Intermediate 135B: 5-bromo-2-(furan-3-yl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00752
  • Intermediate 135A (34.3 mg, 0.092 mmol) and furan-3-ylboronic acid (10.34 mg, 0.092 mmol) were dissolved in DMF (924 μL). PdCl2(dppf)-CH2Cl2 (4.53 mg, 5.55 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 55.5 μL, 0.111 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A, 20 to 100% B in 15 minutes), to give Intermediate 135B (2.9 mg, 0.010 mmol, 10.9%) as a brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 9.07 (s, 1H), 8.24 (s, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.83 (s, 1H), 7.59 (t, J=1.6 Hz, 1H), 7.15-7.11 (m, 1H), 2.58 (s, 3H); LC-MS: Method H, The compound did not ionize.
    • Example 135
  • Intermediate 135B (2.9 mg, 10.03 μmol) and benzofuran-2-ylboronic acid (2.437 mg, 0.015 mmol) were dissolved in toluene (752 μL) and EtOH (251 μL). PdCl2(dppf)-CH2Cl2 (0.491 mg, 0.602 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 6.02 μL, 0.012 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 55 to 90% B in 10 minutes) to give 135 (1.1 mg, 0.0032 mmol, 31.9%): 1H NMR (500 MHz, METHANOL-d4) δ 9.19 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.71-7.64 (m, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.28-7.23 (m, 1H), 7.20 (s, 1H), 2.67 (s, 3H); LC-MS: Method H, RT=1.28 min, MS (ESI) m/z: 327.1 (M+H)+. Analytical HPLC Method B: 95% purity.
    • Example 136 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole
  • Figure US20190292176A1-20190926-C00753
    • Intermediate 136A: 2-bromo-5,6-dihydro-4H-cyclopenta[d]thiazole
  • Figure US20190292176A1-20190926-C00754
  • 5,6-Dihydro-4H-cyclopenta[d]thiazol-2-amine, HCl (50 mg, 0.283 mmol) and isoamyl nitrite (41.9 μL, 0.311 mmol) were dissolved in MeCN (1132 μL). Copper(II) bromide (60.9 mg, 0.425 mmol) was added portionwise over 1 hour. After an additional hour, the reaction mixture was diluted with water and extracted with DCM. The DCM layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 136A, which was volatile and was used as-is for the next reaction: LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 204/206 (M+H)+.
    • Example 136
  • Intermediate I-1 (15 mg, 0.045 mmol) and Intermediate 136A (13.66 mg, 0.067 mmol) were dissolved in DMF (446 μL). PdCl2(dppf)-CH2Cl2 (2.187 mg, 2.68 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 26.8 μL, 0.054 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. More PdCl2(dppf)-CH2Cl2 (2.187 mg, 2.68 μmol) and Sodium carbonate (2 M, 26.8 μL, 0.054 mmol) were added and the reaction mixture was heated to 120° C. in the microwave for 30 minutes. The compound was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 80% B in 10 minutes) then repurified by preparative HPLC (Method D, 45 to 80% B in 20 minutes) to give Example 136 (1.4 mg, 0.00403 mmol, 9.0%): 1H NMR (500 MHz, METHANOL-d4) δ 8.64 (s, 1H), 8.42 (d, J=1.9 Hz, 1H), 7.83-7.51 (m, 2H), 3.03 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.63 (s, 3H), 2.62-2.53 (m, 2H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 333.9 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 137 2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazole
  • Figure US20190292176A1-20190926-C00755
  • Intermediate I-12 (10 mg, 0.043 mmol) and 2-chlorocycloheptanone (6.28 mg, 0.043 mmol) were dissolved in dioxane (857 μL) and heated to 80° C. for 18 hours. More 2-chlorocycloheptanone (6.28 mg, 0.043 mmol) was added and the reaction mixture was heated to 110° C. for 24 hours. The reaction mixture was concentrated in vacuo, diluted with DMF, filtered, and purified by preparative HPLC (Method D, 55 to 95% B in 10 minutes) to give Example 137 (2.9 mg, 0.00873 mmol, 20.4%): 1H NMR (500 MHz, METHANOL-d4) δ 8.48 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 7.66 (s, 1H), 4.11 (s, 3H), 3.08-3.01 (m, 2H), 2.95-2.89 (m, 2H), 2.60 (s, 3H), 1.98-1.87 (m, 2H), 1.83-1.71 (m, 4H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 326.1 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 138 2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00756
    • Intermediate 138A 2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydrobenzo[d]thiazol-7(4H)-one
  • Figure US20190292176A1-20190926-C00757
  • Intermediate I-12 (15 mg, 0.064 mmol) and 2-chlorocyclohexane-1,3-dione (18.85 mg, 0.129 mmol) were dissolved in 1,4-dioxane (1286 μL) and heated to 100° C. for 18 hours. The reaction mixture was concentrated in vacuo, diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 75% B in 10 minutes) to give Intermediate 138A (4.6 mg, 0.014 mmol, 21.6%): 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.53 (s, 1H), 7.86 (s, 1H), 4.08 (s, 3H), 3.10 (t, J=6.1 Hz, 2H), 2.67-2.58 (m, 5H), 2.24-2.15 (m, 2H); LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 326.1 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 138
  • Intermediate 138A (3.68 mg, 0.011 mmol) was dissolved in MeOH (565 μL) and cooled to 0° C. Sodium borohydride (0.642 mg, 0.017 mmol) was added and the reaction mixture was allowed to slowly warm to ambient temperature and stir for 20 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 25 to 65% B in 10 minutes) to give Example 138 (2.3 mg, 0.00703 mmol, 62.1%): 1H NMR (500 MHz, METHANOL-d4) δ 8.49 (s, 1H), 8.30 (d, J=1.7 Hz, 1H), 7.70 (d, J=0.8 Hz, 1H), 5.03 (br. s., 1H), 4.24 (br. s., 1H), 4.11 (s, 3H), 2.96-2.88 (m, 1H), 2.87-2.78 (m, 1H), 2.61 (s, 3H), 2.13 (d, J=9.9 Hz, 2H), 1.95-1.86 (m, 2H); LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 328.2 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 139 7-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00758
  • Example 138 (9.9 mg, 0.030 mmol) was dissolved in THF (605 μL). Sodium hydride (1.330 mg, 0.033 mmol) was added and the reaction mixture was stirred for 30 minutes. Iodomethane (3.78 μL, 0.060 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% B in 10 minutes) to give Example 139 (6.4 mg, 0.018 mmol, 60.8%): 1H NMR (500 MHz, METHANOL-d4) δ 8.51 (s, 1H), 8.33 (d, J=1.7 Hz, 1H), 7.71 (dd, J=1.9, 0.8 Hz, 1H), 7.62 (dd, J=3.0, 1.7 Hz, 1H), 4.12 (s, 3H), 3.54 (s, 3H), 3.00-2.90 (m, 1H), 2.87-2.78 (m, 1H), 2.61 (s, 3H), 2.16-2.00 (m, 3H), 1.96-1.86 (m, 1H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 342.2 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 140 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00759
    • Intermediate 140A: 4-((tert-butyldimethylsilyl)oxy)cyclohexanone
  • Figure US20190292176A1-20190926-C00760
  • 4-hydroxycyclohexanone (500 mg, 4.38 mmol), TBS-Cl (792 mg, 5.26 mmol), and imidazole (447 mg, 6.57 mmol) were dissolved in DCM (8761 μL) for 3 hours. The reaction mixture was diluted with DCM, washed with water, 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 140A as a light yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 4.09 (tt, J=5.1, 2.7 Hz, 1H), 2.69-2.56 (m, 2H), 2.24-2.14 (m, 2H), 1.99-1.77 (m, 4H), 0.88 (s, 9H), 0.06 (s, 6H).
    • Intermediate 140B 2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C00761
  • Intermediate 140A (9.79 mg, 0.043 mmol), magnesium chloride (4.08 mg, 0.043 mmol), and NBS (7.63 mg, 0.043 mmol) were dissolved in dioxane (429 μL) and heated to 70° C. for 1 hour. Intermediate I-12 (10 mg, 0.043 mmol) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was heated to 110° C. for 4 hours. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was dissolved in 90:10:0.1 MeOH:H2O:TFA (ca 1 mL) and allowed to stir overnight. The reaction mixture was concentrated in vacuo. The crude material was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 20 to 60% B in 10 minutes) to give Intermediate 140B (2.7 mg, 0.00825 mmol, 19.2%): 1H NMR (500 MHz, METHANOL-d4) δ 8.48 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 4.26-4.19 (m, 1H), 4.11 (s, 3H), 3.18 (dd, J=16.1, 4.8 Hz, 1H), 3.09-3.00 (m, 1H), 2.95-2.87 (m, 1H), 2.83 (dd, J=16.2, 7.2 Hz, 1H), 2.61 (s, 3H), 2.17-2.09 (m, 1H), 2.04-1.95 (m, 1H); LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 328.3 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 140
  • Intermediate 140B (1.78 mg, 5.44 μmol) was dissolved in THF (109 μL). Sodium hydride (0.239 mg, 5.98 μmol) was added and the reaction mixture was stirred for 30 minutes. Iodomethane (0.680 μL, 10.87 μmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% B in 10 minutes) to give Example 140 (0.9 mg, 0.00264 mmol, 48.5%): 1H NMR (500 MHz, METHANOL-d4) δ 8.48 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 4.11 (s, 3H), 3.88-3.82 (m, 1H), 3.20 (dd, J=16.4, 5.4 Hz, 1H), 3.06-2.97 (m, 1H), 2.94-2.86 (m, 2H), 2.61 (s, 3H), 2.18-2.03 (m, 2H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 342.2 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 141 2-(2-methoxy-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00762
  • 4,4-Dimethylcyclohexanone (6.49 mg, 0.051 mmol), magnesium chloride (4.08 mg, 0.043 mmol), and NBS (9.16 mg, 0.051 mmol) were dissolved in dioxane (429 μL) and heated to 70° C. for 1 hour. Intermediate I-12 (10 mg, 0.043 mmol) was added and the reaction mixture was heated to 110° C. for 18 hours. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 55 to 100% B in 10 minutes) to give Example 141 (3.3 mg, 0.00943 mmol, 22%): 1H NMR (500 MHz, METHANOL-d4) δ 8.48 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.68 (dd, J=1.9, 0.8 Hz, 1H), 4.11 (s, 3H), 2.88 (t, J=6.6 Hz, 2H), 2.66 (s, 2H), 2.61 (s, 3H), 1.72 (t, J=6.5 Hz, 2H), 1.08 (s, 6H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 340.0 (M+H)+; Analytical HPLC Method B: 97% purity.
    • Example 142 2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazol-5-yl) ethanol
  • Figure US20190292176A1-20190926-C00763
    • Intermediate 142A: 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopentanone
  • Figure US20190292176A1-20190926-C00764
  • 3-(2-hydroxyethyl)cyclopentanone (500 mg, 3.90 mmol), TBS-Cl (706 mg, 4.68 mmol), and imidazole (398 mg, 5.85 mmol) were dissolved in DCM (7802 μL) for 3.5 hours. The reaction mixture was diluted with DCM, washed with water, 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 142A as a light yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 3.63-3.52 (m, 2H), 2.35-2.26 (m, 1H), 2.25-2.13 (m, 2H), 2.12-1.99 (m, 2H), 1.73 (ddd, J=17.9, 10.0, 1.3 Hz, 1H), 1.65-1.40 (m, 3H), 0.80 (s, 9H), −0.05 (s, 6H).
    • Example 142
  • Intermediate 142A (18.71 mg, 0.077 mmol), magnesium chloride (6.12 mg, 0.064 mmol), and NBS (13.73 mg, 0.077 mmol) were dissolved in dioxane (643 μL) and heated to 70° C. for 1 hour. 2-Methoxy-7-methylquinoxaline-5-carbothioamide (15 mg, 0.064 mmol) was added and the reaction mixture was heated to 110° C. for 18 hours. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was dissolved in 90:10:0.1 MeOH:H2O:TFA (ca 1 mL) for 18 hours. The reaction mixture was concentrated in vacuo. The crude material was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 35 to 80% B in 10 minutes) to give Example 142 (2.9 mg, 0.00790 mmol, 12.3%): LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 342.0 (M+H)+; Analytical HPLC Method B: 93% purity.
    • Example 143 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00765
    • Intermediate 143A: 2-amino-5,6-dihydrobenzo[d]thiazol-7(4H)-one, HCl
  • Figure US20190292176A1-20190926-C00766
  • 2-chlorocyclohexane-1,3-dione (1 g, 6.82 mmol) and thiourea (0.519 g, 6.82 mmol) were dissolved in EtOH (13.65 mL) and heated to 80° C. for 3 days. The reaction mixture was cooled to ambient temperature and the solid collected by suction filtration, washing with EtOH to give Intermediate 143A (790 mg, 3.86 mmol, 56.6%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ 2.80 (t, J=6.2 Hz, 2H), 2.51 (dd, J=7.2, 5.8 Hz, 2H), 2.15 (quin, J=6.4 Hz, 2H); LC-MS: Method H, RT=0.63 min, MS (ESI) m/z: 169.0 (M+H)+.
    • Intermediate 143B: 2-bromo-5,6-dihydrobenzo[d]thiazol-7(4H)-one
  • Figure US20190292176A1-20190926-C00767
  • Copper(II) bromide (1.466 g, 6.56 mmol) and t-butyl nitrite (0.780 mL, 6.56 mmol) were dissolved in MeCN (15.44 mL) and allowed to stir 10 minutes. Intermediate 143A (0.79 g, 3.86 mmol) was dissolved in MeCN (23.16 mL) and the copper solution was added and the reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed twice with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 143B (817.9 mg, 3.52 mmol, 91%) as an orange solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 3.07 (t, J=6.2 Hz, 2H), 2.64 (dd, 5.7 Hz, 2H), 2.24 (quin, J=6.4 Hz, 2H); LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 232/234 (M+H)+.
    • Intermediate 143C: 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00768
  • Intermediate 143B (500 mg, 2.154 mmol) was dissolved in MeOH (10.8 mL) and cooled to 0° C. Sodium borohydride (163 mg, 4.31 mmol) was added and stirred for 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 143C (488 mg, 2.084 mmol, 97%) as an orange oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 4.93 (br. s., 1H), 2.89-2.79 (m, 1H), 2.79-2.69 (m, 1H), 2.17-2.07 (m, 1H), 2.06-1.98 (m, 1H), 1.92-1.80 (m, 2H); LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 234/236 (M+H)+.
    • Example 143
  • Intermediate I-2 was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 20% MeOH in DCM) to give dimethyl (2-(methoxymethyl)-7-methylquinoxalin-5-yl)boronate (25 mg, 0.096 mmol), Intermediate 143C (27.0 mg, 0.115 mmol), and potassium phosphate tribasic (40.8 mg, 0.192 mmol) were dissolved in DMF (961 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (11.11 mg, 9.61 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. at for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 20 to 60% B in 20 minutes) to give Example 143 (5.4 mg, 0.015 mmol, 15.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H), 5.56 (d, J=6.3 Hz, 1H), 4.92 (br. s., 1H), 4.80 (s, 2H), 3.47 (s, 3H), 2.87-2.73 (m, 2H), 2.65 (s, 3H), 2.07-1.99 (m, 2H), 1.84-1.70 (m, 2H); LC-MS: Method H, RT=1.02 min, MS (ESI) m/z: 342.2 (M+H)+; Analytical HPLC Method B: 92% purity.
    • Example 144 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00769
    • Intermediate 144A: 2-(tributylstannyl)-4,5,6,7-tetrahydrobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00770
  • 2-Bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (25 mg, 0.115 mmol) was dissolved in Et2O (458 μL) and cooled to −78° C. BuLi (60.0 μL, 0.126 mmol) was added and the reaction mixture was stirred for 30 minutes. Tributylchlorostannane (31.1 μL, 0.115 mmol) was added and stirred for 40 minutes. The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude material was suspended in hexanes and filtered through dry celite. The residue was concentrated in vacuo to give Intermediate 144A, which was used directly in the subsequent reaction.
    • Example 144
  • Intermediate I-2E (15 mg, 0.056 mmol), Intermediate 144A (30.1 mg, 0.070 mmol), and potassium acetate (11.02 mg, 0.112 mmol) were dissolved in dioxane (814 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (3.24 mg, 2.81 μmol) was added and the reaction mixture was sealed and heated to 120° C. in the microwave for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, 1 N HCl, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% B in 20 minutes) and repurified by preparative HPLC (Method D, 50 to 85% B in 20 minutes) to give Example 144 (1.9 mg, 0.00584 mmol, 10.4%): 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.59 (s, 1H), 7.92 (s, 1H), 4.79 (s, 2H), 3.46 (s, 3H), 2.88 (br. s., 2H), 2.82 (br. s., 2H), 2.64 (s, 3H), 1.87 (br. s., 4H); LC-MS: Method H, RT=1.23 min, MS (ESI) m/z: 326.3 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 145 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00771
    • Intermediate 145A: 2-amino-6,6-dimethyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one, HCl
  • Figure US20190292176A1-20190926-C00772
  • 2-bromo-4,4-dimethylcyclohexane-1,3-dione (0.5 g, 2.282 mmol) and thiourea (0.174 g, 2.282 mmol) were dissolved in EtOH (4.56 mL) and heated to 75° C. for 18 hours. The reaction mixture was cooled to ambient temperature then to 0° C. and the solid was collected by suction filtration, washing with cold EtOH to give Intermediate 145A (128.3 mg, 0.551 mmol, 24.2%) as an off-white solid: 1H NMR (400 MHz, METHANOL-d4) δ 2.90 (t, J=6.2 Hz, 2H), 2.08 (t, J=6.2 Hz, 2H), 1.20 (s, 6H); LC-MS: Method H, RT=0.85 min, MS (ESI) m/z: 197.1 (M+H)+.
    • Intermediate 145B: 2-bromo-6,6-dimethyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one
  • Figure US20190292176A1-20190926-C00773
  • Copper(II) bromide (248 mg, 1.111 mmol) and t-butyl nitrite (132 μL, 1.111 mmol) were dissolved in MeCN (2615 μL) and allowed to stir 10 minutes. Intermediate 145A (128.3 mg, 0.654 mmol) was dissolved in MeCN (3922 μL) and the copper solution was added and stirring continued for 1.5 hours. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 145B (110 mg, 0.423 mmol, 64.7%): 1H NMR (400 MHz, CHLOROFORM-d) δ 3.08 (t, J=6.2 Hz, 2H), 2.06 (t, J=6.2 Hz, 2H), 1.25 (s, 6H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 260/262 (M+H)+.
    • Intermediate 145C: 2-bromo-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol
  • Figure US20190292176A1-20190926-C00774
  • Intermediate 145B (110 mg, 0.423 mmol) was dissolved in MeOH (2114 μL) and cooled to 0° C. Sodium borohydride (32.0 mg, 0.846 mmol) was added and the reaction mixture stirred for 40 minutes. The reaction mixture was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 145C (107 mg, 0.408 mmol, 97%) as a yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 4.45 (d, J=6.4 Hz, 1H), 2.88-2.68 (m, 2H), 1.93 (d, J=7.5 Hz, 1H), 1.82 (dt, J=13.8, 5.9 Hz, 1H), 1.70-1.63 (m, 1H), 1.07 (s, 3H), 1.02 (s, 3H); LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 263.9 (M+H)+.
    • Example 145
  • Intermediate I-2 was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 20% MeOH in DCM) to give dimethyl (2-(methoxymethyl)-7-methylquinoxalin-5-yl)boronate (20 mg, 0.077 mmol), Intermediate 145C (24.19 mg, 0.092 mmol), and potassium phosphate tribasic (32.6 mg, 0.154 mmol) were dissolved in DMF (7694) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (8.89 mg, 7.69 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% B in 20 minutes) to give Example 145 (5.6 mg, 0.015 mmol, 18.9%): 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.60 (d, J=1.4 Hz, 1H), 7.94 (s, 1H), 5.58 (d, J=6.9 Hz, 1H), 4.80 (s, 2H), 4.48 (d, J=6.3 Hz, 1H), 3.47 (s, 3H), 2.82-2.74 (m, 2H), 2.65 (s, 3H), 1.86-1.78 (m, 1H), 1.70-1.62 (m, 1H), 1.03 (s, 3H), 0.91 (s, 3H); LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 370.1 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 146 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine
  • Figure US20190292176A1-20190926-C00775
    • Intermediate 146A: 2-bromothiazolo[4,5-c]pyridine
  • Figure US20190292176A1-20190926-C00776
  • Copper(II) bromide (71.6 mg, 0.320 mmol) and t-butyl nitrite (38.1 μL, 0.320 mmol) were dissolved in MeCN (754 μL) and allowed to stir 10 minutes. Thiazolo[4,5-c]pyridin-2-amine, TFA (50 mg, 0.189 mmol) was dissolved in MeCN (1131 μL) and the copper solution was added and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 146A (12.5 mg, 0.058 mmol, 30.8%) as a brown solid: LC-MS: Method H, RT=0.68 min, MS (ESI) m/z: 215/217 (M+H)+.
    • Example 146
  • Intermediate I-2 (10 mg, 0.032 mmol) and Intermediate 146A (10.27 mg, 0.048 mmol) were dissolved in DMF (318 μL). PdCl2(dppf)-CH2Cl2 (1.560 mg, 1.910 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 19.10 μL, 0.038 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 25 to 65% B in 20 minutes) to give Example 146 (3.0 mg, 0.00893 mmol, 28.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.43 (br. s., 1H), 9.14 (br. s., 1H), 8.92 (br. s., 1H), 8.57 (br. s., 1H), 8.30 (br. s., 1H), 8.14 (br. s., 1H), 4.84 (br. s., 2H), 3.49 (br. s., 3H), 2.72 (br. s., 3H); LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 323.3 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 147 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00777
    • Intermediate 147A: 2-bromo-5-methoxythiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00778
  • Copper(II) bromide (64.3 mg, 0.288 mmol) and t-butyl nitrite (34.2 μL, 0.288 mmol) were dissolved in MeCN (677 μL) and allowed to stir 10 minutes. 5-methoxythiazolo[5,4-b]pyridin-2-amine, TFA (50 mg, 0.169 mmol) was dissolved in MeCN (1016 μL) and the copper solution was added and the reaction mixture was stirred for 1.5 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 147A as a tan solid: 1H NMR (500 MHz, CHLOROFORM-d) δ 8.08 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 4.02 (s, 3H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 245/247 (M+H)+.
    • Example 147
  • Intermediate I-2 (10 mg, 0.032 mmol) and Intermediate 147A (11.70 mg, 0.048 mmol) were dissolved in DMF (318 μL). PdCl2(dppf)-CH2Cl2 (1.560 mg, 1.910 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 19.10 μL, 0.038 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45 to 85% B in 20 minutes) to give Example 147 (3.1 mg, 0.00862 mmol, 27.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.14 (br. s., 1H), 8.81 (br. s., 1H), 8.43 (d, J=8.0 Hz, 1H), 8.08 (br. s., 1H), 7.08 (d, J=8.8 Hz, 1H), 4.84 (br. s., 2H), 4.02 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s., 3H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 353.2 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 148 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00779
  • Intermediate I-2 (10 mg, 0.032 mmol) and 2-bromothiazolo[5,4-b]pyridine (10.27 mg, 0.048 mmol) (10.27 mg, 0.048 mmol) were dissolved in DMF (318 μL). PdCl2(dppf)-CH2Cl2 (1.560 mg, 1.910 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 19.10 μL, 0.038 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 30 to 70% B in 20 minutes) to give Example 148 (3.0 mg, 0.00893 mmol, 28.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.17 (br. s., 1H), 8.89 (br. s., 1H), 8.70 (br. s., 1H), 8.54 (d, J=8.3 Hz, 1H), 8.14 (br. s., 1H), 7.66 (br. s., 1H), 4.84 (br. s., 2H), 3.49 (br. s., 3H), 2.72 (br. s., 3H); LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 323.2 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 149 7-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine
  • Figure US20190292176A1-20190926-C00780
  • Intermediate I-2 (10 mg, 0.032 mmol) and 2-bromo-7-chlorothiazolo[5,4-c]pyridine (11.91 mg, 0.048 mmol) were dissolved in DMF (318 μL). PdCl2(dppf)-CH2Cl2 (1.560 mg, 1.910 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 19.10 μL, 0.038 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45 to 85% B in 12 minutes) to give Example 149 (3.1 mg, 0.00834 mmol, 26.2%): 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.17 (s, 1H), 8.96 (d, J=1.9 Hz, 1H), 8.75 (s, 1H), 8.21 (s, 1H), 4.86 (s, 2H), 3.49 (s, 3H), 2.75 (s, 3H); LC-MS: Method H, RT=1.28 min, MS (ESI) m/z: 357.1 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 150 5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00781
  • Intermediate I-9 (10 mg, 0.033 mmol), 2-bromo-5-methoxythiazolo[5,4-b]pyridine (9.80 mg, 0.040 mmol), and potassium phosphate tribasic (14.14 mg, 0.067 mmol) were dissolved in DMF (333 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (3.85 mg, 3.33 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 60 to 100% B in 20 minutes) to give Example 150 (1.1 mg, 0.00325 mmol, 9.8%): LC-MS: Method H, RT=1.50 min, MS (ESI) m/z: 339.1 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 151 7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine
  • Figure US20190292176A1-20190926-C00782
  • Intermediate I-9 (10 mg, 0.033 mmol), 2-bromo-7-chlorothiazolo[5,4-c]pyridine (9.98 mg, 0.040 mmol), and potassium phosphate tribasic (14.14 mg, 0.067 mmol) were dissolved in DMF (333 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (3.85 mg, 3.33 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 24 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 50 to 100% B in 20 minutes) then repurified by preparative (Method D, 45 to 85% B in 20 minutes) to give Example 151 (0.9 mg, 0.00252 mmol, 7.6%): 1H NMR (500 MHz, CHLOROFORM-d) δ 9.17 (br. s., 1H), 8.88 (br. s., 1H), 8.68 (br. s., 1H), 8.62 (br. s., 1H), 7.89 (br. s., 1H), 4.18 (br. s., 3H), 2.73 (br. s., 3H); LC-MS: Method H, RT=1.40 min, MS (ESI) m/z: 343.1 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 152 methyl 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00783
  • Intermediate I-9 (99 mg, 0.331 mmol), Intermediate I-20C (100 mg, 0.331 mmol), and potassium phosphate tribasic (141 mg, 0.662 mmol) were dissolved in DMF (3310 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (38.2 mg, 0.033 mmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with water and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 60 to 100% B in 15 minutes) to give Example 152 (2.7 mg, 0.00676 mmol, 2%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 8.77 (br. s., 1H), 8.61 (br. s., 1H), 8.04 (br. s., 1H), 7.87 (br. s., 1H), 7.57 (br. s., 1H), 4.10 (br. s., 3H), 4.01 (br. s., 3H), 3.93 (br. s., 3H), 2.67 (br. s., 3H); LC-MS: Method H, RT=1.40 min, MS (ESI) m/z: 396.1 (M+H)+; Analytical HPLC Method B: 99% purity.
    • Example 153 6-methoxy-2-(3-(methoxymethyl)-6-methyl-1,7-naphthyridin-8-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00784
    • Intermediate 153A: 2-nitroacetamide
  • Figure US20190292176A1-20190926-C00785
  • Ethyl 2-nitroacetate (1 g, 7.51 mmol) was dissolved in NH3 in MeOH (7 M, 16.10 mL, 113 mmol) and heated to 65° C. in a sealed tube at for 5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give Intermediate 153A, which was used directly in the subsequent reaction.
    • Intermediate 153B: ethyl 6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-4-carboxylate
  • Figure US20190292176A1-20190926-C00786
  • Intermediate 153A (782 mg, 7.51 mmol), ethyl 2,4-dioxovalerate (1161 μL, 8.27 mmol), and piperidinium acetate (1091 mg, 7.51 mmol) were dissolved in water (37.6 mL) and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The crude material was dissolved in DCM, filtered and purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 20% MeOH in DCM) to give Intermediate 153B (890 mg, 3.93 mmol, 52.4%) as an orange solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 6.49 (d, J=0.7 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 2.49 (d, J=0.7 Hz, 3H), 1.38 (t, J=7.2 Hz, 3H); LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 227.2 (M+H)+.
    • Intermediate 153C: ethyl 2-(benzyloxy)-6-methyl-3-nitroisonicotinate
  • Figure US20190292176A1-20190926-C00787
  • Intermediate 153B (400 mg, 1.768 mmol) was suspended in toluene (11.8 mL). Silver oxide (1025 mg, 4.42 mmol) then benzyl bromide (210 μL, 1.768 mmol) were added and the reaction mixture was heated to 40° C. for 4 days. The reaction mixture was diluted with EtOAc and filtered through a micron filter. The residue was concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 153C (260 mg, 0.822 mmol, 46.5%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.30 (m, 5H), 7.22 (d, J=0.4 Hz, 1H), 5.53 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.57 (d, J=0.4 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H); LC-MS: Method H, RT=1.32 min, MS (ESI) m/z: 317.1 (M+H)+.
    • Intermediate 153D: (2-(benzyloxy)-6-methyl-3-nitropyridin-4-yl)methanol
  • Figure US20190292176A1-20190926-C00788
  • Sodium borohydride (93 mg, 2.466 mmol) and calcium chloride (137 mg, 1.233 mmol) were dissolved in THF (3288 μL). After 1 hour, a solution of Intermediate 153C (260 mg, 0.822 mmol) in THF (822 μL) was added dropwise. After 18 hours, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 153D (169 mg, 0.616 mmol, 75%) as a yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.44 (m, 2H), 7.42-7.36 (m, 2H), 7.36-7.31 (m, 1H), 7.04 (s, 1H), 5.53 (s, 2H), 4.75 (s, 2H), 2.54 (s, 3H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 275.1 (M+H)+.
    • Intermediate 153E: (3-amino-2-(benzyloxy)-6-methylpyridin-4-yl)methanol
  • Figure US20190292176A1-20190926-C00789
  • Intermediate 153D (169 mg, 0.616 mmol) was dissolved in MeOH (4213 μL) and THF (527 μL). Ammonium chloride (659 mg, 12.32 mmol) and zinc (403 mg, 6.16 mmol) were added and the reaction mixture was heated to 40° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. The crude material was redissolved in EtOAc/saturated sodium carbonate and allowed to stir vigorously for 15 minutes. The mixture was filtered through a sintered glass funnel. The organic layer was washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 153E (146.7 mg, 0.601 mmol, 97%) as a yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.52-7.47 (m, 2H), 7.44-7.31 (m, 4H), 6.55 (s, 1H), 5.44 (s, 2H), 4.66 (s, 2H), 4.10 (br. s., 2H), 2.39 (d, J=0.4 Hz, 3H); LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 245.2 (M+H)+.
    • Intermediate 153F: 3-amino-2-(benzyloxy)-6-methylisonicotinaldehyde
  • Figure US20190292176A1-20190926-C00790
  • Intermediate 153E (146 mg, 0.598 mmol) was dissolved in CHCl3 (3984 μL). Manganese dioxide (312 mg, 3.59 mmol) was added. After 2.5 hours, the reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate 153F (125.7 mg, 0.519 mmol, 87%) as an orange oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 9.81 (s, 1H), 7.43-7.37 (m, 2H), 7.35-7.23 (m, 3H), 6.75 (s, 1H), 6.08 (br. s., 2H), 5.36 (s, 2H), 2.33 (d, J=0.7 Hz, 3H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 243.3 (M+H)+.
    • Intermediate 153G: 8-(benzyloxy)-3-(methoxymethyl)-6-methyl-1,7-naphthyridine
  • Figure US20190292176A1-20190926-C00791
  • Intermediate 153F (125 mg, 0.516 mmol), 3-methoxypropanal (50.0 mg, 0.568 mmol), and sodium methoxide (0.5 M, 1135 μL, 0.568 mmol) were dissolved in MeOH (5159 μL) and heated to reflux for 3.5 hours. The reaction mixture was diluted with saturated NH4Cl and EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 153G (47 mg, 0.160 mmol, 30.9%) as a yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.85 (d, J=2.0 Hz, 1H), 7.96-7.91 (m, 1H), 7.65-7.59 (m, 2H), 7.41-7.34 (m, 2H), 7.33-7.29 (m, 1H), 7.03 (d, J=0.7 Hz, 1H), 7.04-7.00 (m, 1H), 5.74 (s, 2H), 4.66 (d, J=0.7 Hz, 2H), 3.49 (s, 3H), 2.57 (d, J=0.7 Hz, 3H); LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 295.3 (M+H)+.
    • Intermediate 153H: 3-(methoxymethyl)-6-methyl-1,7-naphthyridin-8-ol
  • Figure US20190292176A1-20190926-C00792
  • Intermediate 153G (47 mg, 0.160 mmol) was dissolved in MeOH (1597 μL). Palladium on carbon (16.99 mg, 0.016 mmol) was added and the reaction mixture was sealed under a balloon of hydrogen for 30 minutes. The reaction mixture was filtered through a micron filter and concentrated in vacuo to give Intermediate 153H (29.6 mg, 0.145 mmol, 91%) as a yellow solid: LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: 205.2 (M+H)+.
    • Intermediate 153I: 8-chloro-3-(methoxymethyl)-6-methyl-1,7-naphthyridine
  • Figure US20190292176A1-20190926-C00793
  • Intermediate 153H (29.6 mg, 0.145 mmol) was dissolved in POCl3 (675 μL, 7.25 mmol) and heated to 90° C. for 5 hours. The reaction mixture was diluted with EtOAc and quenched with water. The organic layer was washed with saturated NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 153I (24.3 mg, 0.109 mmol, 75%) as a brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.99 (d, J=2.0 Hz, 1H), 8.09-8.04 (m, 1H), 7.44 (s, 1H), 4.72 (d, J=0.9 Hz, 2H), 3.53 (s, 3H), 2.72 (s, 3H); LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 223.2 (M+H)+.
    • Intermediate 153J: 6-methoxy-4-methyl-2-(tributylstannyl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00794
  • Intermediate I-3 (20 mg, 0.077 mmol) was dissolved in Et2O (310 μL) and cooled to −78° C. BuLi (2.5 M, 34.1 μL, 0.085 mmol) was added. After 30 minutes, tributylchlorostannane (21.02 μL, 0.077 mmol) was added. After 45 minutes, the reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude material was suspended in hexanes and filtered through dry celite. The residue was concentrated in vacuo to give Intermediate 153J, which was used directly in the next reaction.
    • Example 153
  • Intermediate 153I (10 mg, 0.045 mmol), Intermediate 153J (30.5 mg, 0.065 mmol), and potassium acetate (8.82 mg, 0.090 mmol) were dissolved in dioxane (449 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (2.59 mg, 2.245 μmol) was added and the reaction mixture was sealed and heated to 120° C. in the microwave for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 20 to 60% B in 15 minutes) to give Example 153 (6 mg, 0.016 mmol, 35.8%): 1H NMR (500 MHz, DMSO-d6) δ 9.06 (d, J=2.2 Hz, 1H), 8.39-8.34 (m, 1H), 7.91 (s, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.07-6.99 (m, 1H), 4.75 (s, 2H), 3.88 (s, 3H), 3.44 (s, 3H), 2.78 (s, 3H), 2.76 (s, 3H); LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 366.1 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 154 (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol
  • Figure US20190292176A1-20190926-C00795
  • Intermediate I-9 (12.77 mg, 0.043 mmol), Intermediate I-20D (14 mg, 0.051 mmol), and potassium phosphate tribasic (18.07 mg, 0.085 mmol) were dissolved in DMF (426 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (4.92 mg, 4.26 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% B in 10 minutes) to give Example 154 (4.5 mg, 0.011 mmol, 26.5%): 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.59 (s, 1H), 7.82 (s, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 5.38 (t, J=5.8 Hz, 1H), 5.13 (d, J=5.5 Hz, 2H), 4.09 (s, 3H), 3.89 (s, 3H), 2.65 (s, 3H); LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 368.2 (M+H)+; Analytical HPLC Method B: 92% purity.
    • Example 155 (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) methanol
  • Figure US20190292176A1-20190926-C00796
  • Intermediate I-2 (13.37 mg, 0.043 mmol), Intermediate I-20D (14 mg, 0.051 mmol), and potassium phosphate tribasic (18.07 mg, 0.085 mmol) were dissolved in DMF (426 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (4.92 mg, 4.26 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 30 to 70% B in 12 minutes) to give Example 155 (3.9 mg, 0.01012 mmol, 23.8%): 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.81 (s, 1H), 8.04 (s, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 5.40 (t, J=5.6 Hz, 1H), 5.14 (d, J=5.5 Hz, 2H), 4.82 (s, 2H), 3.90 (s, 3H), 3.49 (s, 3H), 2.71 (s, 3H); LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 382.1 (M+H)+; Analytical HPLC Method B: 99% purity.
    • Example 156 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) ethanol
  • Figure US20190292176A1-20190926-C00797
    • Intermediate 156A: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C00798
  • Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) and cooled to −78° C. Methylmagnesium bromide (61.2 μL, 0.184 mmol) was added. After 1 hour, the reaction mixture was warmed to 0° C. and stirred for 18 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 156A (26.8 mg, 0.093 mmol, 63.3%) as a clear oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.17-7.11 (m, 1H), 7.08-7.04 (m, 1H), 5.41-5.31 (m, 1H), 3.87 (s, 3H), 3.44-3.34 (m, 1H), 1.66-1.60 (m, 3H); LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 288/290 (M+H)+.
    • Example 156
  • Intermediate I-2 (12.18 mg, 0.039 mmol), Intermediate 156A (13.4 mg, 0.047 mmol), and potassium phosphate tribasic (16.45 mg, 0.078 mmol) were dissolved in DMF (388 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (4.48 mg, 3.88 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 30 to 70% B in 20 minutes) to give Example 156 (5.1 mg, 0.012 mmol, 31.9%): 1H NMR (500 MHz, DMSO-d6) δ 9.11 (br. s., 1H), 8.80 (br. s., 1H), 8.05 (br. s., 1H), 7.61 (br. s., 1H), 7.25 (br. s., 1H), 5.68 (d, J=4.7 Hz, 1H), 4.83 (br. s., 2H), 3.89 (br. s., 3H), 3.49 (br. s., 3H), 2.71 (br. s., 3H), 1.57 (d, J=5.0 Hz, 3H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 396.2 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 157 2-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) propan-2-ol
  • Figure US20190292176A1-20190926-C00799
    • Intermediate 157A: 2-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)propan-2-ol
  • Figure US20190292176A1-20190926-C00800
  • Intermediate I-20C (50 mg, 0.165 mmol) was dissolved in THF (331 μL) and cooled to −78° C. Methylmagnesium bromide (124 μL, 0.372 mmol) was added and the reaction mixture warmed to 0° C. for 18 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 157A (13.6 mg, 0.045 mmol, 27.2%) as a clear oil: LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 302/304 (M+H)+.
    • Example 157
  • Intermediate I-2 (11.78 mg, 0.038 mmol), Intermediate 157A (13.6 mg, 0.045 mmol), and potassium phosphate tribasic (15.92 mg, 0.075 mmol) were dissolved in DMF (375 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (4.33 mg, 3.75 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% B in 15 minutes) to give Example 157 (8.1 mg, 0.020 mmol, 52.2%): 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.07-8.02 (m, 1H), 7.62 (d, J=2.5 Hz, 1H), 7.36 (d, J=2.8 Hz, 1H), 5.42 (s, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.49 (s, 3H), 2.71 (s, 3H), 1.84 (s, 6H); LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 410.2 (M+H)+; Analytical HPLC Method B: 99% purity.
    • Example 158 Cyclopropyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazol-4-yl)methanol
  • Figure US20190292176A1-20190926-C00801
    • Intermediate 158A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclopropyl)methanol
  • Figure US20190292176A1-20190926-C00802
  • Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) and cooled to −78° C. Cyclopropylmagnesium bromide (367 μL, 0.184 mmol) was added and the reaction mixture was warmed to 0° C. for 18 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 158A (24.5 mg, 0.078 mmol, 53%) as a yellow oil, which was used directly in the subsequent reaction.
    • Example 158
  • Intermediate I-2 (14.40 mg, 0.046 mmol), Intermediate 158A (12 mg, 0.038 mmol), and potassium phosphate tribasic (16.21 mg, 0.076 mmol) were dissolved in DMF (382 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (4.41 mg, 3.82 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 75% B in 15 minutes) to give Example 158 (9.2 mg, 0.022 mmol, 57.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.78 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 5.35 (d, J=4.7 Hz, 1H), 5.14 (dd, J=6.5, 5.1 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H), 1.36-1.27 (m, 1H), 0.62 (dt, J=9.1, 4.5 Hz, 1H), 0.54 (td, J=9.1, 5.1 Hz, 1H), 0.49-0.42 (m, 1H), 0.42-0.34 (m, 1H); LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 421.8 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 159 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-N,N-dimethylmethanamine
  • Figure US20190292176A1-20190926-C00803
    • Intermediate 159A: methyl 5-methoxy-2-nitrobenzoate
  • Figure US20190292176A1-20190926-C00804
  • 5-methoxy-2-nitrobenzoic acid (2 g, 10.14 mmol) was dissolved in MeOH (50.7 mL). SOCl2 (2.96 mL, 40.6 mmol) was added and the reaction mixture was heated to reflux for 20 hours. The reaction mixture was concentrated in vacuo. The crude material was dissolved in EtOAc and washed with 1 N NaOH, then water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 159A (1.7786 g, 8.42 mmol, 83%) as a brown oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (d, J=9.0 Hz, 1H), 7.07-6.99 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H); LC-MS: Method H, The compound did not ionize.
    • Intermediate 159B: (5-methoxy-2-nitrophenyl)methanol
  • Figure US20190292176A1-20190926-C00805
  • Intermediate 159A (1.676 g, 7.94 mmol) was dissolved in toluene (52.9 mL) and THF (26.5 mL) and cooled to −78° C. DIBAL-H (17.46 mL, 17.46 mmol) was added for 30 minutes. The reaction mixture was warmed to ambient temperature for 2 hours. The reaction was quenched with 1 N HCl and stirred for 18 hours. The reaction mixture was diluted with EtOAc, filtered through celite, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 159B (1.21 g, 6.61 mmol, 83%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d, J=9.0 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 6.90 (dd, J=9.0, 2.9 Hz, 1H), 5.00 (d, J=6.4 Hz, 2H), 3.92 (s, 3H), 2.55 (t, J=6.6 Hz, 1H); LC-MS: Method H, The compound did not ionize.
    • Intermediate 159C: 5-methoxy-2-nitrobenzyl methanesulfonate
  • Figure US20190292176A1-20190926-C00806
  • Intermediate 159B (0.2 g, 1.092 mmol) and TEA (0.457 mL, 3.28 mmol) were dissolved in DCM (21.84 mL). Methanesulfonic anhydride (0.228 g, 1.310 mmol) was added for 45 minutes. The reaction mixture was diluted with DCM and washed with saturated NaHCO3, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 159C. The material was used crude in the next step.
    • Intermediate 159D: 1-(5-methoxy-2-nitrophenyl)-N,N-dimethylmethanamine
  • Figure US20190292176A1-20190926-C00807
  • Intermediate 159C (0.285 g, 1.091 mmol), DIEA (0.286 mL, 1.636 mmol), and dimethylamine (1.091 mL, 2.182 mmol) were dissolved in THF (10.91 mL) for 18 hours. The reaction mixture was concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 159D (66.4 mg, 0.316 mmol, 29%) as a yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (d, J=9.0 Hz, 1H), 7.24 (d, J=2.9 Hz, 1H), 6.83 (dd, J=9.0, 2.9 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 2H), 2.27 (s, 6H); LC-MS: Method H, RT=0.54 min, MS (ESI) m/z: 211.2 (M+H)+.
    • Intermediate 159E: 2-((dimethylamino)methyl)-4-methoxyaniline, TFA
  • Figure US20190292176A1-20190926-C00808
  • Intermediate 159D (66 mg, 0.314 mmol) was dissolved in MeOH (2147 μL) and THF (268 μL). Ammonium chloride (336 mg, 6.28 mmol) and zinc (205 mg, 3.14 mmol) were added and the reaction mixture was heated to 40° C. for 4.5 hours. The reaction mixture was diluted with EtOAc and saturated sodium carbonate and allowed to stir vigorously for 15 minutes. The mixture was filtered through a sintered glass funnel. The organic layer was washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A, 20 to 100% B in 12 minutes) to give Intermediate 159E (34.3 mg, 0.117 mmol, 37.1%) as a brown oil: 1H NMR (400 MHz, MeOH-d4) δ 6.99-6.94 (m, 2H), 6.93-6.89 (m, 1H), 4.30 (s, 2H), 3.77 (s, 3H), 2.87 (s, 6H); LC-MS: Method H, RT=0.55 min, MS (ESI) m/z: 181.2 (M+H)+.
    • Intermediate 159F: 4-((dimethylamino)methyl)-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C00809
  • Intermediate 159E (34.3 mg, 0.117 mmol) was dissolved in MeCN (583 μL). Ammonium thiocyanate (13.31 mg, 0.175 mmol) was added, followed by benzyltrimethylammonium tribromide (45.5 mg, 0.117 mmol) for 18 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 159F (10.3 mg, 0.043 mmol, 37.2%) as a yellow oil: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 238.1 (M+H)+.
    • Intermediate 159G: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-N,N-dimethylmethanamine
  • Figure US20190292176A1-20190926-C00810
  • Copper(II) bromide (16.00 mg, 0.072 mmol) and t-butyl nitrite (8.52 μL, 0.072 mmol) were dissolved in MeCN (1694) and allowed to stir 10 minutes. Intermediate 159F (10 mg, 0.042 mmol) was dissolved in MeCN (2534) and the copper solution was added at and the reaction mixture was stirred for 75 minutes. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 159G (9.8 mg, 0.033 mmol, 77%), which was used as-is for the subsequent step: LC-MS: Method H, RT=1.017 min, MS (ESI) m/z: 301/303 (M+H)+.
    • Example 159
  • Intermediate I-2 (12.27 mg, 0.039 mmol), Intermediate 159G (9.8 mg, 0.033 mmol), and potassium phosphate tribasic (13.81 mg, 0.065 mmol) were dissolved in DMF (325 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (3.76 mg, 3.25 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 20 to 60% B in 20 minutes) then repurified by preparative HPLC (Method D, 20 to 60% B in 15 minutes) to give Example 159 (2.8 mg, 0.00651 mmol, 20%): 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.90 (d, J=1.7 Hz, 1H), 8.08 (s, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 4.82 (s, 2H), 4.59 (br. s., 2H), 3.91 (s, 3H), 3.48 (s, 3H), 2.72 (s, 6H) (1 methyl group buried under the water peak); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 408.8 (M+H)+; Analytical HPLC Method B: 95% purity.
    • Example 160 Cyclopropyl(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) methanol
  • Figure US20190292176A1-20190926-C00811
  • Intermediate I-9 (13.76 mg, 0.046 mmol), Intermediate 158A (12 mg, 0.038 mmol), and potassium phosphate tribasic (16.21 mg, 0.076 mmol) were dissolved in DMF (382 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (4.41 mg, 3.82 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45 to 85% B in 15 minutes) to give Example 160 (4.2 mg, 0.0103 mmol, 27%): 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.55 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 5.35 (d, J=5.0 Hz, 1H), 5.13 (dd, J=6.5, 5.1 Hz, 1H), 4.09 (s, 3H), 3.89 (s, 3H), 2.65 (s, 3H), 1.34-1.27 (m, 1H), 0.61 (dt, J=9.0, 4.4 Hz, 1H), 0.57-0.50 (m, 1H), 0.49-0.42 (m, 1H), 0.42-0.34 (m, 1H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 407.8 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 161 (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) (phenyl)methanol
  • Figure US20190292176A1-20190926-C00812
    • Intermediate 161A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)(phenyl)methanol
  • Figure US20190292176A1-20190926-C00813
  • Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) and cooled to −78° C. Phenylmagnesium bromide (61.2 μL, 0.184 mmol) was added and the reaction mixture was warmed to 0° C. for 18 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 161A (33.6 mg, 0.096 mmol, 65.3%) as a white solid: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 350/352 (M+H)+.
    • Example 161
  • Intermediate I-2 (14.80 mg, 0.047 mmol), Intermediate 161A (16.5 mg, 0.047 mmol), and potassium phosphate tribasic (20.00 mg, 0.094 mmol) were dissolved in DMF (471 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (5.44 mg, 4.71 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 75% B in 15 minutes) to give Example 161 (11 mg, 0.024 mmol, 50%): 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.83 (d, J=1.7 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.65-7.57 (m, 3H), 7.35-7.27 (m, 3H), 7.23-7.16 (m, 1H), 6.72 (d, J=4.1 Hz, 1H), 6.10 (d, J=4.4 Hz, 1H), 4.82 (s, 2H), 3.87 (s, 3H), 3.48 (s, 3H), 2.74 (s, 3H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 457.8 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 162 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylic acid
  • Figure US20190292176A1-20190926-C00814
    • Intermediate 162A: 5-methoxy-2-nitrobenzoyl chloride
  • Figure US20190292176A1-20190926-C00815
  • 5-Methoxy-2-nitrobenzoic acid (1 g, 5.07 mmol) was dissolved in DCM (50.7 mL). Oxalyl chloride (0.958 mL, 11.16 mmol) then DMF (0.039 mL, 0.507 mmol) was added at ambient temperature and the reaction mixture was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo and stored on HIVAC to give Intermediate 162A, which was used directly in the subsequent reaction.
    • Intermediate 162B: tert-butyl 5-methoxy-2-nitrobenzoate
  • Figure US20190292176A1-20190926-C00816
  • Intermediate 162A (1.094 g, 5.07 mmol) was dissolved in THF (50.7 mL). Potassium tert-butoxide (0.854 g, 7.61 mmol) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 162B (910 mg, 3.59 mmol, 70.8%) as a brown oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J=9.0 Hz, 1H), 7.03 (d, J=2.9 Hz, 1H), 6.98 (dd, J=9.0, 2.6 Hz, 1H), 3.91 (s, 3H), 1.58 (s, 9H); LC-MS: Method H, the compound did not ionize.
    • Intermediate 162C: tert-butyl 2-amino-5-methoxybenzoate
  • Figure US20190292176A1-20190926-C00817
  • Intermediate 162B (0.910 g, 3.59 mmol) was dissolved in EtOH (5.13 mL). Palladium on carbon (0.076 g, 0.072 mmol) then ammonium formate (1.133 g, 17.97 mmol) was added and the reaction mixture was heated to reflux for 1.5 hours. The reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate 162C (795 mg, 3.56 mmol, 99%) as a brown oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (d, J=2.9 Hz, 1H), 6.92 (dd, J=8.8, 3.1 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 5.36 (br. s., 2H), 3.76-3.74 (m, 3H), 1.59 (s, 9H); LC-MS: Method H, The compound did not ionize.
    • Intermediate 162D: tert-butyl 2-amino-6-methoxybenzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00818
  • Intermediate 162C (0.795 g, 3.56 mmol) was dissolved in MeCN (17.80 mL). Ammonium thiocyanate (0.407 g, 5.34 mmol) was added, followed by benzyltrimethylammonium tribromide (1.389 g, 3.56 mmol) for 18 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 162D (685.8 mg, 2.446 mmol, 68.7%) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ 7.46 (d, J=2.6 Hz, 1H), 7.29 (d, J=2.6 Hz, 1H), 5.71 (br. s., 2H), 3.85 (s, 3H), 1.63 (s, 9H); LC-MS: Method H, RT=1.32 min, MS (ESI) m/z: 282.1 (M+H)+.
    • Intermediate 162E: tert-butyl 2-bromo-6-methoxybenzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00819
  • Copper(II) bromide (0.928 g, 4.15 mmol) and t-butyl nitrite (0.494 mL, 4.15 mmol) were dissolved in MeCN (9.77 mL) and allowed to stir 10 minutes. Intermediate 162D (0.685 g, 2.443 mmol) was dissolved in MeCN (14.66 mL) and the copper solution was added for 2.5 hours. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 162E (323.8 mg, 0.941 mmol, 38.5%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (d, J=2.6 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 3.90 (s, 3H), 1.65 (s, 9H); LC-MS: The compound did not ionize.
    • Intermediate 162F: tert-butyl 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylate
  • Figure US20190292176A1-20190926-C00820
  • Intermediate I-2 (22.82 mg, 0.073 mmol), Intermediate 162E (25 mg, 0.073 mmol), and potassium phosphate tribasic (30.8 mg, 0.145 mmol) were dissolved in DMF (726 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (8.39 mg, 7.26 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 hours. The reaction mixture was diluted with water and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 162F (14.7 mg, 0.033 mmol, 44.8%) as an orange solid: LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 452.2 (M+H)+.
    • Example 162
  • Intermediate 162F (14.7 mg, 0.033 mmol) was dissolved in DCM (1085 μL) and cooled to 0° C. 2,6-Lutidine (11.38 μL, 0.098 mmol) and TMS-OTf (17.65 μL, 0.098 mmol) were added and the reaction mixture was warmed to ambient temperature for 45 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 20 to 60% B in 12 minutes) to give Example 162 (5.5 mg, 0.014 mmol, 42.3%): LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 396.1 (M+H)+; Analytical HPLC Method B: 99% purity.
    • Example 163 (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(phenyl)methanol
  • Figure US20190292176A1-20190926-C00821
  • Example 161 (8 mg, 0.017 mmol) was purified by SFC chromatography (Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5 micron, 25% MeOH/75% CO2, 45 mL/min flow rate) to give Enantiomer 1 (1.54 mg, 0.0032 mmol, 19%) and Example 163 (Enantiomer 2, 3.4 mg, 0.00706 mmol, 40.4%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 9.08 (s, 1H), 8.75 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J=7.5 Hz, 2H), 7.39-7.33 (m, 2H), 7.32 (d, J=2.4 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.40 (d, J=5.7 Hz, 1H), 5.78 (d, J=6.2 Hz, 1H), 4.84 (s, 2H), 3.86 (s, 3H), 3.58 (s, 3H), 2.70 (s, 3H); LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 458.3 (M+H)+; 95% purity.
    • Example 164 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C00822
    • Intermediate 164A: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C00823
  • Intermediate I-20 (100 mg, 0.367 mmol) was dissolved in THF (3675 μL) and cooled to −78° C. tert-Butylmagnesium chloride (1 M, 735 μl, 0.735 mmol) was added and warmed to 0° C. for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 164A (74.2 mg, 0.225 mmol, 61.1%) as a yellow solid: LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 330/332 (M+H)+.
    • Intermediate 164B: 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C00824
  • Intermediate I-2 (58.8 mg, 0.187 mmol) and Intermediate 164A (74.2 mg, 0.225 mmol) were dissolved in DMF (1872 μL). PdCl2(dppf)-CH2Cl2 (9.17 mg, 0.011 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 112 μL, 0.225 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 164B (45 mg, 0.103 mmol, 54.9%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.45 (d, J=4.7 Hz, 1H), 5.34 (d, J=4.7 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H), 0.97 (s, 9H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 438.2 (M+H)+.
    • Example 164
  • Intermediate 164B (62 mg, 0.017 mmol) was purified by SFC chromatography (Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5 micron, 25% MeOH/75% CO2, 45 mL/min flow rate) to give Enantiomer 1 (15.2 mg, 0.034 mmol, 24.3%) and Example 164 (Enantiomer 2, 18.3 mg, 0.040 mmol, 28%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.45 (d, J=4.7 Hz, 1H), 5.34 (d, J=4.7 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H), 0.97 (s, 9H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 438.2 (M+H)+; 95% purity.
    • Example 165 Cyclohexyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-methanol
  • Figure US20190292176A1-20190926-C00825
    • Intermediate 165A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclohexyl)methanol
  • Figure US20190292176A1-20190926-C00826
  • Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) and cooled to −78° C. Cyclohexylmagnesium bromide (1 M, 147 μL, 0.147 mmol) was added and the reaction mixture was warmed to 0° C. for 5 hours. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 165A (5.3 mg, 0.015 mmol, 20.2%) as a clear oil: LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 356/358 (M+H)+.
    • Example 165
  • Intermediate I-2 (5.61 mg, 0.018 mmol) and Intermediate 165A (5.3 mg, 0.015 mmol) were dissolved in DMF (149 μL). PdCl2(dppf)-CH2Cl2 (0.729 mg, 0.893 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 8.93 μL, 0.018 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 70 to 100% B in 20 minutes) to give Example 165 (2.9 mg, 0.00626 mmol, 42.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.75 (d, J=1.7 Hz, 1H), 8.04 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.37 (t, J=5.6 Hz, 1H), 5.22 (d, J=5.2 Hz, 1H), 4.82 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H), 1.89 (br. s., 1H), 1.81 (d, J=5.8 Hz, 1H), 1.70 (br. s., 1H), 1.66 (d, J=3.6 Hz, 1H), 1.59 (br. s., 1H), 1.44 (d, J=9.4 Hz, 1H), 1.21-1.09 (m, 5H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 464.3 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 166 Cyclobutyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol
  • Figure US20190292176A1-20190926-C00827
    • Intermediate 166A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclobutyl)methanol
  • Figure US20190292176A1-20190926-C00828
  • Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) and cooled to −78° C. Cyclobutylmagnesium bromide (0.25 M, 588 μL, 0.147 mmol) was added and the reaction mixture was warmed to 0° C. for 18 hours. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 166A (4 mg, 0.012 mmol, 16.6%): LC-MS: Method H, RT=0.82 min, MS (ESI) m/z: 328/330 (M+H)+.
    • Example 166
  • Intermediate I-2 (4.59 mg, 0.015 mmol) and Intermediate 166A (4 mg, 0.012 mmol) were dissolved in DMF (122 μL). PdCl2(dppf)-CH2Cl2 (0.597 mg, 0.731 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 7.31 μL, 0.015 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 50 to 100% B in 23 minutes) to give Example 166 (2.7 mg, 0.00595 mmol, 48.8%): 1H NMR (500 MHz, CHLOROFORM-d) δ 9.01 (s, 1H), 8.67 (d, J=1.4 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J=2.2 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 4.95 (d, J=8.0 Hz, 1H), 4.77 (s, 2H), 3.87-3.82 (m, 3H), 3.51 (s, 3H), 2.92-2.84 (m, 1H), 2.65 (s, 3H), 2.18-2.06 (m, 2H), 1.91 (br. s., 1H), 1.86-1.75 (m, 3H); LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 436.2 (M+H)+; Analytical HPLC Method B: 96% purity.
    • Example 167 (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-2-yl)methanol
  • Figure US20190292176A1-20190926-C00829
    • Intermediate 167A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)(pyridin-2-yl)methanol
  • Figure US20190292176A1-20190926-C00830
  • Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) and cooled to −78° C. Pyridin-2-ylmagnesium bromide (0.25 M, 588 μL, 0.147 mmol) was added and the reaction mixture was warmed to 0° C. for 18 hours. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 167A (9.1 mg, 0.026 mmol, 35.3%) as a yellow oil: LC-MS: Method H, RT=0.66 min, MS (ESI) m/z: 351/353 (M+H)+.
    • Example 167
  • Intermediate I-2 (9.77 mg, 0.031 mmol) and Intermediate 167A (9.1 mg, 0.026 mmol) were dissolved in DMF (259 μL). PdCl2(dppf)-CH2Cl2 (1.270 mg, 1.555 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 15.55 μL, 0.031 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% B in 20 minutes) to give Example 167 (2.7 mg, 0.00548 mmol, 21.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.72 (d, J=1.4 Hz, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.04 (s, 1H), 7.90-7.80 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.31-7.22 (m, 1H), 7.14 (d, J=2.2 Hz, 1H), 6.72 (s, 1H), 6.22 (br. s., 1H), 4.82 (s, 2H), 3.86 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 459.2 (M+H)+; Analytical HPLC Method B: 93% purity.
    • Example 168 (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) (pyridin-3-yl)methanol
  • Figure US20190292176A1-20190926-C00831
    • Intermediate 168A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)(pyridin-3-yl)methanol
  • Figure US20190292176A1-20190926-C00832
  • Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) and cooled to −78° C. Pyridin-3-ylmagnesium bromide (0.25 M, 588 μL, 0.147 mmol) was added and the reaction mixture was warmed to 0° C. for 18 hours. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 168A (14.6 mg, 0.042 mmol, 56.6%) as a white solid: LC-MS: Method H, RT=0.65 min, MS (ESI) m/z: 351/353 (M+H)+.
    • Example 168
  • Intermediate I-2 (15.67 mg, 0.050 mmol) and Intermediate 168A (14.6 mg, 0.042 mmol) were dissolved in DMF (416 μL). PdCl2(dppf)-CH2Cl2 (2.037 mg, 2.494 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 24.94 μL, 0.050 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 75% B in 20 minutes) to give Example 168 (10 mg, 0.022 mmol, 51.9%): 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.86 (s, 1H), 8.80 (s, 1H), 8.41 (d, J=4.4 Hz, 1H), 8.04 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 6.73 (d, J=4.1 Hz, 1H), 6.29 (d, J=4.4 Hz, 1H), 4.82 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.73 (s, 3H); LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 459.2 (M+H)+; Analytical HPLC Method B: 99% purity.
    • Example 169 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d1
  • Figure US20190292176A1-20190926-C00833
    • Intermediate 169A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)methanol-d2
  • Figure US20190292176A1-20190926-C00834
  • Intermediate I-20C (370 mg, 1.225 mmol) was dissolved in toluene (8164 μL) and THF (4082 μL) and cooled to −78° C. DIBAL-D (3849 μL, 2.69 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to ambient temperature. After 1.5 hours, the reaction was quenched with 1 N HCl, stirred for 1 hour, and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 169A (76.5 mg, 0.277 mmol, 22.5%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.17 (dd, J=7.7, 2.4 Hz, 1H), 7.05 (dd, 2.5 Hz, 1H), 3.87 (s, 3H), 2.95 (d, J=15.0 Hz, 1H); LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 276/278 (M+H)+.
    • Intermediate 169B: 2-bromo-6-methoxybenzo[d]thiazole-4-carbaldehyde-d1
  • Figure US20190292176A1-20190926-C00835
  • Intermediate 169A (76 mg, 0.275 mmol) was dissolved in CHCl3 (1835 μL). Manganese dioxide (144 mg, 1.651 mmol) was added and the reaction mixture was heated to 40° C. for 18 hours. More manganese dioxide (144 mg, 1.651 mmol) was added and heating continued for 36 hours. The reaction mixture was filtered through celite and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 169B (35.7 mg, 0.131 mmol, 47.5%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.62 (dd, J=5.1, 2.6 Hz, 1H), 7.54 (dd, J=8.1, 2.6 Hz, 1H), 3.93 (s, 3H); LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 275/277 (M+H)+.
    • Intermediate 169C: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d1
  • Figure US20190292176A1-20190926-C00836
  • Intermediate 169B (35 mg, 0.128 mmol) was dissolved in THF (1281 μL) and cooled to −78° C. tert-Butylmagnesium chloride (384 μL, 0.384 mmol) was added and the reaction mixture was warmed to 0° C. for 18 hours. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 169C (27.1 mg, 0.082 mmol, 63.8%) as a white solid: LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 331/333 (M+H)+.
    • Intermediate 169D: 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d1
  • Figure US20190292176A1-20190926-C00837
  • Intermediate I-2 (30.8 mg, 0.098 mmol) and Intermediate 169C (27.1 mg, 0.082 mmol) were dissolved in DMF (818 μL). PdCl2(dppf)-CH2Cl2 (4.01 mg, 4.91 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 49.1 μL, 0.098 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 169D (17.3 mg, 0.039 mmol, 48.2%) as a yellow solid: LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 439.3 (M+H)+.
    • Example 169
  • Intermediate 169D (17.3 mg, 0.039 mmol) was purified by SFC chromatography (Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5 micron, 25% MeOH/75% CO2, 45 mL/min flow rate) to give Enantiomer 1 (6.5 mg, 0.014 mmol, 35.7%) and Example 169 (Enantiomer 2, 6.5 mg, 0.014 mmol, 35.7%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 9.08 (s, 1H), 8.69 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 5.71 (s, 1H), 4.85 (s, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 2.72 (s, 3H), 1.05 (s, 9H); LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 439.3 (M+H)+; 95% purity.
    • Example 170 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-d5
  • Figure US20190292176A1-20190926-C00838
    • Intermediate 170A: 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-d5
  • Figure US20190292176A1-20190926-C00839
  • Intermediate I-25 (39.6 mg, 0.124 mmol) and Intermediate 164A (41 mg, 0.124 mmol) were dissolved in DMF (1242 μL). PdCl2(dppf)-CH2Cl2 (6.08 mg, 7.45 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 74.5 μL, 0.149 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 170A (17.8 mg, 0.040 mmol, 32.4%) as a yellow solid: LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 443.3 (M+H)+.
    • Example 170
  • Intermediate 170A (19.8 mg, 0.045 mmol) was purified by SFC chromatography (Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5 micron, 25% MeOH/75% CO2, 45 mL/min flow rate) to give Enantiomer 1 (7.7 mg, 0.017 mmol, 36.9%) and Example 170 (Enantiomer 2, 7.8 mg, 0.017 mmol, 37.4%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 9.08 (s, 1H), 8.69 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 5.74 (br. s., 1H), 4.77 (br. s., 1H), 3.92 (s, 3H), 2.72 (s, 3H), 1.05 (s, 9H); LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 443.3 (M+H)+; 95% purity.
    • Example 171 2,2,2-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C00840
    • Intermediate 171A: 2-chloro-6-methoxybenzo[d]thiazole-4-carbaldehyde
  • Figure US20190292176A1-20190926-C00841
  • Intermediate I-20 (250 mg, 0.919 mmol) was dissolved in THF (8352 μL) and concentrated HCl (835 μL) for 2.5 hours. The reaction mixture was diluted with EtOAc, washed with water, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 171A (207 mg, 0.909 mmol, 99%) as an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 10.85 (s, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 3.93 (s, 3H); LC-MS: Method H, RT=1.02 min, MS (ESI) m/z: 242.1 (M+Na)+.
    • Intermediate 171B: 1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2,2-trifluoroethanol
  • Figure US20190292176A1-20190926-C00842
  • Intermediate 171A (207 mg, 0.909 mmol) was dissolved in THF (18.2 mL). (Trifluoromethyl)trimethylsilane (161 μL, 1.091 mmol) then TBAF (1091 μL, 1.091 mmol) were added and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed with water, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 171B (70.8 mg, 0.238 mmol, 26.2%) as a white solid: LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 298.1 (M+H)+.
    • Example 171
  • Intermediate I-2 (30.0 mg, 0.096 mmol) and Intermediate 171B (23.7 mg, 0.080 mmol) were dissolved in DMF (796 μL). PdCl2(dppf)-CH2Cl2 (3.90 mg, 4.78 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 47.8 μL, 0.096 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45 to 95% B in 20 minutes) to give Example 171 (9.8 mg, 0.021 mmol, 26.6%): 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.83 (br. s., 1H), 8.07 (br. s., 1H), 7.84 (br. s., 1H), 7.33 (br. s., 1H), 7.07 (d, J=5.8 Hz, 1H), 6.22 (br. s., 1H), 4.83 (s, 2H), 3.92 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H); LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 450.2 (M+H)+; Analytical HPLC Method B: 97% purity.
    • Example 172 (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-4-yl)methanol
  • Figure US20190292176A1-20190926-C00843
    • Intermediate 172A: (2-amino-6-methoxybenzo[d]thiazol-4-yl)(pyridin-4-yl)methanol
  • Figure US20190292176A1-20190926-C00844
  • Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μL). Sodium hydride (8.49 mg, 0.212 mmol) was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was cooled to −78° C. and BuLi (2.3 M, 101 μL, 0.232 mmol) was added, and the reaction mixture was stirred for 1 hour. Isonicotinaldehyde (41.3 mg, 0.386 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 172A, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.47 min, MS (ESI) m/z: 288.2 (M+H)+.
    • Intermediate 172B: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(pyridin-4-yl)methanol
  • Figure US20190292176A1-20190926-C00845
  • Copper(II) chloride (36.0 mg, 0.268 mmol) and t-butyl nitrite (34.1 μL, 0.287 mmol) were dissolved in MeCN (766 μL) and allowed to stir 10 minutes. Intermediate 172A (55 mg, 0.191 mmol) was dissolved in MeCN (1148 μL) and the copper solution was added and the reaction mixture was heated to 60° C. for 2 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The reaction mixture was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 20% MeOH in DCM) to give Intermediate 172B (11.5 mg, 0.037 mmol, 19.6%) as a yellow solid: LC-MS: Method H, RT=0.63 min, MS (ESI) m/z: 307.1 (M+H)+.
    • Example 172
  • Intermediate I-2 (14.13 mg, 0.045 mmol) and Intermediate 172B (11.5 mg, 0.037 mmol) were dissolved in DMF (375 μL). PdCl2(dppf)-CH2Cl2 (1.837 mg, 2.249 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 22.49 μL, 0.045 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 75% B in 20 minutes) to give Example 172 (6 mg, 0.013 mmol, 34.9%): 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.83 (s, 1H), 8.57 (br. s., 2H), 8.06 (s, 1H), 7.70 (br. s., 2H), 7.67 (d, J=2.1 Hz, 1H), 7.26 (s, 2H), 6.75 (s, 1H), 4.83 (s, 2H), 3.88 (s, 3H), 2.74 (s, 3H); LC-MS: Method H, RT=0.78 min, MS (ESI) m/z: 459.3 (M+H)+; Analytical HPLC Method B: 100% purity.
    • Example 173 3,3,3-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-1-ol
  • Figure US20190292176A1-20190926-C00846
    • Intermediate 173A: 1-(2-amino-6-methoxybenzo[d]thiazol-4-yl)-3,3,3-trifluoropropan-1-ol
  • Figure US20190292176A1-20190926-C00847
  • Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μL). Sodium hydride (8.49 mg, 0.212 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was cooled to −78° C. and BuLi (2.3 M, 101 μL, 0.232 mmol) was added and the reaction mixture was stirred for 30 minutes. 3,3,3-Trifluoropropanal (43.2 mg, 0.386 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 173A, which was used directly in the subsequent step: LC-MS: Method H, RT=0.65 min, MS (ESI) m/z: 293.2 (M+H)+.
    • Intermediate 173B: 1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-3,3,3-trifluoropropan-1-ol
  • Figure US20190292176A1-20190926-C00848
  • Copper(II) chloride (36.3 mg, 0.270 mmol) and t-butyl nitrite (34.4 μL, 0.289 mmol) were dissolved in MeCN (772 μL) and allowed to stir 10 minutes. Intermediate 173A (56.4 mg, 0.193 mmol) was dissolved in MeCN (1158 μL) and the copper solution was added and the reaction mixture was heated to 60° C. After 3 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 173B (9.4 mg, 0.030 mmol, 15.6%) as a yellow oil: LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 312.1 (M+H)+.
    • Example 173
  • Intermediate I-2 (11.37 mg, 0.036 mmol) and Intermediate 173B (9.4 mg, 0.030 mmol) were dissolved in DMF (302 μL). PdCl2(dppf)-CH2Cl2 (1.478 mg, 1.809 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 18.09 μL, 0.036 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. More PdCl2(dppf)-CH2Cl2 (1.478 mg, 1.809 μmol) was added and the reaction mixture was heated to 100° C. for 30 minutes in the microwave. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45 to 85% B in 25 minutes) to give Example 173 (2.5 mg, 0.00523 mmol, 17.4%): 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.75 (s, 1H), 8.05 (s, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 5.93 (d, J=5.5 Hz, 1H), 5.85 (br. s., 1H), 4.82 (s, 2H), 3.91 (s, 3H), 3.02-2.90 (m, 1H), 2.84-2.73 (m, 1H), 2.69 (s, 3H) (1 methyl group under DMSO); LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 464.2 (M+H)+; Analytical HPLC Method B: 97% purity.
    • Example 174 2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C00849
  • Intermediate I-9 (20.09 mg, 0.067 mmol) and Intermediate 171B (16.6 mg, 0.056 mmol) were dissolved in DMF (558 μL). PdCl2(dppf)-CH2Cl2 (2.73 mg, 3.35 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 33.5 μL, 0.067 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% B in 25 minutes) to give Example 174 (4.6 mg, 0.0104 mmol, 18.6%): 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.57 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.31 (s, 1H), 7.16 (d, J=6.1 Hz, 1H), 6.24-6.15 (m, 1H), 4.08 (s, 3H), 3.90 (s, 3H), 2.64 (s, 3H); LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 436.2 (M+H)+; Analytical HPLC Method B: 98% purity.
    • Example 175 5-(benzofuran-2-yl)-2-methoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00850
  • Intermediate I-9A (0.053 g, 0.209 mmol) and benzofuran-2-ylboronic acid (0.051 g, 0.314 mmol) were dissolved in toluene (3.14 mL) and EtOH (1.047 mL). PdCl2(dppf)-CH2Cl2 adduct (10.26 mg, 0.013 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. 2 M aqueous Na2CO3 (0.126 mL, 0.251 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 120° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc, filtered through a micron filter, and concentrated in vacuo. The reaction mixture was purified on Prep HPLC using Method A to yield Example 175 (2.57 mg, 8.41 μmol, 4.02% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.52 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.08 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.63 (d, J=0.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.32 (td, J=7.7, 1.3 Hz, 1H), 7.25-7.22 (m, 1H), 4.14-4.10 (m, 3H), 2.63 (s, 3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 291.1 (M+H)+. Analytical HPLC: Method A, 94.5% purity.
    • Example 176 Methyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00851
    • Intermediate 176A: ethyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00852
  • Intermediate I-15B (0.250 g, 0.847 mmol) and benzofuran-2-ylboronic acid (0.137 g, 0.847 mmol) were dissolved in DMF (20 mL). PdCl2(dppf)-CH2Cl2 adduct (0.042 g, 0.051 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3 (3 mL, 6.00 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The reaction mixture was purified by ISCO to remove any Pd or ligand based impurities. 40 g column with a 0-100% gradient of EtOAc in hexanes was used. Fractions pooled and the residue was purified on Prep HPLC using Method A to yield Intermediate 176A (0.074 g, 0.223 mmol, 26.3% yield) LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 333.0 (M+H)+.
    • Intermediate 176B: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylic acid
  • Figure US20190292176A1-20190926-C00853
  • Intermediate 176A (0.050 g, 0.150 mmol) was dissolved in THF (3 mL) and MeOH (0.300 mL). NaOH, 1 N in water (0.500 mL, 0.500 mmol) was added and the reaction mixture was allowed to stir at room temperature for 18 h. Diluted with 1 N HCl and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc (×3). The organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 176B (0.046 g, 0.151 mmol, 100% yield) as a yellow solid. Used without further purification in the next step. NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.44 (s, 2H), 8.00 (s, 1H), 7.82 (d, J=7.4 Hz, 1H), 7.72 (dd, J=8.3, 0.8 Hz, 1H), 7.43 (td, J=7.7, 1.4 Hz, 1H), 7.36-7.30 (m, 1H), 2.71 (s, 3H). LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 305.1 (M+H)+.
    • Intermediate 176C: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carbonyl chloride
  • Figure US20190292176A1-20190926-C00854
  • Intermediate 176B (0.046 g, 0.151 mmol) was dissolved in DCM (3 mL) and oxalyl chloride (0.013 mL, 0.151 mmol) was added. DMF (1.170 μl, 0.015 mmol) was added and the reaction mixture was allowed to stir at room temperature for 30 min. The reaction mixture was concentrated and stored under vacuum for 1 h. Used without further purification in the next step. LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 319.0 (M+H)+. Methyl ester mass observed by LC/MS.
    • Example 176
  • Intermediate 176C (0.0125 g, 0.039 mmol) was dissolved in DCM (3 mL). DMAP (0.473 mg, 3.87 μmol), TEA (10.80 μl, 0.077 mmol), and methanol (1.241 mg, 0.039 mmol) were added and the reaction mixture was allowed to stir at room temperature over the weekend. The reaction mixture was concentrated. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 50 to 90% B in 10 minutes) to give Example 176 (0.0057 g, 0.017 mmol, 44.8% yield): 1H NMR (500 MHz, METHANOL-d4)) δ 9.53 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.29-7.22 (m, 1H), 3.37 (s, 3H), 2.69 (s, 3H). LC-MS: method H, RT=1.18 min, MS (ESI) m/z: 319.1 (M+H)+. Analytical HPLC Method B: 97.0% purity.
    • Example 177 8-(benzofuran-2-yl)-3-methoxy-6-methylquinoline
  • Figure US20190292176A1-20190926-C00855
    • Intermediate 177A: (Z)-3-((2-bromo-4-methylphenyl)amino)-2-nitroacrylaldehyde
  • Figure US20190292176A1-20190926-C00856
  • 2-Bromo-4-methylaniline (0.380 g, 2.044 mmol) was dissolved in hydrochloric acid, 2 N in water (1 mL) and sodium (Z)-2-nitro-3-oxoprop-1-en-1-olate hydrate (0.321 g, 2.044 mmol) in water (2.5 mL) was added to the reaction mixture. The reaction mixture was allowed to stir for 30 min and the solid was collected to yield Intermediate 177A (0.537 g, 1.884 mmol, 92%). Material carried on without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 12.46 (br. s., 1H), 10.17 (s, 1H), 8.32 (d, J=14.6 Hz, 1H), 7.45 (s, 1H), 7.25-7.22 (m, 2H), 2.34 (s, 3H). LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 285.0 (M+H)+.
    • Intermediate 177B: 8-bromo-6-methyl-3-nitroquinoline
  • Figure US20190292176A1-20190926-C00857
  • Intermediate 177A (0.537 g, 1.884 mmol) and 2-bromo-4-methylaniline hydrochloride (0.419 g, 1.884 mmol) were dissolved in acetic acid (3 mL) and allowed to reflux for 18 h. The reaction mixture was diluted with 1 N NaOH, until basic, and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc (×3). The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure and was purified on ISCO, 40 g column 0-100% EtOAc in hexanes to yield Intermediate 177B (0.188 g, 0.704 mmol, 37.4% yield) as a yellow solid. LC-MS: method H, RT=0.99 min, MS (ESI) m/z: 267.0 (M+H)+.
    • Intermediate 177C: 8-(benzofuran-2-yl)-6-methyl-3-nitroquinoline
  • Figure US20190292176A1-20190926-C00858
  • Intermediate 177B (0.070 g, 0.262 mmol) and benzofuran-2-ylboronic acid (0.042 g, 0.262 mmol) were dissolved in DMF (20 mL). PdCl2(dppf)-CH2Cl2 adduct (0.013 g, 0.016 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3 (0.175 mL, 0.524 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The reaction mixture was purified by ISCO 40 g column with a 0-100% gradient of EtOAc in hexanes was used. Combined impure fractions were diluted with DMF, filtered, and purified by preparative HPLC (Method D, 55 to 90% B in 10 minutes) to yield Intermediate 177C (0.0364 g, 0.120 mmol, 45.6% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 8.97 (d, J=2.5 Hz, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.29 (d, J=0.8 Hz, 1H), 7.75 (s, 1H), 7.73-7.70 (m, 1H), 7.58 (dd, J=8.3, 0.8 Hz, 1H), 7.36 (td, J=7.7, 1.4 Hz, 1H), 7.30-7.27 (m, 1H), 2.69 (s, 3H). LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 304.9 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Intermediate 177D: 8-(benzofuran-2-yl)-6-methylquinolin-3-amine
  • Figure US20190292176A1-20190926-C00859
  • Intermediate 177C (0.031 g, 0.102 mmol) was dissolved in MeOH (5 mL) and Pd/C (1.084 mg, 10.19 μmol) was added. The reaction mixture was evacuated and back filled with argon (×3). The reaction mixture was then evacuated and back filled with hydrogen (0.205 mg, 0.102 mmol) (×3). The reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was filtered to remove the Pd/C and concentrated under reduced pressure to yield Intermediate 177D (0.022 g, 0.080 mmol, 79% yield). Used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (d, J=2.8 Hz, 1H), 8.17 (d, J=0.8 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.55 (dd, J=8.2, 0.6 Hz, 1H), 7.36 (s, 1H), 7.32-7.27 (m, 1H), 7.24 (dd, J=7.5, 1.0 Hz, 1H), 7.20 (d, J=2.8 Hz, 1H), 3.91 (s, 2H), 2.56 (s, 3H). LC-MS: method H, RT=0.95 min, MS (ESI) m/z: 275.3 (M+H)+.
    • Intermediate 177E: 8-(benzofuran-2-yl)-6-methylquinolin-3-ol
  • Figure US20190292176A1-20190926-C00860
  • Intermediate 177D (0.0178 g, 0.065 mmol) was dissolved in MeCN (0.468 mL) and cooled to 0° C. Tetrafluoroboric acid (9.84 μl, 0.071 mmol) was added and stirring continued for 10 minutes. After this time, a solution of tert-butyl nitrite (8.49 μl, 0.071 mmol) in MeCN (0.047 mL) was added dropwise and stirring continued for 10 minutes. After this time, the reaction mixture was cooled to −15° C. and water (0.936 mL) was added. This cooled solution was added into a solution of copper(II) nitrate, trihydrate (3.14 g, 12.98 mmol) and copper(I) oxide (0.418 g, 2.92 mmol) in water (9.36 mL), precooled to 0° C. Stirring was continued at the same temperature for 18 h. The reaction mixture was then extracted thrice with EtOAc. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered through Celite, and concentrated in vacuo. The reaction mixture was purified on Prep HPLC Method A to yield Intermediate 177E 0.018 g, 0.065 mmol, 60%, 65% purity) Used in the next step without further purification. LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 276.1 (M+H)+.
    • Example 177
  • Intermediate 177E (0.018 g, 0.065 mmol) was dissolved in acetone (3 mL) and K2CO3 (0.018 g, 0.131 mmol) was added. MeI (8.18 μl, 0.131 mmol) was added and the reaction mixture was allowed to stir at room temperature for 5h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 85% B in 10 minutes) to give Example 177 (0.0032 g, 10.95 μma 16.75% yield): 1H NMR (500 MHz, METHANOL-d4) δ 8.68 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 8.08 (s, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.56-7.53 (m, 2H), 7.46 (d, J=3.0 Hz, 1H), 7.32-7.27 (m, 1H), 7.26-7.19 (m, 1H), 3.98 (s, 3H), 2.59 (s, 3H)). LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 290.2 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 178 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00861
  • Intermediate I-1 (0.007 g, 0.028 mmol) and 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (6.01 mg, 0.028 mmol) were dissolved in DMF (3 mL). PdCl2(dppf)-CH2Cl2 adduct (1.350 mg, 1.654 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3 (0.018 mL, 0.055 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 50 to 85% B in 10 minutes) to yield Example 178 (0.0052 g, 0.015 mmol, 54.0% yield): 1H NMR (500 MHz, METHANOL-d4) δ 8.64 (s, 1H), 8.43 (d, J=1.7 Hz, 1H), 7.84-7.53 (m, 2H), 2.89 (d, J=5.8 Hz, 4H), 2.64 (s, 3H), 2.00-1.87 (m, 4H). LC-MS: method H, RT=1.26 min, MS (ESI) m/z: 348.0 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 179 5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00862
  • Intermediate I-9 (10 mg, 0.033 mmol), 2-bromo-5-methoxy-7-methylthiazolo[5,4-b]pyridine (10.36 mg, 0.040 mmol), and phosphoric acid, potassium salt (14.14 mg, 0.067 mmol) were dissolved in DMF (333 μl) and degassed by bubbling with argon for 15 minutes. Pd(Ph3P)4 (3.85 mg, 3.33 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 h. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 60% to 100% B in 20 minutes) to yield Example 179 (0.0014 g, 3.89 μmol, 11.69% yield): 1H NMR (500 MHz, CHLOROFORM-d) δ 8.62 (br. s., 1H), 8.56 (br. s., 1H), 7.76 (br. s., 1H), 6.72 (br. s., 1H), 4.15 (br. s., 3H), 4.05 (br. s., 3H), 2.81 (br. s., 3H), 2.69 (br. s., 3H). LC-MS: method H, RT=1.57 min, MS (ESI) m/z: 353.0 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Example 180 6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00863
  • Intermediate I-2 (955 μl, 0.048 mmol), Intermediate I-17 (15.07 mg, 0.057 mmol), and phosphoric acid, potassium salt (20.27 mg, 0.095 mmol) were dissolved in DMF (477 μl) and degassed by bubbling with argon for 15 minutes. Pd(Ph3)4 (5.52 mg, 4.77 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 h. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45% to 75% B in 22 minutes) to yield Example 180 (2.0 mg, 4.91 μmol, 10.29% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.79 (s, 1H), 8.48 (d, J=10.7 Hz, 1H), 8.09 (s, 1H), 4.83 (s, 2H), 4.12 (s, 3H), 3.49 (s, 3H), 2.70 (s, 3H). LC-MS: method H, RT=1.39 min, MS (ESI) m/z: 371.1 (M+H)+. Analytical HPLC Method B: 91% purity.
    • Example 181 5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00864
  • Intermediate I-2 (1273 μl, 0.064 mmol), Intermediate I-16 (19.79 mg, 0.076 mmol), and phosphoric acid, potassium salt (27.0 mg, 0.127 mmol) were dissolved in DMF (637 μl) and degassed by bubbling with argon for 15 minutes. Pd(PPh3)4 (7.36 mg, 6.37 μmol) was added and degassing continued for 5 minutes. The reaction mixture was heated to 85° C. for 18 h. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 60% to 100% B in 20 minutes) to yield Example 181 (11 mg, 0.029 mmol, 45.7% yield): 1H NMR (500 MHz, CHLOROFORM-d) δ 9.06 (s, 1H), 8.82 (d, J=1.7 Hz, 1H), 7.94 (d, J=0.8 Hz, 1H), 6.71 (d, J=0.8 Hz, 1H), 4.84 (s, 2H), 4.03 (s, 3H), 3.58 (s, 3H), 2.79 (d, J=0.6 Hz, 3H), 2.71 (s, 3H) LC-MS: method H, RT=1.43 min, MS (ESI) m/z: 367.1 (M+H)+. Analytical HPLC Method B: 97% purity.
    • Example 182 6-fluoro-5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00865
  • Intermediate I-1 (0.020 g, 0.067 mmol) and Intermediate I-17 (0.018 g, 0.067 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (3.26 mg, 4.00 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and the solid was collected. Recrystallized from DMSO to yield Example 182 (0.0024 g, 6.13 μmol, 9.20% yield) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.57 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.98 (d, J=10.6 Hz, 1H), 7.77 (s, 1H), 4.15 (s, 3H), 4.13 (s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.52 min, MS (ESI) m/z: 357.1 (M+H)+. Analytical HPLC Method A: 91% purity.
    • Example 183 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00866
  • Intermediate I-2 (0.025 g, 0.080 mmol) and Intermediate I-3 (0.021 g, 0.080 mmol) were dissolved in DMF (3 mL). PdCl2(dppf)-CH2Cl2 adduct (3.90 mg, 4.77 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aq. solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on Prep HPLC using Method A yield Example 183 (0.021 g, 0.057 mmol, 72.2% yield): 1H NMR (500 MHz, CHLOROFORM-d) δ 9.08 (s, 1H), 8.88 (s, 1H), 7.93 (s, 1H), 7.27-7.26 (m, 1H), 6.94 (s, 1H), 4.84 (s, 2H), 3.90 (s, 3H), 3.57 (d, J=0.6 Hz, 3H), 2.84 (s, 3H), 2.71 (s, 3H). LC-MS: method H, RT=1.40 min, MS (ESI) m/z: 366.2 (M+H)+. Analytical HPLC: Method A, 92.3% purity.
    • Example 184 5-(benzofuran-2-yl)-2-(1-methoxyethyl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00867
    • Intermediate 184A: ethyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00868
  • Intermediate I-15 (0.650 g, 2.202 mmol) and benzofuran-2-ylboronic acid (0.357 g, 2.202 mmol) were dissolved in DMF (20 mL). PdCl2(dppf)-CH2Cl2 adduct (0.108 g, 0.132 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. 3 M Na2CO3 (1.468 mL, 4.40 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. Purified by ISCO to remove any Pd or ligand based impurities using a 40 g column with a 0-100% gradient of EtOAc in hexanes. Fractions pooled and the residue was purified on Prep HPLC Method A to yield Intermediate 184A (0.117 g, 0.352 mmol, 15.98% yield). LC-MS: method H, RT=1.21 min, MS (ESI) m/z: 333.1 (M+H).
    • Intermediate 184B: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylic acid
  • Figure US20190292176A1-20190926-C00869
  • Intermediate 184A (0.020 g, 0.060 mmol) was dissolved in THF (3 mL) and MeOH. NaOH, 1 N in water (0.500 mL, 0.500 mmol) was added and the reaction mixture was allowed to stir at room temperature for 18 h. Diluted with 1 N HCl and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc (×3). The organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 184B (0.017 g, 0.060 mmol, 99% yield) as a yellow solid. Used without further purification in the next step. 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.42 (d, J=1.4 Hz, 1H), 8.23 (s, 1H), 8.03 (br. s., 1H), 7.81 (d, J=7.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.41 (td, J=7.7, 1.4 Hz, 1H), 7.35-7.29 (m, 1H), 2.69 (s, 3H). LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 305.0 (M+H)+.
    • Intermediate 184C: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carbonyl chloride
  • Figure US20190292176A1-20190926-C00870
  • Intermediate 184B (0.018 g, 0.059 mmol) was dissolved in DCM (3 mL) and oxalyl chloride (5.18 μl, 0.059 mmol) was added. DMF (0.458 μl, 5.92 μmol) was added and the reaction mixture was allowed to stir at room temperature for 30 min. The reaction was concentrated and stored under vacuum for 1 h to yield Intermediate 184C (0.019 g, 0.059 mmol, 100% yield). Used without further purification in the next step. LC-MS: method H, RT=1.16 min, MS (ESI) m/z: 319.1 (M+H)+. Observed mass of the methyl ether in the LC/MS.
    • Intermediate 184D: 5-(benzofuran-2-yl)-N-methoxy-N,7-dimethylquinoxaline-2-carboxamide
  • Figure US20190292176A1-20190926-C00871
  • Intermediate 184C (0.019 g, 0.059 mmol) was dissolved in DCM (3 mL). DMAP (0.719 mg, 5.89 μmol), TEA (0.016 mL, 0.118 mmol), and N,O-dimethylhydroxylamine hydrochloride (5.74 mg, 0.059 mmol) were added and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with water and EtOAc. The layers were extracted and the aqueous layer was back extracted with EtOAc (×3). The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 184D (0.021 g, 0.060 mmol, 100% yield) as a yellow solid. Used without further purification in the next step. NMR (400 MHz, CHLOROFORM-d) δ 8.41 (d, J=1.8 Hz, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.40-7.33 (m, 1H), 7.31-7.25 (m, 2H), 3.83 (br. s., 3H), 3.48 (d, J=15.6 Hz, 3H), 2.74-2.64 (m, 3H). LC-MS: method H, RT=1.13 min, MS (ESI) m/z: 348.1 (M+H)+.
    • Intermediate 184E: 5-(benzofuran-2-yl)-N-methoxy-N,7-dimethylquinoxaline-2-carboxamide
  • Figure US20190292176A1-20190926-C00872
  • Intermediate 184D (0.0698 g, 0.201 mmol) was dissolved in THF (2.009 mL) and cooled to 0° C. methylmagnesium bromide (0.067 mL, 0.201 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature over 3 h. The reaction mixture was diluted with EtOAc and 1 N aqueous HCl. The mixture was allowed to stir for 30 min. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on Prep HPLC using Method A to yield Intermediate 184E (0.0087 g, 0.029 mmol, 14.32% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.54 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.23 (d, J=0.8 Hz, 1H), 7.94 (d, J=0.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.35 (td, J=7.7, 1.3 Hz, 1H), 7.31-7.29 (m, 1H), 2.87 (s, 3H), 2.71 (s, 3H). LC-MS: method H, RT=1.25 min, MS (ESI) m/z: 303.1 (M+H)+.
    • Intermediate 184F: 1-(5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl)ethanol
  • Figure US20190292176A1-20190926-C00873
  • Intermediate 184E (0.010 g, 0.033 mmol) was dissolved in MeOH (1 mL) and cooled to 0° C. CeCl3 (0.012 g, 0.033 mmol) was added to the reaction mixture followed by NaBH4 (5.01 mg, 0.132 mmol). The reaction mixture was allowed to stir for 1 h. The reaction mixture was diluted with saturated NH4Cl solution and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc (×3). The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 184F (0.009 g, 0.030 mmol, 89% yield). Will be used without further purification. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 305.1 (M+H)+.
    • Example 184
  • Intermediate 184F (0.0069 g, 0.023 mmol) was dissolved in DMF and NaH (0.907 mg, 0.023 mmol) was added. The reaction mixture was allowed to stir at room temperature for 10 min and MeI (1.418 μl, 0.023 mmol) was added. The reaction mixture was stirred at room temperature for 3h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure to yield a yellow oil. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 55% to 95% B in 10 minutes) to yield Example 184 (0.0005 g, 1.571 μmol, 6.93% yield): 1H NMR (500 MHz, METHANOL-d4) δ 9.07 (s, 1H), 8.34 (d, J=1.7 Hz, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.36-7.31 (m, 1H), 7.27-7.23 (m, 1H), 4.69 (q, J=6.8 Hz, 1H), 3.42 (s, 3H), 2.68 (s, 3H), 1.62 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 319.1 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 185 6-methoxy-2-(3-(methoxymethyl)-6-methylquinolin-8-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00874
    • Intermediate 185A: methyl 8-bromo-6-methylquinoline-3-carboxylate
  • Figure US20190292176A1-20190926-C00875
  • 8-bromo-6-methylquinoline-3-carboxylic acid (250 mg, 0.940 mmol) was dissolved in MeOH (3758 μl). Thionyl chloride (206 μl, 2.82 mmol) was added and the reaction mixture was heated to reflux for 4h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to yield Intermediate 185A (0.263 g, 0.940 mmol, 100% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 9.52 (d, J=2.0 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.70 (s, 1H), 4.06 (s, 3H), 2.59 (s, 3H). LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 280/282 (M+H)+.
    • Intermediate 185B: (8-bromo-6-methylquinolin-3-yl)methanol
  • Figure US20190292176A1-20190926-C00876
  • NaBH4 (70.2 mg, 1.856 mmol) and calcium chloride (103 mg, 0.928 mmol) were dissolved in THF (2750 μl). A solution of Intermediate 185A (260 mg, 0.928 mmol) in THF (688 μl) was added dropwise. The reaction mixture was allowed to stir for 18 h. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to yield Intermediate 185B (0.146 g, 0.579 mmol, 62% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 8.97 (d, J=1.8 Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 4.97 (d, J=5.5 Hz, 2H), 2.55 (s, 3H), 1.93 (t, J=5.7 Hz, 1H). LC-MS: method H, RT=0.85 min, MS (ESI) m/z: 252/254 (M+H)+.
    • Intermediate 185C: (8-bromo-6-methylquinolin-3-yl)methyl methanesulfonate
  • Figure US20190292176A1-20190926-C00877
  • Intermediate 185B (146 mg, 0.579 mmol) and TEA (242 μl, 1.737 mmol) were dissolved in DCM (16 mL). Methanesulfonic anhydride (121 mg, 0.695 mmol) was added and the reaction mixture was allowed to stir at room temperature for 3h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3, dried sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate 185C (0.191 g, 0.579 mmol, 100% yield). The material will be used crude in the next step. LC-MS: method H, RT=1.03 min, MS (ESI) m/z: 330.0 (M+H)+.
    • Intermediate 185D: 8-bromo-3-(methoxymethyl)-6-methylquinoline
  • Figure US20190292176A1-20190926-C00878
  • Intermediate 185C (190 mg, 0.575 mmol) was dissolved in THF (12 mL). 0.5 M sodium methoxide (2302 μl, 1.151 mmol) and the reaction mixture was allowed to stir for 18 h. The reaction mixture was concentrated in vacuo to remove the THF, diluted with EtOAc and washed with 0.5 N HCl, then brine, dried sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate 185D (0.100 g, 0.376 mmol, 65% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (d, J=2.0 Hz, 1H), 8.07-8.03 (m, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.57 (s, 1H), 4.69 (s, 2H), 3.49 (s, 3H), 2.55 (s, 3H). LC-MS: method H, RT=1.00 min, MS (ESI) m/z: 266.0 (M+H)+.
    • Intermediate 185E: (3-(methoxymethyl)-6-methylquinolin-8-yl)boronic acid
  • Figure US20190292176A1-20190926-C00879
  • Intermediate 185D (100 mg, 0.376 mmol), bis(pinacolato)diboron (143 mg, 0.564 mmol), and potassium acetate (92 mg, 0.939 mmol) were dissolved in dioxane (2099 μl) and degassed for 5 minutes by bubbling with argon. PdCl2(dppf)-CH2Cl2 adduct (24.55 mg, 0.030 mmol) was added and the reaction mixture was degassed for an additional 10 minutes. The reaction mixture was heated to 130° C. in the microwave for 45 minutes. The reaction mixture was then diluted with EtOAc and water. The reaction mixture was further extracted twice with EtOAc. The combined organic layers were washed with brine, dried sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by Prep LC (Axia Luna 5 u C18 30×100 mm column, 12 minute gradient from 30 to 100% B in A, A=10:90:0.1 MeOH:H2O:TFA, B=90:10:0.1 MeOH:H2O:TFA) to yield Intermediate 185E (0.063 g, 0.240 mmol, 64% yield): LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 232.1 (M+H)+ (see mass of methyl boronic ester in the LC/MS).
    • Example 185
  • Intermediate 185E (0.025 g, 0.096 mmol) and Intermediate I-3 (0.025 g, 0.096 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (4.73 mg, 5.79 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aq. solution (0.030 mL, 0.090 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 30% to 70% B in 10 minutes) to yield Example 185 (0.0097 g, 0.026 mmol, 27.0% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=1.9 Hz, 1H), 8.80 (d, J=1.4 Hz, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.00 (d, J=1.4 Hz, 1H), 4.71 (s, 2H), 3.86 (s, 3H), 3.42 (s, 3H), 2.76 (s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 365.3 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Example 186 2-(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00880
    • Intermediate 186A: O-methyl 5-bromo-7-methylquinoxaline-2-carbothioate
  • Figure US20190292176A1-20190926-C00881
  • Methyl 5-bromo-7-methylquinoxaline-2-carboxylate (0.200 g, 0.711 mmol) was dissolved in o-xylenes (2.85 mL) and Lawesson's Reagent (0.576 g, 1.423 mmol) was added. The reaction mixture was heated to reflux for 18 h. The reaction mixture was filtered and the filter cake washed with o-xylenes. o-Xylenes solution was loaded directly on the ISCO column. The reaction mixture was purified on ISCO 40 g column 0-50% EtOAc in hexanes gradient to yield Intermediate 186A (0.005 g, 0.017 mmol, 2.365% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.78 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 8.04 (d, J=0.9 Hz, 1H), 4.49 (s, 3H), 2.64 (s, 3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 296.9 (M+H)+.
    • Intermediate 186B: 5-bromo-2-(difluoro(methoxy)methyl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00882
  • Intermediate 186A (0.068 g, 0.229 mmol) was dissolved in CH2Cl2. Bis-(2-methoxyethyl)aminosulfur trifluoride (0.084 mL, 0.458 mmol) was added and the reaction mixture was allowed to stir at room temperature for 48h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with sodium bicarbonate, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 186B (0.065 g, 0.214 mmol, 94% yield) a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.21 (s, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.01 (s, 1H), 3.91 (s, 3H), 2.64 (s, 3H). LC-MS: method H, RT=1.29 min, MS (ESI) m/z: 302.9 (M+H)+.
    • Intermediate 186C: (2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)boronic acid
  • Figure US20190292176A1-20190926-C00883
  • A mixture of Intermediate 186B (0.070 g, 0.231 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.088 g, 0.346 mmol), potassium acetate (0.057 g, 0.577 mmol) in dioxane (2.309 mL) were degassed by bubbling argon for 5 min. PdCl2(dppf)-CH2Cl2 adduct (9.43 mg, 0.012 mmol) was added and the mixture was sealed and heated in microwave at 130° C. for 30 min. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with water, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on Prep HPLC using Method A to yield Intermediate 186C (0.010 g, 0.037 mmol, 16.16% yield) as a brown solid. LC-MS: method H, RT=0.88 min, MS (ESI) m/z: 269.1 (M+H)+.
    • Example 186
  • Intermediate 186C (0.010 g, 0.029 mmol) and Intermediate I-3 (7.37 mg, 0.029 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (1.399 mg, 1.713 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.050 mL, 0.150 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) to yield Example 186 (0.0064 g, 0.016 mmol, 55.8% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.93 (s, 1H), 8.17 (s, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.02 (d, J=1.1 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.76 (s, 3H), 2.73 (s, 3H). LC-MS: method H, RT=1.50 min, M/S (ESI) m/z: 402.1 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 187 6-methoxy-4-methyl-2-(7-methyl-2-(phenoxymethyl)quinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C00884
    • Intermediate 187A: 1-diazo-3-phenoxypropan-2-one
  • Figure US20190292176A1-20190926-C00885
  • To 2-phenoxyacetyl chloride (0.250 g, 1.465 mmol) in MeCN cooled with ice-bath was added (diazomethyl)trimethylsilane 2.0 M in diethyl ether (1.282 mL, 2.56 mmol). The mixture was allowed to stir at room temperature for 3h. Solvent was removed under reduced pressure. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% EtOAc in hexane over 18 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated (bath temp below 35° C.) to yield Intermediate 187A (0.215 g, 1.220 mmol, 83% yield) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.32 (t, J=8.0 Hz, 2H), 7.03 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 2H), 5.82 (s, 1H), 4.55 (s, 2H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 177.1 (M+H)+.
    • Intermediate 187B: 1-bromo-3-phenoxypropan-2-one
  • Figure US20190292176A1-20190926-C00886
  • Intermediate 187A (0.215 g, 1.220 mmol) was dissolved in Et2O (4.88 mL) and the mixture was cooled to 0° C. and HBr (0.242 mL, 2.136 mmol) was added dropwise. After 5 min at 0° C., the reaction mixture was allowed to stir at room temperature for 10 min. The reaction mixture was diluted with ether, washed with saturated aqueous sodium bicarbonate, washed with brine, and dried over sodium sulfate. The organic layer was concentrated (kept bath below 30° C.) and the product was used immediately without further purification. Intermediate 187B (0.224 g, 0.978 mmol, 80% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (t, J=7.9 Hz, 2H), 7.03 (t, J=7.4 Hz, 1H), 6.91 (d, J=8.1 Hz, 2H), 4.79 (s, 2H), 4.18 (s, 2H). LC-MS: method H, RT=1.09 min, Compound does not ionize well.
    • Intermediate 187C: 5-bromo-7-methyl-2-(phenoxymethyl)quinoxaline
  • Figure US20190292176A1-20190926-C00887
  • To Intermediate I-1B (0.300 g, 0.906 mmol) in anhydrous DMF (30 mL) at 0° C. was added cesium carbonate (0.516 g, 1.585 mmol) in several portions. The brown solution was stirred at 0° C. for 10 min, followed by addition of Intermediate 187B (0.249 g, 1.087 mmol) in DMF (5.0 mL). The brown solution turned yellow. The mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated. The residue was dissolved in ethyl acetate (8 mL) and 4.0 N HCl in dioxane (1.170 mL, 4.68 mmol) was added. The mixture was stirred at room temperature for 45 min. Solvent was removed under vacuum to give the deprotected intermediate as a yellow oil. The deprotected intermediate was dissolved in THF (20 mL). Tin(II) chloride dihydrate (0.290 g, 1.287 mmol) was added, followed by concentrated HCl (0.048 mL, 0.585 mmol). The mixture was placed and stirred in an oil bath pre-heated at 45° C. for 18 h. The reaction mixture was diluted with EtOAc/water and neutralized with saturated sodium bicarbonate. The mixture was stirred at room temperature for 15 min, the precipitate was removed by filtration. The organic layer was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated. The reaction mixture was purified on ISCO, 24 g column 0-100% EtOAc in hexanes to give Intermediate 187C (0.093 g, 0.254 mmol, 65.2% yield) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.13 (s, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.83 (s, 1H), 7.36-7.28 (m, 2H), 7.06-6.95 (m, 3H), 5.44 (s, 2H), 2.60 (s, 3H). LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 329.1 (M+H)+.
    • Intermediate 187D: 7-methyl-2-(phenoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00888
  • A mixture of Intermediate 187C (0.093 g, 0.283 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.108 g, 0.424 mmol), potassium acetate (0.069 g, 0.706 mmol) in dioxane (2.83 mL) were degassed by bubbling argon for 5 min. PdCl2(dppf)-CH2Cl2 adduct (0.012 g, 0.014 mmol) was added and the mixture was sealed and heated in microwave at 130° C. for 30 min. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with water, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 187D (0.100 g, 0.266 mmol, 94% yield). Used without further purification. LC-MS: method H, RT=1.21 min, MS (ESI) m/z: 295.2 (M+H)+(Mass of the boronic acid was observed in LC/MS).
    • Example 187
  • Intermediate 187D (0.025 g, 0.066 mmol) and 2-bromo-6-methoxy-4-methylbenzo[d]thiazole (0.017 g, 0.066 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (3.26 mg, 3.99 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. 3 M aqueous sodium bicarbonate solution (0.022 mL, 0.066 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and concentrated. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) to yield Example 187 (0.0084 g, 0.019 mmol, 28.7% yield): 1H NMR (500 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.93 (s, 1H), 7.97 (s, 1H), 7.36 (t, J=7.8 Hz, 2H), 7.28 (d, J=2.5 Hz, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.05 (t, J=7.3 Hz, 1H), 6.97 (s, 1H), 5.49 (s, 2H), 3.93 (s, 3H), 2.87 (s, 3H), 2.76 (s, 3H). LC-MS: method H, RT=1.53 min, MS (ESI) m/z: 428.2 (M+H)+. Analytical HPLC Method B: 97% purity.
    • Example 188 1-(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)-N,N-dimethylmethanamine
  • Figure US20190292176A1-20190926-C00889
    • Intermediate 188A: Ethyl 5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00890
  • Intermediate I-15 (0.030 g, 0.104 mmol) and Intermediate I-3 (0.027 g, 0.104 mmol) were dissolved in DMF (3 mL). PdCl2(dppf)-CH2Cl2 adduct (5.10 mg, 6.25 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield a black oil. The reaction mixture was purified on ISCO 12 g column 0-100% EtOAc in hexanes to yield Intermediate 188A (0.026 g, 0.066 mmol, 63.5% yield) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.62 (s, 1H), 9.02 (s, 1H), 8.16 (s, 1H), 7.28-7.27 (m, 1H), 6.95 (s, 1H), 4.62 (q, J=7.2 Hz, 2H), 3.91 (s, 3H), 2.84 (s, 3H), 2.74 (s, 3H), 1.51 (br. s., 3H), 1.53-1.51 (m, 3H). LC-MS: method H, RT=1.41 min, MS (ESI) m/z: 394.1 (M+H)+.
    • Intermediate 188B: (5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)methanol
  • Figure US20190292176A1-20190926-C00891
  • Sodium borohydride (4.92 mg, 0.130 mmol) and calcium chloride (7.22 mg, 0.065 mmol) were dissolved in tetrahydrofuran (2 mL) and allowed to stir for 1 h. To this suspension was added Intermediate 188A (0.0256 g, 0.065 mmol) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture diluted with water and EtOAc. The layer were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 188B (0.025 g, 0.071 mmol, 109% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 1H), 8.91 (d, J=1.8 Hz, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.31-7.30 (m, 1H), 6.97 (dd, J=2.5, 0.8 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 3H), 2.87 (s, 3H), 2.75 (s, 3H). LC-MS: method H, RT=1.29 min, MS (ESI) m/z: 352.1 (M+H)+.
    • Intermediate 188C: (5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)methyl methanesulfonate
  • Figure US20190292176A1-20190926-C00892
  • Intermediate 188B (0.025 g, 0.071 mmol) was dissolved in DCM (3 mL) and treated with TEA (0.030 mL, 0.213 mmol). To this solution was added methanesulfonic anhydride (0.015 g, 0.085 mmol) and the reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with EtOAc and saturated sodium bicarbonate. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure to yield Intermediate 188C (0.027 g, 0.063 mmol, 88% yield). Used in next step to without further purification. LC-MS: method H, RT=1.34 min, MS (ESI) m/z: 430.1 (M+H)+.
    • Example 188
  • Intermediate 188C (0.0125 g, 0.029 mmol) was dissolved in tetrahydrofuran (0.291 mL) and DIEA (7.62 μl, 0.044 mmol) was added. To the stirred reaction mixture was added dimethylamine (7.37 μl, 0.146 mmol) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45% to 85% B in 18 minutes) to yield Example 188 (1.7 mg, 4.22 μmol, 14.51% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.79 (d, J=1.7 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.01 (d, J=1.7 Hz, 1H), 3.86 (s, 3H), 3.35 (s, 2H), 2.76 (s, 3H), 2.69 (s, 3H), 2.33 (s, 6H). LC-MS: method H, RT=1.10 min, MS (ESI) m/z: 379.2 (M+H)+. Analytical HPLC Method B: 94% purity.
    • Example 189 2-(2-(ethoxymethyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00893
    • Intermediate 189A: 1-diazo-3-ethoxypropan-2-one
  • Figure US20190292176A1-20190926-C00894
  • To 2-ethoxyacetyl chloride (0.250 g, 2.040 mmol) in MeCN cooled with ice-bath was added (diazomethyl)trimethylsilane 2.0 M in diethyl ether (1.785 mL, 3.57 mmol). The mixture was allowed to stir at room temperature for 3h. Solvent was removed under reduced pressure. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% EtOAc in hexane over 18 min using a 40 g silica gel cartridge). The desired fractions were combined and concentrated (bath temp below 35° C.) to yield Intermediate 189A (0.181 g, 1.413 mmol, 69.2% yield) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 5.77 (s, 1H), 3.99 (s, 2H), 3.56 (q, J=6.9 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H).
    • Intermediate 189B: 1-diazo-3-ethoxypropan-2-one
  • Figure US20190292176A1-20190926-C00895
  • Intermediate 189A (0.145 g, 1.132 mmol) was dissolved in Et2O (4.53 mL) and cooled to 0° C. and HBr (0.224 mL, 1.980 mmol) was added dropwise. After 5 min at 0° C., the reaction mixture was allowed to stir at room temperature for 10 min. The reaction mixture was diluted with ether, washed with saturated sodium bicarbonate, washed with brine, and dried over sodium sulfate. The organic layer was concentrated (kept bath below 30° C.) and the product was used immediately without further purification. Intermediate 189B (0.148 g, 0.818 mmol, 72.2% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.26 (s, 2H), 4.07 (s, 2H), 3.59 (q, J=6.9 Hz, 2H), 1.27 (t, J=6.9 Hz, 3H).
    • Intermediate 189C: tert-butyl (2-bromo-4-methyl-6-nitrophenyl)(3-ethoxy-2-oxopropyl)carbamate
  • Figure US20190292176A1-20190926-C00896
  • To Intermediate I-1B (0.226 g, 0.681 mmol) in anhydrous DMF (30 mL) at 0° C. was added cesium carbonate (0.388 g, 1.192 mmol) in several parts. The brown solution was stirred at 0° C. for 10 min, followed by addition of Intermediate 189B (0.148 g, 0.818 mmol) in DMF (5.0 mL). The brown solution turned yellow. The mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by ISCO (40 g silica gel column, (0% to 60% EtOAc/Hexane over 18 min) to yield Intermediate 189C (0.197 g, 0.457 mmol, 67.0% yield) as a yellow solid. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 431.0 (M+H)+.
    • Intermediate 189D: 5-bromo-2-(ethoxymethyl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00897
  • To Intermediate 189C (0.187 g, 0.434 mmol) in Ethyl acetate (8 mL) was added 4.0 N HCl in dioxane (1.301 mL, 5.20 mmol) and the mixture was stirred at room temperature for 45 min. Solvent was removed under vacuum to give the deprotected intermediate as a yellow oil. The deprotected intermediate was dissolved in THF (20 mL). Tin(II) chloride dihydrate (0.323 g, 1.431 mmol) was added, followed by concentrated HCl (0.053 mL, 0.650 mmol). The mixture was placed and stirred in an oil bath pre-heated at 45° C. for 18 h. The reaction mixture was diluted with EtOAc/water and neutralized with saturated sodium bicarbonate. The mixture was stirred at room temperature for 15 min, the precipitate was removed by a separatory funnel. The organic layer was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated. The reaction mixture was purified on ISCO 24 g column 0-100% EtOAc in hexanes to yield Intermediate 189D (0.056 g, 0.199 mmol, 45.9% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 9.05 (s, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.81 (s, 1H), 4.86 (s, 2H), 3.68 (q, J=7.0 Hz, 2H), 2.58 (s, 3H), 1.31 (t, J=6.9 Hz, 3H). LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 281.1 (M+H)+.
    • Intermediate 189E: 2-(ethoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline
  • Figure US20190292176A1-20190926-C00898
  • A mixture of Intermediate 189D (0.056 g, 0.199 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.076 g, 0.299 mmol), potassium acetate (0.049 g, 0.498 mmol) in dioxane (1.992 mL) were degassed by bubbling argon for 5 min. PdCl2(dppf)-CH2Cl2 adduct (8.13 mg, 9.96 μmol) was added and the mixture was sealed and heated in microwave at 130° C. for 30 min. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with water, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 189E (0.050 g, 0.152 mmol, 76% yield) as a brown oil Used without further purification in the next step. LC-MS: method H, RT=1.06 min, MS (ESI) m/z: 247.2 (M+H)+. Mass of the boronic acid seen in LC/MS.
    • Example 189
  • Intermediate 189E (0.025 g, 0.076 mmol) and Intermediate I-3 (0.020 g, 0.076 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (3.73 mg, 4.57 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. 3 M sodium carbonate solution (0.025 mL, 0.076 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and concentrated. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) to yield Example 189 (0.0003 g, 0.759 μmol, 0.996% yield): 1H NMR (500 MHz, CHLOROFORM-d) δ 9.15 (s, 1H), 8.90 (d, J=1.4 Hz, 1H), 7.95 (s, 1H), 7.31-7.30 (m, 1H), 6.97 (s, 1H), 4.91 (s, 2H), 3.93 (s, 3H), 3.76 (q, J=6.9 Hz, 2H), 2.87 (s, 3H), 2.74 (s, 3H), 1.37 (t, J=6.9 Hz, 3H). LC-MS: method H, RT=1.49 min, MS (ESI) m/z: 380.2 (M+H)+. Analytical HPLC Method B: 96% purity.
    • Example 190 6-methoxy-2-(4-methoxy-3-(methoxymethyl)-6-methylquinolin-8-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00899
    • Intermediate 190A: diethyl 2-(((2-bromo-4-methylphenyl)amino)methylene)malonate
  • Figure US20190292176A1-20190926-C00900
  • 2-bromo-4-methylaniline (0.667 mL, 5.37 mmol) and diethyl 2-(ethoxy methylene)malonate (1.184 mL, 5.91 mmol) were heated to 100° C. under a stream of argon. The reaction mixture stirred for 2h and was cooled to ambient temperature, diluted with hexanes, heated gently to break up the material, and the solid collected by suction filtration Intermediate 190A (1.80 g, 5.05 mmol, 94% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 11.22 (d, J=12.8 Hz, 1H), 8.48 (d, J=13.4 Hz, 1H), 7.42 (s, 1H), 7.21-7.11 (m, 2H), 4.35 (q, J=7.3 Hz, 2H), 4.26 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H).
    • Intermediate 190B: ethyl 8-bromo-4-hydroxy-6-methylquinoline-3-carboxylate
  • Figure US20190292176A1-20190926-C00901
  • Intermediate 190A (0.250 g, 0.702 mmol) was dissolved in biphenyl ether (12.5 mL) was added. The reaction mixture was stirred at 250° C. for 18 h. The reaction mixture was cooled to ambient temperature. The reaction mixture was filtered and washed with Et2O to yield Intermediate 190B (0.187 g, 0.603 mmol, 86% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 12.33 (s, 1H), 9.19 (s, 1H), 8.09 (s, 1H), 7.99 (d, J=1.5 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 2.54 (s, 3H), 1.48 (t, J=7.0 Hz, 3H). LC-MS: method H, RT=0.95 min, MS (ESI) m/z: 310.0 (M+H)+.
    • Intermediate 190C: ethyl 8-bromo-4-chloro-6-methylquinoline-3-carboxylate
  • Figure US20190292176A1-20190926-C00902
  • Intermediate 190B (0.100 g, 0.322 mmol) was dissolved in POCl3 (0.150 mL, 1.612 mmol) and heated to reflux for 3h. The reaction mixture was carefully diluted with water and ice. The layers were separated and the organic layer was washed with aqueous saturated NaHCO3, brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 190C (0.048 g, 0.146 mmol, 45.3% yield) as a pale yellow solid. Used without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.61 (s, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 4.60 (q, J=7.2 Hz, 2H), 2.75 (s, 3H), 1.51 (t, J=7.2 Hz, 3H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 328.0 (M+H)+.
    • Intermediate 190D: methyl 8-bromo-4-methoxy-6-methylquinoline-3-carboxylate
  • Figure US20190292176A1-20190926-C00903
  • Intermediate 190C (0.480 g, 1.461 mmol) was dissolved in THF (10 mL) and sodium methoxide (8.76 mL, 4.38 mmol) was added. The reaction mixture was allowed to stir at room temperature for 30 min. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 190D (0.454 g, 1.464 mmol, 100% yield) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 9.21 (s, 1H), 8.02 (dd, J=1.8, 0.9 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 4.14 (s, 3H), 4.01 (s, 3H), 2.55 (s, 3H). LC-MS: method H, RT=1.16 min, MS (ESI) m/z: 310.0 (M+H)+.
    • Intermediate 190E: (8-bromo-4-methoxy-6-methylquinolin-3-yl)methanol
  • Figure US20190292176A1-20190926-C00904
  • Calcium chloride (0.072 g, 0.645 mmol) and sodium borohydride (0.049 g, 1.290 mmol) were suspended in tetrahydrofuran and allowed to stir for 1 h. To the stirred reaction mixture was added Intermediate 190D (0.200 g, 0.645 mmol) in tetrahydrofuran (25 mL) and the reaction mixture was allowed to stir for 3 days. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified by ISCO 24 g column 0-100% EtOAc in hexanes to yield Intermediate 190E (0.050 g, 0.177 mmol, 27.5% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.96 (s, 1H), 7.91 (d, J=1.4 Hz, 1H), 7.85 (d, J=0.8 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 4.11 (d, J=0.8 Hz, 3H), 2.55 (s, 3H). LC-MS: method H, RT=0.84 min, MS (ESI) m/z: 282.1 (M+H)+.
    • Intermediate 190F: (8-bromo-4-methoxy-6-methylquinolin-3-yl)methyl methanesulfonate
  • Figure US20190292176A1-20190926-C00905
  • Intermediate 190E (0.050 g, 0.177 mmol) was dissolved in DCM (3 mL) and treated with TEA (0.074 mL, 0.532 mmol). To this solution was added methanesulfonic acid (0.037 g, 0.213 mmol), and the reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with EtOAc and saturated sodium bicarbonate. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure to yield Intermediate 190F (0.027 g, 0.073 mmol, 53%). Used without further purification in the next step. LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 296.1 (M+H)+ Observed the methyl ether in LC/MS.
    • Intermediate 190G: 8-bromo-4-methoxy-3-(methoxymethyl)-6-methylquinoline
  • Figure US20190292176A1-20190926-C00906
  • Intermediate 190F (0.180 g, 0.500 mmol) was dissolved in THF (5.00 ml) and DIPEA (0.131 ml, 0.750 mmol) was added. To the stirred reaction was added sodium methoxide (5.00 ml, 2.498 mmol), and the reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 190G (0.068 g, 0.230 mmol, 46%) as a yellow solid. Used without further purification in the next step. LC-MS: method H, RT=0.97 min, MS (ESI) m/z: 298.1 (M+H)+.
    • Intermediate 190H: 4-methoxy-3-(methoxymethyl)-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C00907
  • A mixture of Intermediate 190G (0.027 g, 0.091 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.035 g, 0.137 mmol), potassium acetate (0.022 g, 0.228 mmol) in dioxane (0.912 mL) were degassed by bubbling argon for 5 min. PdCl2(dppf)-CH2Cl2 adduct (3.72 mg, 4.56 μmol) was added and the mixture was sealed and heated in microwave at 130° C. for 30 min. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 190H (0.040, 0.058, 64%) as a brown oil. Used in the next step without further purification. LC-MS: method H, RT=0.98 min, MS (ESI) m/z: 262.2 (M+H)+. Mass of the boronic acid was seen in LC/MS.
    • Example 190
  • Intermediate 190H (0.031 g, 0.090 mmol) and Intermediate I-3 (0.023 g, 0.090 mmol) were dissolved in DMF (3 mL). PdCl2(dppf)-CH2Cl2 adduct (4.43 mg, 5.42 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and concentrated. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 55% to 100% B in 22 minutes) to yield Example 190 (0.0036 g, 8.58 μmol, 9.50% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.82 (s, 1H), 8.10 (s, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.00 (s, 1H), 4.73 (s, 2H), 4.12 (s, 3H), 3.86 (s, 3H), 3.42 (s, 3H), 2.76 (s, 3H), 2.68 (s, 3H). LC-MS: method H, RT=1.10 min, MS (ESI) m/z: 395.2 (M+H)+. Analytical HPLC Method B: 94% purity.
    • Example 191 5-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00908
    • Intermediate 191A: 5-chloro-7-methylthiazolo[5,4-b]pyridin-2-amine
  • Figure US20190292176A1-20190926-C00909
  • Potassium thiocyanate (0.682 g, 7.01 mmol) was dissolved in acetic acid (10 mL) and cooled to 0° C. 6-chloro-4-methylpyridin-3-amine (1.00 g, 7.01 mmol) was dissolved in acetic acid (3.33 mL) and added dropwise. Bromine (0.361 mL, 7.01 mmol) was dissolved in acetic acid (3.33 mL) and added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The resultant residue was diluted with water and neutralized with 1 N NaOH. The aqueous solution was extracted with EtOAc (×3). The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on Prep HPLC using Method A to yield Intermediate 191A (0.890 g, 4.46 mmol, 63.6% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.08 (d, J=0.7 Hz, 1H), 3.39 (dt, J=3.2, 1.6 Hz, 2H), 2.50 (d, J=0.7 Hz, 3H). LC-MS: method H, RT=0.92 min, MS (ESI) m/z: 200.1 (M+H)+.
    • Intermediate 191B: 2-bromo-5-chloro-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C00910
  • Copper(II) bromide (0.295 g, 1.320 mmol) and t-butyl nitrite (0.157 mL, 1.320 mmol) were dissolved in MeCN (3.11 mL) and allowed to stir 10 minutes. Intermediate 191A (0.155 g, 0.776 mmol) was dissolved in MeCN (4.66 mL) and the copper solution was added. The reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, washed with saturated NaHCO3, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate 191B (0.163 g, 0.618 mmol, 80% yield). 1H NMR (400 MHz, METHANOL-d4) δ 7.43 (d, J=0.9 Hz, 1H), 2.68 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 263.0 (M+H)+.
    • Example 191
  • Intermediate 191B (0.025 g, 0.095 mmol) was dissolved in Et2O (0.379 mL) and cooled to −78° C. BuLi (0.042 mL, 0.104 mmol) was added and allowed to stir for 15 min. Tributylchlorostannane (0.026 mL, 0.095 mmol) was added and allowed to stir for 30 min. The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude material was suspended in hexanes and filtered through dry celite. Used immediately without further purification. Intermediate I-2E (0.015 g, 0.056 mmol), stannane, and potassium acetate (0.011 g, 0.112 mmol) were dissolved in dioxane (0.562 mL) and degassed by bubbling with argon for 15 minutes. Pd(Ph3P)4 (3.24 mg, 2.81 μmol) was added and the reaction mixture was sealed and heated to 120° C. in the microwave for 2 hours. The reaction mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 65% to 100% B in 12 minutes) to yield Example 191 (0.0023 g, 6.08 μmol, 10.82% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.88 (s, 1H), 8.14 (s, 1H), 7.62 (s, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.84 (s, 3H), 2.73 (s, 3H). LC-MS: method H, RT=1.11 min, MS (ESI) m/z: 371.2 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Example 192 (5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl) methanol
  • Figure US20190292176A1-20190926-C00911
    • Intermediate 192A: 2-methoxy-5-nitroisonicotinic acid
  • Figure US20190292176A1-20190926-C00912
  • 2-chloro-5-nitroisonicotinic acid (0.100 g, 0.494 mmol) was dissolved in DCM (4.94 mL) and oxalyl chloride (0.043 mL, 0.494 mmol) was added. To the stirred reaction mixture was added 2 drops of DMF. The reaction mixture was stirred for 30 min and concentrated under reduced pressure. The compound was used without further purification in the next step. The residue was dissolved in tetrahydrofuran (4.98 mL) and sodium methoxide (3.98 mL, 1.991 mmol) was added. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with water and EtOAc. 1 N HCl was added and the layers were separated. The organic layer was washed brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 192A (0.078 g, 0.394 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.97 (s, 1H), 6.95 (s, 1H), 4.08 (s, 3H). LC-MS: method H, RT=0.82 min, MS (ESI) m/z: 198.9 (M+H)+.
    • Intermediate 192B: methyl 2-methoxy-5-nitroisonicotinate
  • Figure US20190292176A1-20190926-C00913
  • Intermediate 192A (0.085 g, 0.429 mmol) was dissolved in DCM (4.29 mL) and oxalyl chloride (0.038 mL, 0.429 mmol) was added. To the stirred reaction mixture was added 2 drops of DMF. The reaction mixture was stirred for 30 min and concentrated under reduced pressure. The compound was used without further purification in the next step. The residue dissolved in MeOH (4.16 mL) and sodium methoxide (0.831 mL, 0.416 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with water, brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 192B (0.060 g, 0.283 mmol, 68.1% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.96 (s, 1H), 6.86 (s, 1H), 4.06 (s, 3H), 3.96 (s, 3H). LC-MS: method H, RT=0.83 min, MS (ESI) m/z: 213.1 (M+H)+.
    • Intermediate 192C: methyl 5-amino-2-methoxyisonicotinate
  • Figure US20190292176A1-20190926-C00914
  • Intermediate 192B (60 mg, 0.283 mmol) was dissolved in EtOH (1.131 mL). Pd/C (6.02 mg, 5.66 μmol) then ammonium formate (89 mg, 1.414 mmol) were added and the reaction mixture was heated to reflux for 1 h. The reaction mixture was filtered through celite and concentrated in vacuo to yield Intermediate 192C (47.5 mg, 0.261 mmol, 92% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 7.80 (s, 1H), 7.15 (s, 1H), 5.09 (br. s., 2H), 3.91 (s, 3H), 3.87 (s, 3H). LC-MS: method H, RT=0.67 min, MS (ESI) m/z: 183.1 (M+H)+.
    • Intermediate 192D: methyl 2-amino-5-methoxythiazolo[5,4-b]pyridine-7-carboxylate, 2 AcOH
  • Figure US20190292176A1-20190926-C00915
  • Potassium thiocyanate (0.029 g, 0.299 mmol) was dissolved in acetic acid (10 mL) and cooled to 0° C. Intermediate 192C (0.0545 g, 0.299 mmol) was dissolved in acetic acid (3.33 mL) and added dropwise. Bromine (0.015 mL, 0.299 mmol) was dissolved in acetic acid (3.33 mL) and added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stir for 18 h. The reaction mixture was concentrated under reduced pressure. The resultant residue was diluted with water and neutralized with 1 N NaOH. The aqueous solution was extracted with EtOAc (×3). The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 192D (0.100 g, 0.278 mmol, 93% yield). 1H NMR (400 MHz, METHANOL-d4) δ 7.10 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H). LC-MS: method H, RT=0.67 min, MS (ESI) m/z: 240.1 (M+H)+.
    • Intermediate 192E: methyl 2-bromo-5-methoxythiazolo[5,4-b]pyridine-7-carboxylate
  • Figure US20190292176A1-20190926-C00916
  • Copper(II) bromide (0.106 g, 0.473 mmol) and t-butyl nitrite (0.056 mL, 0.473 mmol) were dissolved in MeCN (1.113 mL) and allowed to stir 10 minutes. Intermediate 192D (0.100 g, 0.278 mmol) was dissolved in MeCN (1.670 mL) and the copper solution was added. The reaction mixture was stirred for 1 h. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, washed with saturated NaHCO3, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate 192E (0.025 g, 0.082 mmol, 29.6% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 7.31 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H). LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 303.0 (M+H)+.
    • Intermediate 192F: (2-bromo-5-methoxythiazolo[5,4-b]pyridin-7-yl)methanol
  • Figure US20190292176A1-20190926-C00917
  • Intermediate 192E (25 mg, 0.082 mmol) was dissolved in toluene (550 μl) and THF (275 μl) and cooled to −78° C. 1 M DIBAL-H (181 μl, 0.181 mmol) was added, and the reaction mixture was allowed to stir for 18 h. The reaction mixture was quenched with 1 N HCl (1 mL), diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 192F (0.02 g, 0.029 mmol, 35.3% yield). Used without further purification in the next step. LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 275.0 (M+H)+.
    • Example 192
  • Intermediate I-2 (0.020 g, 0.064 mmol) and Intermediate 192E (0.018 g, 0.064 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (3.12 mg, 3.82 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 25% to 55% B in 20 minutes) to yield Example 192 (0.0012 g, 3.01 μmol, 4.73% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.07 (s, 1H), 7.05 (s, 1H), 5.64 (t, J=5.6 Hz, 1H), 5.13 (d, J=5.2 Hz, 2H), 4.83 (s, 2H), 4.01 (s, 3H), 3.49 (s, 3H), 2.71 (s, 3H). LC-MS: method H, RT=1.02 min, MS (ESI) m/z: 383.1 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Example 193 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00918
    • Intermediate 193A: 2-amino-7-methylthiazolo[5,4-b]pyridin-5-ol, 2hydrobromide
  • Figure US20190292176A1-20190926-C00919
  • Intermediate I-16 (0.750 g, 3.84 mmol) was dissolved HBr in acetic acid (2.61 mL, 23.05 mmol) and the reaction mixture was stirred at 130° C. for 3h. The reaction mixture was concentrated under reduced pressure to yield Intermediate 193A (1.48 g, 4.31 mmol, 100%) as a tan solid. 1H NMR (400 MHz, METHANOL-d4) δ 6.66 (d, J=0.9 Hz, 1H), 2.48 (d, J=0.7 Hz, 3H) LC-MS: method H, RT=0.47 min, MS (ESI) m/z: 182.1 (M+H)+.
    • Intermediate 193B: tert-butyl (2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00920
  • Intermediate 193A (0.100 g, 0.332 mmol) was dissolved in DMF (3.32 mL). t-Butyl (2-bromoethyl)carbamate (0.089 g, 0.398 mmol) and Cs2CO3 (0.541 g, 1.659 mmol) were added and the reaction mixture was stirred at 40° C. for 3h. The reaction mixture was diluted with water and EtOAc. The layers were separated. The organic layer was washed with brine dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on ISCO using a 24 g column with a 0-100% gradient of EtOAc in hexanes to yield Intermediate 193B (0.038 g, 0.117 mmol, 35.3% yield) a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.53 (s, 1H), 5.14 (br. s., 2H), 4.33 (t, J=5.2 Hz, 2H), 3.71 (t, J=5.0 Hz, 1H), 3.52 (d, J=5.1 Hz, 2H), 2.49 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=0.77 min, MS (ESI) m/z: 325.2 (M+H)+.
    • Intermediate 193C: tert-butyl (2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C00921
  • Copper(II) bromide (0.044 g, 0.199 mmol) and t-butyl nitrite (0.024 mL, 0.199 mmol) were dissolved in MeCN (0.469 mL) and allowed to stir 10 minutes. Intermediate 193B (0.038 g, 0.117 mmol) was dissolved in MeCN (0.703 mL) and the copper solution was added. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, washed with saturated NaHCO3, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield Intermediate 193C (0.042 g, 0.108 mmol, 92% yield). LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 390.0 (M+H)+.
    • Intermediate 193D: 2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanamine
  • Figure US20190292176A1-20190926-C00922
  • To a mixture of Intermediate 193C (0.042 g, 0.108 mmol) in DCM (1) was added 2,6-lutidine (0.038 mL, 0.325 mmol) followed by TMS-OTf (0.078 mL, 0.433 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted by EtOAc and NaHCO3. The organic layer was washed by brine, dried by sodium sulfate and concentrated to Intermediate 193D (0.0185 g, 0.064 mmol, 59.4% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.68 (d, J=0.9 Hz, 1H), 4.37 (t, J=5.3 Hz, 2H), 3.11 (t, J=5.3 Hz, 2H), 2.63 (d, J=0.9 Hz, 3H), 2.53 (s, 1H). LC-MS: method H, RT=0.68 min, MS (ESI) m/z: 290.1 (M+H)+.
    • Intermediate 193E: N-(2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00923
  • To a solution of Intermediate 193D (0.018 g, 0.062 mmol) in DMF (1 mL) was added DIEA (0.109 mL, 0.625 mmol) and 4-fluorobenzene-1-sulfonyl chloride (0.015 g, 0.075 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure to yield Intermediate 193E (0.028 g, 0.063 mmol, 100% yield) as a yellow glass. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.89-7.84 (m, 2H), 7.15 (t, J=8.7 Hz, 2H), 6.55 (d, J=0.9 Hz, 1H), 4.97 (br. s., 1H), 4.43-4.32 (m, 2H), 3.47-3.37 (m, 2H), 2.63 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 446.0 (M+H)+.
    • Example 193
  • Intermediate I-2 (0.010, 0.032 mmol) and Intermediate 193E (0.014 g, 0.032 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (1.560 mg, 1.910 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45% to 90% B in 20 minutes) to yield Example 193 (0.0053 g, 9.48 μmol, 29.8% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.76 (d, J=1.7 Hz, 1H), 8.03 (s, 1H), 7.92-7.88 (m, 2H), 7.44-7.39 (m, 2H), 6.73 (s, 1H), 4.82 (s, 2H), 4.34 (t, J=5.5 Hz, 2H), 3.49 (s, 3H), 3.26 (q, J=5.6 Hz, 2H), 2.73 (s, 3H), 2.69 (s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 554.1 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 194 4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00924
  • Intermediate I-2 (0.010, 0.032 mmol) and Example 193E (0.015 g, 0.032 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (1.560 mg, 1.910 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 60% to 90% B in 20 minutes) to yield Example 194 (0.0043 g, 7.65 μmol, 23% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.55 (d, J=1.4 Hz, 1H), 8.01 (t, J=5.8 Hz, 1H), 7.89 (dd, J=8.8, 5.2 Hz, 2H), 7.83 (s, 1H), 7.41 (t, J=8.8 Hz, 2H), 6.72 (s, 1H), 4.33 (t, J=5.5 Hz, 2H), 4.09 (s, 3H), 3.26 (d, J=5.8 Hz, 2H), 2.72 (s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 540.1 (M+H)+. Analytical HPLC Method B: 96% purity.
    • Example 195 5-(benzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C00925
    • Intermediate 195A: ethyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate
  • Figure US20190292176A1-20190926-C00926
  • Intermediate I-15 (0.250 g, 0.847 mmol) and benzofuran-2-ylboronic acid (0.137 g, 0.847 mmol) were dissolved in DMF (20 mL). PdCl2(dppf)-CH2Cl2 adduct (0.042 g, 0.051 mmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3 (3 mL, 6.00 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. Purified by ISCO to remove any Pd or ligand based impurities. 40 g column with a 0-100% gradient of EtOAc in hexanes was used. Fractions pooled and the residue was purified on Prep HPLC using Method A to yield Intermediate 195A (0.074 g, 0.223 mmol, 26.3% yield) LC-MS: method H, RT=1.19 min, MS (ESI) m/z: 333.0 (M+H)+.
    • Intermediate 195B: (5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl)methanol
  • Figure US20190292176A1-20190926-C00927
  • Intermediate 195A (0.010 g, 0.030 mmol) was dissolved in THF (1 mL). LiBH4 (1.311 mg, 0.060 mmol) was added and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 195B. LC-MS: method H, RT=1.07 min, MS (ESI) m/z: 291.1 (M+H)+. Used without further purification in the next step.
    • Example 195
  • Intermediate 195B (0.0087 g, 0.030 mmol), Cs2CO3 (0.024 g, 0.075 mmol), and MeI (1.874 μl, 0.030 mmol) were dissolved in DMF (1 mL) and allowed to stir at 50° C. for over the weekend. The reaction mixture was diluted with water and EtOAc. The aqueous layer was back extracted with EtOAc and the combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 45% to 80% B in 20 minutes) to yield Example 195 (0.0006 g, 1.932 μmol, 6.45% yield): 1H NMR (500 MHz, METHANOL-d4) δ 9.05 (s, 1H), 8.34 (d, J=1.7 Hz, 1H), 8.15 (d, J=0.8 Hz, 1H), 7.80 (d, J=0.8 Hz, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.58-7.55 (m, 1H), 7.33 (td, J=7.7, 1.1 Hz, 1H), 7.28-7.22 (m, 1H), 4.82 (s, 2H), 3.58 (s, 3H), 2.68 (s, 3H). LC-MS: method H, RT=1.17 min, MS (ESI) m/z: 305.3 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 196 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl pyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C00928
    • Intermediate 196A: 2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C00929
  • Example 193A (0.050 g, 0.146 mmol) was dissolved in DMF. 2-Bromomethyl acetate (0.058 g, 0.350 mmol) and Cs2CO3 (0.237 g, 0.729 mmol) were added and the reaction mixture was stirred at 40° C. for 18 h. The reaction mixture was diluted with EtOAc and water. The layers were separated. The organic layer was washed with brine dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on ISCO using a 24 g column with a 0-100% EtOAc in hexanes gradient to yield Intermediate 196A (0.044 g, 0.165 mmol, 56.5% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.53-6.53 (m, 1H), 5.01 (br. s., 2H), 4.52-4.48 (m, 2H), 4.44-4.39 (m, 2H), 2.49 (d, J=0.7 Hz, 3H), 2.09 (s, 3H). LC-MS: method H, RT=0.72 min, MS (ESI) m/z: 268.2 (M+H)+.
    • Intermediate 196B: 2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C00930
  • Copper(II) bromide (0.063 g, 0.280 mmol) and t-butyl nitrite (0.033 mL, 0.280 mmol) were dissolved in MeCN (0.658 mL) and allowed to stir 10 minutes. Intermediate 196A (0.044 g, 0.165 mmol) was dissolved in MeCN (0.988 mL) and the copper solution was added. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate 196B (0.046 g, 0.139 mmol, 84% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J=0.9 Hz, 1H), 4.57-4.53 (m, 2H), 4.44-4.41 (m, 2H), 2.63 (d, J=0.9 Hz, 3H), 2.09 (s, 3H). LC-MS: method H, RT=1.07 min, MS (ESI) m/z: 331.0 (M+H)+.
    • Intermediate 196C: 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C00931
  • Intermediate I-9 (0.042 g, 0.140 mmol) and Intermediate 196B (0.046 g, 0.140 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (6.86 mg, 8.40 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was purified on ISCO using 24 g column with a 0-100% EtOAc in hexanes gradient to yield Intermediate 196C (0.021 g, 0.049 mmol, 35.4% yield) as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.60 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 7.75 (s, 1H), 6.74 (s, 1H), 4.63 (dd, J=5.8, 3.6 Hz, 2H), 4.51-4.43 (m, 2H), 4.13 (s, 3H), 2.79 (s, 3H), 2.66 (s, 3H), 2.11 (s, 3H). LC-MS: method H, RT=1.34 min, MS (ESI) m/z: 425.1 (M+H)+.
    • Intermediate 196D: 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00932
  • To a suspension of Intermediate 196C (0.143 g, 0.337 mmol) in THF (3 mL) and MeOH (1 mL) was added NaOH (1.011 mL, 1.011 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted by EtOAc and 1N HCl, extracted by EtOAc, the combined organic layer was washed by water and brine and dried by sodium sulfate, and concentrated to yield Intermediate 196D (0.120 g, 0.314 mmol, 93% yield) as a tan solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.61 (s, 1H), 8.58 (s, 1H), 7.78 (s, 1H), 6.82 (s, 1H), 4.48-4.45 (m, 2H), 4.40-4.36 (m, 1H), 4.13 (s, 3H), 3.94-3.90 (m, 2H), 2.77 (s, 3H), 2.66 (s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 383.9 (M+H)+.
    • Intermediate 196E: 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C00933
  • To a solution of Intermediate 196D (0.025 g, 0.065 mmol) in THF (3 mL) at room temperature was added 15% phosgene in toluene (0.231 mL, 0.327 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to give Intermediate 196E (0.030 g, 0.067 mmol, 100% yield) as an yellow solid. It was used for the next step without any purification. LC-MS: method H, RT=1.35 min, MS (ESI) m/z: 444.7 (M+H)+.
    • Example 196
  • To a solution of Intermediate 196E (20 mg, 0.045 mmol) in DCM (1 mL) and THF (0.5 mL) was added pyridin-3-amine (14.81 mg, 0.157 mmol) followed by DIEA (0.079 mL, 0.450 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and water. The combined organic layer was washed by brine and concentrated under vacuum. The reaction mixture was diluted with DMSO, filtered, and purified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) to yield Example 196 (0.003 g, 5.61 μmol, 12.48% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.56 (d, J=1.4 Hz, 1H), 8.22 (d, J=4.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.34 (dd, J=8.3, 4.7 Hz, 1H), 6.93 (s, 1H), 4.67-4.63 (m, 2H), 4.55-4.48 (m, 2H), 4.09 (s, 3H), 2.75 (s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 503.9 (M+H)+. Analytical HPLC Method B: 94% purity.
    • Example 197 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C00934
  • To a solution of Intermediate 196E (20 mg, 0.045 mmol) in DCM (1 mL) and THF (0.5 mL) was added 5-aminopicolinonitrile (18.74 mg, 0.157 mmol) followed by DIEA (0.079 mL, 0.450 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was allowed to stir for 18 h at 40° C. The reaction mixture was diluted with EtOAc and water. The combined organic layer was washed by brine and concentrated under vacuum. The reaction mixture was diluted with DMSO, filtered, and purified by preparative HPLC (Method D, 50% to 85% B in 20 minutes) to yield Example 197 (3.2 mg, 5.88 μmol, 13% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.73 (d, J=2.2 Hz, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.11 (dd, J=8.7, 2.3 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 6.92 (s, 1H), 4.71-4.66 (m, 2H), 4.58-4.53 (m, 2H), 4.09 (s, 3H), 2.74 (s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 527.8 (M+H)+. Analytical HPLC Method B: 97% purity.
    • Example 198 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl (6-cyanopyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C00935
    • Intermediate 198A: 2-amino-6-fluorothiazolo[5,4-b]pyridin-5-ol, 2hydrobromide
  • Figure US20190292176A1-20190926-C00936
  • Intermediate I-17 (0.500 g, 2.510 mmol) was dissolved HBr in acetic acid (1.704 mL, 15.06 mmol), and the reaction was stirred at 130° C. for 3 h. The reaction was concentrated under reduced pressure to yield Intermediate 198A (0.422 g, 1.216 mmol, 48.5% yield) as a tan solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.67 (d, J=9.7 Hz, 1H). LC-MS: method H, RT=0.44 min, MS (ESI) m/z: 186.1 (M+H)+.
    • Intermediate 198B: 2-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C00937
  • Intermediate 198A (0.100 g, 0.288 mmol) was dissolved in DMF (2.88 ml) and Cs2CO3 (0.376 g, 1.153 mmol) was added followed by 2-bromoethyl acetate (0.058 g, 0.346 mmol). The reaction was stirred at room temperature for 3 h. Reaction was diluted with water and EtOAc. The layers were separated, and the aqueous layer was washed with EtOAc thrice. The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 198B (0.079 g, 0.291 mmol, 101% yield) as a brown solid. Will be used without further purification in the next step. (0.079 g, 0.291 mmol, 100% yield): 1H NMR (400 MHz, CHLOROFORM-d6) δ 7.46 (d, J=10.6 Hz, 1H), 4.65-4.54 (m, 2H), 4.49-4.43 (m, 2H), 2.10 (s, 4H). LC-MS: method H, RT=0.67 min, MS (ESI) m/z: 272.1 (M+H)+.
    • Intermediate 198C: 2-((2-bromo-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C00938
  • Copper(II) bromide (0.078 g, 0.347 mmol) and t-butyl nitrite (0.041 ml, 0.347 mmol) were dissolved in MeCN (0.818 ml) and allowed to stir for 10 minutes. Intermediate 198B (0.080 g, 0.204 mmol) was dissolved in MeCN (1.226 ml), and the copper solution was added. The reaction was stirred for 1 h. The reaction was diluted with EtOAc, washed with 1 N HCl, washed with saturated NaHCO3, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate 198C (0.069 g, 0.206 mmol, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.7 Hz, 1H), 4.69-4.65 (m, 2H), 4.51-4.46 (m, 2H), 2.10 (s, 3H). LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 335.0 (M+H)+.
    • Intermediate 198D: 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C00939
  • Intermediate I-9 (0.062 g, 0.206 mmol) and Intermediate 198C (0.069 g, 0.206 mmol) were dissolved in DMF (1 ml). PdCl2(dppf)-CH2Cl2 adduct (10.09 mg, 0.012 mmol) was added, and the reaction was degassed by bubbling with argon for 15 minutes. A 3 M aqueous solution of Na2CO3 (0.100 ml, 0.300 mmol) was added, and the reaction was degassed for 5 minutes. The reaction vessel was sealed and heated to 90° C. in the microwave for 30 minutes. The reaction was filtered and purified on ISCO using 24 g column with a 0-100% EtOAc in hexanes gradient to yield Intermediate 198D (0.069 g, 0.161 mmol, 78% yield) as an off white solid. LC-MS: method H, RT=0.55 min, MS (ESI) m/z: 429.1 (M+H)+.
    • Intermediate 198E: 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C00940
  • To a suspension of Intermediate 198D (0.021 g, 0.049 mmol) in THF (1 mL) and MeOH (0.333 mL) was added NaOH (0.147 mL, 0.147 mmol) at room temperature. The mixture was stirred for 1 h. The mixture was diluted with EtOAc and 1N HCl. The layers were separated, and the aqueous layer was back extracted with EtOAc. The combined organic layer was washed with water, washed with brine, dried with Na2SO4, and concentrated under reduced pressure to yield Intermediate 198E (0.020 g, 0.052 mmol, 106% yield) as a white solid. Will be used without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.58 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.01 (d, J=10.1 Hz, 1H), 7.79-7.77 (m, 1H), 4.71-4.63 (m, 2H), 4.13 (s, 3H), 4.08 (d, J=7.5 Hz, 2H), 2.65 (s, 3H). LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 387.1 (M+H)+.
    • Intermediate 198F: 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C00941
  • To a solution of Intermediate 198E (0.025 g, 0.065 mmol) in THF (3 mL) at room temperature was added 15% phosgene in toluene (0.228 mL, 0.323 mmol), and the mixture was stirred at room temperature for 2 h. Solvent was completely removed and the sample was under vacuum overnight to yield Intermediate 198F (0.029 g, 0.065 mmol, 100% yield) as a yellow solid. LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 448.6 (M+H)+.
    • Example 198
  • To a solution of Intermediate 198F (15 mg, 0.033 mmol) in DCM (1 mL) and THF (0.5 mL) was added 5-aminopicolinonitrile (13.93 mg, 0.117 mmol) followed by DIEA (0.058 mL, 0.334 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 0.2 mL of MeOH. The reaction mixture was concentrated. The reaction mixture was diluted with DMSO, filtered, and purified by preparative HPLC (Method D, 55% to 85% B in 20 minutes) to yield Example 198 (4.6 mg, 8.22 μmol, 24.60% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.56 (br. s., 1H), 8.72 (d, J=8.8 Hz, 2H), 8.56 (br. s., 1H), 8.50 (d, J=11.3 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.96-7.94 (m, 1H), 7.88 (br. s., 1H), 4.82 (br. s., 2H), 4.61 (br. s., 2H), 4.10 (br. s., 3H), 2.65 (br. s., 3H). LC-MS: method H, RT=1.16 min, MS (ESI) m/z: 532.1 (M+H)+. Analytical HPLC Method B: 95% purity.
    • Example 199 N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00942
  • In a vial charged with a stirring bar, Intermediate I-28 (130 mg, 0.406 mmol) and Intermediate I-5 (235 mg, 0.527 mmol) were dissolved in 1,4-dioxane (8 mL). Na2CO3 (6 mL, 12.00 mmol) was added, followed by PdCl2(dppf)-CH2Cl2 adduct (16.56 mg, 0.020 mmol). The mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted by adding 30 mL of EtOAc and 20 mL of water. After separation, the aqueous layer was extracted with 20 mL of EtOAc. Then organic phases were combined, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (40 g silica gel column, 0-100% EtOAc/Hexane) to give Example 199 as a yellow solid (203 mg, 90%). 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.03 (br s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz, 2H), 7.48-7.39 (m, 3H), 6.85 (d, J=1.4 Hz, 1H), 4.07 (s, 3H), 4.04 (s, 2H), 3.22 (br s, 2H), 2.70 (s, 3H); LC-MS: method J, RT=1.27 min, MS (ESI) m/z: 559.1 (M+H)+.
    • Examples 200 to 225
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 199 and the examples above.
  • LCMS LCMS
    Ex. [M + H]+ RT (Min)/
    No. Structure m/z Method NMR
    200
    Figure US20190292176A1-20190926-C00943
         		573.2  1.15/J 1H NMR (500 MHz, chloroform-d) δ 9.14 (s, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.97- 7.90 (m, 2H), 7.20 (t, J = 8.5 Hz, 2H), 7.16 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 4.98 (t, J = 6.3 Hz, 1H), 4.86 (s, 2H), 4.11 (t, J = 5.2 Hz, 2H), 3.60 (s, 3H), 3.45 (d, J = 5.5 Hz, 2H), 2.83 (s, 3H).
    201
    Figure US20190292176A1-20190926-C00944
         		386.1  1.29/H 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.77 (br s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H).
    202
    Figure US20190292176A1-20190926-C00945
         		372.10 2.19/L 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.77 (br s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H).
    203
    Figure US20190292176A1-20190926-C00946
         		436.15 2.882/L 1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.82 (br s, 1H), 8.20 (br s, 1H), 7.59 (br s, 1H), 7.04 (br s, 1H), 4.86 (s, 2H), 3.87 (d, J = 1.1 Hz, 3H), 3.50 (s, 3H), 2.76 (s, 3H).
    204
    Figure US20190292176A1-20190926-C00947
         		410.2  2.434/L 1H NMR (500 MHz, DMSO-d6) δ 9.38 (d, J = 1.9 Hz, 1H), 9.26 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.03 (s, 1H), 4.86 (s, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 3.50 (s, 3H), 2.76 (s, 3H).
    205
    Figure US20190292176A1-20190926-C00948
         		597.15 2.323/L 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J = 1.7 Hz, 1H), 9.23 (s, 1H), 8.65 (d, J = 1.9 Hz, 1H), 8.04 (br s, 1H), 7.94-7.85 (m, 2H), 7.50-7.38 (m, 3H), 6.88 (s, 1H), 4.85 (s, 2H), 4.06 (t, J = 5.1 Hz, 2H), 4.02 (s, 3H), 3.49 (s, 3H), 3.23 (t, J = 5.0 Hz, 2H), 2.74 (s, 3H).
    206
    Figure US20190292176A1-20190926-C00949
         		370.2  1.23/J 1H NMR (400 MHz, chloroform-d) δ 9.12 (s, 1H), 8.85 (dd, J = 9.9, 2.9 Hz, 1H), 7.78 (dd, J = 8.6, 2.9 Hz, 1H), 6.96 (d, J = 1.3 Hz, 1H), 4.86 (s, 2H), 3.91 (s, 3H), 3.60 (s, 3H), 2.83 (s, 3H).
    207
    Figure US20190292176A1-20190926-C00950
         		557.2  1.12/J 1H NMR (400 MHz, chloroform-d) δ 9.12 (s, 1H), 8.85 (dd, J = 9.7, 2.9 Hz, 1H), 7.99-7.88 (m, 2H), 7.79 (dd, J = 8.4, 2.9 Hz, 1H), 7.24-7.15 (m, 3H), 6.86 (s, 1H), 4.99 (t, J = 5.8 Hz, 1H), 4.86 (s, 2H), 4.11 (t, J = 5.0 Hz, 2H), 3.60 (s, 3H), 3.45 (q, J = 5.5 Hz, 2H), 2.85-2.79 (m, 3H).
    208
    Figure US20190292176A1-20190926-C00951
         		420.05 2.74/L 1H NMR (500 MHz, METHANOL-d4) δ 9.22 (s, 1H), 9.13 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 6.92 (s, 1H), 4.86 (s, 2H), 3.88 (s, 3H), 3.59 (s, 3H), 2.78 (s, 3H).
    209
    Figure US20190292176A1-20190926-C00952
         		629.05 (M + Na)+ 2.625/L 1H NMR (500 MHz, METHANOL-d4) δ 9.23 (s, 1H), 9.13 (d, J = 1.5 Hz, 1H), 8.40 (s, 1H), 7.94-7.87 (m, 2H), 7.26-7.09 (m, 3H), 6.82 (s, 1H), 4.87 (s, 2H), 4.06 (t, J = 5.4 Hz, 2H), 3.59 (s, 3H), 3.35 (t, J = 5.4 Hz, 2H), 2.77 (s, 3H).
    210
    Figure US20190292176A1-20190926-C00953
         		406.1  1.23/H 1H NMR (400 MHz, chloroform-d) δ 9.14 (s, 1H), 9.08 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 4.86 (s, 2H), 3.93 (s, 3H), 3.60 (s, 3H).
    211
    Figure US20190292176A1-20190926-C00954
         		363.0  2.633/L 1H NMR (500 MHz, DMSO-d6) δ 8.97 (br s, 1H), 8.94 (s, 1H), 8.54 (br s, 1H), 7.58 (br s, 1H), 7.05 (br s, 1H), 4.14 (br s, 3H), 3.87 (br s, 3H), 2.78 (br s, 3H).
    212
    Figure US20190292176A1-20190926-C00955
         		372.0  1.06/J 1H NMR (400 MHz, chloroform-d) δ 9.17 (s, 1H), 9.14 (dd, J = 7.5, 1.3 Hz, 1H), 8.20 (dd, J = 8.1, 1.3 Hz, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 4.88 (s, 2H), 3.93 (s, 3H), 3.60 (s, 3H).
    213
    Figure US20190292176A1-20190926-C00956
         		539.20 2.542/L 1H NMR (500 MHz, DMSO-d6) δ 9.16 (br s, 1H), 9.01-8.94 (m, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.06 (br s, 2H), 7.90 (br s, 2H), 7.49-7.38 (m, 3H), 6.86 (br s, 1H), 4.83 (br s, 2H), 4.05 (br s, 2H), 3.47 (br s, 3H), 3.22 (br s, 2H), 2.73 (br s, 3H).
    214
    Figure US20190292176A1-20190926-C00957
         		393.6  1.23/J 1H NMR (400 MHz, chloroform-d) δ 8.86 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 6.7, 1.9 Hz, 1H), 4.15 (s, 3H), 4.02 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ −146.29 (d, J = 18.3 Hz, 1F), −160.18 (dd, J = 18.3, 6.9 Hz, 1F).
    215
    Figure US20190292176A1-20190926-C00958
         		410.0  1.45/J 1H NMR (400 MHz, Dioxane) δ 8.85 (d, J = 2.4 Hz, 1H), 8.63 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 4.11 (s, 3H), 3.97 (s, 3H); 19F NMR (376 MHz, dioxane) δ −136.60 (s, 1F).
    216
    Figure US20190292176A1-20190926-C00959
         		404.05 2.289/L 1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.90 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 2.54 (s, 3H), 2.29 (s, 3H).
    217
    Figure US20190292176A1-20190926-C00960
         		385.10 2.341/K 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.99 (s, 1H), 8.59 (s, 1H), 6.86 (d, J = 7.7 Hz, 1H), 3.99 (s, 3H), 3.25 (br s, 3H).
    218
    Figure US20190292176A1-20190926-C00961
         		406.05 2.049/L 1H NMR (500 MHz, DMSO-d6) δ 8.74 (br s, 2H), 8.01-7.89 (m, 2H), 5.66 (br s, 1H), 4.83 (br s, 2H), 4.09 (br s, 3H), 3.97 (br s, 3H).
    219
    Figure US20190292176A1-20190926-C00962
         		382.15 2.228/L 1H NMR (500 MHz, DMSO-d6) δ 8.76 (br s, 2H), 7.91 (br s, 1H), 7.55 (br s, 1H), 5.63 (d, J = 3.9 Hz, 1H), 4.85 (br s, 2H), 4.11 (br s, 3H), 3.91 (br s, 3H), 2.76 (br s, 3H), 2.26 (br s, 3H).
    220
    Figure US20190292176A1-20190926-C00963
         		390.15 1.957/L 1H NMR (500 MHz, DMSO-d6) δ 8.70 (br s, 2H), 7.90 (br s, 1H), 7.76 (br s, 1H), 5.66 (br s, 1H), 4.83 (br s, 2H), 4.10 (br s, 3H), 3.98 (br s, 3H).
    221
    Figure US20190292176A1-20190926-C00964
         		367.10 2.234/L 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.88 (d, J = 1.9 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.05-7.98 (m, 2H), 4.13 (s, 3H), 3.97 (s, 3H).
    222
    Figure US20190292176A1-20190926-C00965
         		372.10 1.851/L 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.01-7.88 (m, 3H), 5.62 (t, J = 5.8 Hz, 1H), 4.82 (d, J = 5.8 Hz, 2H), 4.09 (s, 3H), 3.96 (s, 3H).
    223
    Figure US20190292176A1-20190926-C00966
         		369.15 2.010/L 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.68 (s, 1H), 7.91 (s, 1H), 6.87 (s, 1H), 5.62 (t, J = 5.8 Hz, 1H), 4.82 (d, J = 5.5 Hz, 2H), 4.09 (s, 3H), 3.95 (s, 3H), 2.72 (s, 3H).
    224
    Figure US20190292176A1-20190926-C00967
         		424.15 2.106/L 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.61 (s, 1H), 6.21 (s, 1H), 4.87 (d, J = 5.8 Hz, 2H), 4.12 (s, 3H), 3.98 (s, 3H).
    • Example 225 8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carboxamide
  • Figure US20190292176A1-20190926-C00968
    • Intermediate 225A: 8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carboxylic acid
  • Figure US20190292176A1-20190926-C00969
  • Example 205 (223 mg, 0.374 mmol) was dissolved in THF (10 mL) and water (10 mL). The mixture was treated with LiOH.H2O (31.4 mg, 0.748 mmol) at 40° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted by adding 30 mL of EtOAc and 10 ml of water, followed by 2 mL of 1N HCl (aq.). After shaking and separation, the organic phase was washed with 10 mL of brine and dried over Na2SO4. Concentration gave the desired product as a white solid (145 mg, 63.9%). 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.21 (s, 1H), 8.63 (s, 1H), 8.04 (t, J=5.4 Hz, 1H), 7.90 (dd, 5.4 Hz, 2H), 7.51-7.35 (m, 3H), 6.86 (s, 1H), 4.85 (s, 2H), 4.05 (t, J=5.0 Hz, 2H), 3.48 (br s, 3H), 3.22 (d, J=5.0 Hz, 2H), 2.74 (s, 3H); LC-MS: method L, RT=1.939 min, MS (ESI) m/z: 583.15 (M+H)+.
    • Example 225
  • Intermediate 225A (30 mg, 0.051 mmol) was dissolved in DMF (1 mL). NH4Cl (8.26 mg, 0.154 mmol) was added, followed by HATU (23.49 mg, 0.062 mmol) and DIEA (0.027 mL, 0.154 mmol). The mixture was stirred at room temperature for 3 h. LCMS showed starting material remained. Another 3 equivalents of DIEA and NH4Cl and 1 equivalents of HATU were added. The reaction mixture was stirred at room temperature for an additional 2 h. The crude material was purified via preparative LC with condition D and dried via centrifugal evaporation to yield the desired product (5.5 mg, 0.0095 mmol, 18.4%). 1H NMR (500 MHz, DMSO-d6) δ 9.38 (d, J=1.4 Hz, 1H), 9.22 (s, 1H), 8.74 (d, J=1.7 Hz, 1H), 8.50 (br s, 1H), 8.02 (br s, 1H), 7.90 (dd, J=8.5, 5.2 Hz, 2H), 7.82 (br s, 1H), 7.47 (s, 1H), 7.43 (t, J=8.8 Hz, 2H), 6.88 (s, 1H), 4.86 (s, 2H), 4.06 (t, J=5.2 Hz, 2H), 3.49 (s, 3H), 3.27-3.16 (m, 2H), 2.76 (s, 3H); LC-MS: method L, RT=1.80 min, MS (ESI) m/z: 582.15 (M+H)+.
    • Examples 226 to 228
  • The following additional examples were prepared, isolated and characterized using the methods described above for Example 225.
    • Example 226 8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)-N,N-dimethylquinoxaline-6-carboxamide
  • Figure US20190292176A1-20190926-C00970
  • 1H NMR (500 MHz, DMSO-d6) δ 9.38 (d, J=1.4 Hz, 1H), 9.22 (s, 1H), 8.74 (d, J=1.7 Hz, 1H), 8.50 (br s, 1H), 8.02 (br s, 1H), 7.90 (dd, 5.2 Hz, 2H), 7.82 (br s, 1H), 7.47 (s, 1H), 7.43 (t, J=8.8 Hz, 2H), 6.88 (s, 1H), 4.86 (s, 2H), 4.06 (t, J=5.2 Hz, 2H), 3.49 (s, 3H), 3.27-3.16 (m, 2H), 2.76 (s, 3H); LC-MS: method L, RT=1.80 min, MS (ESI) m/z: 582.15 (M+H)+.
    • Example 227 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(piperidine-1-carbonyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00971
  • 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 8.03 (br s, 1H), 7.90 (dd, 5.2 Hz, 2H), 7.47 (s, 1H), 7.43 (t, J=8.8 Hz, 2H), 6.87 (s, 1H), 4.84 (s, 2H), 4.10-4.02 (m, 2H), 3.71 (br s, 2H), 3.48 (s, 3H), 3.42 (br s, 2H), 3.22 (br s, 2H), 2.72 (br s, 3H), 1.66 (br s, 4H), 1.54 (br s, 2H); LC-MS: method L, RT=2.27 min, MS (ESI) m/z: 650.25 (M+H)+.
    • Example 228 8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-N-(2-methoxyethyl)-3-(methoxymethyl)quinoxaline-6-carboxamide
  • Figure US20190292176A1-20190926-C00972
  • 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J=1.7 Hz, 1H), 9.22 (s, 1H), 9.08 (br s, 1H), 8.71 (d, J=1.7 Hz, 1H), 8.03 (br s, 1H), 7.93-7.87 (m, 2H), 7.48 (s, 1H), 7.42 (t, J=8.8 Hz, 2H), 6.88 (s, 1H), 4.86 (s, 2H), 4.06 (t, J=5.0 Hz, 2H), 3.55 (br s, 5H), 3.49 (s, 3H), 3.31 (s, 2H), 3.26-3.19 (m, 2H), 2.76 (s, 3H); LC-MS: method L, RT=1.92 min, MS (ESI) m/z: 640.20 (M+H)+.
    • Example 229 4-fluoro-N-(2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00973
  • To a vial charged with a stirring bar was added Example 199 (20 mg, 0.036 mmol), potassium vinyl trifluoroborate (9.58 mg, 0.072 mmol), Cs2CO3 (35.0 mg, 0.107 mmol), (S)-BINAP (4.46 mg, 7.16 μmol) and PdOAc2 (0.803 mg, 3.58 μmol). DMF (1 mL) was added. After degassing with bubbling N2 for 10 minutes, the vial was sealed and was heated at 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted by adding 10 mL of EtOAc and 10 mL of water. After separation, the organic phase was passed through anhydrous Na2SO4 and concentrated on a rotary evaporator. The crude material was purified via preparative LC/MS (method C) and dried via centrifugal evaporation to yield the Example 229 (1.9 mg, 0.0034 mmol, 9.6%). 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 8.05 (d, J=1.7 Hz, 1H), 8.03 (br s, 1H), 7.97-7.83 (m, 2H), 7.49-7.38 (m, 3H), 7.08 (dd, J=17.6, 11.0 Hz, 1H), 6.86 (d, J=1.4 Hz, 1H), 6.19 (d, J=17.9 Hz, 1H), 5.57 (d, J=11.0 Hz, 1H), 4.09 (s, 3H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (br s, 2H), 2.74 (s, 3H);); LC-MS: method K, RT=2.59 min, MS (ESI) m/z: 559.1 (M+H)+.
    • Example 230 N-(2-((2-(7-ethynyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00974
    • Intermediate 230A: 4-fluoro-N-(2-((2-(2-methoxy-7-((trimethylsilyl)ethynyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00975
  • In a microwave vial charged with a stirring bar, a solution of Example 199 (20 mg, 0.036 mmol), PdCl2(CH3CN)2(1.856 mg, 7.16 mol), 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (6.82 mg, 0.014 mmol) and Cs2CO3 (29.1 mg, 0.089 mmol) in acetonitrile (1 mL)) was stirred for 0.5 h at room temperature under N2 atmosphere. To the mixture was added ethynyltrimethylsilane (35.1 mg, 0.358 mmol), and the resultant mixture was stirred for 1 hour at 90° C. in the microwave. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (24 g silica gel column, 0-50% EtOAc/Hexane gradient) to give Intermediate 230A as a yellow solid (13.6 mg, 61.2%). LC-MS: method B, RT=3.0 min, MS (ESI) m/z: 621.1 (M+H)+.
    • Example 230
  • Intermediate 230A (10 mg, 0.016 mmol) was dissolved in MeOH (0.5 mL)/DCM (0.5 mL) and was treated with K2CO3 (1.113 mg, 8.05 μmol) for 1 hour. The solid was filtered and solvent was removed on a rotary evaporator. The crude material was purified via preparative LC/MS (method C) and dried via centrifugal evaporation to yield the title compound (1.4 mg, 0.0025 mmol, 16%). 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.70 (d, J=1.7 Hz, 1H), 8.02 (d, J=1.7 Hz, 2H), 7.90 (dd, 5.4 Hz, 2H), 7.47-7.38 (m, 3H), 6.86 (s, 1H), 4.58 (s, 1H), 4.09 (s, 3H), 4.05 (t, J=5.2 Hz, 2H), 3.22 (d, J=5.2 Hz, 2H), 2.72 (s, 3H); LC-MS: method L, RT=2.58 min, MS (ESI) m/z: 549.15 (M+H)+.
    • Example 231 N-(2-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00976
  • Example 199 (40 mg, 0.072 mmol), Pd2(dba)3 (19.66 mg, 0.021 mmol), DPPF (23.80 mg, 0.043 mmol), dicyanozinc (8.40 mg, 0.072 mmol) and zinc (7.02 mg, 0.107 mmol) were mixed in NMP (1 mL) in a microwave vial that was flushed with N2 for 10 minutes. The resulting mixture was heated at 120° C. with vigorous stirring until LCMS showed the disappearance of starting material (3 h). The mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), and then washed with water and brine. After drying over Na2SO4, the ethyl acetate solution was concentrated by rotary evaporation. The crude material was purified via preparative LC/MS-HPLC, method D and dried via centrifugal evaporation to give Example 231 (7.4 mg, 0.013 mmol, 18.8%). 1H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.87 (d, J=1.7 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H), 7.90 (dd, J=8.5, 5.5 Hz, 3H), 7.45-7.39 (m, 3H), 6.87 (s, 1H), 4.11 (s, 3H), 4.05 (t, J=5.1 Hz, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.72 (s, 3H); LC-MS: method L, RT=2.205 min, MS (ESI) m/z: 550.10 (M+H)+.
    • Examples 232 and 233
  • Examples 232 and 233 were prepared, isolated and characterized using the methods described in Example 231 above.
    • Example 232 N-(2-((2-(7-cyano-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00977
  • Example 232 was made from Example 200. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.02 (d, J=1.7 Hz, 1H), 8.77 (d, J=1.7 Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz, 3H), 7.44 (d, J=9.1 Hz, 2H), 6.86 (d, J=1.1 Hz, 1H), 4.84 (s, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.49 (s, 3H), 3.23 (t, J=5.1 Hz, 2H), 2.72 (s, 3H); LC-MS: method L, RT=2.074 min, MS (ESI) m/z: 564.15 (M+H)+.
    • Example 233 8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carbonitrile
  • Figure US20190292176A1-20190926-C00978
  • Example 233 was made from Example 201. 1H NMR (400 MHz, chloroform-d) δ 9.28 (s, 1H), 9.25 (d, J=2.0 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 7.28-7.27 (m, 1H), 6.99 (dd, J=2.6, 0.9 Hz, 1H), 4.90 (s, 2H), 3.93 (s, 3H), 3.63 (s, 3H), 2.04 (s, 3H); LC-MS: method J, RT=1.08 min, MS (ESI) m/z: 377.1 (M+H)+.
    • Example 234 4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00979
  • To a vial charged with a stirring bar was added Example 200 (40 mg, 0.070 mmol), potassium vinyl trifluoroborate (18.70 mg, 0.140 mmol), Cs2CO3 (68.2 mg, 0.209 mmol), (S)-BINAP (17.39 mg, 0.028 mmol) and PdOAc2 (3.13 mg, 0.014 mmol). DMF (1 mL) was added. After degassing with bubbling N2 for 10 minutes, the vial was sealed and was heated at 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted by adding 10 mL of EtOAc and 10 mL of water. After separation, the organic phase was passed through Na2SO4 and concentrated on a rotary evaporator. The crude material was purified via preparative LC/MS with condition D and dried via centrifugal evaporation to yield Example 234 (10.6 mg, 0.018 mmol, 25.5%). 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.04 (d, J=1.7 Hz, 1H), 8.26 (d, J=1.4 Hz, 1H), 8.04 (br s, 1H), 7.90 (dd, 5.2 Hz, 2H), 7.48-7.39 (m, 3H), 7.13 (dd, J=17.6, 11.0 Hz, 1H), 6.86 (s, 1H), 6.23 (d, J=17.3 Hz, 1H), 5.62 (d, J=11.0 Hz, 1H), 4.81 (s, 2H), 4.06 (t, J=5.1 Hz, 2H), 3.47 (s, 3H), 3.22 (t, J=5.2 Hz, 2H), 2.75 (s, 3H); LC-MS: method L, RT=2.203 min, MS (ESI) m/z: 565.15 (M+H)+.
    • Example 235 4-fluoro-N-(2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00980
    • Intermediate 235A: 4-fluoro-N-(2-((2-(7-formyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00981
  • Sodium periodate (0.424 g, 1.983 mmol) was added to a solution of Example 229 (0.364 g, 0.661 mmol) and osmium(VIII) oxide (0.084 mL, 0.013 mmol) in THF (10 mL) and water (3 mL). After 6 h, 20 mL of water and 30 mL of EtOAc was added. Phases were separated, and the aqueous phase was extracted with ethyl acetate (20 mL) and then the combined organic phases were washed with sodium thiosulfate solution and brine, dried over sodium sulfate, filtered and concentrated to give Intermediate 235A (0.319 g, 0.576 mmol, 87.2% yield) as a yellow solid. LC-MS: method J, RT=1.30 min, MS (ESI) m/z: 553.1 (M+H)+.
    • Example 235
  • Intermediate 235A (16 mg, 0.029 mmol) was dissolved in 1,4-dioxane (1 mL)/MeOH (1 mL) and was treated with NaBH4 (2.191 mg, 0.058 mmol) at room temperature for 30 minutes. Several drops of saturated NH4Cl (aq.) were added to quench the reaction. The reaction mixture was diluted by adding 15 mL of EtOAc and 10 mL of water. After separation, the organic phase was washed with brine, dried over Na2SO4, filtered, and solvent was removed to give crude product. The crude material was purified via preparative LC/MS with the condition C and dried via centrifugal evaporation to yield Example 235 (6.3 mg, 0.011 mmol, 39%). 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.73 (s, 1H), 8.03 (t, J=5.8 Hz, 1H), 7.94-7.87 (m, 3H), 7.46-7.39 (m, 3H), 6.86 (s, 1H), 5.61 (t, J=5.8 Hz, 1H), 4.83 (d, J=5.5 Hz, 2H), 4.09 (s, 3H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (q, J=5.4 Hz, 2H), 2.73 (s, 3H); LC-MS: method L, RT=2.046 min, MS (ESI) m/z: 555.15 (M+H)+.
    • Example 236 N-(2-((2-(7-(1,2-dihydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00982
  • Example 229 (7 mg, 0.013 mmol) was suspended in acetone (1 mL)/water (0.3 mL). 4-Methylmorpholine N-oxide (1.787 mg, 0.015 mmol) was added, followed by OsO4 (1.616 μl, 0.254 μmol). The mixture was stirred at room temperature overnight. On the next day, solvent was removed on a rotary evaporator and the residue was dissolved in 5 mL of EtOAc and was washed with 5 mL of water, dried over Na2SO4, filtered and concentrated to give the crude product. The crude material was purified via preparative LC/MS with the condition D and dried via centrifugal evaporation to afford Example 236 (3.9 mg, 0.0064 mmol, 50%). 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.03 (br s, 1H), 7.93 (d, J=1.7 Hz, 1H), 7.92-7.87 (m, 2H), 7.46-7.39 (m, 3H), 6.86 (d, J=1.7 Hz, 1H), 5.68 (d, J=3.3 Hz, 1H), 4.87 (br s, 2H), 4.09 (s, 3H), 4.05 (t, J=5.2 Hz, 2H), 3.69-3.56 (m, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.73 (s, 3H); LC-MS: method L, RT=1.833 min, MS (ESI) m/z: 585.20 (M+H)+.
    • Example 237 4-fluoro-N-(2-((2-(7-(2-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00983
  • To a solution of Example 229 (20 mg, 0.036 mmol) in THF (1 mL) under N2 at 0° C. was added BH3.THF (0.036 mL, 0.036 mmol) slowly. The reaction mixture was allowed to warm to room temperature and stir at room temperature for 3 h. The reaction mixture was cooled in an ice bath, and NaOH (2.91 mg, 0.073 mmol) in EtOH/H2O (2:1, 0.6 mL) was added, followed by H2O2 (0.011 mL, 0.109 mmol) dropwise. The mixture was warmed to room temperature and stirred at room temperature for 18 h. On the next day, a small amount of saturated NH4Cl (aq.) was added to quench the reaction. The reaction mixture was diluted by adding 15 mL EtOAc and 10 mL of water. After separation, the aqueous layer was passed through anhydrous Na2SO4 and solvent was removed on a rotary evaporator. The crude product was purified by prep-HPLC with method B and dried on a lyophilizer to give Example 237 (1.32 mg, 0.002 mmol, 5.9%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.04 (br s, 1H), 7.95-7.86 (m, 3H), 7.48-7.40 (m, 3H), 6.87 (d, J=1.5 Hz, 1H), 4.77 (t, J=5.3 Hz, 1H), 4.10 (s, 3H), 4.06 (t, J=5.3 Hz, 2H), 3.85-3.78 (m, 2H), 3.23 (br s, 2H), 3.07 (t, J=6.6 Hz, 2H), 2.74 (s, 3H); LC-MS: method J, RT=0.83 min, MS (ESI) m/z: 569.1 (M+H)+.
    • Example 238 N-(2-((2-(7-(aminomethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00984
    • Intermediate 238A: N-(2-((2-(7-(((2,4-dimethoxybenzyl)amino)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00985
  • Intermediate 235A (110 mg, 0.199 mmol) was dissolved in THF (2 mL) and mixed with (2,4-dimethoxy phenyl) methanamine (133 mg, 0.796 mmol). Acetic acid (0.114 mL, 1.991 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Sodium Triacetoxyborohydride (93 mg, 0.438 mmol) was added. The mixture was stirred at room temperature for 6 h. The reaction mixture was diluted by adding 30 mL of EtOAc and was washed with saturated NaHCO3(aq.) and brine, and concentrated on a rotary evaporator to give crude product that was purified by flash chromatography (24 g, 30-100% EtOAc/Hexane in 20 minutes) to give the title compound (79 mg, 0.092 mmol, 46.2% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.78 (s, 1H), 8.59 (s, 1H), 7.99 (s, 1H), 7.93 (dd, J=8.1, 5.1 Hz, 2H), 7.23-7.17 (m, 3H), 7.15 (s, 1H), 6.82 (s, 1H), 6.49-6.44 (m, 2H), 4.96 (br s, 1H), 4.14 (s, 3H), 4.12-4.05 (m, 5H), 3.87-3.83 (m, 5H), 3.82 (s, 3H), 3.44 (br s, 2H), 2.83 (s, 3H); LC-MS: method H, RT=1.13 min, MS (ESI) m/z: 704.2 (M+H)+.
    • Example 238
  • Intermediate 238A (76 mg, 0.108 mmol) was dissolved in DCM (1 mL) and was treated with TFA (1 ml, 12.98 mmol) at room temperature for 18 h. No product was shown on LCMS. Then mixture was transferred to a microwave vial and was irradiated at 100° C. for 2 h. Then solvent was removed on a rotary evaporator, residue was dissolved in small amount of DCM/MeOH and evaporated. The crude product was purified on prep-HPLC condition D and dried via centrifugal evaporation to afford Example 238 (24 mg, 0.043 mmol, 40%). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=9.9 Hz, 1H), 7.99 (s, 1H), 7.96-7.86 (m, 2H), 7.48-7.38 (m, 3H), 6.86 (br s, 1H), 4.09 (br s, 3H), 4.06 (d, J=4.4 Hz, 2H), 3.36-3.29 (m, 2H), 3.23 (d, J=4.4 Hz, 2H), 2.74 (s, 2H), 2.52 (br s, 3H); LC-MS: method L, RT=1.617 min, MS (ESI) m/z: 554.20 (M+H)+.
    • Example 239 4-fluoro-N-(2-((2-(7-(1-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00986
  • Intermediate 235A (15 mg, 0.027 mmol) was dissolved in THF (2 mL) and was treated with CH3MgBr in ether (0.018 mL, 0.054 mmol) at −78° C. After addition, the mixture was warmed to room temperature slowly, and a small amount of NH4Cl (sat., aq.) was added to quench the reaction. 10 mL of EtOAc and 5 mL of water was added to dilute the reaction mixture. After separation, the organic phase was passed through Na2SO4 and solvent was removed on a rotary evaporator. The crude material was purified via preparative LC/MS and dried via centrifugal evaporation to yield Example 239 (1.6 mg, 0.0027 mmol, 10%). 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.03 (br s, 1H), 7.94-7.87 (m, 3H), 7.46-7.41 (m, 3H), 6.86 (d, J=1.7 Hz, 1H), 5.58 (d, J=4.1 Hz, 1H), 5.09-5.02 (m, 1H), 4.09 (s, 3H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (t, J=5.4 Hz, 2H), 2.73 (s, 3H), 1.49 (d, J=6.6 Hz, 3H); LC-MS: method K, RT=2.119 min, MS (ESI) m/z: 569.2 (M+H)+.
    • Example 240 4-fluoro-N-(2-((2-(7-(hydroxy(phenyl)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00987
  • Example 240 was made by following the procedure of Example 239. 1H NMR (500 MHz, chloroform-d) δ 8.83 (d, J=1.9 Hz, 1H), 8.58 (s, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.94-7.89 (m, 2H), 7.51 (d, J=7.4 Hz, 2H), 7.41-7.35 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.19 (t, J=8.5 Hz, 2H), 7.12 (d, J=2.2 Hz, 1H), 6.81 (d, J=1.7 Hz, 1H), 6.14 (d, J=3.3 Hz, 1H), 4.97 (s, 1H), 4.12 (s, 3H), 4.08 (t, J=5.1 Hz, 2H), 3.46-3.40 (m, 2H), 2.79 (s, 3H), 2.51 (d, J=3.6 Hz, 1H); LC-MS: method L, RT=2.380 min, MS (ESI) m/z: 631.2 (M+H)+.
    • Example 241 4-fluoro-N-(2-((2-(2-methoxy-7-(prop-1-en-2-yl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00988
  • Example 199 (42.5 mg, 0.076 mmol) was dissolved in 1,4-dioxane (1.5 mL) and mixed with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25.6 mg, 0.152 mmol). Na2CO3 (1 mL, 2.000 mmol) was added, followed by PdCl2(dppf)-CH2Cl2 adduct (6.21 mg, 7.60 μmol). The mixture was stirred in a microwave at 120° C. for 1 hour. After it cooled to room temperature, the reaction mixture was diluted by adding 15 mL of EtOAc and 10 mL of water. After separation, the organic phase was washed with brine and dried over Na2SO4. Removing solvent on a rotary evaporator gave crude product that was purified by flash chromatography (4 g silica column, 0-50% EtOAc/Hexane gradient) to give Example 241 (22 mg, 0.035 mmol, 46.6% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.98 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.00-7.90 (m, 3H), 7.24-7.16 (m, 2H), 7.13 (d, J=2.2 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 5.75 (s, 1H), 5.36 (s, 1H), 5.03 (t, J=6.1 Hz, 1H), 4.15 (s, 3H), 4.09 (t, J=5.0 Hz, 2H), 3.44 (q, J=5.5 Hz, 2H), 2.82 (s, 3H), 2.35 (s, 3H); LC-MS: method H, RT=1.17 min, MS (ESI) m/z: 565.1 (M+H)+.
    • Example 242 4-fluoro-N-(2-((2-(7-(2-hydroxypropan-2-yl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00989
    • Intermediate 242A: N-(2-((2-(7-acetyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C00990
  • Sodium periodate (22.73 mg, 0.106 mmol) was added into a solution of Example 241 (20 mg, 0.035 mmol), Osmium tetroxide (5.56 μl, 0.708 μmol) in THF (1 ml) and water (0.3 mL), and stirred for 6 h. 10 mL of water and 20 mL of EtOAc was added. After separation, the aqueous layer was extracted with ethyl acetate (10 mL) and then the combined organic phases were washed with sodium thiosulfate solution and brine, dried over sodium sulfate, filtered and concentrated to give Intermediate 242A (20.07 mg, 0.035 mmol, 100% yield) as product. LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 566.8 (M+H)+.
    • Example 242
  • Intermediate 242A (20 mg, 0.035 mmol) was dissolved in THF (2 mL) under N2 and was cooled to −78° C. CH3MgBr (0.047 mL, 0.141 mmol) was added into the reaction mixture slowly. The mixture was warmed to room temperature slowly, and a small amount of NH4Cl (saturated aq.) was added to quench the reaction. The reaction mixture was diluted by adding 10 mL of EtOAc and 10 mL of water. After separation, the organic phase was concentrated, purified via preparative LC/MS with condition D, and dried via centrifugal evaporation to yield Example 242 (2.4 mg, 0.0038 mmol, 11%). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.06 (br s, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz, 2H), 7.45-7.40 (m, 3H), 6.85 (d, J=1.7 Hz, 1H), 5.51 (s, 1H), 4.09 (s, 3H), 4.04 (t, J=5.4 Hz, 2H), 3.21 (t, J=5.1 Hz, 2H), 2.73 (s, 3H), 1.60 (s, 6H); LC-MS: method L, RT=2.183 min, MS (ESI) m/z: 583.2 (M+H)+.
    • Example 243 (8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl) methanol
  • Figure US20190292176A1-20190926-C00991
    • Intermediate 243A: 5-fluoro-6-methoxy-2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C00992
  • Intermediate 243A was made by following the procedure in Example 234. LC-MS: method J, RT=1.05 min, MS (ESI) m/z: 382.1 (M+H)+.
    • Intermediate 243B: 8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbaldehyde
  • Figure US20190292176A1-20190926-C00993
  • Intermediate 243B was made by following the procedure in Intermediate 235A. LC-MS: method J, RT=0.86 min, MS (ESI) m/z: 384.1 (M+H)+.
    • Example 243
  • Example 243 was made by following the procedure in Example 235. 1H NMR (500 MHz, chloroform-d) δ 8.81 (s, 1H), 8.60 (s, 1H), 7.97 (s, 1H), 7.30 (d, J=7.7 Hz, 1H), 5.02 (d, J=3.0 Hz, 2H), 4.14 (s, 3H), 3.99 (s, 3H), 2.78 (s, 3H), 2.01 (br s, 1H); LC-MS: method L, RT=2.059 min, MS (ESI) m/z: 386.15 (M+H)+.
    • Examples 244 to 246
  • Examples 244 to 246 were made by following the general procedure described in Example 239.
    • Example 244 1-(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl) ethanol
  • Figure US20190292176A1-20190926-C00994
  • 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.76 (s, 1H), 7.93 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 5.61 (br s, 1H), 5.06 (br s, 1H), 4.09 (s, 3H), 3.93 (s, 3H), 2.69 (br s, 3H), 1.49 (d, J=5.8 Hz, 3H); LC-MS: method L, RT=2.234 min, MS (ESI) m/z: 400.15 (M+H)+.
    • Example 245 (8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl) (phenyl)methanol
  • Figure US20190292176A1-20190926-C00995
  • 1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.73 (s, 1H), 7.94 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.28-7.22 (m, 1H), 6.35 (br s, 1H), 6.06 (br s, 1H), 4.07 (s, 3H), 3.92 (s, 3H), 2.66 (s, 3H); LC-MS: method L, RT=2.428 min, MS (ESI) m/z: 462.20 (M+H)+.
    • Example 246 Cyclopropyl(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00996
  • 1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.77 (s, 1H), 7.97 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 5.62 (br s, 1H), 4.31 (br s, 1H), 4.09 (s, 3H), 3.94 (s, 3H), 2.69 (br s, 3H), 1.28-1.11 (m, 1H), 0.59-0.43 (m, 4H); LC-MS: method L, RT=2.324 min, MS (ESI) m/z: 426.15 (M+H)+.
    • Example 247 4-fluoro-N-(2-((2-(7-fluoro-2-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C00997
  • Example 247 was a side product isolated from the synthesis of Example 207. 1H NMR (400 MHz, chloroform-d) δ 8.86 (s, 1H), 8.80 (dd, J=9.8, 3.0 Hz, 1H), 7.99-7.90 (m, 2H), 7.73 (dd, J=8.5, 3.0 Hz, 1H), 7.21 (t, J=8.6 Hz, 2H), 7.16 (d, J=2.4 Hz, 1H), 6.85 (s, 1H), 5.03-4.96 (m, 1H), 4.11 (t, J=5.0 Hz, 2H), 3.45 (q, J=5.6 Hz, 2H), 2.84 (s, 3H), 2.82 (s, 3H); LC-MS: method J, RT=1.15 min, MS (ESI) m/z: 527.1 (M+H)+.
    • Example 248 (8-(5-fluoro-6-isopropoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol
  • Figure US20190292176A1-20190926-C00998
  • Example 248 was prepared from Intermediate I-35 by following the procedure described in Example 199. 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.67 (s, 1H), 7.92 (d, J=3.7 Hz, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 4.80 (d, J=5.8 Hz, 2H), 4.72 (dt, J=12.1, 6.0 Hz, 1H), 4.06 (s, 3H), 1.35 (d, J=6.1 Hz, 6H); LC-MS: method L, RT=2.16 min, MS (ESI) m/z: 399.95 (M+H)+.
    • Example 249 N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) ethyl)pyridine-3-sulfonamide
  • Figure US20190292176A1-20190926-C00999
    • Intermediate 249A: tert-butyl (2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C01000
  • Intermediate 249A was made from Intermediate I-28 and Intermediate I-5D by following the procedure described in Example 199. LC-MS: method J, RT=1.28 min, MS (ESI) m/z: 501.1 (M+H)+.
    • Intermediate 249B: 2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanamine, TFA Salt
  • Figure US20190292176A1-20190926-C01001
  • Intermediate 249A (237 mg, 0.473 mmol) was dissolved in DCM (2 mL) and was treated with TFA (1 mL, 12.98 mmol) at room temperature for 1 hour. After 1 hour, the solvent was removed on a rotary evaporator and the residue coevaporated with DCM (3×). The residue was dried in vacuo and the crude product was used in the next step without further purification. LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 400.7 (M+H)+.
    • Example 249
  • Intermediate 249B (20 mg, 0.050 mmol) was suspended in DCM (4 mL). Pyridine-3-sulfonyl chloride hydrochloride (16.02 mg, 0.075 mmol) was added, followed by DIEA (0.035 mL, 0.200 mmol) and the mixture was stirred at room temperature for 30 minutes. Solvent was removed and the crude material was purified via preparative LC/MS with condition C to yield Example 249 (3.5 mg, 0.0064, 13%). 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=1.9 Hz, 1H), 8.81 (dd, J=4.8, 1.2 Hz, 1H), 8.77 (s, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.26 (t, J=5.8 Hz, 1H), 8.22 (dt, J=8.3, 1.8 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.63 (dd, J=7.8, 4.8 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 6.82 (d, J=1.4 Hz, 1H), 4.08 (s, 3H), 4.06 (t, J=5.2 Hz, 2H), 3.29 (m, 2H), 2.70 (s, 3H); LC-MS: method L, RT=2.554 min, MS (ESI) m/z: 542.15 (M+H)+.
    • Example 250 Ethyl 2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy) acetate
  • Figure US20190292176A1-20190926-C01002
  • Example 250 was prepared from Intermediate I-28 and Intermediate I-39 by following the procedure described in Example 199. 1H NMR (400 MHz, chloroform-d) δ 8.81 (d, J=2.4 Hz, 1H), 8.60 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 7.01 (dd, J=2.4, 0.9 Hz, 1H), 4.71 (s, 2H), 4.31 (q, J=7.3 Hz, 2H), 4.14 (s, 3H), 2.84 (s, 3H), 1.33 (t, J=7.2 Hz, 3H); LC-MS: method L, RT=2.834 min, MS (ESI) m/z: 444.10 (M+H)+.
    • Example 251 2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetic acid
  • Figure US20190292176A1-20190926-C01003
  • Example 251 was another product isolated during purification of 250. 1H NMR (500 MHz, chloroform-d) δ 8.81 (d, J=2.2 Hz, 1H), 8.60 (s, 1H), 7.94 (d, J=1.9 Hz, 1H), 7.27 (s, 1H), 7.02 (s, 1H), 4.77 (s, 2H), 4.14 (s, 3H), 2.85 (s, 3H); LC-MS: method L, RT=2.398 min, MS (ESI) m/z: 416.05 (M+H)+.
    • Example 252 2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-methoxypyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01004
    • Intermediate 252A: 2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01005
  • Example 250 (230 mg, 0.518 mmol) was dissolved in 1,4-dioxane (5 mL) and was cooled to 0° C. under N2. The mixture was treated with LiBH4 (16.93 mg, 0.777 mmol) at room temperature for 18 h. On the next morning, a small amount of saturated NH4Cl (aq.) was added to quench the reaction. The reaction mixture was diluted by adding 50 mL of EtOAc and 20 mL of water. After shaking and separation, 30 mL of EtOAc was used to extract the aqueous phase. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give Intermediate 252A, which was used without purification. LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 402.1 (M+H)+.
    • Intermediate 252B: 2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01006
  • Intermediate 252B was prepared from Intermediate 252A by following procedure described in Example 229. LC-MS: method J, RT=0.81 min, MS (ESI) m/z: 394.1 (M+H)+.
    • Intermediate 252C: 2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C01007
  • Phosgene in toluene (0.922 mL, 1.398 mmol) was added dropwise to Intermediate 252B (110 mg, 0.280 mmol) dissolved in anhydrous THF (10 mL). The mixture was stirred at room temperature for 4 hours. Solvent was removed by rotary evaporator and the residue was used in the next step without purification. LC-MS: method J, RT=1.10 min, MS (ESI) m/z: 456.1 (M+H)+.
    • Intermediate 252D: 2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-methoxypyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01008
  • Intermediate 252C (30 mg, 0.066 mmol) was mixed with DIEA (0.046 mL, 0.263 mmol) in DCM (1 mL) and 6-methoxypyridin-3-amine (24.51 mg, 0.197 mmol) was added. The mixture was stirred at room temperature for 18 hours. On the next day, the reaction mixture was purified by flash chromatography (12 g silica column, 0-100% EtOAc/Hexane gradient), and the product was purified again by preparative HPLC with method B and dried on a lyophilizer to give Intermediate 252D (5.6 mg, 10.30 μmol, 15.66% yield) as a yellow solid. LC-MS: method H, RT=1.21 min, MS (ESI) m/z: 544.1 (M+H)+.
    • Intermediate 252E: 2-((2-(7-formyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl (6-methoxypyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01009
  • Intermediate 252E was prepared from Intermediate 252D by following the procedure described in Intermediate 235A. LC-MS: method H, RT=1.11 min, MS (ESI) m/z: 545.8 (M+H)+.
    • Example 252
  • Example 252 was prepared from Intermediate 252E by following the procedure described in Example 235. 1H NMR (500 MHz, DMSO-d6) δ 9.77 (br s, 1H), 8.75 (s, 1H), 8.72 (d, J=1.7 Hz, 1H), 8.24 (br s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 5.61 (t, J=5.8 Hz, 1H), 4.83 (d, J=5.8 Hz, 2H), 4.54-4.41 (m, 2H), 4.40-4.27 (m, 2H), 4.09 (s, 3H), 3.80 (s, 3H), 2.75 (s, 3H); LC-MS: method L, RT=1.955 min, MS (ESI) m/z: 548.2 (M+H)+.
    • Example 253 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01010
    • Intermediate 253A: 2-bromo-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01011
  • To a black solution of Copper (II) bromide (149 mg, 0.666 mmol) in Acetonitrile (1 mL) was added t-Butyl nitrite (0.095 mL, 0.721 mmol) at room temperature followed by 6-methoxybenzo[d]thiazol-2-amine (100 mg, 0.555 mmol). Immediate bubbling and a mild exotherm was observed upon benzothiazole addition. After 3 hours, the reaction mixture was diluted with EtOAc and washed with 1.0 M HCl, saturated NaHCO3, and then Brine. The organic phase was dried over MgSO4, filtered and concentrated to a reddish-brown solid. The crude material was purified by ISCO flash chromatography (0-15% EtOAc/Hex over 20 min, 12 g silica gel cartridge, Product at 5%). The desired fractions were combined and concentrated to yield Intermediate 253A (84 mg, 0.344 mmol, 62.0% yield) as an off-white solid. LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 244.0, 246.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.0 Hz, 1H), 7.28 (1H under CDCl3), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H)
    • Example 253
  • Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 253A (15.78 mg, 0.065 mmol) were solvated in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (2.82 mg, 3.45 μmol) was added and the solution was degassed by sparging with argon for 10 min. Sodium carbonate (9.14 mg, 0.086 mmol) was then added, followed by water (0.100 mL), and the solution was further degassed for an additional 5 min. The vial was sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 40-80% over 20 minutes) to yield Example 253 (6.7 mg, 0.019 mmol, 43.8% yield). LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 353.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.0 Hz, 1H), 7.28 (1H Under CDCl3), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H).
    • Example 254 4-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01012
    • Intermediate 254A: 4-fluoro-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01013
  • To a solution of 2-fluoro-4-methoxyaniline (150 mg, 1.063 mmol) in Acetonitrile (5.314 mL) was added ammonium thiocyanate (121 mg, 1.594 mmol). The mixture was stirred at room temperature for 5 min until fully solvated. Benzyltrimethylammonium tribromide (414 mg, 1.063 mmol) was then added at room temperature causing the solution to take on a bright yellow color with solids precipitating. The mixture was allowed to stir at room temperature overnight, at which point LCMS indicated complete conversion. The mixture was diluted with EtOAc and washed with saturated sodium bicarbonate. The organic layer was collected, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by ISCO (0-10% DCM/MeOH over 20 min using a 24 g silica gel cartridge) to give Intermediate 254A (101 mg, 0.510 mmol, 47.9% yield). LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 199.1 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.01 (d, J=2.0 Hz, 1H), 6.67 (dd, J=12.4, 2.3 Hz, 1H), 3.78 (s, 3H), 3.33-3.28 (m, 2H).
    • Intermediate 254B: 4-fluoro-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01014
  • To a dark green solution of Copper (II) bromide (125 mg, 0.560 mmol) and Intermediate 254A (101 mg, 0.510 mmol) solvated in acetonitrile (1 mL) and THF (2 mL) was added t-butyl nitrite (0.088 mL, 0.662 mmol). After stirring for 4 h at room temperature, the mixture was dilute with EtOAc and washed with 1.0 M HCl followed by Brine. The organic phase was concentrated and purified by ISCO flash chromatography (0-10% EtOAc/Hex over 20 min, 24 g silica gel cartridge-product at 5%) to afford Intermediate 254B (63 mg, 0.240 mmol, 47.2% yield) as a white solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 262.0, 264.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.05 (dd, J=2.2, 0.9 Hz, 1H), 6.83 (dd, J=11.6, 2.3 Hz, 1H), 3.87 (s, 3H).
    • Example 254
  • Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 254B (14.68 mg, 0.056 mmol) were solvated in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (2.82 mg, 3.45 μmol) was added and the solution was degassed by bubbling argon for 10 min. Sodium Carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was then added, and the solution was further degassed for an additional 5 min. The microwave vial was sealed and heated to 100° C. in the microwave for 30 min. The crude reaction mixture was diluted with Et2O and washed with water followed by brine. The organic phase was concentrated and purified by ISCO (24 g, 0-50% EtOAc/Hex, 18 min—recovered SM at 10%, Product at 20%). Example 254 (2.2 mg, 5.78 μmol, 13.40% yield) was isolated as a bright yellow solid. LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 370.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.09 (s, 1H), 8.94 (s, 1H), 7.97 (s, 1H), 7.29-7.21 (m, 2H under CDCl3), 6.88 (dd, J=11.8, 2.3 Hz, 1H), 4.86 (s, 2H), 3.93 (s, 3H), 3.59 (s, 3H), 2.71 (s, 3H).
    • Example 255 6-ethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01015
    • Intermediate 255A: 2-bromo-6-ethoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01016
  • To a solution of Copper (II) bromide (138 mg, 0.618 mmol) in acetonitrile (1 mL) was added t-butyl nitrite (0.088 mL, 0.669 mmol) at room temperature followed by 6-ethoxybenzo[d]thiazol-2-amine (100 mg, 0.515 mmol). The reaction mixture was heated to 50° C. for 45 min. The mixture was cooled to room temperature, diluted with EtOAc and washed with 1.0 M HCl followed by brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude material was purified by ISCO (24 g, 0-15% EtOAc/Hex). Example 255A (62 mg, 0.240 mmol, 46.7% yield) was isolated as a light brown solid. LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 258.2, 260.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J=9.0 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.06 (dd, J=8.9, 2.3 Hz, 1H), 4.09 (q, J=7.0 Hz, 2H), 1.46 (t, J=6.9 Hz, 3H).
    • Example 255
  • Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 255A (16.69 mg, 0.065 mmol) were solvated in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (2.82 mg, 3.45 μmol) was added and the solution was degassed by bubbling argon for 10 min. Sodium Carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was then added, and the solution was further degassed for an additional 5 min. The vial was sealed and heated to 100° C. in the microwave for 30 min in the microwave. The crude solution was filtered and purified by preparative HPLC (Method D, 50-90% over 10 minutes) to yield Example 255 (5.4 mg, 0.015 mmol, 34.3% yield). LC-MS: Method H, RT=1.38 min, MS (ESI) m/z: 366.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.0 Hz, 1H), 7.28 (1H Under CDCl3), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H).
    • Example 256 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01017
    • Intermediate 256A: 2-bromo-6-ethoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01018
  • To a solution of copper (II) bromide (134 mg, 0.600 mmol) in Acetonitrile (1 mL) was added benzo[d]thiazol-2-amine (100 mg, 0.666 mmol) at room temperature. t-Butyl nitrite (0.106 mL, 0.800 mmol) was then added. Bubbling immediately observed. After 30 min, diluted with EtOAc and washed with 1.0 M HCl followed by brine. The organic phase was concentrated and purified by ISCO flash chromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gel cartridge—product at 2.5%) to afford Intermediate 256A (80 mg, 0.374 mmol, 56.1% yield) as a pink oil. LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 214.0, 216.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.53-7.37 (m, 2H).
    • Example 256
  • Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 256A (10.0 mg, 0.047 mmol) were solvated in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (3.05 mg, 3.74 μmol) was added and the solution was degassed by bubbling argon for 10 min. Sodium Carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was then added, and the solution was further degassed for an additional 5 min. The vial was sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 45-90% over 10 minutes) to yield 256 (3.2 mg, 0.008 mmol, 34.3% yield). LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 322.0 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.87 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.52-7.46 (m, 1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.70 (s, 3H).
    • Example 257 4,6-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01019
    • Intermediate 257A: 2-bromo-4,6-difluorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01020
  • To a black solution of copper (II) bromide (144 mg, 0.645 mmol) in Acetonitrile (1 mL) was added t-Butyl nitrite (0.092 mL, 0.698 mmol) followed by 4,6-difluorobenzo[d]thiazol-2-amine (100 mg, 0.537 mmol). The reaction mixture was heated to 50° C. After 40 min, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed with 1.0 M HCl followed by brine. The crude material was concentrated and purified by flash chromatography (0-15% EtOAc/Hex over 18 min, 12 g silica gel cartridge). The desired fractions were combined and concentrated to yield Intermediate 257A (126 mg, 0.504 mmol, 94% yield) as a white solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: None (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.35 (d, J=7.5 Hz, 1H), 7.03 (td, J=9.6, 2.2 Hz, 1H). 19F NMR (CHLOROFORM-d) δ −85.7, −91.7
    • Example 257
  • Intermediate I-2 (15.1 mg, 0.048 mmol), PdCl2(dppf)-CH2Cl2 adduct (2.61 mg, 3.20 μmol) and Intermediate 257A (10 mg, 0.040 mmol) were solvated in DMF (1 mL). Sodium carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was added, and the solution was degassed with argon for 10 min. The vial was then sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 45-85% over 10 minutes) to yield Example 257 (8.3 mg, 0.021 mmol, 52.3% yield). LC-MS: Method H, RT=1.41 min, MS (ESI) m/z: 358.0 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.09 (s, 1H), 8.03-7.97 (m, 1H), 7.51 (t, J=9.4 Hz, 1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.70 (s, 3H).
    • Example 258 4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01021
    • Intermediate 258A: 2-bromo-4,6-dimethoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01022
  • To a solution of copper (II) bromide (127 mg, 0.571 mmol) in acetonitrile (1 mL) was added 4,6-dimethoxybenzo[d]thiazol-2-amine (100 mg, 0.476 mmol) at room temperature. t-Butyl nitrite (0.082 mL, 0.618 mmol) was then added dropwise at room temperature causing immediate bubbling. After 1 hr, the reaction mixture was diluted with EtOAc and washed with 1.0 M HCl. The organic phase was dried over MgSO4, filtered and concentrated. The crude material was purified by ISCO flash chromatography (0-30% EtOAc/Hex over 35 min, 12 g silica gel cartridge). Intermediate 258A (56 mg, 0.204 mmol, 43% yield) as a white solid. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 274.0, 276.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.81 (d, J=2.0 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.86 (s, 3H).
    • Example 258
  • Intermediate I-2 (13.8 mg, 0.044 mmol), PdCl2(dppf)-CH2Cl2 adduct (2.38 mg, 2.92 μmol) and Intermediate 258A (10 mg, 0.036 mmol) were solvated in DMF (1 mL). Sodium carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was added, and the solution was degassed with argon for 10 min. The vial was then sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 45-85% over 10 minutes) to yield Example 258 (6.4 mg, 0.015 mmol, 41.9% yield). LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 382.0 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.77 (s, 1H), 8.02 (s, 1H), 7.29 (s, 1H), 6.68 (s, 1H), 4.81 (s, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 3.47 (s, 3H), 2.69 (s, 3H).
    • Example 259 4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01023
    • Intermediate 259A: 2-bromo-4-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01024
  • Copper (II) bromide (112 mg, 0.499 mmol) and 4-methoxybenzo[d]thiazol-2-amine (100 mg, 0.555 mmol) were solvated in Acetonitrile (1 mL) t-Butyl nitrite (0.081 mL, 0.610 mmol) was added at room temperature. After 30 min, the reaction mixture was dilute with EtOAc and washed with 1.0 M HCl followed by brine. The crude material was concentrated and purified by ISCO flash chromatography (0-10% EtOAc/Hex over 20 min, 24 g silica gel cartridge) to afford Intermediate 259A (68 mg, 0.279 mmol, 50.2% yield). LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 242.0. 244.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.36 (m, 2H), 6.92 (dd, J=6.2, 2.9 Hz, 1H), 4.05 (s, 3H).
    • Example 259
  • Intermediate I-2 (15.4 mg, 0.049 mmol), PdCl2(dppf)-CH2Cl2 adduct (2.68 mg, 3.28 μmol) and Intermediate 259A (10 mg, 0.041 mmol) were solvated in DMF (1 mL). Sodium Carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was added, and the solution was degassed with argon for 10 min. The vial was then sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 45-85% over 10 minutes) to yield Example 259 (4.1 mg, 0.012 mmol, 28.5% yield). LC-MS: Method H, RT=1.30 min, MS (ESI) m/z: 352.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.82 (s, 2H), 4.03 (s, 3H), 3.47 (s, 3H), 2.71 (s, 3H).
    • Example 260 4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01025
    • Intermediate 260A: 2-bromo-4-chlorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01026
  • Copper (II) bromide (134 mg, 0.600 mmol) and 4-chlorobenzo[d]thiazol-2-amine (100 mg, 0.542 mmol) were solvated in acetonitrile (1 mL) and THF (1 mL). t-Butyl nitrite (0.086 mL, 0.650 mmol) was then added at room temperature. After 30 min, the reaction mixture was dilute with EtOAc and washed with 1.0 M HCl followed by brine. The crude material was concentrated and purified by ISCO flash chromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gel cartridge, product at 2.5%.) to afford Intermediate 260A (88 mg, 0.279 mmol, 65.4% yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 248.0. 250.0, 252.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.41-7.33 (m, 1H).
    • Example 260
  • Intermediate I-2 (15.1 mg, 0.048 mmol), PdCl2(dppf)-CH2Cl2 adduct (2.63 mg, 3.22 μmol) and Intermediate 260A (10 mg, 0.040 mmol) were solvated in DMF (1 mL). Sodium Carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was added, and the solution was degassed with argon for 10 min. The vial was then sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 45-85% over 10 minutes) to yield Example 260 (4.6 mg, 0.012 mmol, 30.5% yield). LC-MS: Method H, RT=1.44 min, MS (ESI) m/z: 356.0, 358.0 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.19 (d, J=7.7 Hz, 1H), 8.11 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 4.83 (s, 2H), 3.47 (s, 3H), 2.72 (s, 3H).
    • Example 261 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01027
    • Intermediate 261A: 2-bromo-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01028
  • Copper (II) bromide (122 mg, 0.546 mmol) and 2-bromo-4-methylbenzo[d]thiazole (100 mg, 0.609 mmol) were solvated in acetonitrile (1 mL) and THF (1 mL). t-Butyl nitrite (0.096 mL, 0.728 mmol) was then added at room temperature. After 30 min, the reaction mixture was dilute with EtOAc and washed with 1.0 M HCl followed by brine. The crude material was concentrated and purified by ISCO flash chromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gel cartridge, product at 2.5%.) to afford Intermediate 261A (88 mg, 0.386 mmol, 63.6% yield). LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 227.9, 229.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.64 (dt, J=7.7, 0.8 Hz, 1H), 7.34-7.27 (m, 2H), 2.72 (s, 3H).
    • Example 261
  • Intermediate I-2 (16.7 mg, 0.053 mmol), PdCl2(dppf)-CH2Cl2 adduct (2.53 mg, 3.10 μmol) and Intermediate 261A (10 mg, 0.044 mmol) were solvated in DMF (1 mL). Sodium Carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was added, and the solution was degassed with argon for 10 min. The vial was then sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 55-85% over 10 minutes) to yield Example 261 (4.5 mg, 0.013 mmol, 29.1% yield). LC-MS: Method H, RT=1.52 min, MS (ESI) m/z: 336.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 8.02-7.97 (m, 1H), 7.38 (d, J=3.9 Hz, 2H), 4.82 (s, 2H), 3.47 (s, 3H), 2.81 (s, 3H), 2.71 (s, 3H).
    • Example 262 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl-6-(trifluoromethoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01029
    • Intermediate 262A: 4-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01030
  • To a solution of 2-methyl-4-(trifluoromethoxy)aniline (150 mg, 0.785 mmol) in acetonitrile (3.924 mL) was added ammonium thiocyanate (90 mg, 1.177 mmol) followed by benzyltrimethylammonium tribromide (306 mg, 0.785 mmol) causing the reaction mixture to become a bright yellow, heterogeneous suspension. The reaction mixture was allowed to stir at room temperature overnight. After 13 h, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 followed by brine. The bright yellow organic phase was dried over MgSO4, filtered and concentrated. The resulting crude mixture was purified by ISCO (24 g Column, 0-70% EtOAc/Hex, 18 min. Product at 37%) to give Intermediate 262A (112 mg, 0.451 mmol, 57.5% yield) as a white powder. LC-MS: Method H, RT=1.03 min, MS (ESI) m/z: 249.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.32 (s, 1H), 7.02 (s, 1H), 5.24 (br. s., 2H), 2.57 (s, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −58.12 (s, 1F).
    • Intermediate 262B: 2-bromo-4-methyl-6-(trifluoromethoxy)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01031
  • Copper (II) bromide (100 mg, 0.479 mmol) and Intermediate 262A (108 mg, 0.435 mmol) were solvated in acetonitrile (2 mL). t-Butyl nitrite (0.075 mL, 0.566 mmol) was then added at room temperature. After 30 min, the reaction mixture was dilute with EtOAc and washed with 1.0 M HCl followed by brine. The crude material was concentrated and purified by ISCO flash chromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gel cartridge, product at 2.5%.) to afford Intermediate 262B (124 mg, 0.386 mmol, 91% yield). LC-MS: Method H, RT=1.42 min, MS (ESI) m/z: 312.0, 314.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.51 (s, 1H), 7.17 (s, 1H), 2.73 (s, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −57.93 (s, 1F).
    • Example 262
  • Intermediate I-2 (15.7 mg, 0.050 mmol), PdCl2(dppf)-CH2Cl2 adduct (2.72 mg, 3.33 μmol) and Intermediate 262B (13 mg, 0.042 mmol) were solvated in DMF (1 mL). Sodium carbonate (2.0 M in H2O) (100 μL, 0.200 mmol) was added, and the solution was degassed with argon for 10 min. The vial was then sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC (Method D, 55-100% over 20 minutes) to yield Example 262 (5.9 mg, 0.014 mmol, 33.4% yield). LC-MS: Method H, RT=1.56 min, MS (ESI) m/z: 420.0 (M+H)+. 1H NMR (500 MHz, METHANOL-d4) δ 9.10 (s, 1H), 8.91 (d, J=1.5 Hz, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.21 (s, 1H), 4.86 (s, 2H), 3.61 (s, 3H), 2.88 (s, 3H), 2.74 (s, 3H).
    • Preparation of 2-Aminobenzothiazoles
  • The following 2-aminobenzothiazoles were made according to the following general procedure, which is analogous to the examples described above
  • The appropriately substituted aniline (1.0 equiv) was solvated in acetonitrile (0.2 M). To this mixture was added ammonium thiocyanate (1.3 equiv) followed by benzyltrimethylammonium tribromide (1.0 equiv). After being allowed to stir at room temperature for the designated amount of time, the reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 followed by brine. The organic phase was dried over MgSO4, filtered and concentrated before being purified by silica gel chromatography to provide the desired material.
  • LCMS
    Retention
    LCMS Time
    [M + H]+ (Min)
    Intermediate Structure Time Yield m/z Method H NMR
    263A
    Figure US20190292176A1-20190926-C01032
         		 3 d 80% 231.1 0.95 1H NMR (400 MHz, CHLOROFORM- d) δ 7.26 (s, 1H), 6.95 (s, 1H), 6.90 (t, J = 74.8 Hz, 1H), 5.39 (br. s., 2H), 2.40 (s, 3H). 19F NMR (376 MHz, CHLOROFORM- d) δ −81.04 (s, 1F).
    265A
    Figure US20190292176A1-20190926-C01033
         		 7 d 24%  233.3, 235.1 1.04 1H NMR (400 MHz, CD3OD-d) δ 7.11 (d, J = 7.5 Hz, 1H), 3.87 (s, 3H).
    266A
    Figure US20190292176A1-20190926-C01034
         		16 h 72% 203.0 205.0 0.94 1H NMR (400 MHz, METHANOL-d4) δ 7.37 (dd, J = 8.0, 2.5 Hz, 1H), 7.13 (dd, J = 9.1, 2.5 Hz, 1H).
    269A
    Figure US20190292176A1-20190926-C01035
         		16 h 77% 217.1 0.89 1H NMR (400 MHz, METHANOL-d4) δ 7.24 (dd, J = 9.6, 6.9 Hz, 1H), 4.06 (d, J = 1.1 Hz, 3H).
    270A
    Figure US20190292176A1-20190926-C01036
         		16 h 64% 199.1 0.74 1H NMR (400 MHz, METHANOL-d4) δ 6.96 (dd, J = 8.1, 2.4 Hz, 1H), 6.70 (dd, J = 11.2, 2.4 Hz, 1H), 3.91 (s, 3H).
    271A
    Figure US20190292176A1-20190926-C01037
         		16 h 73% 229.1 0.79 1H NMR (400 MHz, METHANOL-d4) δ 7.08 (d, J = 7.3 Hz, 1H), 4.01 (d, J = 1.1 Hz, 3H), 3.85 (s, 3H).
    276A
    Figure US20190292176A1-20190926-C01038
         		16 h 67% 195.2 0.66 1H NMR (400 MHz, CHLOROFORM- d) δ 7.33 (d, J = 0.7 Hz, 1H), 7.04 (s, 1H), 4.97 (br. s., 2H), 3.84 (s, 3H), 2.27 (s, 3H).
    277A
    Figure US20190292176A1-20190926-C01039
         		 4 d 49% 199.1 0.56 1H NMR (400 MHz, METHANOL-d4) δ 7.34 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 11.9 Hz, 1H), 3.86 (s, 3H).
    • Preparation of 2-Bromobenzothiazoles
  • The following 2-bromobenzothiazoles were made according to the following general procedure, which is analogous to the examples described above
  • The appropriately substituted 2-aminobenzothiazole (1.0 equiv) was suspended in acetonitrile (0.2 M). To this mixture was added copper (II) bromide (1.0 equiv) followed by t-butyl nitrite (1.3 equiv). After being allowed to stir at room temperature for 30 min, the reaction mixture was diluted with EtOAc and washed with 1.0 M HCl followed by brine. The organic phase was dried over MgSO4, filtered and concentrated before being purified by silica gel chromatography to provide the desired material.
  • LCMS
    Retention
    LCMS Time
    [M + H]+ (Min)
    Intermediate Structure Yield m/z Method H NMR
    263B
    Figure US20190292176A1-20190926-C01040
         		64% 294.1, 296.1  1.24 1H NMR (400 MHz, CHLOROFORM-d) δ 7.45 (s, 1H), 7.10 (s, 1H), 7.04 (t, J = 74.4 Hz, 1H), 2.48 (s, 3H).
    264A
    Figure US20190292176A1-20190926-C01041
         		45% 272.1, 274.1  1.22 1H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (d, J = 1.3 Hz, 1H), 8.16 (dd, J = 8.6, 1.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 3.98 (s, 3H).
    265B
    Figure US20190292176A1-20190926-C01042
         		28% 295.9, 297.9, 298.9  1.32 1H NMR (400 MHz, CHLOROFORM-d) δ 7.22 (d, J = 7.3 Hz, 1H), 3.99 (s, 3H).
    266B
    Figure US20190292176A1-20190926-C01043
         		62% 265.9, 267.9, 270.0  1.22 1H NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.42 (m, 1H), 7.37-7.30 (m, 1H).
    268A
    Figure US20190292176A1-20190926-C01044
         		44% 278.0, 280.0, 282.0  1.22 1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (s, 1H), 7.30 (s, 1H), 3.98 (s, 4H).
    269B
    Figure US20190292176A1-20190926-C01045
         		60% 278.1, 280.1  1.21 1H NMR (400 MHz, CHLOROFORM-d) δ 7.27 (dd, J = 6.4, 2.6 Hz, 1H), 4.33 (d, J = 2.0 Hz, 3H).
    270B
    Figure US20190292176A1-20190926-C01046
         		49% 262.1, 264.1  1.11 1H NMR (400 MHz, CHLOROFORM-d) δ 7.09 (dd, J = 7.7, 2.2 Hz, 1H), 6.70 (dd, J = 10.9, 2.3 Hz, 1H), 4.03 (s, 3H).
    271B
    Figure US20190292176A1-20190926-C01047
         		53% 292.1, 294.1  1.14 1H NMR (400 MHz, CHLOROFORM-d) δ 7.00 (d, J = 7.0 Hz, 1H), 4.28 (d, J = 2.0 Hz, 3H), 3.95 (s, 3H).
    272A
    Figure US20190292176A1-20190926-C01048
         		88% 232.0, 234.0  1.17 1H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (dd, J = 9.0, 4.8 Hz, 1H), 7.51 (dd, J = 7.9, 2.4 Hz, 1H), 7.23 (appar. td, J = 8.9, 2.6 Hz, 1H).
    273A
    Figure US20190292176A1-20190926-C01049
         		91% 232.0, 234.0  1.17 1H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (d, J = 8.1 Hz, 1H), 7.40 (appar. td, J = 8.1, 4.6 Hz, 1H), 7.20 (dd, J = 9.6, 8.7 Hz, 1H).
    274A
    Figure US20190292176A1-20190926-C01050
         		73% 248.0, 250.1, 252.1  1.25 1H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (d, J = 8.6 Hz, 1H), 7.82-7.79 (m, 1H), 7.45 (dd, J = 8.7, 2.1 Hz, 1H).
    275A
    Figure US20190292176A1-20190926-C01051
         		73% 281.9, 283.9  1.32 1H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H).
    276B
    Figure US20190292176A1-20190926-C01052
         		74% 258.1, 260.1  1.05 1H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (d, J = 0.7 Hz, 1H), 7.16 (s, 1H), 3.89 (s, 3H), 2.32 (d, J = 0.7 Hz, 3H).
    277B
    Figure US20190292176A1-20190926-C01053
         		45% 262.0, 264.0  0.96 1H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (d, J = 11.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 3.96 (s, 3H).
    • Preparation of Quinoxaline-Benzothiazole Examples
  • The following Quinoxaline-Benzothiazole adducts were made according to the following general procedure, which is analogous to the examples described above
  • The appropriately substituted 2-bromobenzothiazole (1.0 equiv), PdCl2(dppf)-CH2Cl2 adduct (0.08 equiv), and the appropriate boronic acid or ester (1.0 equiv) were solvated in DMF (0.05 M). A 2.0 M solution of aqueous sodium carbonate (4.0 equiv) was then added, and the mixture was degassed by bubbling argon through the solution for 10 min. The vial was then sealed and heated to 100° C. in the microwave for 30 min. The crude solution was filtered and purified by preparative HPLC to yield the desired example.
  • LCMS
    LCMS RT HPLC
    [M + (Min) Prep
    H]+ Method Method
    Ex Structure B(OR)2 Br—Bzt m/z H D NMR
    263
    Figure US20190292176A1-20190926-C01054
         		I-2 263B 402.2 1.43 50-90% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.68 (t, J = 74.3 Hz, 1H), 7.21 (s, 1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.71 (s, 3H) [another (s, 3H) was buried under DMSO at 2.5 ppm].
    264
    Figure US20190292176A1-20190926-C01055
         		I-2 264A 380.2 1.35 55-100% 11 min 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.92 (d, J = 1.7 Hz, 1H), 8.87 (d, J = 1.7 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.15-8.10 (m, 2H), 4.83 (s, 2H), 3.93 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H).
    265
    Figure US20190292176A1-20190926-C01056
         		I-2 265B 404.1 406.1 1.43 70-100% 10 min 1H NMR (400 MHz, CHLOROFORM- d) δ 9.10 (s, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.30-7.27 (m, 1H- under CDCl3), 4.86 (s, 2H), 4.02 (s, 3H), 3.59 (s, 3H), 2.73 (s, 3H).
    266
    Figure US20190292176A1-20190926-C01057
         		I-2 266B  374.1, 376.1 1.45 55-100% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.84 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 8.11 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.72 (s, 3H).
    267
    Figure US20190292176A1-20190926-C01058
         		I-2 I-41 388.2 1.34 50-90% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.10 (br. s., 1H), 8.81 (br. s., 1H), 8.06 (br. s., 1H), 7.86 (d, J = 5.8 Hz, 1H), 4.83 (br. s., 2H), 4.00 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s., 3H).
    268
    Figure US20190292176A1-20190926-C01059
         		I-2 268A  385.5, 387.5 1.32 50-90% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.11 (br. s., 1H), 8.79 (br. s., 1H), 8.20 (br. s., 1H), 8.06 (br. s., 1H), 7.99 (br. s., 1H), 4.83 (br. s., 2H), 3.99 (br. s., 3H), 3.49 (br. s., 3H), 2.69 (br. s., 3H).
    269
    Figure US20190292176A1-20190926-C01060
         		I-2 269B 388.1 1.40 55-90% 25 min 1H NMR (500 MHz, DMSO-d6) δ 9.11 (br. s., 1H), 8.86 (br. s., 1H), 8.11 (br. s., 1H), 8.03 (br. s., 1H), 4.83 (br. s., 2H), 4.44 (br. s., 3H), 3.48 (br. s., 3H), 2.72 (br. s., 3H).
    270
    Figure US20190292176A1-20190926-C01061
         		I-2 270B 370.2 1.30 45-85% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.79 (s, 1H), 8.05 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 9.6 Hz, 1H), 4.81 (s, 2H), 4.04 (s, 3H), 3.46 (s, 3H), 2.69 (s, 3H).
    271
    Figure US20190292176A1-20190926-C01062
         		I-2 271B 400.2 1.30 45-85% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 4.81 (s, 2H), 4.34 (s, 3H), 3.94 (s, 3H), 3.47 (s, 3H), 2.69 (s, 3H).
    272
    Figure US20190292176A1-20190926-C01063
         		I-2 272A 340.1 1.38 35-75% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.85 (s, 1H), 8.17 (dd, J = 8.9, 4.8 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H), 7.46 (td, J = 8.9, 2.1 Hz, 1H), 4.83 (s, 2H), 3.48 (s, 3H), 2.70 (s, 3H).
    273
    Figure US20190292176A1-20190926-C01064
         		I-2 273A 340.1 1.37 40-80% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s., 1H), 8.90 (s., 1H), 8.12 (s., 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.52 (s., 1H), 7.47-7.39 (m, J = 9.6 Hz, 1H), 4.84 (s., 2H), 3.49 (s., 3H), 2.72 (s., 3H).
    274
    Figure US20190292176A1-20190926-C01065
         		I-2 274A  356.3, 358.2 1.47 60-100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.62 (dd, J = 8.5, 2.2 Hz, 1H), 4.84 (s, 2H), 3.48 (s, 3H), 2.71 (s, 3H).
    275
    Figure US20190292176A1-20190926-C01066
         		I-2 275A  390.1,  392.0, 394.1 1.57 60-100% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 4.84 (s, 2H), 2.73 (s, 2H) [another (s, 3H) was buried under H3O at 3.5 ppm].
    276
    Figure US20190292176A1-20190926-C01067
         		I-2 276B 438.2 1.16 45-85% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.79 (s, 1H), 8.02 (br. s., 1H), 7.91 (s, 1H), 7.71 (s, 1H), 4.82 (s, 2H), 3.93 (s, 3H), 3.49 (s, 3H), 2.69 (s, 3H), 2.34 (s, 3H).
    277
    Figure US20190292176A1-20190926-C01068
         		I-2 277B 370.2 1.13 45-95% 15 min 1H NMR (500 MHz, DMSO-d6) δ 9.11 (br. s., 1H), 8.81 (br. s., 1H), 8.06 (br. s., 1H), 7.99 (d, J = 9.6 Hz, 2H), 4.83 (br. s., 2H), 3.98 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s., 3H).
    278
    Figure US20190292176A1-20190926-C01069
         		I-9 I-41 374.1 1.49 55-95% 15 min 1H NMR (500 MHz, DMSO-d6) δ 8.74 (br. s., 1H), 8.59 (br. s., 1H), 7.92-7.76 (m, 2H), 4.09 (br. s., 3H), 3.99 (br. s., 3H), 2.65 (br. s., 3H).
    279
    Figure US20190292176A1-20190926-C01070
         		I-9 276B 438.2 1.16 45-80% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.59 (d, J = 1.9 Hz, 1H), 7.90 (s, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.70 (s, 1H), 4.10 (s, 3H), 3.93 (s, 3H), 2.65 (s, 3H), 2.33 (s, 3H).
    280
    Figure US20190292176A1-20190926-C01071
         		I-9 277B 356.2 1.22 60-100% 20 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 6.6 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.85 (s, 1H), 4.10 (s, 3H), 3.97 (s, 3H), 2.65 (s, 3H).
    281
    Figure US20190292176A1-20190926-C01072
         		I-2 I-40 352.3 1.24 40-80% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.76 (br. s., 1H), 9.08 (s, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.02 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H), 4.82 (s, 2H), 3.48 (s, 3H), 2.73 (s, 3H), 2.70 (s, 3H).
    282
    Figure US20190292176A1-20190926-C01073
         		I-9 I-43  390.0, 392.0 1.52 70-100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 8.78 (br. s., 1H), 8.63 (br. s., 1H), 7.97 (br. s., 1H), 7.89 (br. s., 1H), 4.10 (br. s., 3H), 3.99 (br. s., 3H), 2.67 (br. s., 3H).
    283
    Figure US20190292176A1-20190926-C01074
         		I-2 I-43  404.1, 406.1 1.16 45-80% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.84 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 4.84 (s, 2H), 4.01 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H).
    284
    Figure US20190292176A1-20190926-C01075
         		I-2 I-47 380.2 1.48 70-100% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.03 (d, J = 0.8 Hz, 1H), 7.58 (s, 1H), 4.83 (s, 2H), 3.91 (s, 3H), 3.49 (s, 3H), 2.77 (s, 3H), 2.71 (s, 3H), 2.27 (s, 3H).
    285
    Figure US20190292176A1-20190926-C01076
         		I-9 I-52 428.1 1.20 60-100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 4.10 (s, 3H), 3.75 (s, 3H), 2.90 (s, 3H), 2.75 (s, 3H).
    286
    Figure US20190292176A1-20190926-C01077
         		I-2 I-52 442.2 1.04 45-85% 15 min 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 5.00 (s, 2H), 4.82 (s, 2H), 3.76 (s, 3H), 3.48 (s, 3H), 2.72 (d, J = 1.4 Hz, 3H), 2.70 (s, 3H).
    287
    Figure US20190292176A1-20190926-C01078
         		I-9 I-57  448.1, 450.1 1.18 60-100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 3.76 (s, 3H), 3.48 (s, 3H), 2.72 (d, J = 1.4 Hz, 3H), 2.70 (s, 3H).
    288
    Figure US20190292176A1-20190926-C01079
         		I-9 I-53 400.2 1.08 45-80% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.61 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.17 (t, J = 4.8 Hz, 2H), 4.09 (s, 3H), 3.82 (q, J = 4.8 Hz, 2H), 2.70 (s, 3H), 2.65 (s, 3H).
    289
    Figure US20190292176A1-20190926-C01080
         		I-2 I-53 414.2 0.89 30-70% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.82 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.82 (s, 2H), 4.17 (t, J = 5.0 Hz, 2H), 3.82 (q, J = 5.1 Hz, 2H), 3.49 (s, 3H), 2.70 (s, 6H).
    290
    Figure US20190292176A1-20190926-C01081
         		I-2 I-46 370.1 0.93 45-85% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.81 (d, J = 1.1 Hz, 1H), 8.02 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 3.48 (s, 3H), 2.70 (s, 3H), 2.69 (d, J = 1.1 Hz, 3H).
    291
    Figure US20190292176A1-20190926-C01082
         		I-2 I-44  390.1, 392.0 1.27 30-70% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.79 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 4.82 (s, 2H), 3.48 (s, 3H), 2.70 (s, 3H).
    292
    Figure US20190292176A1-20190926-C01083
         		I-2 I-57  462.1, 464.1 1.04 30-65% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.84 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 5.07 (s, 2H), 4.84 (s, 2H), 3.77 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H).
    293
    Figure US20190292176A1-20190926-C01084
         		I-2 I-59  434.1, 436.1 0.89 35-70% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.79 (s, 1H), 8.05 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 5.00 (t, J = 5.4 Hz, 1H), 4.82 (s, 2H), 4.22 (t, J = 4.8 Hz, 2H), 3.83 (q, J = 5.0 Hz, 2H), 3.49 (s, 3H), 2.70 (s, 3H).
    294
    Figure US20190292176A1-20190926-C01085
         		I-9 I-45 370.2 1.30 55-95% 10 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.64 (s, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 4.10 (s, 3H), 3.95 (s, 3H), 2.71 (s, 3H), 2.66 (s, 3H).
    295
    Figure US20190292176A1-20190926-C01086
         		I-2 I-45 384.1 1.17 50-85% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 4.83 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H), 2.72 (s, 6H).
    296
    Figure US20190292176A1-20190926-C01087
         		I-2 I-49 438.1 1.14 60-100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 4.94 (s, 2H), 4.82 (s, 2H), 3.76 (s, 3H), 3.49 (s, 3H), 2.78 (s, 3H), 2.71 (s, 3H), 2.33 (s, 3H).
    297
    Figure US20190292176A1-20190926-C01088
         		I-2 I-51 410..2 1.30 45-90% 12 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.56 (s, 1H), 4.90 (t, J = 5.4 Hz, 1H), 4.82 (s, 2H), 4.11 (br. s., 2H), 3.82 (d, J = 4.7 Hz, 2H), 3.48 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.29 (s, 3H).
    298
    Figure US20190292176A1-20190926-C01089
         		I-2 I-56  400.1, 402.1 1.41 70-100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.83 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 4.84 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H), 2.41 (s, 3H).
    299
    Figure US20190292176A1-20190926-C01090
         		I-9 I-56  386.1, 388.1 1.50 70-100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.61 (d, J = 1.7 Hz, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 4.10 (s, 3H), 3.95 (s, 3H), 2.67 (s, 3H), 2.40 (s, 3H).
    300
    Figure US20190292176A1-20190926-C01091
         		I-2 I-54 395.8 1.06 55-100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.85 (br. s., 1H), 8.03 (br. s., 1H), 7.69 (s, 1H), 5.20 (br. s., 2H), 5.10-5.04 (m, 1H), 4.82 (s, 2H), 3.92 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H).
    301
    Figure US20190292176A1-20190926-C01092
         		I-9 I-54 381.8 1.16 50-100% 20 min 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 7.81 (s, 1H), 7.65 (s, 1H), 5.18 (d, J = 5.2 Hz, 2H), 5.09-5.02 (m, 1H), 4.08 (s, 3H), 3.91 (s, 3H), 2.65 (s, 3H), 2.36 (s, 3H).
    302
    Figure US20190292176A1-20190926-C01093
         		I-9 I-62 538.1 1.21 60-100% 13 min 1H NMR (500 MHz, DMSO-d6) δ 10.15 (br. s., 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.30 (br. s., 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.19- 7.12 (m, 1H), 4.55 (br. s., 2H), 4.43 (br. s., 2H), 4.10 (s, 3H), 2.70 (s, 3H), 2.66 (s, 3H).
    303
    Figure US20190292176A1-20190926-C01094
         		I-2 I-62 552.1 1.04 45-100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 10.15 (br. s., 1H), 9.11 (s, 1H), 8.84 (s, 1H), 8.30 (br. s., 1H), 8.05 (br. s., 1H), 7.97 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.8, 3.0 Hz, 1H), 4.83 (s, 2H), 4.55 (d, J = 4.4 Hz, 2H), 4.45 (d, J = 3.6 Hz, 2H), 3.49 (s, 3H), 2.90 (s, 3H), 2.75 (s, 3H).
    304
    Figure US20190292176A1-20190926-C01095
         		I-9 I-63  558.1, 560.1 1.18 70-100% 12 min 1H NMR (400 MHz, THF) δ 8.83 (d, J = 1.5 Hz, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.18-8.08 (m, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 6.95 (dd, J = 8.8, 3.5 Hz, 1H), 4.64-4.58 (m, 2H), 4.52-4.46 (m, 2H), 4.15 (s, 3H), 2.70 (s, 3H).
    305
    Figure US20190292176A1-20190926-C01096
         		I-2 I-63  572.1, 574.1 1.03 50-100% 10 min 1H NMR (500 MHz, CHLOROFORM- d) δ 9.11 (s, 1H), 9.00 (s, 1H), 8.18 (br. s., 1H), 8.05 (s, 3H), 6.96 (dd, J = 8.8, 3.0 Hz, 1H), 4.88 (s, 2H), 4.69-4.64 (m, 2H), 4.48-4.41 (m, 2H), 3.62 (s, 3H), 2.76 (s, 3H).
    • Example 306 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C01097
    • Intermediate 306A: 2-bromo-6-ethoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01098
  • To a solution of Intermediate I-40 (18 mg, 0.074 mmol) solvated in DMF (1 mL) was added potassium carbonate (51.0 mg, 0.369 mmol) followed by iodoethane (0.018 mL, 0.221 mmol). The reaction mixture was allowed to stir at room temperature overnight. After 15 hours, the reaction mixture was diluted with hexanes and extracted with water. The organic phase was concentrated in vacuo to provide Intermediate 306A (18 mg, 0.066 mmol, 90% yield) which was used without further purification. LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 272.1, 274.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.07 (d, J=2.4 Hz, 1H), 6.87 (dd, J=2.4, 0.7 Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 2.66 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).
    • Example 306
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 306A with Intermediate I-2 afforded Example 306 in 43% yield following purification by preparative HPLC (Method D, 60-100% over 10 min). LC-MS: Method H, RT=1.49 min, MS (ESI) m/z: 380.3 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.80 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.00 (s, 1H), 4.81 (s, 2H), 4.12 (q, J=6.9 Hz, 2H), 3.47 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 1.38 (t, J=7.0 Hz, 3H).
    • Example 307 6-(benzyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01099
    • Intermediate 307A: 6-(benzyloxy)-2-bromo-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01100
  • To a solution of Intermediate I-40 (18 mg, 0.074 mmol) solvated in DMF (1 mL) was added potassium carbonate (51.0 mg, 0.369 mmol) followed by benzyl bromide (0.013 mL, 0.111 mmol). The reaction mixture was allowed to stir at room temperature overnight. After 15 hours, the reaction mixture was diluted with hexanes and extracted with water. The organic phase was concentrated in vacuo to provide Intermediate 307A (23 mg, 0.066 mmol, 91% yield) which was used without further purification. LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 334.1, 336.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.44-7.20 (m, 5H), 7.06 (d, J=2.2 Hz, 1H), 6.89 (s, 1H), 5.02 (s, 2H), 2.59 (s, 3H).
    • Example 307
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 307A with Intermediate I-2 afforded Example 307 in 48% yield following purification by preparative HPLC (Method D, 55-100% over 10 min). LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 442.3 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.38-7.32 (m, 1H), 7.09 (s, 1H), 5.20 (s, 2H), 4.81 (s, 2H), 3.46 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H).
    • Example 308 (2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)methanol
  • Figure US20190292176A1-20190926-C01101
    • Intermediate 308A: ethyl 2-bromobenzo[d]thiazole-6-carboxylate
  • Figure US20190292176A1-20190926-C01102
  • This example was prepared according to the general procedure for 2-aminobenzothiazoles described in the table above. Thus, reaction of ethyl 2-aminobenzo[d]thiazole-6-carboxylate afforded Intermediate 308A in 98% yield. LC-MS: Method A, RT=2.06 min, MS (ESI) m/z: 286.0, 288.0 (M+H)+. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.56 (d, J=1.4 Hz, 1H), 8.18 (dd, J=8.5, 1.7 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H).
    • Intermediate 308B: (2-bromobenzo[d]thiazol-6-yl)methanol
  • Figure US20190292176A1-20190926-C01103
  • Intermediate 308A (0.85 g, 2.97 mmol) was dissolved in THF (20 mL) and cooled to 0° C. 1.0 M Super-Hydride in THF (6.54 mL, 6.54 mmol) was added dropwise to this cooled solution. After stirring at 0° C. for 1 h, the reaction was quenched with saturated ammonium chloride and then diluted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g, 5-60% EtOAc/Hexanes, 18 min) to give Intermediate 308B (0.5 g, 2.048 mmol, 69.0% yield) as a white solid. LC-MS: Method A, RT=1.54 min, MS (ESI) m/z: 244.0 and 246.0 (M+H)+. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.93 (d, J=8.5 Hz, 1H), 7.70 (d, J=0.8 Hz, 1H), 7.39 (dd, 1.5 Hz, 1H), 5.08 (s, 2H).
    • Example 308
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 308B with Intermediate I-2 afforded Example 308 in 19% yield following purification by preparative HPLC (Method D, 20-60% over 10 min). LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 352.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.88 (d, J=1.7 Hz, 1H), 8.13 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.54 (dd, J=8.5, 1.4 Hz, 1H), 5.38 (t, J=5.8 Hz, 1H), 4.83 (s, 2H), 4.69 (d, J=5.8 Hz, 2H), 3.49 (s, 3H), 2.71 (s, 3H).
    • Example 309 6-(methoxymethyl)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01104
    • Intermediate 309A: 2-bromo-6-(methoxymethyl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01105
  • Intermediate 308B (52 mg, 0.213 mmol) was solvated in THF (2.1 mL) and cooled to 0° C. Sodium Hydride (42.6 mg, 1.065 mmol) was added, causing effervescence. After 5 minutes, methyl iodide (0.067 mL, 1.065 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 10 minutes until all of the bubbling subsided. The reaction was quenched with saturated NH4Cl and diluted with EtOAc. The organic phase was extracted, washed with brine, dried over MgSO4 and concentrated. The crude material was purified by ISCO (12 g, 0-20% EtOAc/Hexanes, 18 min. Product at 8%) to afford Intermediate 309A (10 mg, 0.039 mmol, 18% yield). LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 258.1, 260.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.96 (d, J=8.4 Hz, 1H), 7.81 (d, J=0.7 Hz, 1H), 7.43 (dd, J=8.4, 1.5 Hz, 1H), 4.58 (s, 2H), 3.44 (s, 3H).
    • Example 309
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 309A with Intermediate I-2 afforded Example 309 in 27% yield following purification by preparative HPLC (Method D, 45-85% over 10 min). LC-MS: Method H, RT=1.33 min, MS (ESI) m/z: 366.3 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.15 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.09 (s, 1H), 7.54 (d, J=8.3 Hz, 1H), 4.84 (s, 2H), 4.61 (s, 2H), 3.49 (s, 3H), 3.37 (s, 3H), 2.71 (s, 3H).
    • Example 310 6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-ol
  • Figure US20190292176A1-20190926-C01106
    • Intermediate 310A: 3-((tert-butyldimethylsilyl)oxy)-4-methoxyaniline
  • Figure US20190292176A1-20190926-C01107
  • 5-amino-2-methoxyphenol (500 mg, 3.59 mmol) was solvated in DMF (3.00 mL) and DCM (15.000 mL). To this solution was added TBDMS-Cl (596 mg, 3.95 mmol) followed by imidazole (269 mg, 3.95 mmol) at room temperature. After 2 h, the reaction was quenched with saturated NaHCO3 and extracted 2× with DCM. The organic phase was concentrated and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 33 min. Product at 35%) to give Intermediate 310A (576 mg, 1.591 mmol, 44.3% yield). LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 254.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J=8.4 Hz, 1H), 6.31-6.24 (m, 2H), 3.73 (s, 3H), 3.38 (br. s., 2H), 1.00 (s, 9H), 0.16 (s, 6H).
    • Intermediate 310B: 5-((tert-butyldimethylsilyl)oxy)-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01108
  • This example was prepared according to the general procedure for the synthesis of 2-aminobenzothiazoles described in the table above. Thus, Intermediate 310A was reacted to afford Intermediate 310B as a viscous brown oil (36% Yield). LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 311.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.11 (s, 1H), 7.07 (s, 1H), 4.93 (br. s., 2H), 3.83 (s, 3H), 1.02 (s, 9H), 0.18 (s, 6H).
    • Intermediate 310C: 2-bromo-5-((tert-butyldimethylsilyl)oxy)-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01109
  • This intermediate was prepared according to the general procedure for the synthesis of 2-bromobenzothiazoles described in the table above. Thus, Intermediate 310B was reacted to afford Intermediate 310C as a purple oil (53% yield). LC-MS: Method H, RT=1.50 min, MS (ESI) m/z: 374.0, 376.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.08 (s, 1H), 6.99 (s, 1H), 3.69 (s, 3H), 0.84 (s, 9H), 0.00 (s, 6H).
    • Intermediate 310D: 2-bromo-6-methoxybenzo[d]thiazol-5-ol
  • Figure US20190292176A1-20190926-C01110
  • To a solution of Intermediate 310C (76 mg, 0.203 mmol) in THF (2030 μl) was added TBAF (1.0 M in THF) (264 μl, 0.264 mmol) at room temperature. After 10 min, the reaction mixture was diluted with EtOAc and washed with brine. The organic phase was concentrated and purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 18 min. Product at 28%) to give Intermediate 310D (28 mg, 0.108 mmol, 53.0% yield) as a white solid. LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 260.0, 262.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.53 (s, 1H), 7.21 (s, 1H), 5.80 (s, 1H), 3.99 (s, 3H).
    • Example 310
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 310D with Intermediate I-2 afforded Example 310 in 36% yield following purification by preparative HPLC (Method D, 15-55% over 20 min). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 368.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (br. s., 1H), 9.09 (s, 1H), 8.79 (s, 1H), 8.01 (s, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 4.82 (s, 2H), 3.91 (s, 3H), 3.48 (s, 3H), 2.68 (s, 3H).
    • Example 311 5,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01111
    • Intermediate 311A: 2-bromo-5,6-dimethoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01112
  • To a solution of Intermediate 310D (14 mg, 0.054 mmol) solvated in DMF (1 mL) was added potassium carbonate (37.2 mg, 0.269 mmol) followed by iodomethane (10.10 μl, 0.161 mmol). The reaction mixture was allowed to stir at room temperature overnight. After 14 h, the reaction mixture was diluted with hexanes and washed with water followed by brine. The organic phase was dried over MgSO4, filtered and concentrated to provide Intermediate 311A (11 mg, 0.040 mmol, 75% yield) as a white solid, which was taken on without further purification. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 274.0, 276.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.46 (s, 1H), 7.22 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H.)
    • Example 311
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 311A with Intermediate I-2 afforded Example 311 in 30% yield following purification by preparative HPLC (Method D, 30-70% over 10 min). LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 382.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 4.82 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.48 (s, 3H), 2.69 (s, 3H).
    • Example 312 (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-yl) methanol
  • Figure US20190292176A1-20190926-C01113
    • Intermediate 312A: 2-methoxy-5-nitrobenzonitrile
  • Figure US20190292176A1-20190926-C01114
  • To a vessel charged with 2-bromo-1-methoxy-4-nitrobenzene (1 g, 4.31 mmol), zinc cyanide (0.506 g, 4.31 mmol), zinc (0.028 g, 0.431 mmol) and palladium tetrakis (0.174 g, 0.151 mmol) was added DMF (14.37 ml), and the mixture was sparged with argon for 20 min. The vial was sealed and heated to 90° C. overnight. After 22 h, the black solution was diluted with water and EtOAc. The organic phase was extracted, washed with brine, concentrated and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 28 min. Product at 50%) to provide Intermediate 312A (520 mg, 2.92 mmol, 67.7% yield) as an off-white solid. LC-MS: Method H, RT=0.78 min, MS (ESI) m/z: None Observed (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.49 (d, J=2.6 Hz, 1H), 8.48-8.43 (m, 1H), 7.10 (d, J=9.2 Hz, 1H), 4.08 (s, 3H).
    • Intermediate 312B: 2-methoxy-5-nitrobenzaldehyde
  • Figure US20190292176A1-20190926-C01115
  • A solution of Intermediate 312A (520 mg, 2.92 mmol) in Et2O (23.400 mL) was cooled to 0° C. under an atmosphere of N2. A solution of DIBAl-H (1.0 M in Toluene) (4.38 mL, 4.38 mmol) was then added dropwise causing bubbling to occur. After 5 min of stirring, the reaction mixture was allowed to thaw to room temperature. After an additional 3 h, the orange solution was poured into a mixture of ice and 10 mL of glacial acetic acid. This mixture was stirred while the ice melted, diluted with EtOAc and DI water and then extracted. The organic phase was concentrated and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 28 min. Product at 55%) to afford Intermediate 312B (410 mg, 1.811 mmol, 62.0% yield) as a light orange solid. LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 182.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 10.46 (s, 1H), 8.71 (d, J=2.9 Hz, 1H), 8.45 (dd, J=9.2, 2.9 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 4.08 (s, 3H).
    • Intermediate 312C: (2-methoxy-5-nitrophenyl)methanol
  • Figure US20190292176A1-20190926-C01116
  • A solution of Intermediate 312B (410 mg, 2.263 mmol) in Toluene (11.500 mL) and THF (11.50 mL) was cooled to −78° C. under an atmosphere of N2. DIBAL-H (1.0 M in Toluene) (3.40 mL, 3.40 mmol) was then added to the cooled solution dropwise. After the initial bubbling had subsided, the reaction mixture was allowed to thaw to room temperature. After 1 h, the reaction mixture was cooled to 0° C. and quenched with 1.0 M HCl. The resulting suspension was stirred vigorously for 45 min to fully cleave the aluminate complex. The mixture was then diluted with EtOAc and extracted. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The resulting crude product was purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 33 min. Product at 50%) to give Intermediate 312C (370 mg, 1.717 mmol, 76% yield) as a light yellow solid. LC-MS: Method H, RT=0.68 min, MS (ESI) m/z: 184.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (d, J=2.9 Hz, 1H), 8.21 (dd, J=9.0, 2.6 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 4.75 (d, J=6.4 Hz, 2H), 3.97 (s, 3H), 2.07 (t, J=6.4 Hz, 1H).
    • Intermediate 312D: tert-butyl((2-methoxy-5-nitrobenzyl)oxy)dimethylsilane
  • Figure US20190292176A1-20190926-C01117
  • To a solution of Intermediate 312C (370 mg, 1.717 mmol) and triethylamine (0.479 mL, 3.43 mmol) in DCM (17.200 mL) was added TBS-Cl (336 mg, 2.232 mmol) followed by DMAP (42.0 mg, 0.343 mmol). After 2 h, the reaction mixture was concentrated and the crude material was purified by ISCO (80 g, 0-20% EtOAc/Hexanes, 28 min. Product at 15%.) to give Intermediate 312D (490 mg, 1.647 mmol, 96% yield) as a yellow oil. LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: None Observed (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.45-8.35 (m, 1H), 8.17 (dd, 2.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 4.75 (s, 2H), 3.94 (s, 3H), 0.99 (s, 9H), 0.15 (s, 6H).
    • Intermediate 312E: 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxyaniline
  • Figure US20190292176A1-20190926-C01118
  • Degussa grade Pd/C (175 mg, 0.165 mmol) was added to a 250 mL round bottom flask containing Intermediate 312D (490 mg, 1.647 mmol). The mixture was carefully wet with a few mL of MeOH before adding the total volume of solvent (14.0 mL). The head space of the flask was evacuated until the solvent began to slightly bubble and then back-filled with N2. A hydrogen balloon was attached to the flask, and the solution was sparged with H2 for about 5 minutes through a vent needle. The vent was removed and the reaction mixture was stirred vigorously under the H2 atmosphere for 1 h before being filtered over celite to remove the Pd/C. The celite was rinsed with EtOAc, and the filtrate was concentrated to afford Intermediate 312E (430 mg, 1.608 mmol, 98% yield) as a brown oil. LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 268.3 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.88 (d, J=2.9 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.55 (dd, J=8.4, 2.9 Hz, 1H), 4.72 (s, 2H), 3.75 (s, 3H), 3.43 (br. s., 2H), 0.97 (s, 9H).
    • Intermediate 312F: 5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methoxybenzo[d]thiazol-2-amine Intermediate 312G: (2-amino-6-methoxybenzo[d]thiazol-5-yl)methanol
  • Figure US20190292176A1-20190926-C01119
  • To a solution of Intermediate 312E (430 mg, 1.608 mmol) in acetonitrile (13.700 mL) was added ammonium thiocyanate (159 mg, 2.090 mmol). The mixture was stirred at room temperature for 10 min followed by the addition of benzyltrimethylammonium tribromide (627 mg, 1.608 mmol). After 3 days the reaction mixture was diluted with saturated NaHCO3 and extract with EtOAc 3×. The organic phase was dried over MgSO4, filtered, concentrated and purified by ISCO (40 g, 0-100% EtOAc/Hexanes, 19 min. Product at 50%) to give Intermediate 312F (219 mg, 0.675 mmol, 42.0% yield) as a brown oil. LC-MS: Method H, RT=0.89 min, MS (ESI) m/z: 325.3 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (s, 1H), 7.06 (s, 1H), 4.97 (br. s., 2H), 4.80 (d, J=0.9 Hz, 2H), 3.84 (s, 3H), 0.98 (s, 9H), 0.13 (s, 6H). The silica gel column was further flushed (0-20% DCM/MeOH, 19 min. Product at 12%) to afford Intermediate 312G (166 mg, 0.790 mmol, 49.1% yield) as a tan solid. LC-MS: Method H, RT=0.47 min, MS (ESI) m/z: 211.2 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.41 (s, 1H), 7.21 (s, 1H), 4.64 (s, 2H), 3.83 (s, 3H).
    • Intermediate 312H: (2-bromo-6-methoxybenzo[d]thiazol-5-yl)methanol
  • Figure US20190292176A1-20190926-C01120
  • To a suspension of Intermediate 312G (160 mg, 0.761 mmol) in acetonitrile (7610 μl) was added copper (II) bromide (170 mg, 0.761 mmol) followed by t-Butyl nitrite (131 μl, 0.989 mmol). After 1 h of stirring, the reaction mixture was diluted with EtOAc, and poured into a 1.0 M HCl solution. The organic phase was dried over MgSO4, filtered, concentrated and purified by ISCO (40 g, 0-70% EtOAc/Hexanes, 19 min. Product at 35%) to afford Intermediate 312H (119 mg, 0.434 mmol, 57.0% yield) as an off-white solid. LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 274.1, 276.1 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.93 (s, 1H), 7.50 (s, 1H), 4.71 (d, J=0.7 Hz, 2H), 3.91 (s, 3H).
    • Example 312
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 312H with Intermediate I-2 afforded Example 312 in 47% yield following purification by preparative HPLC (Method D, 30-70% over 20 min). LC-MS: Method H, RT=0.96 min, MS (ESI) m/z: 382.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.11 (br. s., 1H), 8.82 (br. s., 1H), 8.08 (br. s., 1H), 8.04 (br. s., 1H), 7.74 (br. s., 1H), 4.83 (br. s., 2H), 4.65 (br. s., 2H), 3.92 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s., 3H).
    • Example 313 6-chloro-5-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl) benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01121
    • Intermediate 313A: 1-chloro-2-fluoro-3-methoxy-4-nitrobenzene
  • Figure US20190292176A1-20190926-C01122
  • To a 0° C. solution of 1-chloro-2-fluoro-3-methoxybenzene (1.606 g, 10 mmol) in acetic acid (5.00 ml) was added fuming nitric acid (0.933 ml, 20.00 mmol) followed by the dropwise addition of sulfuric acid (2.132 ml, 40.0 mmol). After 30 min, the reaction mixture was poured into water and diluted with ethyl acetate. The organic phase was separated and washed 2× with saturated NaHCO3 followed by a final brine wash. The organic solution was then dried over MgSO4, filtered, concentrated and purify by ISCO (120 g, 10-50% EtOAc/Hexanes, 25 min. Desired regioisomer eluted first) affording Intermediate 313A (900 mg, 4.38 mmol, 44% yield) as a yellow solid. LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: None Observed (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (dd, J=9.0, 2.2 Hz, 1H), 7.24 (dd, J=9.0, 6.6 Hz, 1H), 4.11 (d, J=1.8 Hz, 3H). Regiochemistry confirmed through NMR analysis of both regioisomeric products.
    • Intermediate 313B: 4-chloro-3-fluoro-2-methoxyaniline
  • Figure US20190292176A1-20190926-C01123
  • A solution of Intermediate 313A (700 mg, 3.41 mmol) in MeOH (17.000 mL, 0.2 M) was added NH4Cl (3643 mg, 68.1 mmol) and zinc dust (2226 mg, 34.1 mmol) was heated to reflux for 1 h. The resulting mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The resulting residue was diluted with EtOAc and saturated sodium bicarbonate (0.2 M of each) and stirred vigorously for an additional 1 hr. The mixture was filtered over celite, the organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to give Intermediate 313B (466 mg, 2.66 mmol, 78% yield) as a dark brown solid. This material was taken on without further purification. LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 176.1, 178.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.87 (dd, 7.5 Hz, 1H), 6.43 (dd, J=8.7, 1.9 Hz, 1H), 3.92 (d, J=1.5 Hz, 3H), 3.49 (s, 2H).
    • Intermediate 313C: 6-chloro-5-fluoro-4-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01124
  • This example was prepared according to the general procedure for 2-aminobenzothiazoles described in the table above. Thus, reaction of Intermediate 313B afforded Intermediate 313C in 21% yield. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 233.1, 235.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.30 (d, J=6.2 Hz, 1H), 5.38 (br. s., 2H), 4.15 (d, J=1.8 Hz, 3H).
    • Intermediate 313D: 6-chloro-5-fluoro-4-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01125
  • Intermediate 313D was prepared according to the general procedure for 2-bromobenzothiazoles described in the table above. Thus, reaction of Intermediate 313C afforded Intermediate 313D in 58% yield. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 296.0, 298.0, 299.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (d, J=5.7 Hz, 1H), 4.30 (d, J=1.8 Hz, 3H).
    • Example 313
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 313D with Intermediate I-2 afforded Example 313 in 8% yield following purification by preparative HPLC (Method D, 60-100% over 20 min). LC-MS: Method H, RT=1.49 min, MS (ESI) m/z: 404.1, 406.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.89 (s, 1H), 8.20 (d, J=6.1 Hz, 1H), 8.13 (br. s., 1H), 4.84 (s, 2H), 4.41 (s, 3H), 3.48 (s, 3H), 2.73 (s, 3H).
    • Example 314 4-cyclopropyl-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01126
  • Example 283 (19 mg, 0.047 mmol) was solvated in a solution of cyclopropylzinc(II) bromide (0.5 M in THF, 1411 μl, 0.706 mmol) and transferred to a microwave vial containing Pd(dppf)2Cl2—CH2Cl2 adduct (3.84 mg, 4.70 μmol). The solution was sparged with argon for 5 min, sealed and then heated to 100° C. in the microwave. The crude reaction mixture was then concentrated, retaken in DMF, filtered and purified by preparatory HPLC (Method D, 60-100% over 20 min) to afford Example 314 (1.1 mg, 2.69 μmol, 6% yield). LC-MS: Method H, RT=1.47 min, MS (ESI) m/z: 410.1, (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.73 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.75 (d, J=7.7 Hz, 1H), 4.86-4.78 (m, 2H), 3.94 (s, 3H), 3.49 (s, 3H), 2.70 (s, 3H), 2.66-2.58 (m, 1H), 1.18-1.13 (m, 2H), 0.87 (t, J=6.9 Hz, 2H).
    • Example 315 6-ethoxy-4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01127
    • Intermediate 315A: 2-bromo-6-ethoxy-4,5-difluorobenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01128
  • To a vial charged with Intermediate I-42 (13 mg, 0.049 mmol) and Cs2CO3 (80 mg, 0.244 mmol) was added DMF (1 mL). The resulting mixture was vigorously stirred for 5 min before the addition of iodoethane (0.012 mL, 0.147 mmol). After 16 h of stirring at room temperature, the reaction mixture was diluted with hexanes and extracted with water. The organic phase was dried over MgSO4, filtered, concentrated and purified by ISCO (12 g, 0-20% EtOAc/Hexanes, 16 min. Product at 8%) to afford Intermediate 315A (9 mg, 0.031 mmol, 62.6% yield) as a white solid. LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 294.0, 296.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.08 (dd, J=6.6, 2.0 Hz, 1H), 4.16 (q, J=6.9 Hz, 2H), 1.51 (t, J=7.0 Hz, 3H).
    • Example 315
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 315A with Intermediate I-2 afforded Example 315 in 22% yield following purification by preparative HPLC (Method D, 60-100% over 20 min). LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 388.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.62 (s, 1H), 7.87 (s, 1H), 7.83 (d, J=6.9 Hz, 1H), 4.26 (q, J=6.9 Hz, 2H), 4.10 (s, 3H), 2.66 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).
    • Example 316 N-(2-((4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C01129
    • Intermediate 316A: tert-butyl (2-((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C01130
  • A solution of Intermediate I-42 (100 mg, 0.376 mmol) and triphenylphosphine (197 mg, 0.752 mmol) in THF (2 mL) was heated to reflux. To this refluxing mixture was added a pre-mixed solution of DIAD (0.219 mL, 1.128 mmol) and tert-butyl (2-hydroxyethyl)carbamate (182 mg, 1.128 mmol) in THF (2 mL) over the course of 2 h via syringe pump. The crude reaction mixture was concentrated and purified by ISCO (40 g, 0-30% DCM/EtOAc, 22 min, Product at 8%) to afford Intermediate 316A (53 mg, 0.130 mmol, 34.5% yield) as a yellow amorphous solid. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 409.0, 411.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.11 (dd, J=6.5, 1.9 Hz, 1H), 5.03 (br. s., 1H), 4.14 (t, J=5.2 Hz, 2H), 3.60 (q, J=5.4 Hz, 2H), 1.45 (s, 9H).
    • Intermediate 316B: 2((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethanamine HCl
  • Figure US20190292176A1-20190926-C01131
  • To a flask charged with Intermediate 316A (53 mg, 0.130 mmol) was added 4.0 N HCl in dioxane (2.43 mL, 9.71 mmol) causing a white slurry to immediately form. After 1 h, the solution was concentrated in vacuo to afford Intermediate 316B as an HCl salt. LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 265.1, 267.1 (M+H—CH2CH2NH2)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.59 (dd, J=6.9, 2.1 Hz, 1H), 4.42-4.36 (m, 2H), 3.46 (t, J=4.8 Hz, 2H).
    • Intermediate 316C: N-(2-((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C01132
  • To a solution of Intermediate 316B (44 mg, 0.127 mmol) in THF (1.5 mL) was added DIEA (0.067 mL, 0.382 mmol) and 3-fluorobenzene-1-sulfonyl chloride (37.2 mg, 0.191 mmol). The white slurry was stirred for 1 hr before being quenched with water and extracted with EtOAc. The organic phase was further washed with brine, concentrated, and purified by ISCO (12 g, 0-50% EtOAc/Hexanes, 20 min. Product at 38%) to afford Intermediate 316C (53 mg, 0.113 mmol, 89% yield) as a pale yellow, amorphous solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 467.0, 469.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.72-7.67 (m, 1H), 7.63-7.56 (m, 1H), 7.51 (td, 5.3 Hz, 1H), 7.31-7.24 (m, 1H), 7.03 (dd, J=6.6, 2.0 Hz, 1H), 5.16 (t, J=6.2 Hz, 1H), 4.16 (t, J=5.1 Hz, 2H), 3.53-3.46 (m, 2H).
    • Example 316
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 316C with Intermediate I-9 afforded Example 316 in 43% yield following purification by preparative HPLC (Method D, 50-100% over 20 min). LC-MS: Method H, RT=1.36 min, MS (ESI) m/z: 561.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.23 (br. s., 1H), 7.79 (s, 1H), 7.72-7.67 (m, 2H), 7.67-7.61 (m, 2H), 7.48 (td, J=8.5, 1.9 Hz, 1H), 4.18 (t, J=5.1 Hz, 2H), 4.08 (s, 3H), 3.36-3.30 (m, 2H-buried under DMSO), 2.62 (s, 3H).
    • Example 317 N-(2-((4,5-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide
  • Figure US20190292176A1-20190926-C01133
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 316C with Intermediate I-2 afforded Example 317 in 6% yield following purification by preparative HPLC (Method D, 45-90% over 20 min). LC-MS: Method H, RT=1.30 min, MS (ESI) m/z: 575.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.25-9.04 (m, 1H), 8.83 (br. s., 1H), 8.25 (br. s., 1H), 8.08 (br. s., 1H), 7.79 (d, J=6.1 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.46 (br. s., 1H), 4.82 (br. s., 2H), 4.20 (d, J=4.4 Hz, 2H), 3.49 (d, J=5.0 Hz, 3H), 3.36-3.30 (m, 2H-buried under DMSO) 2.70 (br. s., 3H).
    • Example 318 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01134
    • Intermediate 318A: 2-((4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01135
  • A 20 mL microwave vial was charged with Intermediate I-1 (623 mg, 1.853 mmol), Intermediate I-59 (605 mg, 1.853 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (76 mg, 0.093 mmol). These solids were suspended in a combination of Toluene (11.600 mL), EtOH (3.87 mL) and a 2.0 M solution of Na2CO3 (1.389 mL, 2.78 mmol). The resulting mixture was sparged with argon for 10 min, sealed and then heated in a microwave at 130° C. for 30 min. The crude reaction mixture was diluted with 100 mL EtOAc and filtered over celite. The organic solution was concentrated onto celite and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 36 min. Product dragged from 50%-100%) to afford Intermediate 318A (630 mg, 1.382 mmol, 74.6% yield) as a bright yellow solid. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 456.0, 458.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.76 (d, J=1.8 Hz, 1H), 8.03 (d, J=7.7 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.90 (t, J=71.1 Hz, 1H), 4.99 (t, J=5.5 Hz, 1H), 4.22 (t, J=4.8 Hz, 2H), 3.82 (q, J=5.2 Hz, 2H), 2.70 (s, 3H).
    • Example 318
  • To a solution of Intermediate 318A (630 mg, 1.382 mmol) in THF (27.600 mL) was added a 0.5 M solution of NaOMe in MeOH (27.6 mL, 13.82 mmol). After 1 h of stirring, the reaction mixture was quenched with 1.0 N HCl (27.6 mL) and diluted with EtOAc. The organic phase was washed with brine, and concentrated in vacuo to afford Example 318 (650 mg, 1.393 mmol, 91% yield). The majority of this crude material was taken on without further purification, but a small portion was further purified by preparative HPLC for characterization (Method D, 45-80% over 13 min, 100% for 5 min). LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 420.1, 422.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.87 (s, 1H), 4.99 (t, J=5.4 Hz, 1H), 4.22 (t, J=5.0 Hz, 2H), 4.10 (s, 3H), 3.82 (q, J=5.2 Hz, 2H), 2.67 (s, 3H).
    • Example 319 1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C01136
    • Intermediate 319A: 1-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)-2-methylpropan-2-ol
  • Figure US20190292176A1-20190926-C01137
  • A solution of Intermediate I-49 (16 mg, 0.048 mmol) in THF (1 mL) was cooled to −78° C. To this cold solution was added MeMgBr (3.0 M in Et2O) (0.162 mL, 0.485 mmol) dropwise. The resulting mixture was allowed to warm to 0° C. Once at 0° C. the reaction was quenched with 1 mL of 1 M HCl. This mixture was then concentrated and purified by ISCO (12 g, 0-50% EtOAc/Hexanes, 16 min. Product at 25%,) to afford Intermediate 319A (5 mg, 0.015 mmol, 31.2% yield) as a colorless oil. LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 330.1, 332.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.06 (s, 1H), 3.83 (s, 2H), 2.65 (s, 3H), 2.30 (s, 3H), 2.14 (s, 1H), 1.40 (s, 6H).
    • Example 319
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 319A with Intermediate I-2 afforded Example 319 in 67% yield following purification by preparative HPLC (Method D, 70-100% over 10 min). LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 438.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.53 (s, 1H), 4.82 (s, 2H), 4.71 (s, 1H), 3.83 (s, 2H), 3.49 (s, 3H), 2.77 (s, 3H), 2.70 (s, 3H), 2.31 (s, 3H), 1.30 (s, 6H).
    • Example 320 2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethyl methyl carbonate
  • Figure US20190292176A1-20190926-C01138
    • Intermediate 320A: 2-((2-chloro-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethyl methyl carbonate
  • Figure US20190292176A1-20190926-C01139
  • To a solution of Intermediate I-51 (30 mg, 0.099 mmol) in THF (1 mL) was added Hunig's Base (0.087 mL, 0.496 mmol) followed by a solution of phosgene (15% by wt in toluene) (0.210 mL, 0.298 mmol). After 15 min of stirring, 1 mL of MeOH was added and the reaction mixture was concentrated. The crude residue was purified by ISCO (12 g, 0-30% EtOAc/Hexanes, 16 min. Product at 15%) to afford Intermediate 320A (12 mg, 0.038 mmol, 38.3% yield) as a white solid. LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 316.1, 318.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.02 (d, J=8.4 Hz, 1H), 4.59-4.53 (m, 2H), 4.25-4.18 (m, 2H), 3.82 (s, 3H), 2.63 (d, J=5.1 Hz, 3H), 2.26 (s, 3H).
    • Example 320
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 320A with Intermediate I-2 afforded Example 320 in 50% yield following purification by preparative HPLC (Method D, 60-100% over 15 min). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 468.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.82 (s, 1H), 8.01 (s, 1H), 7.59 (s, 1H), 4.82 (s, 2H), 4.54 (br. s., 2H), 4.32 (br. s., 2H), 3.76 (s, 3H), 3.49 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.25 (s, 3H).
    • Example 321 2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-1-ol (racemate)
  • Figure US20190292176A1-20190926-C01140
    • Intermediate 321A: 2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-1-ol
  • Figure US20190292176A1-20190926-C01141
  • This example was prepared in a manner analogous to Intermediate I-51. Thus, Intermediate I-50 (rac) was reacted to afford Intermediate 321A (rac) (91% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 314.0, 316.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.14 (s, 1H), 4.57-4.46 (m, 1H), 3.80 (d, J=5.3 Hz, 2H), 2.64 (s, 3H), 2.26 (s, 3H), 1.30 (d, J=6.4 Hz, 3H), 1.26 (br. s, 1H).
    • Example 321
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 321A (rac) with Intermediate I-2 afforded Example 321 (rac) in 66% yield following purification by preparative HPLC (Method D, 40-75% over 10 min, 100% for 5 min). LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 423.9 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 4.88 (t, J=5.5 Hz, 1H), 4.82 (s, 2H), 4.60-4.48 (m, 1H), 3.66 (dt, J=11.1, 5.3 Hz, 1H), 3.60-3.52 (m, 1H), 3.49 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.27 (s, 3H), 1.30 (d, J=5.8 Hz, 3H).
    • Example 322 1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-2-ol (racemate)
  • Figure US20190292176A1-20190926-C01142
    • Intermediate 322A: 2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetaldehyde
  • Figure US20190292176A1-20190926-C01143
  • A solution of Intermediate I-51 (20 mg, 0.066 mmol) in DCM (1 mL) was cooled to 0° C. To this cooled mixture was added Dess-Martin Periodinane (84 mg, 0.199 mmol). After 1 h, the solution was allowed to thaw to room temperature and stirred vigorously for an additional 5 h. The reaction mixture was then concentrated and the residue was purified by ISCO (12 g, 0-50% EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate 322A (11 mg, 0.037 mmol, 55.4% yield) as a white solid. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 317.7, 319.7 (M+H+H2O)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.90 (t, J=1.1 Hz, 1H), 6.93 (s, 1H), 4.62 (d, J=1.1 Hz, 2H), 2.69-2.63 (m, 3H), 2.35 (s, 3H).
    • Intermediate 322B: 1-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-2-ol (racemate)
  • Figure US20190292176A1-20190926-C01144
  • A solution of Intermediate 322A (11 mg, 0.037 mmol) in THF (2 mL) was cooled to −78° C. MeMgBr (3.0 M in Et2O) (0.122 mL, 0.366 mmol) was then added dropwise to this cold solution. After 1 h of vigorous stirring, the reaction mixture was quenched with saturated NH4Cl and then allowed to thaw to room temperature. Once at room temperature, the mixture was diluted with EtOAc, the organic phase was extracted, dried over MgSO4, filtered, concentrated, and purified by ISCO (12 g, 0-50% EtOAc/Hexanes, 16 min. Product at 28%) to afford Intermediate 322B (rac) (6 mg, 0.013 mmol, 36.2% yield). LC-MS: Method H, RT=1.57 min, MS (ESI) m/z: 315.9, 317.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.06 (s, 1H), 4.62 (d, J=1.1 Hz, 1H), 4.27 (ddd, J=10.1, 6.8, 3.2 Hz, 1H), 4.01-3.94 (m, 1H), 3.85 (dd, J=9.1, 7.4 Hz, 1H), 2.64 (s, 3H), 2.28 (s, 3H), 1.33 (d, J=6.6 Hz, 3H)
    • Example 322
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 322B with Intermediate I-2 afforded Example 322 (rac) in 46% yield following purification by preparative HPLC (Method D, 45-90% over 10 min, 100% for 5 min). LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 424.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.83 (s, 1H), 8.02 (s, 1H), 7.55 (s, 1H), 4.92 (d, J=3.9 Hz, 1H), 4.82 (s, 2H), 4.11-4.03 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.85 (m, 1H), 3.49 (s, 3H), 2.77 (s, 3H), 2.71 (s, 3H), 2.29 (s, 3H), 1.25 (d, J=6.1 Hz, 3H).
    • Example 323 3-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)butan-2-ol (diastereomeric mixture)
  • Figure US20190292176A1-20190926-C01145
    • Intermediate 323A: 2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propanal (racemate)
  • Figure US20190292176A1-20190926-C01146
  • This example was prepared in a manner analogous to Intermediate 322A. Thus, Intermediate 321A (rac) was reacted to afford Intermediate 323A (rac) (71% yield). LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 214.0, 216.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.72 (d, J=2.0 Hz, 1H), 6.93 (s, 1H), 4.64 (qd, 2.0 Hz, 1H), 2.66 (s, 3H), 2.33 (s, 3H), 1.55 (d, J=6.8 Hz, 3H).
    • Intermediate 323B: 3-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)butan-2-ol (diastereomeric mixture)
  • Figure US20190292176A1-20190926-C01147
  • This example was prepared in a manner analogous to Intermediate 322B. Thus, Intermediate 323A (rac) was reacted to afford Intermediate 323B (diastereomeric mixture) (57% yield). LC-MS: Method H, RT=1.40 min, MS (ESI) m/z: 330.0, 332.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.10 (s, 1H), 4.36 (qd, J=6.3, 3.4 Hz, 1H), 4.06 (br. s., 1H), 2.64 (s, 3H), 2.27 (s, 3H), 1.95 (br. s., 1H), 1.30 (d, J=6.4 Hz, 3H), 1.30-1.25 (m, 3H) [Major Diastereomer]. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.13 (s, 1H), 4.20 (quin, J=6.3 Hz, 1H), 3.97-3.88 (m, 1H), 2.64 (s, 3H), 2.42 (br. s., 1H), 2.27 (s, 3H), 1.30 (d, J=6.4 Hz, 3H), 1.30-1.24 (m, 3H) [Minor Diastereomer].
    • Example 323
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 323B (diastereomeric mixture) with Intermediate I-2 afforded Example 323 (diastereomeric mixture) in 62% yield following purification by preparative HPLC (Method D, 50-100% over 40 min). LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 438.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.23-6.95 (m, 1H), 4.82 (s, 2H), 4.36 (d, J=5.8 Hz, 1H), 3.81 (d, J=4.4 Hz, 1H), 3.49 (s, H), 2.76 (s, 3H), 2.71 (s, 3H), 2.27 (s, 3H), 1.30 (d, J=5.8 Hz, 3H), 1.21 (d, J=6.1 Hz, 3H) [Major Diastereomer]. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.02 (s, 1H), 7.60 (br. s., 1H), 7.24-6.96 (m, 1H), 4.82 (s, 2H), 4.45 (br. s., 1H), 3.88 (d, J=3.6 Hz, 1H), 3.49 (s, 3H), 2.76 (s, 3H), 2.71 (s, 3H), 2.27 (s, 3H), 1.26 (d, J=5.5 Hz, 3H), 1.17 (d, J=6.1 Hz, 3H) [Minor Diastereomer].
    • Example 324 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-1-morpholinoethanone
  • Figure US20190292176A1-20190926-C01148
    • Intermediate 324A: 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)acetic acid
  • Figure US20190292176A1-20190926-C01149
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate I-58 with Intermediate I-9 afforded Intermediate 324A in 52% yield. LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 434.0, 436.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.60 (s, 1H), 7.86 (s, 1H), 7.64 (d, J=7.3 Hz, 1H), 4.38 (br. s., 2H), 4.09 (s, 3H), 2.66 (s, 3H).
    • Example 324
  • To a suspension of Intermediate 324A (10 mg, 0.023 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.024 mL, 0.138 mmol) followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in DMF) (0.041 mL, 0.069 mmol). The reaction mixture was stirred at room temperature for 2 min until all of starting material had solvated, then morpholine (5.96 μl, 0.069 mmol) was added. After 15 min, the reaction mixture was filtered and purified by preparative HPLC (Method D, 45-85% over 20 min, 100% for 5 min) to afford Example 324 (3.0 mg, 5.96 μmol, 26% yield). LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 503.1, 505.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.62 (s, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.88 (s, 1H), 5.13 (s, 2H), 4.10 (s, 3H), 3.69 (br. s., 2H), 3.62 (br. s., 2H), 3.49 (br. s., 4H), 2.67 (s, 3H).
    • Example 325 (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl) methanol (bis-deuterated)
  • Figure US20190292176A1-20190926-C01150
    • Intermediate 325A: (2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)methanol (bis-deuterated)
  • Figure US20190292176A1-20190926-C01151
  • A solution of Intermediate I-54D (50 mg, 0.158 mmol) in toluene (791 μl) and THF (791 μl) was cooled to −78° C. under an atmosphere of N2. To this mixture was added DIBAL-D (0.7 M in toluene) (904 μl, 0.633 mmol). After 30 min of stirring, the solution was allowed to thaw to room temperature before being quenched with 3 mL 1 M HCl. The resulting mixture was stirred vigorously for 30 min before being dilute with EtOAc. The organic phase was then extracted, washed with brine, dried over MgSO4, filtered, concentrated and purified by ISCO (12 g, 0-100% EtOAc/Hexanes, 16 min. Product at 38%) to afford Intermediate 325A (5 mg, 0.017 mmol, 10.90% yield) as a white solid. LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 289.7, 291.7 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.14 (s, 1H), 3.88 (s, 3H), 3.35 (s, 1H), 2.33 (s, 3H)
    • Example 325
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 325A with Intermediate I-2 afforded Example 325 in 61% yield following purification by preparative HPLC (Method D, 30-65% over 15 min, 100% for 5 min). LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 397.8 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.85 (d, J=1.7 Hz, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 5.02 (s, 1H), 4.82 (s, 2H), 3.92 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H).
    • Example 326 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C01152
    • Intermediate 326A: 1-(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C01153
  • A solution of Intermediate I-55 (40 mg, 0.140 mmol) in THF (1398 μl) was cooled to −78° C. MeMgBr (3.0 M in Et2O) (466 μl, 1.398 mmol) was added dropwise to this cold mixture. After 30 min, the reaction was quenched with saturated NH4Cl and the resulting mixture was allowed to thaw to room temperature. Once at room temperature, the mixture was diluted with EtOAc and washed with saturated NH4Cl followed by brine. The organic phase was dried over MgSO4, filtered, concentrated and purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 16 min. Product at 20%) to afford Intermediate 326A (12 mg, 0.040 mmol, 28.4% yield). LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 302.0, 304.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.10 (s, 1H), 5.33-5.29 (m, 1H), 3.87 (s, 3H), 2.26 (s, 3H), 1.62-1.58 (m, 3H).
    • Example 326
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 326A with Intermediate I-2 afforded Example 326 in 54% yield following purification by preparative HPLC (Method D, 45-80% over 20 min, 100% for 5 min). LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 410.2 (M+H)+. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.09 (s, 1H), 8.71 (s, 1H), 7.95 (s, 1H), 7.29 (s, 1H), 6.72 (d, J=10.7 Hz, 1H), 5.49-5.39 (m, 1H), 4.85 (s, 2H), 3.94 (s, 3H), 3.74 (s, 1H), 3.58 (s, 3H), 2.71 (s, 3H), 2.32 (s, 3H), 1.72 (d, J=6.6 Hz, 3H).
    • Example 327 2-((4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01154
    • Intermediate 327A: 2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-ol
  • Figure US20190292176A1-20190926-C01155
  • This example was prepared in a manner analogous to Intermediate I-44. Thus, Intermediate I-56 was reacted to afford Intermediate 327A (36% yield) as a light pink solid. LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 277.7, 279.7, 281.6 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.19 (s, 1H), 2.37 (s, 3H).
    • Intermediate 327B: methyl 2((2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-yl)oxy) acetate
  • Figure US20190292176A1-20190926-C01156
  • This example was prepared in a manner analogous to Intermediate I-49. Thus, Intermediate 327A was reacted to afford Intermediate 327B (79% yield) as an off-white solid. LC-MS: Method H, RT=1.02 min, MS (ESI) m/z: 350.0, 352.0, 353.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.01 (s, 1H), 4.71 (s, 2H), 3.82 (s, 3H), 2.48 (s, 3H).
    • Intermediate 327C: 2-((2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01157
  • This intermediate was prepared in a manner analogous to Intermediate I-51. Thus, Intermediate 327B was reacted to afford Intermediate 327C (82% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 321.9, 324.0, 325.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.13 (s, 1H), 4.17-4.12 (m, 2H), 4.05 (q, J=4.9 Hz, 2H), 2.43 (s, 3H), 1.99 (t, J=6.1 Hz, 1H)
    • Example 327
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 327C with Intermediate I-2 afforded Example 327 in 49% yield following purification by preparative HPLC (Method D, 45-90% over 20 min, 100% for 5 min). LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 430.1, 432.1 (M+H)+. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.07 (s, 1H), 8.95 (s, 1H), 7.95 (s, 1H), 7.31 (s, 1H), 4.84 (s, 2H), 4.21 (t, J=4.3 Hz, 2H), 4.08 (d, J=3.9 Hz, 2H), 3.58 (s, 3H), 2.71 (s, 3H), 2.49 (s, 3H), 2.08-1.98 (m, 1H).
    • Example 328 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (racemate)
  • Figure US20190292176A1-20190926-C01158
    • Intermediate 328A: 1-(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol (racemate)
  • Figure US20190292176A1-20190926-C01159
  • A solution of Intermediate I-55 (20 mg, 0.070 mmol) in THF (1 mL) was cooled to −78° C. tert-butylmagnesium chloride (0.091 mL, 0.091 mmol) was added. After 30 min, the reaction mixture was warmed to −10° C. and then quenched with saturated NH4Cl The resulting mixture was then diluted with EtOAc, and the organic phase was extracted, dried over MgSO4, filtered, concentrated and purified by ISCO (12 g, 0-100% EtOAc/Hexanes, 16 min. Product at 16%) to afford Intermediate 328A (rac) (8.5 mg, 0.025 mmol, 35.3% yield). LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 344.0, 346.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.12 (s, 1H), 4.96 (d, J=11.4 Hz, 1H), 3.88 (s, 3H), 2.28 (s, 3H), 0.96 (s, 9H).
    • Example 328
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 328A (rac) with Intermediate I-2 afforded Example 328 (rac) in 18% yield following purification by preparative HPLC (Method D, 65-100% over 15 min). LC-MS: Method H, RT=1.23 min, MS (ESI) m/z: 452.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.64 (s, 1H), 8.07 (s, 1H), 7.73 (s, 1H), 6.34 (d, J=10.7 Hz, 1H), 5.00 (d, J=10.7 Hz, 1H), 4.83 (br. s., 2H), 3.94 (s, 3H), 3.49 (s, 3H), 2.72 (br. s., 3H), 2.30 (s, 3H), 1.00 (br. s., 9H).
    • Example 329 5-fluoro-6-isopropoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01160
    • Intermediate 329A: 2-bromo-5-fluoro-6-isopropoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01161
  • To a solution of Intermediate I-60 (34 mg, 0.137 mmol) in DMF (685 μl) was added 2-iodopropane (68.5 μl, 0.685 mmol) followed by K2CO3 (47.4 mg, 0.343 mmol). After 3 h of vigorous stirring, the reaction mixture was diluted with EtOAc, filtered over celite, concentrated and purified by ISCO (12 g, 0-10% EtOAc/Hexanes, 16 min. Product at 3%) to afford Intermediate 329A (38 mg, 0.131 mmol, 96% yield) as a white solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 290.1, 292.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.68 (d, J=11.0 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 4.57 (spt, J=6.1 Hz, 1H), 1.41 (d, J=5.9 Hz, 6H).
    • Example 329
  • This example was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 329A with Intermediate I-2 afforded Example 329 in 32% yield following purification by preparative HPLC (Method D, 55-100% over 20 min). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 398.3 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.80 (s, 1H), 8.05 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 4.83 (s, 2H), 4.81-4.73 (m, 1H), 3.49 (s, 3H), 2.69 (s, 3H), 1.39 (d, J=6.1 Hz, 6H).
    • Example 330 N-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide
  • Figure US20190292176A1-20190926-C01162
    • Intermediate 330A: 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethyl methanesulfonate
  • Figure US20190292176A1-20190926-C01163
  • To a solution of Example 318 (18 mg, 0.043 mmol) in DCM (1 mL) was added triethylamine (0.012 mL, 0.086 mmol) followed by methanesulfonic anhydride (9.71 mg, 0.056 mmol). After 30 min, the reaction mixture was further diluted with DCM and washed with saturated NaHCO3 followed by brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford Intermediate 330A (18 mg, 0.036 mmol, 84% yield) as an amorphous yellow solid. This material was taken forward without further purification. LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 498.1, 500.1 (M+H)+. 1H NMR (400 MHz, THF) δ 8.68 (d, J=1.5 Hz, 1H), 8.46 (s, 1H), 7.69 (dd, J=2.0, 0.9 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 4.55-4.47 (m, 2H), 4.39-4.33 (m, 2H), 4.00 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H).
    • Example 330
  • To a solution of Intermediate 330A (8 mg, 0.016 mmol) in DMF (1 mL) was added benzenesulfonamide (7.58 mg, 0.048 mmol) followed by K2CO3 (11.10 mg, 0.080 mmol). The reaction vial was sealed and heated to 100° C. in the microwave for 30 min. The crude reaction mixture was filtered and purified by preparative HPLC (Method D, 60-100% over 20 min) to afford Example 330 (1.6 mg, 2.78 μmol, 17% yield). LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 559.1, 561.2 (M+H)+. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.73 (br. s., 1H), 8.54 (br. s., 1H), 7.91 (br. s., 2H), 7.77 (br. s., 1H), 7.60-7.47 (m, 3H), 7.25 (br. s., 1H), 5.12 (br. s., 1H), 4.19-4.09 (m, 5H), 3.49 (br. s., 2H), 2.67 (br. s., 3H).
    • Example 331 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C01164
  • To a suspension of Example 318 (75 mg, 0.179 mmol) in THF (3.6 mL) was added a solution of phosgene (15% by wt. in toluene) (1.2 mL, 1.790 mmol). After 30 min, the resulting chloroformate intermediate was concentrated down to a yellow residue. This residue was retaken in THF (3.6 mL) and pyridin-3-amine (50.4 mg, 0.537 mmol) was added followed by Hunig's Base (313 μl, 1.79 mmol). After an additional 5 min, the reaction mixture was concentrated, retaken in DMF, filtered and purified by preparative HPLC (Method D, 50-100% over 10 min) to afford Example 331 (17.9 mg, 0.032 mmol, 18.19% yield) as a yellow solid. LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 540.2, 542.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (br. s., 1H), 8.68 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.19 (br. s., 1H), 7.98 (d, J=7.7 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.80 (s, 1H), 7.29 (br. s., 1H), 4.48 (d, J=4.2 Hz, 2H), 4.41 (d, J=4.4 Hz, 2H), 4.02 (s, 3H), 2.59 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ −135.91.
    • Preparation of Carbamate Examples
  • The following carbamates were prepared according to the following general procedure, which is analogous to Example 331 described above
  • To a solution of the appropriately substituted Quinoxaline-Benzothiazole Alcohol (1.0 equiv) in THF (0.05 M) was added a solution of phosgene (15% by wt. in toluene, 10 equiv). The combined solution was stirred at room temperature for the designated amount of time before the intermediate chloroformate was concentrated in vacuo. This intermediate was retaken in THF (0.05 M) and the appropriately substituted aminopyridine, aniline or amine (3.0 equiv) was added. After a minute of vigorous stirring, an excess of diisopropylethylamine (10 equiv) or pyridine (10 equiv) was added. After an additional 5 min of stirring, the resulting mixture was concentrated, retaken in DMF, filtered and purified by preparative HPLC to yield the desired example.
  • LCMS
    LCMS RT HPLC
    [M + (Min) Prep
    H]+ Method Method
    Ex Structure R—OH Time m/z H D NMR
    332
    Figure US20190292176A1-20190926-C01165
         		318 1 h  570.1, 572.1 1.20 65-100% 20 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (br. s., 1H), 8.61 (br. s., 1H), 8.24 (br. s., 1H), 7.97 (br. s., 2H), 7.88 (br. s., 1H), 6.79 (br. s., 1H), 6.59 (br. s., 1H), 4.62- 4.43 (m, 2H), 4.33 (br. s., 2H), 4.10 (br. s., 3H), 3.80 (br. s., 3H), 2.75 (br. s., 3H).
    333
    Figure US20190292176A1-20190926-C01166
         		318 1 h  596.2, 598.2 0.87 55-100% 23 min 1H NMR (500 MHz, DMSO-d6) δ 11.50 (br. s., 1H), 9.87 (br. s., 1H), 8.75 (br. s., 1H), 8.60 (br. s., 1H), 8.05 (br. s., 1H), 7.87 (br. s., 1H), 7.51 (br. s., 1H), 7.17 (br. s., 1H), 7.01 (d, J = 7.7 Hz, 1H), 4.54 (br. s., 2H), 4.48 (br. s., 2H), 4.10 (br. s., 3H), 2.67 (br. s., 3H).
    334
    Figure US20190292176A1-20190926-C01167
         		318 1 h  545.1, 547.1 1.21 55-100% 23 min 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.56 (br. s., 1H), 8.14 (br. s., 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.82 (br. s., 1H), 4.56-4.36 (m, 2H), 4.08 (br. s., 2H), 3.83 (br. s, 3H), 2.65 (br. s., 3H).
    335
    Figure US20190292176A1-20190926-C01168
         		318 1 h  540.2, 542.2 1.19 55-95% 20 min, 100% 5 min 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.78 (s, 1H), 8.62 (s, 1H), 8.39 (d, J = 6.6 Hz, 2H), 8.07 (d, J = 7.3 Hz, 1H), 7.89 (s, 1H), 7.46 (d, J = 6.6 Hz, 2H), 4.58 (br. s., 2H), 4.48 (br. s., 2H), 4.15-4.05 (m, 4H), 2.66 (s, 3H).
    336
    Figure US20190292176A1-20190926-C01169
         		318 1 h  554.2, 556.2 1.14 40-80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.23 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.25 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.84 (br. s., 1H), 7.31 (br. s., 1H), 7.28 (d, J = 4.9 Hz, 1H), 4.56 (br. s., 2H), 4.47 (br. s., 2H), 4.17-4.10 (m, 2H), 4.08 (s, 3H), 2.65 (s, 3H), 2.38 (s, 3H).
    337
    Figure US20190292176A1-20190926-C01170
         		318 1 h  558.2, 600.2 1.17 50-90% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.38 (br. s., 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.91-7.81 (m, 2H), 4.58 (br. s., 2H), 4.49 (br. s., 2H), 4.10 (s, 3H), 2.66 (s, 3H).
    338
    Figure US20190292176A1-20190926-C01171
         		318 1 h  622.1, 624.1 1.16 50-90% 15 min, 100% 5 min
    339
    Figure US20190292176A1-20190926-C01172
         		I-66 1 h 506.2 0.93 40-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.07 (br. s., 1H), 8.76 (s, 1H), 8.66 (br. s., 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.23 (d, J = 4.1 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 11.6 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.34 (dd, J = 8.4, 4.5 Hz, 1H), 4.58-4.53 (m, 2H), 4.48-4.40 (m, 2H), 4.09 (s, 3H), 2.64 (s, 3H).
    340
    Figure US20190292176A1-20190926-C01173
         		I-66 1 h 524.2 1.16 50-85% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.13 (br. s., 1H), 8.73 (s, 1H), 8.56 (s, 1H), 8.29 (br. s., 1H), 8.04 (br. s., 1H), 8.02- 7.96 (m, 2H), 7.82 (s, 1H), 7.15 (dd, J = 8.9, 3.2 Hz, 1H), 4.54 (d, J = 4.1 Hz, 2H), 4.45 (d, J = 4.1 Hz, 2H), 4.08 (s, 3H), 2.63 (s, 3H).
    341
    Figure US20190292176A1-20190926-C01174
         		I-66 1 h 536.2 1.15 50-85% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.24 (br. s., 1H), 8.06-7.96 (m, 3H), 7.85 (s, 1H), 7.78 (br. s., 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.51 (d, J = 4.7 Hz, 2H), 4.44 (d, J = 4.4 Hz, 2H), 4.09 (s, 3H), 3.80 (s, 3H), 2.64 (s, 3H).
    342
    Figure US20190292176A1-20190926-C01175
         		I-66 1 h 506.2 0.95 40-80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.75 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.39 (d, J = 6.1 Hz, 2H), 8.02 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 11.6 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.48- 7.44 (m, 2H), 4.59-4.53 (m, 2H), 4.46 (d, J = 4.1 Hz, 2H), 4.09 (s, 3H), 2.64 (s, 3H).
    343
    Figure US20190292176A1-20190926-C01176
         		I-66 1 h 562.2 1.10 45-80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.87 (br. s., 1H), 8.74 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.04-7.95 (m, 2H), 7.87- 7.81 (m, 1H), 7.50 (br. s., 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.56-4.49 (m, 2H), 4.47-4.39 (m, 2H), 4.09 (s, 3H), 2.63 (s, 3H).
    344
    Figure US20190292176A1-20190926-C01177
         		I-71 16 h  520.2 0.97 35-75% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.20 (br. s., 1H), 8.76-8.70 (m, 2H), 8.57 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.49 (dd, J = 8.5, 5.0 Hz, 1H), 4.91 (td, J = 6.1, 3.2 Hz, 1H), 4.46-4.41 (m, 1H), 4.40- 4.34 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.3 Hz, 3H).
    345
    Figure US20190292176A1-20190926-C01178
         		I-70 16 h  520.2 0.97 50-90% 20 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 10.20 (br. s., 1H), 8.76-8.70 (m, 2H), 8.57 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.49 (dd, J = 8.5, 5.0 Hz, 1H), 4.91 (td, J = 6.1, 3.2 Hz, 1H), 4.46-4.41 (m, 1H), 4.40- 4.34 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.3 Hz, 3H).
    346
    Figure US20190292176A1-20190926-C01179
         		I-68 24 h  520.2 0.98 45-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.98 (br. s., 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.24-8.18 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 11.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.32 (dd, J = 8.3, 4.7 Hz, 1H), 5.27 (td, J = 6.3, 3.2 Hz, 1H), 4.40-4.33 (m, 1H), 4.31- 4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.3 Hz, 3H).
    347
    Figure US20190292176A1-20190926-C01180
         		I-67 24 h  520.2 0.98 45-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.98 (br. s., 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.24-8.18 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 11.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.32 (dd, J = 8.3, 4.7 Hz, 1H), 5.27 (td, J = 6.3, 3.2 Hz, 1H), 4.40-4.33 (m, 1H), 4.31-4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.3 Hz, 3H).
    348
    Figure US20190292176A1-20190926-C01181
         		I-67 24 h  538.2 1.18 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.29 (br. s., 1H), 8.03 (br. s., 1H), 8.02-7.93 (m, 3H), 7.82 (s, 1H), 7.18-7.10 (m, 1H), 5.26 (td, J = 6.3, 3.3 Hz, 1H), 4.40-4.32 (m, 1H), 4.31-4.24 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H).
    349
    Figure US20190292176A1-20190926-C01182
         		I-67 24 h  520.2 0.94 55-95% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.46 (br. s., 3H), 7.94-7.87 (m, 2H), 7.73 (s, 1H), 7.62 (br. s., 2H), 5.75-5.75 (m, 1H), 5.32 (d, J = 2.7 Hz, 1H), 4.37 (d, J = 8.2 Hz, 1H), 4.32-4.24 (m, 1H), 4.05 (s, 3H), 2.58 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H).
    350
    Figure US20190292176A1-20190926-C01183
         		I-67 24 h  576.2 1.13 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.73 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.53- 7.46 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.24 (td, J = 6.3, 3.4 Hz, 1H), 4.40-4.32 (m, 1H), 4.32-4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H).
    351
    Figure US20190292176A1-20190926-C01184
         		I-67 24 h  545.2 1.21 45-100% 25 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.77- 8.72 (m, 2H), 8.58 (d, J = 1.9 Hz, 1H), 8.10 (dd, J = 8.5, 2.5 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 11.6 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 1.8, 1.0 Hz, 1H), 5.29 (td, J = 6.3, 3.2 Hz, 1H), 4.43-4.35 (m, 1H), 4.33- 4.26 (m, 1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.44 (d, J = 6.3 Hz, 3H).
    352
    Figure US20190292176A1-20190926-C01185
         		I-67 24 h  514.2 1.06 35-75% 20 min, 75% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.50 (s, 1H), 7.94-7.87 (m, 2H), 7.76 (s, 1H), 7.33 (br. s., 1H), 7.15 (br. s., 1H), 6.80 (br. s., 1H), 5.06 (br. s., 1H), 4.19 (br. s., 2H), 4.05 (s, 3H), 3.17 (d, J = 5.8 Hz, 2H), 2.59 (s, 3H), 2.24 (t, J = 6.9 Hz, 2H), 1.30 (d, J = 6.1 Hz, 3H).
    353
    Figure US20190292176A1-20190926-C01186
         		I-67 24 h  521.2 1.00 40-80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.21 (d, J = 2.2 Hz, 1H), 8.98 (d, J = 6.1 Hz, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 11.6 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 5.8, 2.8 Hz, 1H), 5.31 (td, J = 6.3, 3.0 Hz, 1H), 4.43-4.37 (m, 1H), 4.30 (dd, J = 11.0, 6.1 Hz, 1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.45 (d, J = 6.3 Hz, 3H).
    354
    Figure US20190292176A1-20190926-C01187
         		I-67 24 h  559.2 1.07 20-100% 10 min, 100% 5 min
    355
    Figure US20190292176A1-20190926-C01188
         		I-67 24 h  558.2 1.21 20-100% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.46 (br. s., 1H), 8.65 (s, 1H), 8.49 (s, 1H), 7.95-7.89 (m, 2H), 7.75 (s, 1H), 7.68 (br. s., 1H), 7.28 (d, J = 3.0 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 6.34 (br. s., 1H), 5.24 (d, J = 3.4 Hz, 1H), 4.40-4.20 (m, 2H), 4.05 (s, 3H), 2.59 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H).
    356
    Figure US20190292176A1-20190926-C01189
         		I-67 24 h  572.2 1.25 20-100% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.49 (br. s., 1H), 8.65 (s, 1H), 8.50 (s, 1H), 7.98-7.88 (m, 2H), 7.76 (s, 1H), 7.68 (br. s., 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.22 (br. s., 1H), 6.33 (br. s., 1H), 5.24 (d, J = 3.0 Hz, 1H), 4.38-4.19 (m, 2H), 4.05 (s, 3H), 3.74 (s, 2H), 2.59 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H).
    357
    Figure US20190292176A1-20190926-C01190
         		I-67 24 h  535.2 1.14 40-80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.03 (br. s., 1H), 8.73 (br. s., 2H), 8.59 (s, 1H), 8.43 (br. s., 1H), 7.86 (d, J = 10.4 Hz, 2H), 7.71 (s, 1H), 5.25 (br. s., 1H), 4.33 (d, J = 8.4 Hz, 1H), 4.24 (dd, J = 10.6, 6.2 Hz, 1H), 4.03 (s, 3H), 3.68 (br. s., 3H), 2.56 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    358
    Figure US20190292176A1-20190926-C01191
         		318 1 h  463.1, 465.1 1.15 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.59 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.86 (br. s., 1H), 6.57 (br. s., 2H), 4.36 (d, J = 7.3 Hz, 4H), 4.09 (s, 3H), 2.66 (s, 3H).
    359
    Figure US20190292176A1-20190926-C01192
         		318 1 h  579.2, 581.2 1.09 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.29 (br. s., 1H), 8.12 (br. s., 1H), 8.02 (d, J = 7.0 Hz, 1H), 7.86 (s, 1H), 7.49 (br. s., 1H), 6.46 (br. s., 1H), 4.60 (br. s., 2H), 4.52 (br. s., 2H), 4.14 (s, 3H), 2.70 (s, 3H).
    360
    Figure US20190292176A1-20190926-C01193
         		318 1 h  578.2, 580.2 1.22 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.57 (br. s., 1H), 8.63 (s, 1H), 8.50 (br. s., 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.78 (br. s., 1H), 7.73 (br. s., 1H), 7.40-7.31 (m, 2H), 7.21 (br. s., 1H), 6.41 (br. s., 1H), 4.57 (br. s., 2H), 4.48 (br. s., 2H), 4.11 (s, 3H), 2.66 (br. s., 3H).
    361
    Figure US20190292176A1-20190926-C01194
         		318 1 h  598.2, 600.2 1.18 65-95% 25 min, 95% 10 min 1H NMR (500 MHz, CHLOROFORM- d) δ 8.67 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.08-8.03 (m, 1H), 7.71 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 6.95 (br. s., 1H), 4.59 (br. s., 2H), 4.34 (br. s., 2H), 4.06 (s, 3H), 3.92 (s, 3H), 2.60 (s, 3H).
    362
    Figure US20190292176A1-20190926-C01195
         		318 1 h  555.2, 557.2 1.16 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, CHLOROFORM- d) δ 8.74-8.61 (m, 3H), 8.47 (s, 1H), 7.71 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 6.66 (br. s., 1H), 4.61-4.52 (m, 2H), 4.35-4.31 (m, 2H), 4.06 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H).
    363
    Figure US20190292176A1-20190926-C01196
         		318 1 h  577.2, 579.2 1.19 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, CHLOROFORM- d) δ 8.76 (br. s., 1H), 8.57 (br. s., 1H), 7.80 (br. s., 1H), 7.63 (br. s., 1H), 7.44 (br. s., 1H), 4.67 (br. s., 2H), 4.43 (br. s., 2H), 4.16 (br. s., 6H), 2.69 (br. s., 3H).
    364
    Figure US20190292176A1-20190926-C01197
         		318 1 h  529.2, 531.2 1.16 50-80% 25 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.60 (br. s., 2H), 4.55 (br. s., 2H), 4.46 (br. s., 2H), 4.11 (s, 3H), 2.67 (s, 3H).
    365
    Figure US20190292176A1-20190926-C01198
         		318 1 h  543.2, 545.2 1.21 50-90% 25 min, 100% 10 min 1H NMR (500 MHz, CD2Cl2) δ 8.65 (br. s., 1H), 8.46 (br. s., 1H), 7.70 (br. s., 1H), 7.51 (br. s., 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.27 (br. s., 1H), 6.49 (br. s., 1H), 4.50 (br. s., 2H), 4.30 (br. s., 2H), 4.05 (br. s., 3H), 3.76 (br. s., 3H), 2.59 (br. s., 3H).
    366
    Figure US20190292176A1-20190926-C01199
         		318 1 h  545.1, 547.1 1.12 60-90% 22 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.49 (br. s., 1H), 7.92 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.77 (br. s., 1H), 4.49 (br. s., 2H), 4.38 (br. s., 2H), 4.04 (s, 3H), 2.88 (s, 3H), 2.72 (s, 3H).
    367
    Figure US20190292176A1-20190926-C01200
         		318 1 h  607.2, 609.2 1.19 60-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.67 (br. s., 1H), 8.60 (s, 1H), 8.47 (br. s., 1H), 8.15 (br. s., 1H), 7.90 (br. s., 2H), 7.75 (br. s., 1H), 6.15 (br. s., 1H), 4.51 (br. s., 2H), 4.43 (br. s., 2H), 4.04 (s, 3H), 3.51 (s, 3H), 2.60 (s, 3H), 2.38 (br. s., 3H).
    368
    Figure US20190292176A1-20190926-C01201
         		318 1 h  554.2, 556.2 1.02 50-95% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.55 (s, 1H), 8.46 (br. s., 1H), 8.43 (br. s., 1H), 7.93 (br. s., 2H), 7.82 (s, 1H), 7.64 (br. s., 1H), 7.33 (br. s., 1H), 4.38 (d, J = 9.8 Hz, 4H), 4.22 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H), 2.63 (s, 3H).
    369
    Figure US20190292176A1-20190926-C01202
         		318 1 h  554.2, 556.2 1.01 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.72 (br. s., 1H), 8.60-8.51 (m, 3H), 8.11- 7.88 (m, 2H), 7.85 (br. s., 1H), 7.32 (d, J = 4.6 Hz, 2H), 4.47 (d, J = 15.9 Hz, 4H), 4.30 (d, J = 6.1 Hz, 2H), 4.13 (s, 3H), 2.69 (s, 3H).
    370
    Figure US20190292176A1-20190926-C01203
         		I-69 24 h   575.4, 577.4 1.19 60-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.71 (br. s., 1H), 8.56 (br. s., 1H), 7.99 (d, J = 7.02 Hz, 1H), 7.83 (br. s., 1H), 5.33 (br. s., 1H), 4.41 (d, J = 10.68 Hz, 1H), 4.30 (br. s., 1H), 4.09 (br. s., 3H), 1.43 (d, J = 5.49 Hz, 3H).
    371
    Figure US20190292176A1-20190926-C01204
         		I-69 24 h   579.4, 581.4 1.22 70-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.73 (br. s., 1H), 8.63 (br. s., 1H), 8.48 (br. s., 1H), 8.08 (d, J = 8.55 Hz, 1H), 7.86-8.00 (m, 3H), 7.76 (br. s., 1H), 5.30 (br. s., 1H), 4.22-4.46 (m, 2H), 4.06 (br. s., 3H), 2.62 (br. s., 3H), 1.44 (d, J = 4.88 Hz, 3H).
    372
    Figure US20190292176A1-20190926-C01205
         		I-69 24 h   554.1, 556.1 1.24 60-100% 13 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.97 (br. s., 1H), 8.65 (br. s., 2H), 8.50 (br. s., 1H), 8.21 (br. s., 1H), 7.86-8.00 (m, 2H), 7.78 (br. s., 1H), 7.33 (br. s., 1H), 5.28 (br. s., 1H), 4.24-4.45 (m, 2H), 4.07 (s, 3H), 2.62 (s, 3H), 1.43 (d, J = 5.80 Hz, 3H).
    373
    Figure US20190292176A1-20190926-C01206
         		I-69 24 h   611.1, 613.1 1.20 65-100% 13 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.63- 9.76 (m, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 7.98-8.05 (m, 1H), 7.85 (s, 1H), 7.71- 7.79 (m, 1H), 7.36-7.49 (m, 1H), 7.05- 7.17 (m, 1H), 6.89-6.97 (m, 1H), 4.99- 5.34 (m, 1H), 4.23-4.43 (m, 2H), 4.08 (s, 3H), 3.08-3.19 (m, 1H), 2.64 (s, 3H), 1.40 (d, J = 6.10 Hz, 3H).
    374
    Figure US20190292176A1-20190926-C01207
         		I-69 24 h   622.2, 624.2 1.36 60-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.39 (br. s., 1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 8.55 Hz, 1H), 7.98 (d, J = 7.63 Hz, 1H), 7.74-7.87 (m, 2H), 5.29 (br. s., 1H), 4.22-4.47 (m, 2H), 4.07 (s, 3H), 2.62 (s, 3H), 1.43 (d, J = 6.41 Hz, 3H).
    375
    Figure US20190292176A1-20190926-C01208
         		I-69 24 h   593.2, 595.2 1.15 55-85% 16 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 11.43 (br. s., 1H), 9.42-9.72 (m, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.19 (br. s., 1H), 8.02 (br. s., 1H), 7.84-7.94 (m, 1H), 7.74 (s, 1H), 7.39 (br. s., 1H), 6.37 (br. s., 1H), 5.24 (d, J = 3.36 Hz, 1H), 4.19-4.40 (m, 2H), 4.04 (s, 3H), 2.59 (s, 3H), 1.40 (d, J = 6.41 Hz, 3H).
    376
    Figure US20190292176A1-20190926-C01209
         		I-69 24 h   568.2, 570.2 1.06 40-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.46 (br. s., 1H), 8.66 (br. s., 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.30 (d, J = 4.58 Hz, 1H), 7.84 (d, J = 7.63 Hz, 1H), 7.68 (s, 1H), 7.48 (d, J = 5.19 Hz, 1H), 5.22 (dd, J = 3.05, 6.10 Hz, 1H), 4.14-4.41 (m, 2H), 3.99 (s, 3H), 2.54 (s, 3H), 2.13-2.33 (m, 3H), 1.37 (d, J = 6.41 Hz, 3H).
    377
    Figure US20190292176A1-20190926-C01210
         		I-69 24 h   568.2, 570.2 1.07 60-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.11-8.68 (m, 3H), 7.59- 7.89 (m, 3H), 7.15 (d, J = 8.24 Hz, 1H), 5.23 (br. s., 1H), 4.20-4.48 (m, 2H), 4.02 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H), 1.40 (d, J = 6.41 Hz, 3H).
    378
    Figure US20190292176A1-20190926-C01211
         		318 1 h  600.2, 602.2 1.28 50-85% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 9.48- 9.57 (m, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.90-8.00 (m, 1H), 7.80 (s, 1H), 6.95- 7.11 (m, 1H), 6.52-6.68 (m, 1H), 4.25- 4.47 (m, 4H), 4.03 (s, 3H), 3.64 (br. s., 2H), 3.34-3.45 (m, 6H), 2.59 (s, 3H).
    • Example 379 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-yl pyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C01212
    • Intermediate 379A: 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-ol
  • Figure US20190292176A1-20190926-C01213
  • To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) in THF (1 mL) was added tetrabutylammonium bromide (28.3 mg, 0.088 mmol) followed by a 0.33 M solution of KOH (0.20 mL, 0.066 mmol). 2-(isobutoxymethyl)oxirane (0.1 mL) was then added, and the resulting mixture was heated to 65° C. in a sealed tube. After 16 h, the reaction was quenched with saturated NH4Cl and diluted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered, concentrated and purified by ISCO (4 g, 0-60% EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate 379A (14 mg, 0.024 mmol, 54.1% yield) as a yellow solid. LC-MS: Method H, RT=1.23 min, MS (ESI) m/z: 472.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.60 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 4.30-4.22 (m, 1H), 4.22-4.15 (m, 2H), 4.13 (s, 3H), 3.70-3.61 (m, 2H), 3.32-3.25 (m, 2H), 2.65 (s, 3H), 2.62 (d, J=4.8 Hz, 1H), 1.97-1.80 (m, 1H), 0.92 (d, J=6.8 Hz, 6H).
    • Example 379
  • This example was prepared according to the general procedure for carbamates described in the table above. Thus, reaction of Intermediate 379A with 3-aminopyridine afforded Example 379 in 77% yield following purification by preparative HPLC (Method D, 45-100% over 15 min). LC-MS: Method H, RT=1.03 min, MS (ESI) m/z: 592.3 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (br. s., 1H), 8.79 (br. s., 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.36 (d, J=4.3 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 7.82 (s, 1H), 7.61-7.53 (m, 1H), 5.42-5.32 (m, 1H), 4.53-4.45 (m, 1H), 4.45-4.37 (m, 1H), 4.09 (s, 3H), 3.80 (d, J=5.2 Hz, 2H), 3.37-3.29 (m, 1H), 3.28-3.22 (m, 1H), 2.63 (s, 3H), 1.84 (dt, J=13.2, 6.7 Hz, 1H), 0.93-0.81 (m, 6H).
    • Example 380 1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl pyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C01214
    • Intermediate 380A: 1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C01215
  • To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) in THF (1 mL) was added tetrabutylammonium bromide (28.3 mg, 0.088 mmol) followed by a 0.33 M solution of KOH (0.20 mL, 0.066 mmol). 2-((benzyloxy)methyl)oxirane (72.2 mg, 0.439 mmol) was then added, and the resulting mixture was heated to 65° C. in a sealed tube. After 16 h, the reaction was quenched with saturated NH4Cl and diluted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered, concentrated and purified by ISCO (4 g, 0-60% EtOAc/Hexanes, 16 min. Product at 35%) to afford Intermediate 380A (16 mg, 0.032 mmol, 72.0% yield) as a yellow solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 506.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.60 (d, J=2.0 Hz, 1H), 8.53 (s, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.74 (dd, J=1.8, 0.9 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.38-7.27 (m, 5H), 4.61 (s, 2H), 4.33-4.24 (m, 1H), 4.23-4.17 (m, 2H), 4.12 (s, 3H), 3.77-3.68 (m, 2H), 2.66-2.62 (m, 4H).
    • Example 380
  • Example 380 was prepared according to the general procedure for carbamates described in the table above. Thus, reaction of Intermediate 380A with 3-aminopyridine afforded Example 380 in 34% yield following purification by preparative HPLC (Method D, 45-100% over 18 min). LC-MS: Method H, RT=1.02 min, MS (ESI) m/z: 626.3 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (br. s., 1H), 8.74 (br. s., 2H), 8.58 (br. s., 1H), 8.31 (br. s., 1H), 8.07-7.95 (m, 3H), 7.85 (br. s., 1H), 7.50 (br. s., 1H), 7.39-7.27 (m, 5H), 5.41 (br. s., 1H), 4.60 (d, J=7.3 Hz, 2H), 4.47 (d, J=17.4 Hz, 2H), 4.09 (br. s., 3H), 3.86 (br. s., 2H), 2.64 (br. s., 3H).
    • Example 381 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate (racemate)
  • Figure US20190292176A1-20190926-C01216
    • Intermediate 381A: methyl 2((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) propanoate (racemate)
  • Figure US20190292176A1-20190926-C01217
  • Intermediate 381A was prepared in a manner analogous to Intermediate I-50. Thus, Intermediate I-44 was reacted to afford Intermediate 381A (rac) (46% yield) as a white solid. LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 368.0, 370.0, 372.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.23 (d, J=6.8 Hz, 1H), 4.81 (q, J=6.8 Hz, 1H), 3.78 (s, 3H), 1.71 (d, J=6.8 Hz, 3H).
    • Intermediate 381B: 2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-1-ol (racemate)
  • Figure US20190292176A1-20190926-C01218
  • Intermediate 381B was prepared in a manner analogous to Intermediate I-51. Thus, Intermediate 381A (rac) was reacted to afford Intermediate 381B (rac) (75% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 339.9, 341.9, 343.9 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ 7.71 (d, J=7.3 Hz, 1H), 4.64-4.52 (m, 1H), 3.79-3.67 (m, 2H), 1.34 (d, J=6.2 Hz, 3H)
    • Intermediate 381C: 2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate (racemate)
  • Figure US20190292176A1-20190926-C01219
  • Intermediate 381C was prepared according to the general procedure for carbamates described in the table above. Thus, reaction of Intermediate 381B (rac) with 3-amino-6-methoxypyridine afforded Intermediate 381C (rac) in 90% yield. LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 489.9, 491.9, 493.9 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (br. s., 1H), 7.73 (br. s., 1H), 7.35 (d, J=7.3 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.53 (br. s., 1H), 4.76-4.59 (m, 1H), 4.36 (d, J=5.3 Hz, 2H), 3.91 (s, 3H), 1.43 (d, J=6.4 Hz, 3H).
    • Example 381
  • Example 381 was prepared according to the general procedure for quinoxaline-benzothiazoles described in the table above. Thus, reaction of Intermediate 381C (rac) with Intermediate I-9 afforded Example 381 (rac) in 23% yield following purification by preparative HPLC (Method D, 55-95% over 30 min). LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 584.1, 586.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.71 (br. s., 1H), 8.73 (s, 1H), 8.58 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H), 7.85 (s, 1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td, J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 2.66 (s, 3H), 1.43 (d, J=6.3 Hz, 3H)
    • Example 382 (S)-2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl (6-methoxypyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01220
  • This example was prepared by subjecting Example 381 (rac) to chiral, super-critical fluid chromatography conditions (Berger Multigram II SFC, Chiralpak OJ, 21×250 mm, 5 micron, 45% EtOH/−0.1% DEA/55% CO2, 40 mL/min flow rate) to give Example 382 as the second eluting enantiomer. The absolute stereochemistry of this example was assigned by analogy to other biologically active enantiomers in the same series. LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 584.1, 586.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.71 (br. s., 1H), 8.73 (s, 1H), 8.58 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H), 7.85 (s, 1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td, J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 2.66 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).
    • Example 383 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-chlorothiazol-4-yl)carbamate
  • Figure US20190292176A1-20190926-C01221
  • To a suspension of Example 318 (12 mg, 0.029 mmol) and 2-chlorothiazole-4-carboxylic acid (9.35 mg, 0.057 mmol) in Toluene (1 mL) was added triethylamine (7.97 μl, 0.057 mmol) followed by diphenylphosphoryl azide (15.73 mg, 0.057 mmol). The reaction vessel was then sealed and heated to 110° C. for 3 hours. The resulting mixture was cooled to room temperature, concentrated and purified by preparative HPLC (Method D, 60-100% over 20 min, hold at 100% for 10 min) to afford Example 383 in 20% yield. LC-MS: Method H, RT=1.35 min, MS (ESI) m/z: 580.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.71 (br. s., 1H), 8.73 (s, 1H), 8.58 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H), 7.85 (s, 1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td, J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 2.66 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).
    • Example 384 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl thiazol-5-ylcarbamate
  • Figure US20190292176A1-20190926-C01222
  • Example 384 was prepared in a manner analogous to Example 383. Thus, Example 318 was reacted with thiazole-5-carboxylic acid to afford Example 384 (3% yield) following purification by preparative HPLC (Method D, 40-80% over 20 min, hold at 100% for 5 min). LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 546.1, 548.1 (M+H)+. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.66-8.85 (m, 1H), 8.53-8.62 (m, 1H), 8.38-8.51 (m, 1H), 7.71-7.85 (m, 1H), 7.53-7.64 (m, 1H), 7.36-7.45 (m, 1H), 7.28-7.33 (m, 1H), 4.67 (br. s., 2H), 4.41 (br. s., 2H), 4.14 (br. s., 3H), 2.68 (br. s., 3H).
    • Example 385 (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01223
    • Intermediate 385A: (5-aminopyridin-2-yl)methanol
  • Figure US20190292176A1-20190926-C01224
  • To a suspension of methyl 5-aminopicolinate (70 mg, 0.460 mmol) in THF (3 mL) was added a solution of LAH (1 M in THF) (0.920 mL, 0.920 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. After 16 h, the reaction was quenched with water (0.1 mL) at 0° C. A solution of sodium hydroxide (2 N, 0.1 mL) was subsequently added followed by an additional quantity of water (0.3 mL). Magnesium sulfate was added and the mixture was stirred for 1 hour before being filtered over a pad of celite and washed with THF. The filtrate was concentrated in vacuo to afford Intermediate 385A (35 mg, 0.282 mmol, 61.3% yield) as a yellow solid. This material was taken on without further purification. LC-MS: Method H, RT=0.44 min, MS (ESI) m/z: 125.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.88 (m, 1H), 7.05-7.16 (m, 1H), 6.83-6.96 (m, 1H), 4.88-5.04 (m, 1H), 4.27-4.41 (m, 2H).
    • Intermediate 385B: 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine
  • Figure US20190292176A1-20190926-C01225
  • To a stirred solution of crude Intermediate 385A (225 mg, 1.812 mmol) in DMF (5 mL) was added TBDMS-Cl (410 mg, 2.72 mmol) followed by imidazole (222 mg, 3.26 mmol). The reaction mixture was stirred for 1 h at room temperature before being concentrated and purified by ISCO (24 g, 0-100% EtOAc/Hexanes, 15 min. Product at 65%) to afford Intermediate 385B (132 mg, 0.554 mmol, 30.5% yield), as a yellow solid. LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 239.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=2.64 Hz, 1H), 7.00 (s, 1H), 6.77-6.91 (m, 1H), 5.13 (s, 2H), 4.50 (s, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
    • Intermediate 385C: (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01226
  • This intermediate was prepared according to the general procedure for carbamates described in the table above. Thus, reaction of Intermediate I-69 with Intermediate 385B afforded Intermediate 385C, which was telescoped into the subsequent silyl-deprotection reaction. LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 698.5, 700.5 (M+H)+.
    • Example 385
  • Intermediate 385C was concentrated and redissolved in 10 mL mixture of MeOH (9.5 mL) and 12 M HCl (0.5 mL). The resulting solution was stirred for 10 minutes before being concentrated down and purified by preparative HPLC (Method D, 50-100% over 10 min, hold at 100% for 10 min) to afford Example 385 in 9% overall yield as a yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 584.3, 586.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.69-9.99 (m, 1H), 8.77 (s, 1H), 8.60-8.65 (m, 1H), 8.53-8.57 (m, 1H), 8.02-8.10 (m, 1H), 7.82-7.93 (m, 2H), 7.33-7.42 (m, 1H), 5.21-5.37 (m, 2H), 4.46-4.52 (m, 2H), 4.38-4.45 (m, 1H), 4.24-4.35 (m, 1H), 2.67 (s, 4H), 1.43 (d, J=6.38 Hz, 3H).
    • Example 386 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01227
  • Example 386 was prepared according to the general procedure for carbamates described in the table above. Thus, reaction of Intermediate I-72 with 2-methylpyrimidin-5-amine and pyridine afforded Example 386 in 46% yield following purification by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 549.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.74 (s, 2H), 8.63 (d, J=1.5 Hz, 1H), 8.57 (s, 1H), 7.85 (d, J=11.4 Hz, 1H), 7.79 (s, 1H), 7.58-7.52 (m, 1H), 6.51 (br. s., 1H), 5.18 (dd, J=6.5, 3.0 Hz, 1H), 4.69-4.59 (m, 1H), 4.16 (s, 3H), 2.70 (s, 3H), 2.68 (s, 3H), 1.50 (d, J=6.6 Hz, 3H), 1.46 (d, J=6.4 Hz, 3H).
    • Example 387 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01228
  • Example 387 was prepared according to the general procedure for carbamates described in the table above. Thus, reaction of Intermediate I-72 with 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine afforded the TBS-protected intermediate of the desired product. The crude reaction mixture was concentrated and retaken in a 20:1 mixture of MeOH/concentrated HCl to affect the desired silyl deprotection and afford Example 387 in 46% yield following purification by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 578.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.79 (br. s., 1H), 8.73 (s, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.53 (br. s., 1H), 8.04 (d, J=8.4 Hz, 1H), 7.96 (d, J=11.7 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=7.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.10 (qd, J=6.5, 2.9 Hz, 1H), 4.82-4.73 (m, 1H), 4.08 (s, 3H), 3.67 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.63 (s, 3H), 1.39 (m, 6H)
    • Example 388 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate
  • Figure US20190292176A1-20190926-C01229
  • Example 388 was prepared according to the general procedure for carbamates described in the table above. Thus, reaction of Intermediate I-72 with 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-4-amine afforded the TBS-protected intermediate of the desired product. Excess TBAF (10 equiv, 1 M in THF) was added to the crude reaction mixture to afford Example 388 in 26% yield following purification by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 594.2 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.99 (s, 1H), 8.67 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.89 (d, J=11.7 Hz, 1H), 7.86 (d, J=5.9 Hz, 1H), 7.77 (s, 1H), 6.96 (dd, J=5.7, 1.8 Hz, 1H), 6.83 (d, J=1.3 Hz, 1H), 5.10-5.00 (m, 1H), 4.76-4.67 (m, 2H), 4.12 (t, J=5.1 Hz, 2H), 4.01 (s, 3H), 3.58 (q, J=5.4 Hz, 2H), 2.56 (s, 3H), 1.32 (m, 6H).
    • Example 389 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01230
  • To a solution of Intermediate I-73 (30 mg, 0.051 mmol) in THF (1.5 mL) was added ethanol (0.5 mL, 8.56 mmol) followed by sodium hydride (20.53 mg, 0.513 mmol, 60% suspension in mineral oil). The reaction mixture was stirred for 10 min at room temperature before being quenched with saturated NH4Cl (˜0.15 mL). The resulting mixture was diluted with EtOAc, filtered over celite, concentrated, retaken in DMF, filtered and purified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to afford Example 389 (17.7 mg, 0.030 mmol, 58% yield) as a yellow solid. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 563.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s., 1H), 8.71 (br. s., 2H), 8.63 (s, 1H), 8.50 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.91 (d, J=11.3 Hz, 1H), 7.75 (s, 1H), 5.10 (dd, J=6.7, 2.4 Hz, 1H), 4.78 (d, J=4.0 Hz, 1H), 4.49 (q, J=7.0 Hz, 2H), 2.59 (s, 3H), 2.50 (s, 3H-buried under d-DMSO), 1.42 (t, J=7.2 Hz, 3H), 1.38 (m, 6H).
    • Example 390 (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylamino)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01231
  • To a vial charged with Intermediate I-73(10 mg, 0.017 mmol) was added methanamine (33% solution in EtOH) (1 mL, 8.00 mmol). The mixture was stirred at room temperature for 16 h before being concentrated and purified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to afford Example 390 (17.7 mg, 0.030 mmol, 58% yield) as a yellow solid. LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 548.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.97 (br. s., 1H), 8.72 (br. s., 2H), 8.42 (s, 1H), 8.27 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.92 (d, J=11.3 Hz, 1H), 7.56 (s, 1H), 5.10 (d, J=4.9 Hz, 1H), 4.79 (d, J=4.0 Hz, 1H), 2.96 (s, 3H), 2.50 (s, 3H-buried under d-DMSO), 1.38 (m, 6H).
    • Example 391 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-carbamoylpyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01232
  • To a vial charged with Intermediate I-74 (20 mg, 0.034 mmol) was added ammonia (7M solution in MeOH) (1 mL, 14.00 mmol). The mixture was sealed and heated to 65° C. for 24 h before being concentrated and purified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to afford Example 391 (8 mg, 0.013 mmol, 38% yield) as a yellow solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 577.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (br. s., 1H), 8.71-8.61 (m, 2H), 8.52 (s, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.98-7.89 (m, 3H), 7.79 (s, 1H), 7.45 (br. s., 1H), 5.12 (d, J=5.8 Hz, 1H), 4.80 (d, J=6.1 Hz, 1H), 4.05 (s, 3H), 2.60 (s, 3H), 1.39 (m, 6H).
    • Example 392 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01233
  • To a solution of Intermediate I-74 (10 mg, 0.017 mmol) in THF (1 mL) was added ethanolamine (0.1 mL). The reaction mixture was allowed to stir at room temperature for 16 h before being concentrated and purified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to afford Example 392 (8.7 mg, 0.014 mmol, 81% yield) as a yellow solid. LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 621.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (br. s., 1H), 8.63 (d, J=5.8 Hz, 2H), 8.53-8.43 (m, 2H), 7.97 (d, J=8.5 Hz, 2H), 7.94-7.86 (m, 2H), 7.76 (s, 1H), 5.11 (d, J=5.8 Hz, 1H), 4.89-4.84 (m, 1H), 4.81 (br. s., 1H), 4.04 (s, 3H), 3.48 (d, J=5.5 Hz, 2H), 3.32 (d, J=5.5 Hz, 2H), 2.58 (s, 3H), 1.38 (m, 6H).
    • Example 393 (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01234
  • To a solution of Intermediate I-75 (13 mg, 0.022 mmol) in THF (1 mL) was added methanamine (33% solution in EtOH) (0.2 mL, 1.60 mmol). The reaction mixture was allowed to stir at room temperature for 16 h before being concentrated and purified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to afford Example 393 (5 mg, 0.008 mmol, 37% yield) as a yellow solid. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 576.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.07 (d, J=4.9 Hz, 1H), 8.83 (s, 1H), 8.73 (br. s., 2H), 8.11-8.01 (m, 2H), 7.94 (d, J=11.6 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.3 Hz, 1H), 2.98-2.90 (m, 3H), 2.70 (s, 3H), 2.52 (br. s., 3H), 1.40 (m, 6H).
    • Preparation of Carbamate Examples
  • The Carbamates in the table below were prepared according to the following general procedure, which is analogous to Intermediate I-82 described above
  • To a solution of the appropriately substituted quinoxaline-benzothiazole alcohol (1.0 equiv) in THF (0.05 M) was added a solution of phosgene (15% by wt. in toluene, 10 equiv). This solution was stirred at room temperature overnight, and the intermediate chloroformate was concentrated in vacuo. This crude chloroformate was then retaken in THF (0.05 M) and added dropwise to a pre-mixed solution of pyridine (10 equiv) and the appropriately substituted amino-heterocycle or amine (3.0 equiv) in either THF (0.05 M) or DCM (0.05) (whichever gave the best reagent solubility). After 10 min of stirring, the combined mixture was concentrated and purified by preparative HPLC to yield the desired example.
  • LCMS
    LCMS RT HPLC
    [M + (Min) Prep
    Ex. H]+ Method Method
    No. Structure R—OH m/z H D NMR
    394
    Figure US20190292176A1-20190926-C01235
         		I-67 568.3 1.13 30- 65% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 7.99-7.94 (m, 2H), 7.83 (s, 1H), 7.14 (t, J = 5.5 Hz, 1H), 5.13-5.04 (m, 1H), 4.27- 4.16 (m, 2H), 4.09 (s, 3H), 3.31-3.16 (m, 6H), 2.63 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.88-1.78 (m, 2H), 1.73 (quin, J = 6.7 Hz, 2H), 1.32 (d, J = 6.6 Hz, 3H)
    395
    Figure US20190292176A1-20190926-C01236
         		318 565.2, 567.3 1.22 60- 100% 20 min, 100% 8 min —
    396
    Figure US20190292176A1-20190926-C01237
         		318 545.2, 556.2 1.02 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.53 (br. s., 1H), 8.46 (br. s., 1H), 7.92 (br. s., 1H), 7.88 (d, J = 6.4 Hz, 1H), 7.81 (br. s., 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.38-7.30 (m, 1H), 7.29-7.21 (m, 1H), 4.39 (d, J = 1.6 Hz, 4H), 4.28 (d, J = 5.8 Hz, 2H), 4.05 (s, 3H), 2.62 (s, 3H)
    397
    Figure US20190292176A1-20190926-C01238
         		318 557.2, 559.3 1.21 45- 90% 30 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.45 (br. s., 1H), 7.85-7.81 (m, 1H), 7.72 (br. s., 1H), 7.51 (br. s., 1H), 7.40 (s, 1H), 6.82 (s, 1H), 4.31 (d, J = 8.2 Hz, 4H), 4.00 (m, 5H), 3.47 (br. s., 3H), 2.56 (s, 3H)
    398
    Figure US20190292176A1-20190926-C01239
         		318 557.2, 559.2 1.21 45- 100% 20 min, 100% 5 min 1H NMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 8.47 (s, 1H), 7.70 (s, 1H), 7.33 (d, J = 6.9 Hz, 1H), 7.20 (br. s., 1H), 6.10 (s, 1H), 5.19 (br. s., 1H), 4.46 (br. s., 2H), 4.32 (d, J = 5.5 Hz, 2H), 4.27 (br. s., 2H), 4.06 (s, 3H), 3.78 (s, 3H), 2.60 (s, 3H)
    399
    Figure US20190292176A1-20190926-C01240
         		318 557.2, 559.2 1.18 45- 80% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.47 (s, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.74 (s, 1H), 7.58 (br. s., 1H), 7.47 (s, 1H), 7.24 (s, 1H), 4.31 (d, J = 8.2 Hz, 4H), 4.01 (s, 3H), 3.97 (d, J = 5.8 Hz, 2H), 3.71 (s, 3H), 2.57 (s, 3H)
    400
    Figure US20190292176A1-20190926-C01241
         		I-69 580.2, 582.2 1.30 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.73 (s, 1H), 8.58 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 5.36 (br. s., 1H), 4.53-4.45 (m, 1H), 4.38 (dd, J = 10.8, 6.0 Hz, 1H), 4.13 (s, 3H), 2.69 (s, 3H), 1.51 (d, J = 6.4 Hz, 3H)
    401
    Figure US20190292176A1-20190926-C01242
         		I-69 590.2, 592.2 1.34 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 2H), 8.74 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.86 (s, 1H), 5.27 (td, J = 6.3, 3.0 Hz, 1H), 4.44-4.39 (m, 1H), 4.32 (dd, J = 10.9, 5.9 Hz, 1H), 4.09 (s, 3H), 2.65 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H)
    402
    Figure US20190292176A1-20190926-C01243
         		I-69 586.1, 588.1 1.35 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.54 (s, 1H), 8.13 (br. s., 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.91 (br. s., 1H), 7.81 (s, 1H), 5.31 (br. s., 1H), 4.47-4.39 (m, 1H), 4.34 (dd, J = 10.4, 6.1 Hz, 1H), 4.12 (s, 3H), 2.67 (s, 3H), 2.25 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H)
    403
    Figure US20190292176A1-20190926-C01244
         		I-69 632.0, 634.0, 636.0 1.30 60- 90% 20 min, 100% 5 min 1H NMR (400 MHz, THF) δ 9.25 (br. s., 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.41 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 8.7, 2.8 Hz, 1H), 7.83 (dd, J = 1.8, 0.9 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 5.42-5.26 (m, 1H), 4.44-4.27 (m, 2H), 4.15 (s, 3H), 2.70 (s, 3H), 1.55-1.49 (m, 3H)
    404
    Figure US20190292176A1-20190926-C01245
         		I-81 568.2, 570.2 1.10 40- 80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.07 (br. s., 1H), 8.67 (br. s., 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.24 (br. s., 1H), 7.98 (d, J = 6.7 Hz, 2H), 7.75 (s, 1H), 7.45 (br. s., 1H), 5.08 (d, J = 6.7 Hz, 1H), 4.76 (br. s., 1H), 4.01 (s, 3H), 2.57 (s, 3H), 1.36 (d, J = 6.1 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H)
    405
    Figure US20190292176A1-20190926-C01246
         		I-72 548.1 1.05 15- 100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.49 (br. s., 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.77 (br. s., 1H), 7.19 (d, J = 7.9 Hz, 1H), 5.09 (d, J = 4.6 Hz, 1H), 4.77 (br. s., 1H), 4.07 (s, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 1.38 (m, 6H)
    406
    Figure US20190292176A1-20190926-C01247
         		I-72 590.1 1.22 25- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.67 (br. s., 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.81 (s, 1H), 7.45 (br. s., 1H), 7.12 (br. s., 1H), 6.96 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.77 (br. s., 1H), 4.06 (s, 3H), 2.61 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.7 Hz, 3H)
    407
    Figure US20190292176A1-20190926-C01248
         		I-72 565.1 1.26 50- 100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.88 (br. s., 1H), 8.77 (s, 1H), 8.68 (br. s., 2H), 8.62 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 11.6 Hz, 1H), 7.88 (s, 1H), 5.15 (d, J = 6.4 Hz, 1H), 4.87 (d, J = 6.4 Hz, 1H), 4.14 (s, 3H), 3.90 (s, 3H), 2.68 (s, 3H), 1.48- 1.40 (m, 6H)
    408
    Figure US20190292176A1-20190926-C01249
         		I-67 551.1 1.22 50- 100% 12 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.91 (br. s., 1H), 8.69 (s, 1H), 8.63 (br. s., 2H), 8.52 (s, 1H), 7.99- 7.90 (m, 2H), 7.78 (s, 1H), 5.23 (br. s., 1H), 4.38- 4.31 (m, 1H), 4.29-4.21 (m, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.60 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H)
    409
    Figure US20190292176A1-20190926-C01250
         		I-67 521.1 1.22 45- 78% 25 min, 100% 7 min 1H NMR (400 MHz, DMSO-d6) δ 10.20 (br. s., 1H), 8.89 (s, 2H), 8.84 (s, 1H), 8.73 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 11.7 Hz, 1H), 7.82 (dd, J = 2.0, 0.9 Hz, 1H), 5.35-5.22 (m, 1H), 4.43-4.35 (m, 1H), 4.33-4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H)
    410
    Figure US20190292176A1-20190926-C01251
         		I-72 535.1 1.25 45- 90% 20 min, 100% 5 min 1H NMR (400 MHz, DMSO-d6) δ 10.13 (br. s., 1H), 8.87 (s, 2H), 8.82 (s, 1H), 8.73 (s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 11.7 Hz, 1H), 7.84 (dd, J = 2.0, 0.9 Hz, 1H), 5.14 (qd, J = 6.4, 2.8 Hz, 1H), 4.87-4.77 (m, 1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.44-1.38 (m, 6H)
    411
    Figure US20190292176A1-20190926-C01252
         		I-67 519.2 1.27 45- 90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.73 (br. s., 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.99-7.91 (m, 2H), 7.80 (s, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 5.25 (br. s., 1H), 4.38- 4.31 (m, 1H), 4.30-4.22 (m, 1H), 4.07 (s, 3H), 2.61 (s, 3H), 1.42 (d, J = 6.1 Hz, 3H)
    412
    Figure US20190292176A1-20190926-C01253
         		I-72 564.1 1.12 70- 100% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.97-7.91 (m, 2H), 7.78 (s, 1H), 7.01 (d, J = 5.4 Hz, 1H), 6.91 (s, 1H), 5.12 (dd, J = 6.4, 2.4 Hz, 1H), 4.79 (d, J = 3.7 Hz, 1H), 4.06 (s, 3H), 3.77 (s, 3H), 2.60 (s, 3H), 1.39 (m, 6H)
    413
    Figure US20190292176A1-20190926-C01254
         		I-72 535.1 1.06 40- 95% 21 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 10.54 (br. s., 1H), 9.19 (br. s., 1H), 9.00 (br. s., 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.81 (br. s., 2H), 5.16 (br. s., 1H), 4.81 (br. s., 1H), 4.07 (s, 3H), 2.62 (s, 3H), 1.41 (d, J = 5.8 Hz, 6H)
    414
    Figure US20190292176A1-20190926-C01255
         		I-72 577.2 1.27 45- 100% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.90 (br. s., 1H), 8.72 (br. s., 2H), 8.66 (s, 1H), 8.51 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 11.3 Hz, 1H), 7.78 (s, 1H), 5.09 (d, J = 4.3 Hz, 1H), 4.80 (d, J = 3.7 Hz, 1H), 4.05 (s, 3H), 2.71 (t, J = 7.3 Hz, 2H), 2.59 (s, 3H), 1.66 (sxt, J = 7.3 Hz, 2H), 1.38 (t, J = 5.8 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H)
    415
    Figure US20190292176A1-20190926-C01256
         		I-72 603.1 1.31 60- 100% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.51 (br. s., 1H), 9.01 (s, 2H), 8.64 (s, 1H), 8.49 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 11.4 Hz, 1H), 7.77 (s, 1H), 5.14 (dd, J = 6.6, 2.2 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 1.40 (d, J = 5.7 Hz, 6H)
    416
    Figure US20190292176A1-20190926-C01257
         		I-72 549.2 1.11 55- 95% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 10.4 Hz, 2H), 7.83 (s, 1H), 7.52 (d, J = 9.2 Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.76 (d, J = 5.8 Hz, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 2.50 (s, 3H-buried under d-DMSO), 1.41 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H)
    417
    Figure US20190292176A1-20190926-C01258
         		I-72 549.2 1.27 60- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.96 (s, 1H), 8.72 (br. s., 1H), 8.57 (br. s., 1H), 8.25 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 11.3 Hz, 1H), 7.84 (br. s., 1H), 5.19 (dd, J = 6.4, 2.7 Hz, 1H), 4.82 (d, J = 3.4 Hz, 1H), 4.12 (s, 3H), 2.66 (s, 3H), 2.46 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H), 1.44 (d, J = 6.7 Hz, 3H)
    418
    Figure US20190292176A1-20190926-C01259
         		I-72 549.1 1.15 50- 100% 19 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.04 (br. s., 1H), 8.72 (s, 1H), 8.56 (d, J = 1.5 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 5.20-5.09 (m, 1H), 4.82 (dd, J = 6.4, 2.7 Hz, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 2.51 (br. s., 3H-Buried under d-DMSO signal), 1.41 (d, J = 6.4 Hz, 6H)
    419
    Figure US20190292176A1-20190926-C01260
         		I-72 548.2 1.26 25- 100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.19 (br. s., 1H), 8.73 (s, 1H), 8.61 (br. s., 1H), 8.57 (s, 1H), 8.23 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99-7.91 (m, 2H), 7.84 (s, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.82 (d, J = 5.8 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 2.32 (s, 3H), 1.41 (d, J = 4.6 Hz, 6H)
    420
    Figure US20190292176A1-20190926-C01261
         		I-72 564.2 1.28 30- 100% 15 min, 100% 5 min (Meth C) 1H NMR (500 MHz, DMSO-d6) δ 10.06 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.31 (br. s., 1H), 8.08- 8.00 (m, 2H), 7.96 (d, J = 11.3 Hz, 1H), 7.83 (s, 1H), 7.64 (br. s., 1H), 5.12 (d, J = 6.4 Hz, 1H), 4.81 (d, J = 6.1 Hz, 1H), 4.08 (s, 3H), 3.81 (s, 2H), 2.63 (s, 3H), 1.40 (t, J = 5.3 Hz, 6H)
    421
    Figure US20190292176A1-20190926-C01262
         		I-72 559.3 1.49 50- 100% 10 min, 100% 10 min (Meth C) 1H NMR (500 MHz, DMSO-d6) δ 10.27 (br. s., 1H), 8.83 (br. s., 1H), 8.71 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.25 (br. s., 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.82 (s, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.83 (d, J = 6.1 Hz, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.41 (d, J = 6.1 Hz, 6H)
    422
    Figure US20190292176A1-20190926-C01263
         		I-72 578.2 1.45 60- 100% 10 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.50 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.95 (d, J = 11.3 Hz, 1H), 7.82 (s, 1H), 7.59 (br. s., 1H), 5.06 (d, J = 5.2 Hz, 1H), 4.79 (d, J = 5.8 Hz, 1H), 4.08 (s, 3H), 3.80 (s, 3H), 2.63 (s, 3H), 2.08 (s, 3H), 1.38 (t, J = 7.6 Hz, 6H)
    423
    Figure US20190292176A1-20190926-C01264
         		I-72 534.0 1.00 60- 100% 20 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.93 (br. s., 1H), 8.72 (s, 1H), 8.66 (br. s., 1H), 8.56 (s, 1H), 8.22 (d, J = 4.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.91 (br. s., 1H), 7.83 (s, 1H), 7.35 (dd, J = 8.1, 4.7 Hz, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 3.7 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.41 (t, J = 6.3 Hz, 6H)
    424
    Figure US20190292176A1-20190926-C01265
         		I-66 520.9 1.10 45- 90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br. s., 1H), 8.77 (d, J = 4.3 Hz, 3H), 8.59 (s, 1H), 8.06-7.97 (m, 2H), 7.86 (s, 1H), 4.57 (br. s., 2H), 4.46 (br. s., 2H), 4.10 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H)
    425
    Figure US20190292176A1-20190926-C01266
         		I-81 582.9, 584.9 1.26 60- 100% 20 min, 100% 7 min (Meth C) 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.78-8.67 (m, 3H), 8.57 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 5.13 (dd, J = 6.6, 2.3 Hz, 1H), 4.85 (d, J = 6.4 Hz, 1H), 4.09 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H)
    • Example 426 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01267
  • To a vial charged with Intermediate I-74 (10 mg, 0.017 mmol) was added DCM (1 mL). To this solution was added magnesium chloride (16.09 mg, 0.169 mmol) followed by morpholine (0.1 mL, 1.148 mmol). The resulting mixture was sealed, stirred vigorously and heated to 65° C. overnight before being diluted with EtOAc, filtered over Celite, concentrated, and purified by Prep HPLC (Method C, 25-100% over 15 min, hold 100% for 5 min) to afford Example 426 (9.6 mg, 0.015 mmol, 86% yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 647.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (br. s., 1H), 8.64 (s, 1H), 8.59 (br. s., 1H), 8.49 (s, 1H), 7.98 (d, J=7.9 Hz, 2H), 7.91 (d, J=11.6 Hz, 1H), 7.76 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 5.12 (d, J=4.6 Hz, 1H), 4.80 (d, J=5.8 Hz, 1H), 4.05 (s, 3H), 3.62 (d, J=15.9 Hz, 2H), 3.49 (d, J=17.1 Hz, 2H), 2.59 (s, 3H), 2.52 (br. s., 4H), 1.39 (m, 6H).
    • Preparation of Amide Examples
  • The amides in the accompanying table were prepared according to the following three general procedures, which are analogous to the ones used to synthesize Examples 391-392 and 426 described above.
  • Primary Amides
  • To a vial charged with the appropriately substituted hetero-aryl ester (1.0 equiv) was added ammonia (7M solution in MeOH) (0.02 M). The resulting mixture was sealed and heated to 65° C. overnight before being concentrated and purified by Prep HPLC (Method D unless otherwise indicated) to afford the desired example.
  • Secondary Amides
  • To a solution of the appropriately substituted hetero-aryl ester (1.0 equiv) in THF (0.02 M) was added the desired amine (100 equiv). The resulting mixture was sealed and heated to 65° C. overnight before being concentrated and purified by Prep HPLC (Method D unless otherwise indicated) to afford the desired example.
  • Tertiary Amides
  • To a solution of the appropriately substituted hetero-aryl ester (1.0 equiv) in DCM (0.02 M) was added MgCl2 (10 equiv) followed by the desired amine (100 equiv). The resulting mixture was sealed, stirred vigorously and heated to 65° C. overnight before being diluted with EtOAc, filtered over Celite, concentrated and purified by Prep HPLC (Method D unless otherwise indicated) to afford the desired example.
  • LCMS
    LCMS RT HPLC
    [M + (Min) Prep
    Ex. H]+ Method Method
    No. Structure Ester m/z H D NMR
    427
    Figure US20190292176A1-20190926-C01268
         		I-87 597.1, 599.2 1.16 45-95% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.83 (s, 1H), 7.63 (br. s., 1H), 7.57 (br. s., 1H), 5.30 (br. s., 1H), 4.46-4.37 (m, 1H), 4.31 (d, J = 5.8 Hz, 1H), 4.07 (s, 3H), 2.64 (s, 3H), 1.44 (d, J = 6.1 Hz, 3H)
    428
    Figure US20190292176A1-20190926-C01269
         		I-87 611.1, 613.1 1.17 45-95% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.71-8.63 (m, 2H), 8.54 (s, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 4.9 Hz, 1H), 5.29 (br. s., 1H), 4.40 (d, J = 8.5 Hz, 1H), 4.30 (dd, J = 10.5, 6.3 Hz, 1H), 4.07 (s, 3H), 2.78 (d, J = 4.9 Hz, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H)
    429
    Figure US20190292176A1-20190926-C01270
         		I-84 564.1 1.10 60-100% 13 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 2H), 8.65 (s, 1H), 8.48 (s, 1H), 8.05 (br. s., 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 7.63 (br. s., 1H), 5.32-5.17 (m, 1H), 4.39-4.30 (m, 1H), 4.29-4.21 (m, 1H), 4.02 (s, 3H), 2.56 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H)
    430
    Figure US20190292176A1-20190926-C01271
         		I-84 578.1 1.12 50-100% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 2H), 8.77-8.69 (m, 2H), 8.55 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.29 (br. s., 1H), 4.40 (d, J = 8.2 Hz, 1H), 4.29 (dd, J = 10.7, 6.1 Hz, 1H), 4.07 (s, 3H), 2.78 (d, J = 4.6 Hz, 3H), 2.62 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    431
    Figure US20190292176A1-20190926-C01272
         		I-84 592.2 1.15 60-100% 13 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.39 (br. s., 1H), 8.92 (s, 2H), 8.71 (s, 1H), 8.54 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.29 (d, J = 2.7 Hz, 1H), 4.42-4.35 (m, 1H), 4.32-4.25 (m, 1H), 4.06 (s, 3H), 2.98 (s, 3H), 2.77 (s, 3H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    432
    Figure US20190292176A1-20190926-C01273
         		I-82 577.2 1.17 15-100% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.26 (br. s., 1H), 8.68 (s, 2H), 8.59 (d, J = 4.6 Hz, 1H), 8.52 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.99-7.90 (m, 3H), 7.79 (s, 1H), 5.27 (d, J = 3.1 Hz, 1H), 4.37 (d, J = 7.9 Hz, 1H), 4.31-4.23 (m, 1H), 4.06 (s, 3H), 2.77 (d, J = 4.6 Hz, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H)
    433
    Figure US20190292176A1-20190926-C01274
         		I-82 563.1 1.15 25-65% 20 min, 100% 9 min 1H NMR (500 MHz, DMSO-d6) δ 10.24 (br. s., 1H), 8.64 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.03-7.97 (m, 1H), 7.95-7.85 (m, 4H), 7.72 (s, 1H), 7.43 (br. s., 1H), 5.27-5.19 (m, 1H), 4.36-4.29 (m, 1H), 4.26-4.19 (m, 1H), 4.01 (s, 3H), 2.55 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H)
    434
    Figure US20190292176A1-20190926-C01275
         		I-82 591.1 1.16 10-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.19 (br. s., 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.02-7.89 (m, 3H), 7.77 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 5.27 (d, J = 3.1 Hz, 1H), 4.36 (d, J = 7.9 Hz, 1H), 4.31-4.23 (m, 1H), 4.05 (s, 3H), 2.97 (s, 3H), 2.96 (s, 3H), 2.59 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H)
    435
    Figure US20190292176A1-20190926-C01276
         		I-82 633.1 1.17 10-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.22 (br. s., 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.98-7.90 (m, 2H), 7.77 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.27 (d, J = 2.7 Hz, 1H), 4.36 (d, J = 7.9 Hz, 1H), 4.27 (dd, J = 10.7, 6.1 Hz, 1H), 4.05 (s, 3H), 3.62 (m, 4H), 3.52 (m, 4H), 2.59 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H)
    436
    Figure US20190292176A1-20190926-C01277
         		I-74 591.1 1.18 25-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.13 (br. s., 1H), 8.67 (s, 1H), 8.64 (br. s., 1H), 8.55 (d, J = 4.6 Hz, 1H), 8.52 (s, 1H), 8.04-7.96 (m, 2H), 7.95-7.88 (m, 2H), 7.79 (s, 1H), 5.11 (dd, J = 6.4, 2.4 Hz, 1H), 4.82 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.60 (s, 3H), 1.39 (m, 6H)
    437
    Figure US20190292176A1-20190926-C01278
         		I-86 648.2 1.18 20-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.25 (br. s., 1H), 8.85 (s, 2H), 8.63 (s, 1H), 8.47 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 11.6 Hz, 1H), 7.74 (s, 1H), 5.08 (dd, J = 6.6, 2.6 Hz, 1H), 4.75 (m, 1H), 4.00 (s, 3H), 3.57 (m, 4H), 3.40 (br. s., 2H), 3.17-3.08 (br. s., 2H), 2.55 (s, 3H), 1.34 (m, 6H)
    438
    Figure US20190292176A1-20190926-C01279
         		I-74 605.2 1.19 40-80% 20 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 10.07 (br. s., 1H), 8.65 (s, 1H), 8.58 (br. s., 1H), 8.50 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.77 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 4.3 Hz, 1H), 4.79 (d, J = 4.6 Hz, 1H), 4.04 (s, 3H), 2.95 (s, 3H), 2.91 (s, 3H), 2.58 (s, 3H), 1.38 (m, 6H)
    439
    Figure US20190292176A1-20190926-C01280
         		I-74 635.2 1.18 25-100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.19 (br. s., 1H), 8.71-8.64 (m, 2H), 8.53 (s, 1H), 8.41 (t, J = 6.0 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 11.0 Hz, 2H), 7.80 (s, 1H), 5.12 (dd, J = 6.6, 2.3 Hz, 1H), 4.87-4.77 (m, 2H), 4.06 (s, 3H), 3.75 (dt, J = 11.7, 5.6 Hz, 1H), 3.34 (br. s., 1H), 3.19-3.09 (m, 1H), 2.61 (s, 3H), 1.40 (m, 6H), 1.04 (d, J = 6.4 Hz, 3H)
    440
    Figure US20190292176A1-20190926-C01281
         		I-86 592.1 1.15 30-80% 18 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.71 (d, J = 4.9 Hz, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.79 (s, 1H), 5.13 (d, J = 4.3 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 2.76 (d, J = 4.9 Hz, 3H), 2.60 (s, 3H), 1.40 (d, J = 6.4 Hz, 6H)
    441
    Figure US20190292176A1-20190926-C01282
         		I-74 635.2 1.19 45-90% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.18 (br. s., 1H), 8.66 (s, 2H), 8.52 (s, 1H), 8.41 (t, J = 5.8 Hz, 1H), 8.00 (m, 2H), 7.94 (s, 1H), 7.92 (d, J = 4.6 Hz, 1H), 7.78 (s, 1H), 5.12 (d, J = 6.4 Hz, 1H), 4.86 (d, J = 4.6 Hz, 1H), 4.81 (d, J = 6.1 Hz, 1H), 4.05 (s, 3H), 3.75 (dt, J = 11.3, 5.6 Hz, 1H), 3.29 (dt, J = 12.4, 6.1 Hz, 1H), 3.16-3.07 (m, 1H), 2.59 (s, 3H), 1.39 (t, J = 5.3 Hz, 6H), 1.04 (d, J = 6.1 Hz, 3H)
    442
    Figure US20190292176A1-20190926-C01283
         		I-83 607.1 1.08 45-90% 20 min, 100% 8 min 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.69 (t, J = 5.8 Hz, 1H), 8.60 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 11.6 Hz, 1H), 7.86 (s, 1H), 7.72 (dd, J = 5.5, 1.8 Hz, 1H), 5.36 (d, J = 3.1 Hz, 1H), 4.44 (d, J = 7.9 Hz, 1H), 4.38-4.31 (m, 1H), 4.13 (s, 3H), 3.57 (q, J = 5.6 Hz, 2H), 2.67 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H)
    443
    Figure US20190292176A1-20190926-C01284
         		I-83 577.1 1.12 50-100% 20 min, 100% 8 min 1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.77 (d, J = 4.9 Hz, 1H), 8.74 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 11.6 Hz, 1H), 7.84 (s, 1H), 7.70 (dd, J = 5.3, 2.0 Hz, 1H), 5.36 (d, J = 2.7 Hz, 1H), 4.48-4.41 (m, 1H), 4.38-4.31 (m, 1H), 4.12 (s, 3H), 2.86 (d, J = 4.9 Hz, 3H), 2.66 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H)
    444
    Figure US20190292176A1-20190926-C01285
         		I-83 563.1 1.11 25-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 8.05 (br. s., 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J = 5.5 Hz, 1H), 7.60 (br. s., 1H), 5.29 (br. s., 1H), 4.40-4.34 (m, 1H), 4.31-4.24 (m, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    445
    Figure US20190292176A1-20190926-C01286
         		I-82 607.0 1.22 30-70% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.29 (br. s., 1H), 8.70 (br. s., 1H), 8.65 (s, 1H), 8.57- 8.51 (m, 1H), 8.50 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.00-7.89 (m, 3H), 7.77 (s, 1H), 5.29 (br. s., 1H), 4.89 (t, J = 4.9 Hz, 1H), 4.42-4.34 (m, 1H), 4.32-4.24 (m, 1H), 4.06 (s, 3H), 3.53-3.48 (m, 2H), 3.36 (d, J = 5.8 Hz, 2H), 2.60 (s, 3H), 1.44 (d, J = 6.1 Hz, 3H)
    446
    Figure US20190292176A1-20190926-C01287
         		I-74 663.1 1.28 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.15 (br. s., 1H), 8.70-8.59 (m, 3H), 8.50 (s, 1H), 8.04-7.97 (m, J = 8.2 Hz, 2H), 7.94-7.88 (m, 2H), 7.77 (s, 1H), 5.13 (d, J = 6.1 Hz, 1H), 4.83 (d, J = 5.8 Hz, 1H), 4.06 (s, 3H), 3.35 (m, 2H), 2.60 (s, 3H), 1.61 (t, J = 7.2 Hz, 2H), 1.41 (t, J = 6.3 Hz, 6H), 1.14 (s, 6H)
    447
    Figure US20190292176A1-20190926-C01288
         		I-83 591.0 1.14 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H), 7.96-7.89 (m, 2H), 7.76 (s, 1H), 7.59 (s, 1H), 7.51 (d, J = 5.5 Hz, 1H), 5.29 (br. s., 1H), 4.37 (d, J = 9.8 Hz, 1H), 4.27 (dd, J = 10.5, 6.0 Hz, 1H), 4.06 (s, 3H), 2.98 (s, 3H), 2.89 (s, 3H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    448
    Figure US20190292176A1-20190926-C01289
         		I-82 635.1 1.24 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.30 (br. s., 1H), 8.70 (br. s., 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.37-8.29 (m, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.95-7.89 (m, 2H), 7.75 (s, 1H), 5.29 (br. s., 1H), 4.80 (s, 1H), 4.41-4.34 (m, 1H), 4.31-4.24 (m, 1H), 4.05 (s, 3H), 3.26 (d, J = 5.8 Hz, 2H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.10 (s, 6H)
    449
    Figure US20190292176A1-20190926-C01290
         		I-82 621.2 1.18 45-90% 25 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.22 (br. s., 1H), 8.70-8.61 (m, 2H), 8.50 (s, 1H), 8.49-8.45 (m, 1H), 8.01 (br. s., 1H), 7.96- 7.89 (m, 3H), 7.80 (s, 1H), 5.34-5.22 (m, J = 8.1 Hz, 1H), 4.37 (d, J = 8.8 Hz, 1H), 4.30-4.22 (m, 1H), 4.05 (s, 3H), 3.80 (m, 1H), 3.28 (d, J = 5.4 Hz, 1H), 3.20- 3.07 (m, 1H), 2.60 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H)
    450
    Figure US20190292176A1-20190926-C01291
         		I-82 621.2 1.18 45-90% 25 min, 100% 8 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.73 (s, 1H), 8.60 (s, 1H), 8.44 (br. s., 1H), 8.11-7.96 (m, 4H), 7.86 (s, 1H), 5.31 (br. s., 1H), 4.84 (d, J = 4.9 Hz, 1H), 4.41 (d, J = 8.5 Hz, 1H), 4.34-4.28 (m, 1H), 4.10 (s, 3H), 3.79 (br. s., 1H), 3.39-3.28 (m, 1H), 3.21-3.12 (m, 1H), 2.65 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.1 Hz, 3H)
    451
    Figure US20190292176A1-20190926-C01292
         		I-85 621.3 1.08 60-95% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.68 (s, 1H), 8.62 (t, J = 5.7 Hz, 1H), 8.53 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J = 3.7 Hz, 1H), 5.15 (dd, J = 6.4, 2.4 Hz, 1H), 4.86-4.78 (m, 2H), 4.07 (s, 3H), 3.51 (q, J = 5.8 Hz, 2H), 3.40-3.31 (m, 2H), 2.61 (s, 3H), 1.41 (d, J = 4.7 Hz, 6H)
    452
    Figure US20190292176A1-20190926-C01293
         		I-85 653.3 1.11 60-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.69 (s, 1H), 8.60-8.51 (m, 2H), 8.43 (d, J = 5.7 Hz, 1H), 8.16 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.4 Hz, 1H), 7.80 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 5.15 (dd, J = 6.4, 2.4 Hz, 1H), 4.81 (dd, J = 6.4, 2.4 Hz, 1H), 4.07 (s, 3H), 3.82-3.71 (m, 1H), 3.43-3.27 (m, 1H), 3.22-3.10 (m, 1H), 2.61 (s, 3H), 1.41 (m, 6H), 1.06 (d, J = 6.1 Hz, 3H)
    453
    Figure US20190292176A1-20190926-C01294
         		I-85 577.2 1.10 60-100% 18 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 8.16 (s, 1H), 8.08-8.01 (m, 2H), 7.95 (d, J = 11.4 Hz, 1H), 7.80 (s, 1H), 7.66-7.56 (m, 2H), 5.15 (d, J = 4.4 Hz, 1H), 4.81 (d, J = 4.0 Hz, 1H), 4.07 (s, 3H), 2.62 (s, 3H), 1.41 (m, 6H)
    454
    Figure US20190292176A1-20190926-C01295
         		I-86 578.2 1.12 45-90% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.39 (br. s., 1H), 8.97 (s, 2H), 8.71 (s, 1H), 8.55 (s, 1H), 8.09 (br. s., 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 11.4 Hz, 1H), 7.81 (s, 1H), 7.67 (br. s., 1H), 5.21-5.11 (m, 1H), 4.83 (d, J = 4.0 Hz, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 1.42 (m, 6H)
    455
    Figure US20190292176A1-20190926-C01296
         		I-86 622.3 1.09 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.38 (br. s., 1H), 8.96 (s, 2H), 8.70 (s, 1H), 8.64 (t, J = 5.9 Hz, 1H), 8.55 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.4 Hz, 1H), 7.81 (s, 1H), 5.15 (d, J = 6.7 Hz, 1H), 4.88-4.83 (m, 1H), 4.81 (t, J = 5.6 Hz, 1H), 4.07 (s, 3H), 3.51 (q, J = 6.1 Hz, 2H), 3.34 (m, 2H), 2.62 (s, 3H), 1.42 (m, 6H)
    456
    Figure US20190292176A1-20190926-C01297
         		I-86 636.3 1.11 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.39 (br. s., 1H), 8.97 (br. s., 2H), 8.69 (s, 1H), 8.59- 8.50 (m, 2H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.80 (s, 1H), 5.15 (d, J = 6.4 Hz, 1H), 4.85 (d, J = 4.7 Hz, 2H), 4.07 (s, 3H), 3.83-3.71 (m, 1H), 3.28 (dt, J = 12.4, 6.1 Hz, 1H), 3.16 (dt, J = 12.9, 6.2 Hz, 1H), 2.62 (s, 3H), 1.42 (m, 6H), 1.06 (d, J = 6.1 Hz, 3H)
    457
    Figure US20190292176A1-20190926-C01298
         		I-86 650.3 1.13 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.40 (br. s., 1H), 8.98 (s, 2H), 8.69 (s, 1H), 8.54 (s, 1H), 8.39 (t, J = 6.1 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.81 (s, 1H), 5.15 (d, J = 4.4 Hz, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.71 (s, 1H), 4.07 (s, 3H), 3.25 (d, J = 6.4 Hz, 2H), 2.62 (s, 3H), 1.42 (m, 6H), 1.10 (s, 6H)
    458
    Figure US20190292176A1-20190926-C01299
         		I-86 664.2 1.14 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.35 (br. s., 1H), 8.94 (s, 2H), 8.79 (t, J = 5.6 Hz, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H), 7.79 (s, 1H), 5.20-5.09 (m, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.47 (s, 1H), 4.07 (s, 3H), 3.38- 3.30 (m, 2H), 2.61 (s, 3H), 1.62 (t, J = 7.4 Hz, 2H), 1.41 (m, 6H), 1.14 (s, 6H)
    459
    Figure US20190292176A1-20190926-C01300
         		I-85 664.2 1.14 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.35 (br. s., 1H), 8.94 (s, 2H), 8.79 (t, J = 5.6 Hz, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H), 7.79 (s, 1H), 5.20-5.09 (m, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.47 (s, 1H), 4.07 (s, 3H), 3.38-3.30 (m, 2H), 2.61 (s, 3H), 1.62 (t, J = 7.4 Hz, 2H), 1.41 (m, 6H), 1.14 (s, 6H)
    460
    Figure US20190292176A1-20190926-C01301
         		I-74 649.3 1.19 55-95% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.21 (br. s., 1H), 8.68 (s, 2H), 8.53 (s, 1H), 8.30 (t, J = 6.1 Hz, 1H), 8.09-8.00 (m, 2H), 7.99-7.90 (m, 2H), 7.80 (s, 1H), 5.14 (dd, J = 6.4, 2.4 Hz, 1H), 4.83 (d, J = 3.7 Hz, 1H), 4.07 (s, 3H), 3.24 (d, J = 6.4 Hz, 2H), 2.61 (s, 3H), 1.45-1.37 (m, 6H), 1.09 (s, 6H)
    461
    Figure US20190292176A1-20190926-C01302
         		I-85 635.2 1.11 60-100% 18 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.68 (s, 1H), 8.60-8.50 (m, 2H), 8.42 (d, J = 5.7 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J = 3.7 Hz, 1H), 5.15 (dd, J = 6.6, 2.5 Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.81 (dd, J = 6.2, 2.5 Hz, 1H), 4.06 (s, 3H), 3.77 (dt, J = 11.4, 5.6 Hz, 1H), 3.36- 3.27 (m, 1H), 3.20-3.10 (m, 1H), 2.61 (s, 3H), 1.47-1.35 (m, 6H), 1.05 (d, J = 6.1 Hz, 3H)
    462
    Figure US20190292176A1-20190926-C01303
         		I-86 636.3 1.11 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.38 (br. s., 1H), 8.96 (br. s., 2H), 8.67 (s, 1H), 8.56 (t, J = 5.7 Hz, 1H), 8.52 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.4 Hz, 1H), 7.79 (s, 1H), 5.15 (dd, J = 6.6, 2.2 Hz, 1H), 4.90-4.79 (m, 2H), 4.07 (s, 3H), 3.78 (dt, J = 11.3, 5.8 Hz, 1H), 3.29 (dt, J = 12.2, 6.2 Hz, 1H), 3.20-3.10 (m, 1H), 2.61 (s, 3H), 1.41 (m, 6H), 1.06 (d, J = 6.1 Hz, 3H)
    463
    Figure US20190292176A1-20190926-C01304
         		I-86 662.3 1.15 50-100% 22 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.41 (br. s., 1H), 8.97 (s, 2H), 8.70 (s, 1H), 8.55 (s, 1H), 8.36 (t, J = 5.9 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.8 Hz, 1H), 7.81 (s, 1H), 5.40 (s, 1H), 5.20-5.09 (m, 1H), 4.85 (d, J = 6.1 Hz, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 2.01-1.87 (m, 4H), 1.70-1.57 (m, 1H), 1.56-1.43 (m, 1H), 1.42 (m, 6H)
    464
    Figure US20190292176A1-20190926-C01305
         		I-82 649.2 1.21 45-90% 19 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.75 (br. s., 2H), 8.65 (br. s., 1H), 8.18- 7.99 (m, 4H), 7.91 (br. s., 1H), 5.37 (br. s., 1H), 4.46 (br. s., 1H), 4.38 (br. s., 1H), 4.16 (s, 43), 3.46 (m, 2H), 2.71 (s, 3H), 1.70 (m, 2H), 1.51 (d, J = 6.4 Hz, 3H), 1.22 (s, 6H)
    465
    Figure US20190292176A1-20190926-C01306
         		I-85 649.3 1.14 40-80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.44 (d, J = 5.2 Hz, 2H), 8.17 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.81 (s, 1H), 7.66-7.60 (m, 1H), 5.15 (dd, J = 6.7, 2.4 Hz, 1H), 4.81 (dd, J = 6.1, 2.4 Hz, 1H), 4.74 (s, 1H), 4.08 (s, 3H), 3.26 (d, J = 6.1 Hz, 2H), 2.62 (s, 3H), 1.41 (m, 6H), 1.10 (s, 6H)
    466
    Figure US20190292176A1-20190926-C01307
         		I-85 591.1 1.15 45-90% 25 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.73-8.62 (m, 2H), 8.54 (s, 1H), 8.41 (d, J = 4.9 Hz, 1H), 8.13 (br. s., 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 7.62 (br. s., 1H), 5.15 (dd, J = 6.4, 2.7 Hz, 1H), 4.81 (dd, J = 6.3, 2.6 Hz, 1H), 4.07 (s, 3H), 2.79 (d, J = 4.6 Hz, 3H), 2.62 (s, 3H), 1.41 (m, 6H)
    467
    Figure US20190292176A1-20190926-C01308
         		I-85 605.1 1.08 40-75% 25 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.51-7.43 (m, 1H), 5.14 (dd, J = 6.6, 2.6 Hz, 1H), 4.81 (dd, J = 6.3, 2.6 Hz, 1H), 4.07 (s, 3H), 2.98 (s, 3H), 2.89 (s, 3H), 2.61 (s, 3H), 1.41 (m, 6H)
    468
    Figure US20190292176A1-20190926-C01309
         		I-86 606.2 1.19 45-90% 22 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.27 (br. s., 1H), 8.91 (s, 2H), 8.69 (s, 1H), 8.53 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.15 (dd, J = 6.6, 2.6 Hz, 1H), 4.87-4.76 (m, 1H), 4.07 (s, 3H), 2.99 (s, 3H), 2.76 (s, 3H), 2.62 (s, 3H), 1.45-1.37 (m, 6H)
    469
    Figure US20190292176A1-20190926-C01310
         		I-82 607.9 1.06 45-80% 25 min, 80% 4 min 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 2H), 8.67 (t, J = 5.8 Hz, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 7.95-7.87 (m, 2H), 7.75 (s, 1H), 5.35-5.23 (m, 1H), 4.94-4.88 (m, 1H), 4.38 (d, J = 8.2 Hz, 1H), 4.28 (dd, J = 10.7, 6.1 Hz, 1H), 4.05 (s, 3H), 3.55-3.49 (m, 2H), 3.36 (q, J = 6.0 Hz, 2H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    • Preparation of Hindered Amide Examples
  • The sterically hindered amides in the accompanying table were prepared according to the following two-step procedure.
  • Saponification
  • To a solution of the appropriately substituted hetero-aryl ester (1.0 equiv) in THF (0.05 M) was added a 1 M solution of LiOH (5 equiv). The resulting mixture was stirred vigorously at for 3 h before being quenched with a 1 M solution of HCl (10 equiv). The solution was concentrated to a crude residue in vacuo and taken on to the subsequent HATU coupling without purification.
  • HATU Coupling
  • The crude saponified residue above (1.0 equiv) was retaken in DMF (0.1 M) and stirred at room temperature. To this solution was added diisopropylethylamine (10 equiv) and the appropriate amine substrate (1.5 equiv) followed by HATU (1.5 equiv). The resulting mixture was stirred for 10 min before being quenched with methanol (100 equiv), concentrated, and purified by Prep HPLC (Method D, unless otherwise indicated) to afford the desired example.
  • LCMS
    RT HPLC
    LCMS (Min) Prep
    Ex. [M + H]+ Method Method
    No. Structure Ester m/z H D NMR
    470
    Figure US20190292176A1-20190926-C01311
         		I-82 663.1 1.13 45-90% 20 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 10.29 (br. s., 1H), 8.87 (t, J = 6.3 Hz, 1H), 8.72 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.02-7.91 (m, 3H), 7.79 (s, 1H), 5.30 (d, J = 3.1 Hz, 1H), 5.05 (t, J = 5.5 Hz, 1H), 4.39 (d, J = 6.1 Hz, 3H), 4.33-4.23 (m, 3H), 4.07 (s, 3H), 3.64-3.54 (m, 4H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    471
    Figure US20190292176A1-20190926-C01312
         		I-82 621.2 1.10 30-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.22 (br. s., 1H), 8.73 (s, 1H), 8.71-8.64 (m, 1H), 8.57 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 8.03-7.96 (m, 2H), 7.85 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.35 (br. s., 1H), 4.43 (d, J = 8.5 Hz, 1H), 4.38-4.30 (m, 1H), 4.13 (s, 3H), 3.56 (br. s., 3H), 3.47 (br. s., 1H), 3.06 (br. s., 3H), 2.67 (s, 3H), 1.49 (d, J = 6.1 Hz, 3H)
    472
    Figure US20190292176A1-20190926-C01313
         		I-82 649.2 1.22 35-100% 20 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 10.32 (br. s., 1H), 8.79 (s, 1H), 8.76 (br. s., 1H), 8.68 (br. s., 1H), 8.63 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.08-8.01 (m, 3H), 7.90 (s, 1H), 5.37 (br. s., 1H), 4.47 (d, J = 8.5 Hz, 1H), 4.38 (br. s., 1H), 4.16 (s, 3H), 3.28- 3.21 (m, 5H), 2.70 (s, 3H), 1.51 (d, J = 6.1 Hz, 3H), 0.89 (s, 6H)
    473
    Figure US20190292176A1-20190926-C01314
         		I-82 661.3 1.19 50-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.25 (br. s., 1H), 8.72 (s, 1H), 8.66 (d, J = 12.2 Hz, 2H), 8.56 (s, 1H), 8.06 (d, J = 10.4 Hz, 1H), 8.01-7.93 (m, 3H), 7.84 (s, 1H), 5.29 (br. s., 1H), 4.43-4.37 (m, 1H), 4.33- 4.25 (m, 1H), 4.09 (s, 3H), 3.40 (br. s., 4H), 2.63 (s, 3H), 1.86-1.65 (m, 6H), 1.43 (d, J = 6.4 Hz, 3H)
    474
    Figure US20190292176A1-20190926-C01315
         		I-82 649.2 1.15 45-100% 11 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 10.16 (d, J = 12.2 Hz, 1H), 8.65 (s, 1H), 8.64- 8.57 (m, 1H), 8.49 (s, 1H), 7.99 (br. s., 1H), 7.95-7.88 (m, 2H), 7.77 (s, 1H), 7.56-7.46 (m, 1H), 5.28 (br. s., 1H), 4.36 (d, J = 10.1 Hz, 1H), 4.31-4.24 (m, 1H), 4.06 (s, 3H), 3.58 (s, 2H), 3.10-3.00 (m, 3H), 2.60 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.15 (s, 3H), 0.91 (s, 3H)
    475
    Figure US20190292176A1-20190926-C01316
         		I-82 633.2 1.10 45-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.19 (d, J = 6.1 Hz, 1H), 8.64 (s, 2H), 8.49 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.96-7.85 (m, 2H), 7.79-7.67 (m, 2H), 5.28 (br. s., 1H), 4.41-4.33 (m, 1H), 4.33-4.23 (m, 2H), 4.06 (s, 3H), 3.81-3.59 (m, 2H), 3.54-3.37 (m, 2H), 2.59 (s, 3H), 1.96- 1.85 (m, 1H), 1.80 (br. s., 1H), 1.43 (d, J = 6.4 Hz, 3H)
    476
    Figure US20190292176A1-20190926-C01317
         		I-82 647.2 1.10 35-75% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.18 (br. s., 1H), 8.68-8.59 (m, 2H), 8.50 (s, 1H), 8.00 (br. s., 1H), 7.96-7.88 (m, 2H), 7.77 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 5.28 (br. s., 1H), 4.41-4.34 (m, 1H), 4.28 (dd, J = 10.7, 6.1 Hz, 1H), 4.06 (s, 3H), 3.79-3.66 (m, 1H), 3.49-3.35 (m, 3H), 3.34-3.28 (m, 1H), 3.27-3.20 (m, 1H), 2.60 (s, 3H), 2.34-2.24 (m, 1H), 1.96- 1.85 (m, 1H), 1.67-1.55 (m, 1H), 1.43 (d, J = 6.4 Hz, 3H)
    477
    Figure US20190292176A1-20190926-C01318
         		I-82 663.3 1.10 40-85% 16 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.20 (br. s., 1H), 8.67 (s, 1H), 8.63 (br. s., 1H), 8.51 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.97-7.89 (m, 2H), 7.78 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.28 (br. s., 1H), 4.46- 4.33 (m, 2H), 4.28 (dd, J = 10.5, 6.0 Hz, 1H), 4.06 (s, 3H), 3.97-3.84 (m, 1H), 3.77 (br. s., 1H), 3.51-3.33 (m, 3H), 3.31-3.11 (m, 1H), 3.02-2.88 (m, 1H), 2.67 (d, J = 10.1 Hz, 1H), 2.60 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H)
    478
    Figure US20190292176A1-20190926-C01319
         		I-82 633.2 1.10 35-95% 20 min 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.18 (br. s., 1H), 8.67-8.59 (m, 2H), 8.49 (s, 1H), 8.01 (br. s., 1H), 7.95-7.87 (m, 2H), 7.76 (s, 1H), 7.72 (dd, J = 12.5, 8.5 Hz, 1H), 5.28 (d, J = 3.1 Hz, 1H), 4.37 (d, J = 9.5 Hz, 1H), 4.27 (dd, J = 10.5, 6.0 Hz, 2H), 4.05 (s, 3H), 3.78-3.69 (m, 1H), 3.59 (s, 2H), 3.52 (d, J = 11.6 Hz, 1H), 3.42 (d, J = 13.1 Hz, 1H), 2.59 (s, 3H), 1.90 (dd, J = 8.9, 4.0 Hz, 1H), 1.80 (br. s., 1H), 1.43 (d, J = 6.4 Hz, 3H)
    479
    Figure US20190292176A1-20190926-C01320
         		I-82 647.2 1.10 45-90% 19 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.18 (br. s., 1H), 8.65 (s, 1H), 8.62 (br. s., 1H), 8.50 (s, 1H), 8.01 (t, J = 7.3 Hz, 1H), 7.95- 7.88 (m, 2H), 7.77 (s, 1H), 7.73-7.68 (m, 1H), 6.62 (d, J = 8.5 Hz, 1H), 5.28 (br. s., 1H), 4.37 (d, J = 8.2 Hz, 1H), 4.28 (dd, J = 10.8, 6.3 Hz, 1H), 4.06 (s, 3H), 3.78- 3.66 (m, 1H), 3.48-3.35 (m, 3H), 3.34- 3.27 (m, 1H), 3.24 (dd, J = 12.4, 7.2 Hz, 1H), 2.60 (s, 3H), 2.35-2.23 (m, 1H), 1.96- 1.84 (m, 1H), 1.67-1.54 (m, 1H), 1.43 (d, J = 6.7 Hz, 3H)
    480
    Figure US20190292176A1-20190926-C01321
         		I-82 663.3 1.10 40-85% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.20 (br. s., 1H), 8.67 (s, 1H), 8.63 (br. s., 1H), 8.51 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.97-7.87 (m, 2H), 7.78 (s, 1H), 7.59 (d, J = 5.2 Hz, 1H), 5.29 (br. s., 1H), 4.48- 4.23 (m, 3H), 4.06 (s, 3H), 3.96-3.84 (m, 1H), 3.82-3.72 (m, 1H), 3.51-3.06 (m, 4H), 3.00-2.89 (m, 1H), 2.67 (d, J = 9.8 Hz, 1H), 2.60 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H)
    481
    Figure US20190292176A1-20190926-C01322
         		I-74 661.2 1.20 45-90% 25 min, 100% 6 min —
    482
    Figure US20190292176A1-20190926-C01323
         		I-74 661.2 1.17 45-90% 25 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 10.09 (br. s., 1H), 8.70-8.65 (m, 1H), 8.60 (d, J = 6.7 Hz, 1H), 8.53 (s, 1H), 8.07-7.90 (m, 3H), 7.79 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 5.13 (br. s., 1H), 4.83 (br. s., 1H), 4.78-4.65 (m, 1H), 4.12-4.02 (m, 3H), 3.73 (dd, J = 19.1, 11.7 Hz, 1H), 3.66- 3.51 (m, 1H), 3.46-3.35 (m, 3H), 3.35- 3.17 (m, 1H), 2.66-2.59 (m, 3H), 2.35- 2.21 (m, 1H), 1.89 (br. s., 1H), 1.60 (d, J = 7.9 Hz, 1H), 1.41 (t, J = 5.0 Hz, 6H)
    483
    Figure US20190292176A1-20190926-C01324
         		I-74 661.2 1.20 45-90% 25 min, 100% 6 min —
    484
    Figure US20190292176A1-20190926-C01325
         		I-82 647.3 1.22 45-90% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.19 (br. s., 1H), 8.69 (s, 1H), 8.64 (br. s., 1H), 8.53 (s, 1H), 8.07- 7.91 (m, 3H), 7.79 (s, 1H), 7.58-7.46 (m, 1H), 5.29 (br. s., 1H), 4.38 (d, J = 8.9 Hz, 1H), 4.33-4.26 (m, 1H), 4.23 (d, J = 11.3 Hz, 1H), 4.07 (s, 3H), 3.87 (d, J = 13.1 Hz, 1H), 3.67-3.38 (m, 2H), 3.16 (br. s., 1H), 3.06-2.94 (m, 1H), 2.83-2.71 (m, 1H), 2.61 (s, 3H), 1.94-1.81 (m, 1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H), 1.44 (d, J = 6.1 Hz, 4H), 1.38 (d, J = 9.5 Hz, 1H)
    485
    Figure US20190292176A1-20190926-C01326
         		I-82 647.3 1.22 45-90% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.19 (br. s., 1H), 8.69 (s, 1H), 8.63 (br. s., 1H), 8.53 (s, 1H), 8.07- 7.90 (m, 3H), 7.79 (s, 1H), 7.59-7.46 (m, 1H), 5.29 (br. s., 1H), 4.38 (d, J = 8.9 Hz, 1H), 4.33-4.17 (m, 1H), 4.12-4.01 (m, 3H), 3.88 (br. s., 1H), 3.68-3.53 (m, 1H), 3.16 (br. s., 1H), 3.01 (d, J = 7.6 Hz, 1H), 2.77 (t, J = 10.5 Hz, 1H), 2.61 (s, 3H), 1.96-1.80 (m, 1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H), 1.51-1.30 (m, 5H)
    486
    Figure US20190292176A1-20190926-C01327
         		I-74 677.2 1.21 40-90% 19 min, 100% 5 min —
    487
    Figure US20190292176A1-20190926-C01328
         		I-74 677.2 1.20 45-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.11 (br. s., 1H), 8.72 (s, 1H), 8.61 (br. s., 1H), 8.57 (d, J = 1.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.83 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.14 (dd, J = 6.4, 2.4 Hz, 1H), 4.81 (dd, J = 6.3, 2.6 Hz, 1H), 4.32 (br. s., 1H), 4.16-3.98 (m, 4H), 3.97-3.85 (m, 1H), 3.82-3.40 (m, 3H), 2.63 (s, 3H), 1.41 (dd, J = 6.3, 4.1 Hz, 6H).
    488
    Figure US20190292176A1-20190926-C01329
         		I-82 663.3 1.21 40-100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.21 (br. s., 1H), 8.73 (s, 1H), 8.62 (br. s., 1H), 8.56 (s, 1H), 8.05-7.99 (m, 2H), 7.97 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.28 (dd, J = 8.9, 6.1 Hz, 1H), 4.88 (br. s., 1H), 4.42-4.36 (m, 1H), 4.35-4.25 (m, 1H), 4.08 (s, 3H), 4.02 (d, J = 11.3 Hz, 1H), 3.97-3.85 (m, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.70 (d, J = 6.7 Hz, 1H), 3.57 (br. s., 1H), 3.50 (d, J = 13.4 Hz, 1H), 2.63 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    489
    Figure US20190292176A1-20190926-C01330
         		I-82 663.3 1.21 40-100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.21 (br. s., 1H), 8.74 (s, 1H), 8.62 (br. s., 1H), 8.57 (s, 1H), 8.05- 7.94 (m, 3H), 7.83 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.29 (dd, J = 9.2, 6.1 Hz, 1H), 5.00-4.78 (m, 1H), 4.43-4.36 (m, 1H), 4.35-4.24 (m, 1H), 4.16-3.99 (m, 4H), 3.98-3.85 (m, 1H), 3.82-3.66 (m, 1H), 3.66-3.42 (m, 2H), 2.63 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)
    • Example 490 (2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01331
  • To a solution Intermediate I-72B (150 mg, 0.334 mmol) in THF (6.5 mL) was added a 15% phosgene solution in toluene (2354 μl, 3.34 mmol). The resulting slurry was allowed to stir overnight before concentrated down to a crude yellow residue. This intermediate chloroformate was retaken in THF (6.5 mL) and added dropwise to a premixed solution of 2-methylpyrimidin-5-amine (39.9 mg, 0.365 mmol) and pyridine (0.134 mL, 1.660 mmol) in THF (6.5 mL). After 10 min of stirring, the reaction mixture was concentrated and loaded directly onto an ISCO cartridge for purification (40 g, 0-100% EtOAc/DCM, product at 85%) to afford Example 490 (182 mg, 0.331 mmol, 94% yield) as a yellow solid. A small amount of material was purified by Prep HPLC for final characterization (Method D, 50-100% over 10 min, hold 100% for 5 min). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 585.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.72 (br. s., 2H), 8.69 (s, 1H), 7.86-7.78 (m, 2H), 7.66 (t, J=71.8 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 6.49 (br. s., 1H), 5.21-5.12 (m, 1H), 4.63 (dd, J=6.4, 3.3 Hz, 1H), 2.69 (s, 3H), 2.68 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.44 (d, J=6.4 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ −89.78 (s, 3F), −132.17 (s, 1F).
    • Preparation of Substituted Quinoxalines
  • The substituted quinoxalines in the accompanying table were prepared according to the following general procedure, which is analogous to the procedure used to synthesize Example 389.
  • To a solution of THF (0.05 M) and the appropriate alcohol (100 equiv) was added sodium hydride (60% by wt., 10 equiv). After the bubbling subsided, a solution of Example 490 (1.0 equiv) in THF (0.05 M) was added dropwise. After 20 min of vigorous stirring at RT, the reaction mixture was quenched with a few drops of saturated NH4Cl, diluted with EtOAc, filtered over Celite, concentrated and purified by Prep HPLC (Method D, unless otherwise indicated) to afford the desired example.
  • LCMS LCMS HPLC
    Ex. Quinox- [M + H]+ RT (Min) Prep
    No. Structure aline m/z Method H Method D NMR
    491
    Figure US20190292176A1-20190926-C01332
         		490 577.2 1.31 75-100% 15 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.71 (br. s., 2H), 8.64 (s, 1H), 8.49 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 11.3 Hz, 1H), 7.73 (s, 1H), 5.09 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 4.3 Hz, 1H), 4.39 (t, J = 6.6 Hz, 2H), 2.58 (s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.82 (sxt, J = 7.0 Hz, 2H), 1.38 (m, 6H), 1.02 (t, J = 7.3 Hz, 3H)
    492
    Figure US20190292176A1-20190926-C01333
         		490 577.2 1.30 75-100% 15 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.71 (br. s., 2H), 8.59 (s, 1H), 8.50 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 5.45 (dt, J = 12.2, 6.1 Hz, 1H), 5.09 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 4.3 Hz, 1H), 2.59 (s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.41 (d, J = 6.1 Hz, 6H), 1.38 (m, 6H)
    493
    Figure US20190292176A1-20190926-C01334
         		490 579.2 1.07 20-60% 20 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.67 (br. s., 2H), 8.63 (s, 1H), 8.47 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 11.3 Hz, 1H), 7.71 (s, 1H), 5.04 (d, J = 6.1 Hz, 1H), 4.73 (d, J = 4.3 Hz, 1H), 4.43 (d, J = 4.3 Hz, 2H), 3.77 (br. s., 2H), 2.55 (s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.33 (m, 6H)
    • Preparation of Alcohol Examples
  • The Alcohols in the accompanying table were prepared according to the following two general procedures.
  • Primary Alcohols
  • A solution of the appropriately substituted hetero-aryl ester (1.0 equiv) in THF (0.2 M) was cooled to −78° C. To this cooled reaction mixture was added DIBAl-H (1 M solution in toluene, 3.0 equiv) and the reaction mixture was to stirred at −78° C. for 1 hour. The reaction mixture was then quenched with saturated Rochelle's salt and allowed to stir for 2 h at room temperature. The resulting mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried with magnesium sulfate, filtered over a pad of silica gel and concentrated. [Note: If crude NMR analysis of the isolated residue showed a substantial amount of the intermediate aldehyde remaining, then the material was resubjected to the DIBAl-H conditions described above in order to achieve complete reduction.] The crude material was purified by Prep HPLC (Method D, unless otherwise indicated) to afford the desired example.
  • Tertiary Alcohols
  • A solution of the appropriately substituted hetero-aryl ester (1.0 equiv) in THF (0.05 M) was cooled to −78° C. To this cooled reaction mixture was added methyl magnesium bromide (3.0 M solution in ether, 10 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes at ambient temperature. The reaction mixture was then quenched with saturated ammonium chloride, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried with magnesium sulfate, filtered over Celite and concentrated. The resulting residue was purified by Prep HPLC (Method D, unless otherwise indicated) to afford the desired example.
  • LCMS
    RT HPLC
    LCMS (Min) Prep
    Ex. [M + H]+ Method Method
    No. Structure Ester m/z H D NMR
    494
    Figure US20190292176A1-20190926-C01335
         		I-87  584.1, 586.1 1.05 70-95% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 8.05 (d, J = 7.3 Hz, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.38 (br. s., 1H), 5.35 (br. s., 1H), 4.54 (d, J = 5.2 Hz, 2H), 4.49-4.41 (m, 1H), 4.39-4.32 (m, 1H), 4.14 (s, 3H), 2.70 (s, 3H), 1.49 (d, J = 6.1 Hz, 3H)
    495
    Figure US20190292176A1-20190926-C01336
         		I-83 550.2 0.99 40-80% 25 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.93 (br. s., 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.43 (d, J = 6.1 Hz, 1H), 8.03-7.92 (m, 2H), 7.82 (s, 2H), 7.61 (d, J = 5.2 Hz, 1H), 5.32 (br. s., 1H), 4.66 (s, 2H), 4.40 (d, J = 9.2 Hz, 1H), 4.29 (dd, J = 10.8, 6.3 Hz, 1H), 4.07 (s, 3H), 3.90 (s, 1H), 2.62 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H)
    496
    Figure US20190292176A1-20190926-C01337
         		I-84 551.2 1.11 45-90% 25 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.91 (br. s., 2H), 8.77 (s, 1H), 8.60 (s, 1H), 8.09-7.98 (m, 2H), 7.87 (s, 1H), 5.34 (d, J = 3.1 Hz, 1H), 4.60 (d, J = 4.9 Hz, 2H), 4.49-4.40 (m, 1H), 4.34 (dd, J = 10.8, 6.0 Hz, 1H), 4.13 (s, 3H), 2.68 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H)
    497
    Figure US20190292176A1-20190926-C01338
         		I-84 579.2 1.20 40-75% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.85 (br. s., 2H), 8.66 (s, 1H), 8.50 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 11.6 Hz, 1H), 7.76 (s, 1H), 5.33-5.21 (m, 1H), 4.36 (dd, J = 10.7, 2.7 Hz, 1H), 4.30-4.23 (m, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 1.45 (s, 6H), 1.43 (d, J = 6.7 Hz, 3H)
    498
    Figure US20190292176A1-20190926-C01339
         		I-82 578.2 1.03 70-100% 20 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.90 (br. s., 1H), 8.68 (s, 1H), 8.55-8.49 (m, 2H), 7.94 (t, J = 11.0 Hz, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.25 (d, J = 3.4 Hz, 1H), 4.36-4.31 (m, 1H), 4.29-4.22 (m, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.39 (s, 6H)
    499
    Figure US20190292176A1-20190926-C01340
         		I-74 564.1 1.03 30-90% 25 min 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.83 (br. s., 1H), 8.68 (s, 1H), 8.53 (br. s., 2H), 8.01 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 11.6 Hz, 1H), 7.84 (br. s., 1H), 7.79 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 5.09 (dd, J = 6.6, 2.6 Hz, 1H), 4.77 (d, J = 3.7 Hz, 1H), 4.46 (s, 2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.38 (m, 6H)
    500
    Figure US20190292176A1-20190926-C01341
         		I-74 592.1 1.14 45-95% 12 min 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.69 (s, 1H), 8.56-8.48 (m, 2H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.83 (br. s., 1H), 7.79 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 5.5 Hz, 1H), 4.79 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 2.61 (s, 3H), 1.43-1.37 (m, 12H)
    501
    Figure US20190292176A1-20190926-C01342
         		I-86 593.2 1.27 40-90% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.06 (br. s., 1H), 8.83 (br. s., 2H), 8.69 (s, 1H), 8.54 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.13 (d, J = 4.3 Hz, 1H), 4.82 (d, J = 4.0 Hz, 1H), 4.07 (s, 3H), 2.61 (s, 3H), 1.44 (s, 6H), 1.41 (m, 6H)
    502
    Figure US20190292176A1-20190926-C01343
         		I-86 565.0 1.23 30-70% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.08 (br. s., 1H), 8.83 (br. s., 2H), 8.74 (s, 1H), 8.58 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.85 (s, 1H), 5.29 (t, J = 6.1 Hz, 1H), 5.13 (d, J = 5.8 Hz, 1H), 4.82 (br. s., 1H), 4.52 (d, J = 6.1 Hz, 2H), 4.09 (s, 3H), 3.47 (br. s., 2H), 2.64 (s, 3H), 1.40 (m, 6H)
    • Preparation of Quinoxaline Examples
  • The quinoxalines in the accompanying table were prepared according to the following general procedure, which is analogous to the procedure described for Example 263. Thus, the appropriately substituted 2-bromobenzothiazole (1.0 equiv), PdCl2(dppf)-CH2Cl2 adduct (0.08 equiv), and Intermediate I-9 (1.1 equiv) were solvated in a 3:1 mixture of toluene and ethanol (0.05 M). A 2.0 M solution of aqueous sodium carbonate (9 equiv) was then added, and the mixture was degassed by bubbling argon through the solution for 10 min. The vial was then sealed under an atmosphere of argon and heated to 105° C. thermally for 1 h. The resulting crude solution was diluted with EtOAc, filtered over Celite, concentrated, and purified by preparative HPLC (Method D, unless otherwise indicated) to yield the desired example.
  • LCMS LCMS
    Ex. [M + H]+ RT (Min) HPLC Prep
    No. Structure Br-Bzt m/z Method H Method D NMR
    503
    Figure US20190292176A1-20190926-C01344
         		260A  341.9, 343.9 1.38 75-100% 25 min, 100% 4 min 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.68 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.53-7.45 (m, 1H), 4.11 (s, 3H), 2.69 (s, 3H)
    504
    Figure US20190292176A1-20190926-C01345
         		256A 308.0 1.30 60-100% 18 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.67 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.53-7.47 (m, 1H), 4.10 (s, 3H), 2.66 (s, 3H)
    505
    Figure US20190292176A1-20190926-C01346
         		261A 322.0 1.40 80-100% 25 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.67 (s, 1H), 7.99 (d, J = 3.7 Hz, 1H), 7.88 (s, 1H), 7.42-7.34 (m, 2H), 4.10 (s, 3H), 2.81 (s, 3H), 2.67 (s, 3H)
    506
    Figure US20190292176A1-20190926-C01347
         		93D  371.9, 373.9 1.37 60-100% 18 min, 100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.59 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 4.10 (s, 3H), 3.90 (s, 3H), 2.66 (s, 3H)
    507
    Figure US20190292176A1-20190926-C01348
         		268A  371.9, 373.9 1.37 60-100% 18 min, 100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.86 (br. s., 2H), 4.10 (s, 3H), 3.98 (s, 3H), 2.65 (s, 3H)
    509
    Figure US20190292176A1-20190926-C01349
         		I-3 351.9 1.37 60-100% 18 min, 100% 15 min 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.60 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 7.01 (s, 1H), 4.10 (s, 3H), 3.86 (s, 3H), 2.76 (s, 3H), 2.66 (s, 3H)
    510
    Figure US20190292176A1-20190926-C01350
         		273A 326.0 1.32 65-100% 25 min, 100% 4 min 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.68 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.55-7.48 (m, 1H), 7.45-7.38 (m, 1H), 4.11 (s, 3H), 2.67 (s, 3H)
    • Preparation of Quinoline Examples
  • The Quinolines in the accompanying table were prepared according to the following general procedure, which is analogous to the procedure described for Example 263. Thus, Intermediate I-88 (1.0 equiv), PdCl2(dppf)-CH2Cl2 adduct (0.08 equiv), and the appropriately substituted quinoline (1.1 equiv) were solvated in a 3:1 mixture of toluene and ethanol (0.05 M). A 2.0 M solution of aqueous sodium carbonate (9 equiv) was added, and the mixture was degassed by bubbling argon through the solution for 10 min. The vial was then sealed then sealed under an atmosphere of argon and thermally heated to 105° C. 1 h. The crude solution was diluted with EtOAc, filtered over Celite, concentrated and purified by preparative HPLC (Method D, unless otherwise indicated) to yield the desired example.
  • LCMS
    RT HPLC
    LCMS (Min) Prep
    Ex. [M + H]+ Method Method
    No. Structure Quin m/z H D NMR
    512
    Figure US20190292176A1-20190926-C01351
         		I-121  614.0, 616.1 1.14 40-90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.76 (br. s., 1H), 8.58 (d, J = 2.4 Hz, 3H), 8.34 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 11.6 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 5.13-5.03 (m, 1H), 4.74 (d, J = 3.7 Hz, 1H), 4.21 (t, J = 4.6 Hz, 2H), 3.88 (s, 2H), 1.43-1.31 (m, 6H)
    513
    Figure US20190292176A1-20190926-C01352
         		I-126  628.0, 629.9 1.19 50-100% 25 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.61 (br. s., 3H), 8.16 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.3 Hz, 1H), 7.90 (br. s., 1H), 5.10 (d, J = 6.4 Hz, 1H), 4.81 (d, J = 6.1 Hz, 1H), 4.32-4.17 (m, 4H), 3.68 (d, J = 4.6 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H), 1.43-1.32 (m, 6H)
    514
    Figure US20190292176A1-20190926-C01353
         		I-124 594.1 1.03 40-100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.60 (br. s., 3H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.87 (d, J = 6.1 Hz, 2H), 5.09 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 3.4 Hz, 1H), 4.23 (d, J = 4.6 Hz, 2H), 3.99 (s, 3H), 3.69 (d, J = 4.3 Hz, 2H), 2.61 (s, 3H), 1.39 (d, J = 6.1 Hz, 6H)
    515
    Figure US20190292176A1-20190926-C01354
         		I-124 650.,  652.0 1.14 50-90% 23 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 9.06 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.61 (br. s., 2H), 8.35 (d, J = 5.2 Hz, 2H), 8.07 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 11.6 Hz, 1H), 7.51 (t, J = 74.2 Hz, 1H), 5.11 (d, J = 6.1 Hz, 1H), 4.83 (d, J = 4.3 Hz, 1H), 4.24 (t, J = 4.9 Hz, 2H), 3.69 (d, J = 4.9 Hz, 2H), 1.45-1.36 (m, 6H)
    • Example 516 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-methoxypropan-2-yl pyridin-3-ylcarbamate (rac)
  • Figure US20190292176A1-20190926-C01355
    • Intermediate 516A: 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-methoxypropan-2-ol
  • Figure US20190292176A1-20190926-C01356
  • To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) and tetrabutylammonium bromide (28.3 mg, 0.088 mmol) in THF (1 mL) was added potassium hydroxide (0.33 M in H2O) (0.200 mL, 0.066 mmol) followed by racemic 2-(methoxymethyl)oxirane (38.7 mg, 0.439 mmol). The mixture was then sealed and heated to 65° C. overnight. After 15 h, the reaction was quenched with saturated NaHCO3 and diluted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered over Celite, concentrated and purified by ISCO (4 g, 0-60% EtOAc/Hexanes, 16 min. Product at 40%) to afford Intermediate 516A (11 mg, 0.026 mmol, 58.3% yield) as a yellow solid. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 430.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.74 (d, J=0.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 4.26 (quin, J=5.2 Hz, 1H), 4.21-4.16 (m, 2H), 4.12 (s, 3H), 3.69-3.57 (m, 2H), 3.45 (s, 3H), 3.43 (d, J=6.6 Hz, 1H), 2.64 (s, 3H).
    • Example 516 (Rac)
  • To a solution of Intermediate 516A (10 mg, 0.023 mmol) in THF (1 mL) was added 15% phosgene in toluene (0.164 mL, 0.233 mmol) at room temperature. The reaction mixture was allowed to stir overnight. After 16 h, the reaction mixture was concentrated to afford the desired chloroformate intermediate as a crude yellow residue. This crude material was retaken in THF (1 mL) and added dropwise to a pre-mixed solution of pyridin-3-amine (4.38 mg, 0.047 mmol) and pyridine (0.019 mL, 0.232 mmol) After 5 min of stirring, the reaction mixture was concentrated and purified by prep HPLC (Method C, 20-60% over 20 min, hold 100% for 5 min) to afford Example 516 (10.5 mg, 0.023 mmol, 78% yield) as a yellow solid. LC-MS: Method H, RT=0.94 min, MS (ESI) m/z: 550.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (br. s., 1H), 8.81 (br. s., 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.93 (d, J=11.5 Hz, 1H), 7.77 (s, 1H), 7.60 (dd, J=8.4, 5.0 Hz, 1H), 5.37 (d, J=4.6 Hz, 1H), 4.50-4.43 (m, 1H), 4.43-4.36 (m, 1H), 4.07 (s, 3H), 3.82-3.72 (m, 2H), 3.37 (s, 3H), 2.61 (s, 3H).
    • Example 517 (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl pyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C01357
    • Intermediate 517A: (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C01358
  • This intermediate was prepared in a manner analogous to Intermediate 516A. Thus, Intermediate I-64 was reacted with (R)-2-ethyloxirane to afford Intermediate 517A (77% yield) as a yellow solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 414.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.0 Hz, 1H), 8.53 (s, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.74 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 4.16-4.09 (m, 4H), 4.08-3.95 (m, 2H), 2.64 (s, 3H), 2.44 (d, J=3.7 Hz, 1H), 1.74-1.63 (m, 2H), 1.07 (t, J=7.5 Hz, 3H).
    • Example 517
  • This intermediate was prepared in a manner analogous to Example 516. Thus, Intermediate 517A was reacted with phosgene followed by pyridin-3-amine. The crude reaction residue was purified by Prep HPLC (Method D, 55-100% over 20 min, hold 100% for 5 min) to afford Example 517 (68% yield) as a yellow solid. LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 534.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.0 Hz, 1H), 8.53 (s, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.74 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 4.16-4.09 (m, 4H), 4.08-3.95 (m, 2H), 2.64 (s, 3H), 2.44 (d, J=3.7 Hz, 1H), 1.74-1.63 (m, 2H), 1.07 (t, J=7.5 Hz, 3H).
    • Example 518 4-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-N-(pyridin-3-yl)butanamide
  • Figure US20190292176A1-20190926-C01359
    • Intermediate 518A: tert-butyl 4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butanoate
  • Figure US20190292176A1-20190926-C01360
  • To a solution of Intermediate I-65 (100 mg, 0.266 mmol) in DMF (1330 μl) was added tert-butyl 4-bromobutanoate (89 mg, 0.399 mmol) followed by potassium carbonate (73.6 mg, 0.532 mmol). The reaction vessel was sealed and the red colored solution was heated to 65° C. After 2 h, the reaction mixture was cooled to room temperature and quenched with a few drops of AcOH. The resulting mixture was diluted with EtOAc, filtered over Celite and concentrate in vacuo to afford crude Intermediate 518A, which was telescoped into the next reaction without purification. LC-MS: Method H, RT=1.43 min, MS (ESI) m/z: [Not observed](M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.44 (s, 1H), 7.69 (br. s., 1H), 7.29 (d, J=7.5 Hz, 1H), 4.19-4.04 (m, 5H), 2.63 (s, 3H), 2.58-2.44 (m, 2H), 2.15 (dq, J=12.8, 6.4 Hz, 2H), 1.45 (s, 9H).
    • Intermediate 518B: 4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)butanoic acid
  • Figure US20190292176A1-20190926-C01361
  • To a solution of crude Intermediate 518A (138 mg, 0.266 mmol) in DCM (2664 μl) was added TFA (2664 μl). The resulting solution immediately became dark red in color. After stirring at room temperature for 30 min, the reaction mixture was concentrated in vacuo to afford crude Intermediate 518B, which was telescoped into the next reaction without purification. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 462.1, 464.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 7.75-7.70 (m, 1H), 7.33 (d, J=7.3 Hz, 1H), 4.16-4.10 (m, 5H), 2.65 (s, 3H), 2.47 (t, J=7.4 Hz, 2H), 2.04-1.93 (m, 2H).
    • Example 518
  • To a brown suspension crude Intermediate 518B (15 mg, 0.032 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.034 mL, 0.195 mmol) followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in DMF) (0.058 mL, 0.097 mmol). The reaction mixture was stirred at room temperature for 2, then pyridin-3-amine (9.17 mg, 0.097 mmol) was added. After an additional 10 min of stirring, the reaction mixture was concentrated and purified by prep HPLC (Method D, 50-100% over 15 min, hold 100% for 7 min) to afford Example 518 (3.3 mg, 0.006 mmol, 18% yield) as a yellow solid over the three step sequence. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 538.2, 540.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.79 (br. s., 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.27 (d, J=4.3 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.85 (s, 1H), 7.39 (dd, J=8.2, 4.6 Hz, 1H), 4.26 (t, J=6.1 Hz, 2H), 4.08 (s, 3H), 2.65 (s, 3H), 2.60 (t, J=7.3 Hz, 2H), 2.15 (t, J=6.6 Hz, 2H).
    • Example 519 1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-(pyridin-3-yl)urea
  • Figure US20190292176A1-20190926-C01362
    • Intermediate 519A: tert-butyl (2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C01363
  • To a dark red solution of Intermediate I-65 (85 mg, 0.226 mmol) and cesium carbonate (221 mg, 0.679 mmol) in DMF (2262 μl) was added tert-butyl (2-bromoethyl)carbamate (76 mg, 0.339 mmol) as a cold solid from the freezer [Note: did not allow reagent to melt]. The reaction mixture was sealed and heated to 65° C. After 1 h of heating, the reaction was quenched with 0.3 mL AcOH, diluted with EtOAc, filtered over Celite and concentrated to a dark yellow solid. The crude material was purified by ISCO (12 g, 0-20% EtOAc/DCM, 16 min.) to afford Intermediate 519A (81 mg, 0.156 mmol, 69.0% yield) as a yellow solid. LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 519.2, 521.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=1.8 Hz, 1H), 8.43 (s, 1H), 7.69 (dd, J=2.0, 0.9 Hz, 1H), 7.26 (d, J=6.4 Hz, 1H), 5.17 (br. s., 1H), 4.17-4.15 (m, 2H), 4.10 (s, 3H), 3.63 (d, J=5.3 Hz, 2H), 2.63 (s, 3H), 1.48 (s, 9H).
    • Intermediate 519B: 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)ethanamine, TFA
  • Figure US20190292176A1-20190926-C01364
  • To a suspension of Intermediate 519A (40 mg, 0.077 mmol) in DCM (2 mL) was added TFA (1.0 mL). The resulting solution immediately became bright red in color. After stirring at room temperature for 15 min, the reaction mixture was concentrated in vacuo to afford crude Intermediate 519B (41.1 mg, 0.077 mmol, 100% yield). This material was telescoped into subsequent reactions without further purification. LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 419.4, 421.4 (M+H)+.
    • Example 519
  • To a solution of Intermediate 519B (20 mg, 0.038 mmol) in THF (2 mL) was added diisopropylethylamine (0.13 mL, 0.75 mmol) followed by 3-isocyanatopyridine (13.52 mg, 0.113 mmol) at room temperature. After 15 h, the reaction mixture was concentrated and purified by prep HPLC (Method D, 45-95% over 15 min, hold 100% for 5 min) to afford Example 519 (1.2 mg, 0.002 mmol, 6% yield) as a yellow solid over the two step sequence. LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 539.1, 541.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.54 (s, 1H), 8.11 (d, J=4.6 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.26 (dd, J=8.4, 4.7 Hz, 1H), 6.64-6.56 (m, 1H), 4.24 (t, J=5.0 Hz, 2H), 4.07 (s, 3H), 3.59 (d, J=5.5 Hz, 2H), 2.63 (s, 3H).
    • Example 520 1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-1-methyl-3-(2-methylpyrimidin-5-yl)urea
  • Figure US20190292176A1-20190926-C01365
    • Intermediate 520A: tert-butyl (2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)(methyl)carbamate
  • Figure US20190292176A1-20190926-C01366
  • To a suspension of Intermediate 519A (43 mg, 0.083 mmol) in THF (1 mL) was added sodium hydride (9.94 mg, 0.249 mmol). The bright red solution was stirred at room temperature for 5 min before methyl iodide (2.0 M in MTBE) (0.207 mL, 0.414 mmol) was added. The reaction was then allowed to stir overnight before being quenched with AcOH, concentrated, and loaded directly onto an ISCO cartridge for purification (12 g, 0-50% EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate 520A (24 mg, 0.045 mmol, 54.3% yield) as a yellow solid. LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 533.1, 535.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.77 (d, J=0.7 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 4.25 (d, J=17.6 Hz, 2H), 4.13 (s, 3H), 3.74-3.66 (m, 2H), 3.05 (s, 3H), 2.66 (s, 3H), 1.48 (s, 9H).
    • Intermediate 520B: 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-N-methylethanamine, TFA
  • Figure US20190292176A1-20190926-C01367
  • To a suspension of Intermediate 520A (24 mg, 0.045 mmol) in DCM (2 mL) was added TFA (1.0 mL). The resulting solution immediately became bright red in color. After stirring for 20 min at room temperature, the reaction mixture was concentrated in vacuo to afford crude Intermediate 520B (24.63 mg, 0.045 mmol, 100% yield). This material was telescoped into the subsequent reactions without further purification. LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 433.0, 435.0 (M+H)+.
    • Example 520
  • To a mixture of crude Intermediate 520B (12 mg, 0.022 mmol) and DIPEA (0.057 mL, 0.329 mmol) in THF (1 mL) was added 15% phosgene in toluene (0.108 mL, 0.154 mmol) at room temperature. The solution immediately became smoky and deposited white salts. After 10 min, 2-methylpyrimidin-5-amine (7.18 mg, 0.066 mmol) and silver nitrate (18.64 mg, 0.110 mmol) were added. The reaction mixture was then sealed and heated to 65° C. for 1 h. The resulting reaction mixture was cooled to room temperature, diluted with EtOAc, filtered over Celite, concentrated and purified by prep HPLC (Method D, 40-75% over 25 min, hold 100% for 7 min) to afford Example 520 (1.1 mg, 0.002 mmol, 8% yield) as a yellow solid over the two step sequence. LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 568.3, 570.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.69 (s, 1H), 8.55 (s, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.81 (s, 1H), 4.34 (br. s., 2H), 4.07 (s, 3H), 3.81 (br. s., 2H), 3.11 (s, 3H), 2.63 (s, 3H), 2.52 (s, 3H).
    • Example 521 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-yl (6-(morpholinomethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01368
  • To a solution of Example 426 (9 mg, 0.014 mmol) in THF (1 mL) was added diacetoxyzinc (5.11 mg, 0.028 mmol) followed by triethoxysilane (0.026 mL, 0.139 mmol). The resulting mixture was sealed and heated to 65° C. overnight. The resulting reaction mixture was diluted with EtOAc, washed with brine, dried over MgSO4, filtered and purified by prep HPLC (Method D, 45-100% over 20 min, hold 100% for 6 min) to afford Example 521 (1.4 mg, 0.002 mmol, 14% yield) as a yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 633.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.94-9.68 (m, 1H), 8.67 (s, 1H), 8.51 (s, 2H), 7.98 (d, J=8.2 Hz, 1H), 7.90 (d, J=11.6 Hz, 1H), 7.78 (s, 2H), 7.29 (br. s., 1H), 5.04 (d, J=5.8 Hz, 1H), 4.73 (br. s., 1H), 4.01 (s, 3H), 3.52 (br. s., 2H) [note: morpholine protons appear to under-integrate], 2.56 (s, 3H), 1.32 (m, 6H).
    • Example 522 (2R,3S)-3-((2-(2-(dimethylamino)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01369
  • To a vial containing Intermediate I-73 (10 mg, 0.017 mmol) was added dimethylamine (2 M in THF) (1 mL, 2.000 mmol) followed by 2-propanol (1 mL). The vial was sealed and heated to 65° C. After 6 h of heating the reaction mixture was concentrated, and purified by prep HPLC (Method D, 40-80% over 20 min, hold 100% for 5 min) to afford Example 522 (7.8 mg, 0.014 mmol, 80% yield) as a yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 562.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.98 (br. s., 1H), 8.76 (s, 1H), 8.74 (br. s., 2H), 8.30 (s, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.94 (d, J=11.3 Hz, 1H), 7.57 (s, 1H), 5.11 (d, J=6.1 Hz, 1H), 4.83 (d, J=6.4 Hz, 1H), 3.27 (br. s., 6H), 2.55 (br. s., 3H), 1.40 (br. s., 6H).
    • Example 523 5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinic acid, TFA
  • Figure US20190292176A1-20190926-C01370
  • To a solution of Intermediate I-74 (8.5 mg, 0.015 mmol) in THF (1 mL) was added lithium hydroxide (1 M) (0.2 mL, 0.200 mmol). The reaction mixture was sealed and heated to 65° C. After 1 h, the reaction mixture was quenched with 1 M HCl, diluted with EtOAc, extracted, concentrated, and purified by prep HPLC (Method C, 30-100% over 20 min, hold 100% for 5 min) to afford Example 523 (4.6 mg, 0.008, 54% yield) as a yellow solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 578.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.77 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.11-8.01 (m, 3H), 7.98 (d, J=11.6 Hz, 1H), 7.84 (s, 1H), 5.20 (d, J=6.4 Hz, 1H), 4.87 (d, J=4.3 Hz, 1H), 4.13 (s, 3H), 2.66 (s, 3H), 1.47 (t, J=6.3 Hz, 6H).
    • Example 524 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-yl carbamate
  • Figure US20190292176A1-20190926-C01371
  • To a solution Intermediate I-72 (85 mg, 0.206 mmol) in THF (4112 μl) was added 15% phosgene in toluene (1450 μl, 2.056 mmol). The resulting slurry was allowed to stir overnight before being concentrated down to a crude yellow residue. This chloroformate intermediate was retaken in THF (1 mL) and added dropwise to a separate vial containing a solution of ammonia (0.5 M in dioxane) (0.420 mL, 0.210 mmol). After 5 min of stirring at RT, the reaction mixture was concentrated and purified by prep HPLC (Method D, 45-80% over 30 min, hold 100% for 8 min) to afford Example 524 (5.7 mg, 0.012 mmol, 59% yield) as a yellow solid. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 457.3 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.59 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.98 (d, J=11.3 Hz, 1H), 7.85 (s, 1H), 6.63 (br. s., 2H), 4.95 (dd, J=6.3, 3.2 Hz, 1H), 4.71 (dd, J=6.1, 3.4 Hz, 1H), 4.13 (s, 3H), 2.67 (s, 3H), 1.40 (d, J=6.4 Hz, 3H), 1.34 (d, J=6.4 Hz, 3H).
    • Example 525 1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-yl (2-methylpyrimidin-5-yl)carbamate (rac)
  • Figure US20190292176A1-20190926-C01372
  • This example was prepared in a manner analogous to Example 379 above. Thus, reaction of Intermediate 379A with 2-methylpyrimidin-5-amine afforded Example 525 (rac) in 76% yield following purification by preparative HPLC (Method C, 60-95% over 25 min, hold at 100% for 10 min). LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 607.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.17 (br. s., 1H), 8.76 (br. s., 2H), 8.72 (s, 1H), 8.56 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 7.82 (s, 1H), 5.33 (br. s., 1H), 4.50-4.43 (m, 1H), 4.43-4.36 (m, 1H), 4.09 (s, 3H), 3.78 (d, J=5.2 Hz, 2H), 3.42-3.20 (m, 2H), 2.63 (s, 3H), 1.82 (dt, J=13.4, 6.7 Hz, 1H), 0.86 (d, J=6.4 Hz, 6H).
    • Example 526 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01373
  • To a solution of Intermediate I-80 (300 mg, 0.702 mmol) in THF (1.4 mL, 0.05 M) was added 15% phosgene in toluene (4949 μl, 7.02 mmol). The resulting slurry was allowed to stir overnight. After 16 h, the reaction mixture was concentrated down to a yellow residue. This crude chloroformate intermediate was retaken in THF (2 mL) and slowly added to a premixed solution of Intermediate I-109 (33.5 mg, 0.133 mmol) and pyridine (0.083 mL, 1.021 mmol) in THF (2 mL). After 5 min of stirring at room temperature, the reaction mixture was concentrated to remove excess pyridine and then retaken in THF (2 mL). To this mixture was added TBAF (1 M in THF) (0.306 mL, 0.306 mmol), and the resulting solution was stirred at room temperature for 6 h. The resulting mixture was concentrated and purified by prep HPLC (Method D, 50-100% over 20 min, hold 100% for 5 min) to afford Example 526 (31.4 mg, 0.051 mmol, 50% yield) as a yellow solid. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 592.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.73 (s, 1H), 8.60 (s, 1H), 8.58 (br. s., 1H), 8.09 (d, J=8.2 Hz, 1H), 8.00 (d, J=11.6 Hz, 1H), 7.87-7.78 (m, 1H), 7.23 (d, J=8.5 Hz, 1H), 5.16 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.0 Hz, 1H), 4.67 (t, J=5.0 Hz, 1H), 4.58 (q, J=7.0 Hz, 2H), 3.74 (q, J=6.2 Hz, 2H), 2.85 (t, J=6.9 Hz, 2H), 2.67 (s, 3H), 1.50 (t, J=7.0 Hz, 3H), 1.45 (t, J=7.5 Hz, 6H).
    • Example 527 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01374
  • The following example was prepared in a manner analogous to the general hindered amide procedure described in the table above. Thus, Intermediate I-89 was reacted with 1-amino-2-methylpropan-2-ol (100 equiv) and magnesium chloride (10 equiv) to afford Example 527 in 36% yield following purification by preparative HPLC (Method D, 45-90% over 20 min, hold at 100% for 8 min). LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 663.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (br. s., 1H), 8.73 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.35 (t, J=6.1 Hz, 1H), 8.12-8.05 (m, 2H), 8.04-7.98 (m, 2H), 7.84 (s, 1H), 5.19 (dd, J=6.6, 2.6 Hz, 1H), 4.92-4.85 (m, 1H), 4.81 (s, 1H), 4.59 (q, J=7.0 Hz, 2H), 3.33-3.27 (m, 2H), 2.68 (s, 3H), 1.50 (t, J=7.2 Hz, 3H), 1.47 (t, J=5.8 Hz, 6H), 1.15 (s, 6H).
    • Example 528 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01375
  • Intermediate I-86 (55 mg, 0.093 mmol) was solvated in THF (1 mL) and cooled to −78° C. To this mixture was added DIBAl-D (0.7 M in toluene) (0.398 mL, 0.278 mmol). After 1 h of stirring at −78° C., the reaction mixture was quenched with 1 mL of a 1 M HCl solution at −78° C. The resulting mixture was allowed to thaw to room temperature and stirred for a total of 30 min until the solution became fluid and bright yellow. The reaction mixture was then diluted with EtOAc and washed with saturated NH4Cl before being dried over MgSO4 and filtered over a pad of SiO2 gel to remove aluminates. The resulting filtrate was concentrated and resubjected to the reduction conditions above to push any remaining deutero-aldehyde intermediate to the desired deutero-alcohol product. Following a repeat of the previous work-up procedure, the crude product was purified by prep HPLC (Method D, 35-100% over 20 min, hold 100% for 5 min) to afford Example 528 (16.3 mg, 0.028 mmol, 30% yield) as a yellow solid. LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 567.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.80 (br. s., 2H), 8.68 (s, 1H), 8.53 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.92 (d, J=11.6 Hz, 1H), 7.80 (s, 1H), 5.16-5.04 (m, 1H), 4.80 (d, J=3.4 Hz, 1H), 4.48 (d, J=5.5 Hz, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 1.38 (t, J=5.8 Hz, 6H).
    • Example 529 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01376
  • The following example was made in a manner analogous to the primary alcohol procedure described in the table above. Thus, Intermediate I-90 was reacted with DIBAl-H to afford Example 529 in 53% yield following purification by preparative HPLC (Method D, 50-100% over 21 min, hold at 100% for 6 min). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 579.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (br. s., 2H), 8.69 (s, 1H), 8.55 (s, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.95 (d, J=11.6 Hz, 1H), 7.81 (s, 1H), 5.13 (d, J=4.0 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 4.59-4.47 (m, 4H), 2.63 (s, 3H), 1.45 (t, J=7.0 Hz, 3H), 1.40 (t, J=5.5 Hz, 6H).
    • Example 530 (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) propan-2-yl (6-((2-methyl-2-(phosphonooxy)propyl)carbamoyl)pyridin-3-yl)carbamate, TFA
  • Figure US20190292176A1-20190926-C01377
    • Intermediate 530A: (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)(Boc)carbamate
  • Figure US20190292176A1-20190926-C01378
  • To a solution of Example 448 (55 mg, 0.087 mmol) in THF (5 mL) was added DMAP (26.5 mg, 0.217 mmol) followed by BOC-Anhydride (0.024 mL, 0.104 mmol). After 30 min of stirring at room temperature, the reaction was quenched with methanol, concentrated and purified by ISCO (12 g, 0-100% EtOAc/Hex, Product at 75%) to afford Intermediate 530A (52 mg, 0.071 mmol, 82% yield) as a yellow foaming solid. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 735.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.24 (t, J=6.2 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.83 (d, J=11.4 Hz, 1H), 7.75 (dd, J=1.8, 0.9 Hz, 1H), 7.65 (dd, J=8.1, 2.4 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 5.42-5.31 (m, 1H), 4.16-4.08 (m, 5H), 3.99 (dd, J=10.3, 6.8 Hz, 1H), 3.48-3.40 (m, 1H), 3.37-3.29 (m, 1H), 2.64 (s, 3H), 2.04 (s, 1H), 1.42 (s, 9H), 1.38 (d, J=6.4 Hz, 3H), 1.24 (s, 3H), 1.21 (s, 3H).
    • Intermediate 530B: (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl (6-((2-((bis(2-(trimethylsilyl)ethoxy)phosphoryl)oxy)-2-methylpropyl)carbamoyl)pyridin-3-yl)(Boc)carbamate
  • Figure US20190292176A1-20190926-C01379
  • To a solution of Intermediate 530A (20 mg, 0.027 mmol) and 1H-tetrazole (9.53 mg, 0.136 mmol) in DCM (1 mL) was added bis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (49.8 mg, 0.136 mmol). The reaction mixture was sealed and heated to 50° C. for 30 min. After the desired phosphite intermediate was formed (monitored by TLC), the resulting solution was cooled to room temperature and hydrogen peroxide (35% wt. in H2O) (0.119 mL, 1.361 mmol) was added. After 20 min of additional stirring, the crude phosphate was diluted with EtOAc, and washed with saturated Na2S2O3. The organic phase was dried over MgSO4, filtered over Celite and concentrated to give Intermediate 530B (27.6 mg, 0.027 mmol, 100% yield) as a yellow oil. Quantitative yield was assumed and the crude intermediate was telescoped into the next reaction without further purification. LC-MS: Method H, RT=1.55 min, MS (ESI) m/z: 1015.4 (M+H)+.
    • Example 530
  • To a solution of crude Intermediate 530B (28 mg, 0.028 mmol) in DCM (2 mL) was added TFA (1.0 mL) at room temperature. After 10 min of stirring, the reaction mixture was concentrated and purified by Prep HPLC (Method C, 50-100% over 10 min, hold 100% for 5 min) to afford Example 530 (7.4 mg, 0.009 mmol, 31% yield) as a yellow TFA salt over the three step sequence. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 715.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.69 (s, 1H), 8.67-8.59 (m, 2H), 8.52 (d, J=1.5 Hz, 1H), 8.07-8.00 (m, 1H), 7.98-7.88 (m, 3H), 7.78 (d, J=0.9 Hz, 1H), 5.22 (td, J=6.2, 3.2 Hz, 1H), 4.37-4.29 (m, 1H), 4.27-4.17 (m, 1H), 4.02 (s, 3H), 3.49 (d, J=5.1 Hz, 2H), 2.56 (s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (s, 6H). 19F NMR (376 MHz, DMSO-d6) δ −73.51, −134.32.
    • Example 531 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate, TFA
  • Figure US20190292176A1-20190926-C01380
  • Intermediate I-89 (70 mg, 0.116 mmol) was solvated in THF (1.156 mL) and (S)-1-aminopropan-2-ol (0.12 mL, 1.524 mmol) was added to the solution. The reaction vial was sealed and heated to 65° C. After 18 h of heating, the reaction mixture was concentrated and purified by prep HPLC (Method C, 50-100% over 19 min, hold 100% for 10 min) to afford Example 531 (55 mg, 0.070 mmol, 61% yield) as a yellow solid. LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 649.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br. s., 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.42 (t, J=5.8 Hz, 1H), 8.07-7.98 (m, 2H), 7.98-7.89 (m, 2H), 7.76 (s, 1H), 5.13 (d, J=4.0 Hz, 1H), 4.82 (d, J=5.2 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 3.82-3.72 (m, 1H), 3.48 (br. s., 1H), 3.37-3.26 (m, 1H), 3.18-3.08 (m, 1H), 2.61 (s, 3H), 1.47-1.42 (m, 3H), 1.41 (t, J=5.8 Hz, 6H), 1.05 (d, J=6.1 Hz, 3H).
    • Example 532 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((phosphonooxy)methyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01381
    • Intermediate 532A: (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((bis(2-(trimethylsilyl)ethoxy) phosphoryl)oxy)methyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01382
  • To a solution of Example 529 (20 mg, 0.035 mmol) and 1H-tetrazole (24.21 mg, 0.346 mmol) in DCM (3457 μl) was added bis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (126 mg, 0.346 mmol) at room temperature. After 1 h, the reaction mixture was cooled to 0° C. and hydrogen peroxide (35% wt. in H2O) (90.8 μl, 1.037 mmol) was added. The resulting mixture was allowed to thaw to room temperature and stirred vigorously for 30 min. The reaction mixture was then diluted with EtOAc and washed with saturated Na2S2O3. The organic phase was dried over MgSO4, filtered over Celite and concentrated to give Intermediate 532A (29.7 mg, 0.035 mmol, 100% yield) as a yellow oil mixed with excess phosphate reagent. Quantitative yield was assumed, and the crude intermediate was telescoped into the next reaction without further purification. LC-MS: Method H, RT=1.52 min, MS (ESI) m/z: 859.5 (M+H)+.
    • Example 532
  • Crude Intermediate 532A (29 mg, 0.034 mmol) was solvated in DCM (2 mL). TFA (0.500 mL) was added causing the solution to turn dark yellow and bubble vigorously. After 10 min, the reaction mixture was concentrated and purified by Prep HPLC (Method C, 50-100% over 10 min, hold 100% for 5 min) to afford Example 532 (12.2 mg, 0.018, 54% yield) as a yellow solid over the three step sequence. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 659.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (br. s., 1H), 8.78 (s, 2H), 8.62 (s, 1H), 8.48 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.88 (d, J=11.7 Hz, 1H), 7.72 (s, 1H), 5.06 (dd, J=6.4, 2.6 Hz, 1H), 4.83-4.74 (m, 2H), 4.74-4.64 (m, 1H), 4.46 (q, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.37 (t, J=7.0 Hz, 3H), 1.33 (d, J=6.6 Hz, 6H). 19F NMR (376 MHz, DMSO-d6) δ −133.47 (s, 1F). 31P NMR (162 MHz, DMSO-d6) δ 24.2 (s, 1P)
    • Example 533 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-hydroxypyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01383
    • Intermediate 533A: 5-((tert-butyldimethylsilyl)oxy)pyridin-3-amine
  • Figure US20190292176A1-20190926-C01384
  • To a vial containing 5-aminopyridin-3-ol (75 mg, 0.681 mmol) was added DCM (6986 μl) and THF (3493 μl) followed by Et3N (285 μl, 2.043 mmol). TBS-Cl (123 mg, 0.817 mmol) was then added to the solution at room temperature. After 1 h of stirring, MeOH (551 μl, 13.62 mmol) was added to quench the remaining TBS-Cl. The reaction mixture was then diluted with EtOAc and washed with brine. The resulting organic phase was dried over MgSO4, filtered over Celite, concentrated and co-evaporated with toluene to afford Intermediate 533A (150 mg, 0.669 mmol, 98% yield) as a brown oil. LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 225.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=2.4 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 6.49 (t, J=2.3 Hz, 1H), 3.65 (br. s., 2H), 0.98 (s, 9H), 0.21 (s, 6H).
    • Intermediate 533B: (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-((tert-butyldimethyl silyl)oxy)pyridin-3-yl) carbamate
  • Figure US20190292176A1-20190926-C01385
  • To a solution Intermediate I-72 (95 mg, 0.230 mmol) in THF (4595 μl) was added 15% phosgene in toluene (1620 μl, 2.298 mmol). The resulting slurry was allowed to stir at room temperature overnight. After 16 h, the reaction mixture was concentrated to remove excess phosgene. The resulting crude chloroformate was retaken in DCM (2290 μl) and slowly added to a pre-mixed suspension of Intermediate 533A and pyridine (185 μl, 2.290 mmol) in DCM (2290 μl). After 10 min, the reaction mixture was concentrated and purified by ISCO (24 g, 0-80% DCM/EtOAc, Product at 33%) to afford Intermediate 533B (110 mg, 0.133 mmol, 57.9% yield) as a yellow solid. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 664.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.82 (d, J=11.2 Hz, 1H), 7.77 (dd, J=1.8, 0.9 Hz, 1H), 7.60 (br. s., 1H), 7.53 (d, J=7.7 Hz, 1H), 6.67 (br. s., 1H), 5.21-5.12 (m, 1H), 4.60 (qd, J=6.2, 3.3 Hz, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H), 0.23 (s, 6H), 0.00 (s, 9H).
    • Example 533
  • To a solution of Intermediate 533B (25 mg, 0.030 mmol) in THF (1 mL) was added acetic acid (0.017 mL, 0.301 mmol) followed by TBAF (1 M in THF) (0.090 mL, 0.090 mmol) (10:35 am). The resulting mixture was stirred at room temperature for 20 min, before being concentrated and purified by Prep HPLC (Method D, 45-90% over 22 min, hold at 100% for 5 min) to afford Example 533 (9.3 mg, 0.016 mmol, 54% yield). LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 550.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.10 (br. s., 1H), 7.99 (d, J=7.9 Hz, 1H), 7.92 (d, J=11.6 Hz, 1H), 7.77 (s, 2H), 7.45 (br. s., 1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.77 (dd, J=6.4, 2.7 Hz, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 1.39 (dd, J=10.7, 6.4 Hz, 6H).
    • Example 534 (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy) butan-2-yl (5-(2-hydroxyethoxy)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01386
  • Intermediate 534A: methyl 2-((5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyridin-3-yl)oxy)acetate
  • Figure US20190292176A1-20190926-C01387
  • To a solution of Example 533 (25 mg, 0.045 mmol) in DMF (1 mL) was added cesium carbonate (22.23 mg, 0.068 mmol) followed by methyl bromoacetate (5.03 μl, 0.055 mmol). After 1.5 h of vigorous stirring and room temperature, the reaction mixture was diluted with EtOAc and filtered over a short pad of SiO2 gel. The resulting organic phase was concentrated to remove residual DMF, retaken in EtOAc, washed with brine, dried over MgSO4, filtered and concentrated to afford Intermediate 534A (22 mg, 0.035 mmol, 78% yield) as a thick yellow oil. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 622.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.81 (d, J=11.2 Hz, 1H), 7.75 (s, 1H), 7.70 (br. s., 1H), 7.51 (d, J=7.9 Hz, 1H), 6.92 (br. s., 1H), 5.20-5.09 (m, 1H), 4.67 (s, 2H), 4.64-4.54 (m, 1H), 4.12 (s, 3H), 3.81 (s, 3H), 2.64 (s, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.44-1.41 (m, 3H).
    • Example 534
  • A solution of Intermediate 534A (11 mg, 0.018 mmol) in THF (1 mL) was cooled to −78° C. To this mixture was added DIBAL-H (1 M in toluene) (0.088 mL, 0.088 mmol). Following the reagent addition, the reaction mixture was allowed to thaw to room temperature. After 30 min of vigorous stirring, the reaction mixture was quenched with 1 M HCl, concentrated, and purified by Prep HPLC (Method D, 45-90% over 20 min, hold 100% for 5 min) to afford Example 534 (1.8 mg, 0.002 mmol, 16% yield) as a yellow solid. LC-MS: Method H, RT=0.91 min, MS (ESI) m/z: 594.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.87 (br. s., 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.22 (br. s., 1H), 7.98 (d, J=7.9 Hz, 1H), 7.91 (d, J=11.3 Hz, 2H), 7.78 (s, 1H), 7.51 (br. s., 1H), 5.10 (d, J=6.4 Hz, 1H), 4.79 (d, J=4.0 Hz, 1H), 4.06 (s, 3H), 3.99 (t, J=4.6 Hz, 2H), 3.72-3.59 (m, 2H), 2.60 (s, 3H), 1.38 (dd, J=9.6, 6.6 Hz, 6H).
    • Example 535 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((S)-1-hydroxyethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01388
  • A solution of Intermediate I-90 (50 mg, 0.085 mmol) in THF (1693 μl) was cooled to −78° C. To this cooled mixture was added DIBAl-H (1 M in toluene) (425 μl, 0.425 mmol), which caused the solution to take on a reddish hue. After 1 h, the reaction mixture was quenched cold with 1.7 mL of Rochelle's Salt, allowed to thaw to room temperature, and stirred vigorously overnight. After 16 h, the reaction mixture was diluted with EtOAc and extracted. The organic phase was dried over MgSO4, filtered over Celite and concentrated. The crude residue was purified by ISCO (12 g, 0-100% EtOAc/DCM, Pdt at 50%) to afford Example 535 (44 mg, 0.074 mmol, 88% yield) as a diastereomeric mixture. This material was further purified by chiral HPLC (Chiracel OD, Semi-prep-80% Heptane/20% EtOH/MeOH(1:1) isocratic eluent with a 16 mL/min flow rate. Diastereomer retention time 60-75 min) to afford homochiral Example 535 (16.4 mg, 0.027 mmol, 37% yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 593.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.75 (s, 2H), 8.64 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.89 (d, J=11.7 Hz, 1H), 7.75 (dd, 0.9 Hz, 1H), 5.11-4.98 (m, 2H), 4.77-4.69 (m, 1H), 4.68-4.59 (m, 1H), 4.47 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.33 (dd, J=6.5, 2.5 Hz, 6H), 1.28 (d, J=6.4 Hz, 3H).
    • Example 536 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-yl (2-(((R)-1-hydroxyethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01389
  • Example 536 was synthesized concurrently with Example 535 above. Thus, the above diastereomeric mixture was purified by chiral HPLC (Chiracel OD, Semi-prep-80% Heptane/20% EtOH/MeOH(1:1) isocratic eluent with a 16 mL/min flow rate. Diastereomer retention time 85-100 min) to afford homochiral Example 536 (17.2 mg, 0.028 mmol, 37% yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 593.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.75 (s, 2H), 8.64 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.89 (d, J=11.7 Hz, 1H), 7.75 (s, 1H), 5.10-4.99 (m, 2H), 4.74 (dd, J=6.3, 2.8 Hz, 1H), 4.68-4.60 (m, 1H), 4.47 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.33 (dd, J=6.3, 2.5 Hz, 6H), 1.28 (d, J=6.6 Hz, 3H).
    • Example 537 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01390
    • Intermediate 537A: 2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (2-(2-((tert-butyldiphenyl silyl)oxy)ethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01391
  • To a solution Intermediate I-66 (15 mg, 0.039 mmol) in THF (1 mL) was added 15% phosgene in toluene (0.274 mL, 0.389 mmol). The resulting slurry was allowed to stir overnight. After 16 h the reaction mixture was concentrated to a crude yellow residue. The resulting chloroformate intermediate was retaken in THF (1 mL) and added dropwise to a pre-mixed solution of Intermediate I-98 (13.49 mg, 0.036 mmol) and pyridine (0.014 mL, 0.179 mmol) in THF (1 mL). After 10 min of stirring at room temperature, the reaction mixture was concentrated in vacuo to remove excess pyridine, and Intermediate 537A was telescoped into the subsequent deprotection step without further purification. LC-MS: Method H, RT=1.46 min, MS (ESI) m/z: 789.0 (M+H)+.
    • Example 537
  • To a crude solution of Intermediate 537A (14 mg, 0.018 mmol) in THF (0.75 mL) and MeOH (0.75 mL) was added (R)-(−)-camphorsulfonic acid (12.37 mg, 0.053 mmol). The reaction vial was sealed and heated to 65° C. After 1.5 h of heating, the reaction mixture was cooled to room temperature and quenched with triethylamine (0.025 mL, 0.177 mmol). The resulting mixture was concentrated, and purified by Prep HPLC (Method D, 40-80% over 22 min, hold at 100% for 5 min) to afford Example 537 (5.2 mg, 0.009 mmol, 52% yield) as a yellow solid over the three step sequence. LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 550.9 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br. s., 1H), 8.79 (s, 2H), 8.72 (s, 1H), 8.55 (s, 1H), 8.03-7.94 (m, 2H), 7.82 (s, 1H), 4.57 (br. s., 2H), 4.45 (br. s., 2H), 4.08 (s, 3H), 3.82 (q, J=6.4 Hz, 2H), 2.97 (t, J=6.7 Hz, 2H), 2.63 (s, 3H).
    • Example 538 (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01392
  • Example 538 was prepared in a manner analogous to Example 536 above. Thus, Intermediate I-81 was reacted with phosgene, followed by Intermediate I-98, followed by CSA to afford Example 538 (66% yield over the three step sequence) after purification by Prep HPLC (Method D, 55-90% over 25 min, hold at 90% for 4 min). LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 612.9, 614.9 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.97 (br. s., 1H), 8.76 (br. s., 2H), 8.70 (s, 1H), 8.56 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.83 (s, 1H), 5.14 (dd, J=6.6, 2.6 Hz, 1H), 4.85 (d, J=6.4 Hz, 1H), 4.09 (s, 3H), 3.84-3.74 (m, 2H), 3.34 (br. s., 1H), 2.94 (t, J=6.7 Hz, 2H), 2.65 (s, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H).
    • Example 539 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01393
    • Intermediate 539A: methyl 5-(((((2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C01394
  • To a solution Intermediate I-91 (30 mg, 0.069 mmol) in THF (1386 μl) was added 15% phosgene in toluene (489 μl, 0.693 mmol). The resulting slurry was allowed to stir overnight. After 16 h, the mixture was concentrated to remove the excess phosgene. The resulting chloroformate was retaken in DCM (7.00 mL) and slowly added to a pre-mixed solution of Intermediate I-107 (39.6 mg, 0.209 mmol) and pyridine (0.084 mL, 1.044 mmol) in DCM (1.4 mL). After 30 min, the reaction mixture was concentrated and purified by ISCO (12 g, 0-100% EtOAC/DCM) to afford Intermediate 539A (24 mg, 0.029 mmol, 42.3% yield). LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 612.2, 614.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 2H), 8.75 (d, J=3.1 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 7.84-7.75 (m, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.38 (d, J=2.9 Hz, 1H), 5.23-5.10 (m, 1H), 4.70-4.60 (m, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.48 (d, J=6.4 Hz, 3H), 1.45 (d, J=6.4 Hz, 4H).
    • Example 539
  • Example 539 was prepared in a manner analogous to the primary alcohols described in the table above. Thus, Intermediate 539A was reacted with DIBAl-H to afford Example 539 (10% yield) following purification by Prep HPLC (Method D, 45-90% over 22 min, hold at 100% for 5 min). LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 584.2, 586.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.04 (br. s., 1H), 8.88 (br. s., 1H), 8.83 (br. s., 2H), 8.64 (br. s., 1H), 8.21 (br. s., 1H), 8.06 (d, J=7.6 Hz, 1H), 8.01-7.91 (m, 2H), 5.14 (br. s., 1H), 4.82 (br. s., 1H), 4.51 (br. s., 2H), 4.00 (br. s., 3H), 1.41 (br. s., 6H).
    • Example 540 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01395
    • Intermediate 540A: (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01396
  • To a solution of Intermediate I-91 (40 mg, 0.092 mmol) in THF (1848 μl) was added 15% phosgene in toluene (652 μl, 0.924 mmol). The resulting slurry was allowed to stir overnight. After 16 h, the mixture was concentrated to remove the excess phosgene. The resulting chloroformate was retaken in THF (1.0 mL) and added dropwise to a pre-mixed solution of Intermediate I-104 (19.19 mg, 0.068 mmol) and pyridine (0.036 mL, 0.451 mmol) in THF (1 mL). After 10 min, the reaction mixture was concentrated to remove excess pyridine and telescoped into the TBS deprotection without further purification. LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 742.0, 744.0 (M+H)+.
    • Example 540
  • To a crude solution of Intermediate 540A (33 mg, 0.044 mmol) in THF (0.75 mL) and MeOH (0.750 mL) was added R(-(−)-camphor sulfonic acid (31.0 mg, 0.133 mmol). The reaction vial was sealed and heated to 65° C. After 30 min of heating, the mixture was cooled to room temperature and triethylamine (0.062 mL, 0.445 mmol) was added to quench the reaction. The reaction mixture was concentrated and purified by Prep HPLC (Method D, 55-100% over 20 min, hold at 100% for 7 min) to afford Example 540 (17.6, 0.027 mmol, 62% yield) as a yellow solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 628.0, 629.9 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. S., 1H), 8.86 (br. S., 1H), 8.62 (br. S., 3H), 8.19 (s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.97 (d, J=11.3 Hz, 1H), 7.94 (br. S., 1H), 5.10 (d, J=6.4 Hz, 1H), 4.82 (br. S., 1H), 4.12-4.06 (m, 1H), 4.03-3.97 (m, 4H), 3.92 (d, J=10.7 Hz, 1H), 1.40 (t, J=6.3 Hz, 6H), 1.12 (d, J=6.1 Hz, 3H).
    • Example 541 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01397
  • Example 541 was prepared in a manner analogous Example 540 described above. Thus, Intermediate I-91 was reacted with phosgene, followed by Intermediate I-103, followed by CSA to afford Example 541 (72% yield over the three step sequence) after purification by Prep HPLC (Method D, 60-100% over 20 min, hold at 100% for 6 min). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 628.0, 629.9 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.84 (d, J=2.1 Hz, 1H), 8.60 (br. s., 3H), 8.17 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.95 (d, J=11.3 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 5.10 (d, J=6.4 Hz, 1H), 4.89 (d, J=4.9 Hz, 1H), 4.82 (d, J=4.0 Hz, 1H), 4.12-4.05 (m, 1H), 4.05-4.00 (m, 1H), 3.99 (s, 3H), 3.93 (dt, J=11.4, 5.6 Hz, 1H), 1.44-1.34 (m, 6H), 1.11 (d, J=6.4 Hz, 3H).
    • Preparation of Carbamate Examples
  • To a solution of the appropriately substituted quinoxaline-benzothiazole alcohol (1.0 equiv) in THF (0.05 M) was added a solution of phosgene (15% by wt. in toluene, 10 equiv). This solution was stirred at room temperature overnight before the intermediate chloroformate was concentrated in vacuo. This crude chloroformate was retaken in THF (0.05 M) and added dropwise to a pre-mixed solution of pyridine (10 equiv) and the appropriately substituted amino-heterocycle (1.1-3.0 equiv) in either THF (0.05 M) or DCM (0.05), whichever gave the best reagent solubility. After 30 min of stirring, the combined mixture was concentrated, retaken in DMF, filtered and purified by preparative HPLC to yield the desired example.
  • If the reactant amino-heterocycle contained a silyl protecting group, the silyl group was removed according to Procedure J before final purification. If the reactant amino-heterocycle contained an acetonide protecting group, the ketal was removed according to Procedure K before final purification.
  • HPLC
    LCMS LCMS Prep
    Ex. [M + H]+ RT Method
    No. Structure R—OH R—NH2 m/z (Min) D NMR
    542
    Figure US20190292176A1-20190926-C01398
         		I-69 I-109 598.1 Ortho- gonal HPLC method B Injection 2, 2.136 45- 90% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.90 (br. s., 1H), 8.40-8.75 (m, 3H), 7.70-7.99 (m, 3H), 7.26 (d, J = 8.24 Hz, 1H), 5.32 (br. s., 1H), 4.27-4.49 (m, 2H), 4.11 (s, 3H), 3.75 (br. s., 2H), 2.81-2.91 (m, 2H), 2.66 (s, 3H), 1.48 (d, J = 6.10 Hz, 3H).
    543
    Figure US20190292176A1-20190926-C01399
         		I-67 I-109 564.2 Ortho- gonal HPLC method B Injection 2, 1.962 40- 80% 5 min, 100% 20 min 1H NMR (500 MHz, DMSO-d6) δ 9.96-9.57 (m, 1H), 8.75 (s, 1H), 8.62-8.49 (m, 2H), 8.10- 7.94 (m, 2H), 7.84 (s, 1H), 7.81-7.74 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.32-5.15 (m, 1H), 4.67-4.53 (m, 1H), 4.41- 4.23 (m, 2H), 4.13-4.05 (m, 3H), 3.69 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 2.66- 2.59 (m, 3H), 1.42 (d, J = 6.6 Hz, 3H).
    544
    Figure US20190292176A1-20190926-C01400
         		I-67 I-112 564.1 Ortho- gonal HPLC method B Injection 2, 1.961 40- 80% 20 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.34 (br. s., 1H), 7.95-7.81 (m, 3H), 7.72 (s, 1H), 5.19 (d, J = 3.1 Hz, 1H), 4.40 (br. s., 2H), 4.32-4.11 (m, 2H), 2.54 (s, 3H), 2.44 (br. s., 3H), 2.26 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H).
    545
    Figure US20190292176A1-20190926-C01401
         		I-67 I-94 564.15 Ortho- gonal HPLC method B Injection 2, 1.960 50- 100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.21 (d, J = 5.5 Hz, 1H), 7.98-7.84 (m, 2H), 7.74 (s, 1H), 7.29 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H), 5.20 (d, J = 3.1 Hz, 1H), 4.33-4.26 (m, 1H), 4.26-4.16 (m, 1H), 4.00 (s, 3H), 3.63 (t, J = 6.9 Hz, 2H), 2.71 (t, J = 6.7 Hz, 2H), 2.55 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H).
    546
    Figure US20190292176A1-20190926-C01402
         		I-67 I-385B 550.2 Ortho- gonal HPLC method B Injection 2, 1.995 15- 100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s., 1H), 8.70 (s, 1H), 8.62-8.45 (m, 2H), 8.06-7.84 (m, 3H), 7.80 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 5.25 (d, J = 3.1 Hz, 1H), 4.50-4.46 (m, 2H), 4.39-4.18 (m, 2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.50-1.20 (m, 3H).
    547
    Figure US20190292176A1-20190926-C01403
         		I-72 I-94 578.19. Ortho- gonal HPLC method B Injection 2, 2.058 30- 80% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 11.3 Hz, 1H), 7.87 (s, 1H), 7.46-7.28 (m, 2H), 5.18 (d, J = 4.6 Hz, 1H), 4.84 (br. s., 1H), 4.13 (s, 3H), 3.75 (t, J = 6.7 Hz, 2H), 3.57-3.43 (m, 1H), 2.89-2.76 (m, 2H), 2.67 (s, 3H), 1.46 (t, J = 6.4 Hz, 6H).
    549
    Figure US20190292176A1-20190926-C01404
         		I-72 I-111 608.20 Ortho- gonal HPLC method B Injection 2, 2.178 30- 80% 22 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.99-7.89 (m, 2H), 7.82 (s, 1H), 7.01 (d, J = 5.4 Hz, 1H), 6.85 (s, 1H), 5.19-5.01 (m, 2H), 4.89-4.74 (m, J = 3.7 Hz, 1H), 4.08 (s, 3H), 3.56-3.34 (m, 2H), 2.63 (s, 3H), 1.40 (t, J = 6.1 Hz, 6H), 1.17 (d, J = 6.1 Hz, 3H).
    550
    Figure US20190292176A1-20190926-C01405
         		I-72 I-111 608.20 Ortho- gonal HPLC method B Injection 2, 2.167 30- 80% 22 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.05-7.89 (m, 3H), 7.80 (s, 1H), 7.02 (d, J = 4.7 Hz, 1H), 6.91 (s, 1H), 5.12 (d, J = 4.0 Hz, 1H), 4.79 (br. s., 1H), 4.04-3.85 (m, 3H), 2.62 (s, 3H), 1.40 (t, J = 5.6 Hz, 6H), 1.09 (d, J = 6.4 Hz, 3H).
    552
    Figure US20190292176A1-20190926-C01406
         		I-67 I-110 580.1 Ortho- gonal HPLC method B Injection 2, 2.003 30- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.70 (s, 1H), 8.59-8.49 (m, J = 1.5 Hz, 1H), 8.03-7.89 (m, 3H), 7.80 (s, 1H), 7.06 (dd, J = 5.6, 1.7 Hz, 1H), 6.93 (s, 1H), 5.35-5.21 (m, 1H), 4.43-4.24 (m, 2H), 4.24-4.16 (m, J = 5.0, 5.0 Hz, 2H), 4.07 (s, 3H), 3.68 (q, J = 5.5 Hz, 2H), 3.43 (br. s., 2H), 2.62 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H).
    553
    Figure US20190292176A1-20190926-C01407
         		I-67 I-106 595.15. Ortho- gonal HPLC method B Injection 2, 2.265 45- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.85 (br. s., 1H), 8.65 (s, 1H), 8.60 (br. s., 2H), 8.50 (s, 1H), 7.97-7.87 (m, 2H), 7.77 (s, 1H), 5.29-5.19 (m, 1H), 5.10-4.97 (m, 1H), 4.42-4.20 (m, 2H), 4.06 (s, 3H), 3.60-3.55 (m, 2H), 2.60 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H).
    554
    Figure US20190292176A1-20190926-C01408
         		I-72 I-106 609.19 Ortho- gonal HPLC method B Injection 2, 2.348 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.89-9.70 (m, 1H), 8.68 (s, 1H), 8.59 (br. s., 2H), 8.53 (s, H), 8.01 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.20-4.53 (m, 3H), 4.07 (s, 3H), 3.60-3.47 (m, 1H), 2.61 (s, 3H), 1.44-1.31 (m, 6H), 1.21 (d, J = 6.1 Hz, 3H).
    555
    Figure US20190292176A1-20190926-C01409
         		I-67 I-97 581.1. LCMS Method H, 1.11 50- 100% 10 min, 100% 5 min 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.68-8.54 (m, 3H), 8.12-7.94 (m, 2H), 7.85 (s, 1H), 5.34-5.14 (m, 1H), 4.99- 4.75 (m, 1H), 4.44-4.32 (m, 1H), 4.32-4.17 (m, J = 5.0, 5.0 Hz, 3H), 4.09 (s, 3H), 3.75-3.61 (m, 2H), 2.64 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H).
    556
    Figure US20190292176A1-20190926-C01410
         		I-72 I-97 595.2 LCMS Method H, 1.16 50- 100% 10 min, 100% 8 min 1H NMR (400 MHz, DMSO-d6) δ 9.72 (br. s., 1H), 8.67 (s, 1H), 8.53 (br. s., 2H), 8.51 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 11.7 Hz, 1H), 7.77 (d, J = 0.7 Hz, 1H), 5.02 (qd, J = 6.5, 2.8 Hz, 1H), 4.80-4.68 (m, 2H), 4.16 (t, J = 5.1 Hz, 2H), 4.02 (s, 3H), 3.60 (q, J = 5.4 Hz, 2H), 2.56 (s, 3H), 1.31 (m, 6H).
    557
    Figure US20190292176A1-20190926-C01411
         		I-67 I-92 592.36 Ortho- gonal HPLC method B Injection 2, 2.052 40- 100% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.86 (br. s., 1H), 8.67 (s, 1H), 8.57-8.45 (m, 2H), 8.05-7.89 (m, 2H), 7.84-7.71 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 5.30- 5.16 (m, J = 6.3, 3.2 Hz, 1H), 4.40-4.19 (m, 2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.06 (s, 6H).
    558
    Figure US20190292176A1-20190926-C01412
         		I-67 I-105 595.20 Ortho- gonal HPLC method B Injection 2, 2.270 45- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.67 (br. s., 2H), 8.58 (s, 1H), 8.05-7.93 (m, 2H), 7.85 (s, 1H), 5.40-5.25 (m, 1H), 5.15-4.91 (m, 1H), 4.46-4.27 (m, 2H), 3.57 (s, 3H), 2.62 (s, 2H), 1.48 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.1 Hz, 3H).
    559
    Figure US20190292176A1-20190926-C01413
         		I-72 I-92 606.35 Ortho- gonal HPLC method B Injection 2, 2.138 40- 100% 12 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.83-9.57 (m, 1H), 8.62 (s, 1H), 8.52-8.42 (m, 2H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 11.6 Hz, 1H), 7.75 (s, 2H), 7.19 (d, J = 8.5 Hz, 1H), 5.09 (dd, J = 6.4, 2.7 Hz, 1H), 4.77 (dd, J = 6.3, 2.6 Hz, 1H), 4.05 (s, 3H), 1.38 (dd, J = 11.1, 6.3 Hz, 7H), 1.03 (s, 6H).
    560
    Figure US20190292176A1-20190926-C01414
         		I-72 I-105 609.20 Ortho- gonal HPLC method B Injection 2, 2.362 35- 75% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.73 (br. s., 1H), 8.76-8.34 (m, 4H), 8.02-7.85 (m, 3H), 7.75 (s, 1H), 5.16-4.91 (m, 2H), 4.79 (br. s., 1H), 4.09-3.97 (m, 4H), 3.72-3.65 (m, 3H), 2.58 (s, 3H), 1.43-1.33 (m, 6H), 1.18 (d, J = 6.4 Hz, 3H).
    561
    Figure US20190292176A1-20190926-C01415
         		I-72 1-95 606.22 Ortho- gonal HPLC method B Injection 2, 2.253 15- 100% 19 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.57 (s, 1H), 8.04-7.86 (m, 3H), 7.83 (s, 1H), 6.44-6.31 (m, 2H), 6.13 (br. s., 1H), 4.95 (dd, J = 6.4, 3.1 Hz, 1H), 4.73 (dd, J = 6.1, 3.1 Hz, 1H), 4.09 (s, 3H), 3.10-3.02 (m, 1H), 2.99-2.92 (m, 1H), 2.63 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H), 1.37-1.29 (m, J = 5.8, 5.8 Hz, 7H).
    562
    Figure US20190292176A1-20190926-C01416
         		I-72 I-96 622.21 Ortho- gonal HPLC method B Injection 2, 2.199 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.75 (s, 1H), 8.60 (d, J = 1.5 Hz, 1H), 8.16- 7.80 (m, 4H), 7.12-6.86 (m, 2H), 5.30-5.11 (m, J = 6.4, 2.7 Hz, 1H), 4.97-4.81 (m, J = 6.4, 2.7 Hz, 1H), 4.13 (s, 3H), 4.02 (s, 2H), 2.67 (s, 3H), 1.45 (t, J = 6.1 Hz, 6H), 1.20 (s, 6H).
    563
    Figure US20190292176A1-20190926-C01417
         		I-72 I-108 636.26 Ortho- gonal HPLC method B Injection 2, 2.190 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.89-7.81 (m, 2H), 7.73 (s, 1H), 6.92 (d, J = 4.3 Hz, 1H), 6.80 (s, 1H), 5.09-4.99 (m, J = 6.7, 2.7 Hz, 1H), 4.78- 4.67 (m, J = 6.3, 2.6 Hz, 1H), 4.21 (t, J = 7.2 Hz, 2H), 4.00 (s, 3H), 2.55 (s, 3H), 1.71 (t, J = 7.3 Hz, 2H), 1.32 (t, J = 6.6 Hz, 6H), 1.06 (s, 6H).
    564
    Figure US20190292176A1-20190926-C01418
         		I-67 I-98 565.15 Ortho- gonal HPLC method B Injection 2, 2.111 45- 85% 25 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 8.80-8.62 (m, 3H), 8.50 (s, 1H), 7.99-7.88 (m, 2H), 7.78 (s, 1H), 5.27 (d, J = 2.7 Hz, 1H), 4.40-4.32 (m, J = 8.2 Hz, 1H), 4.31-4.20 ( m, J = 10.8, 6.3 Hz, 1H), 4.06 (s, 3H), 3.81 (q, J = 6.4 Hz, 2H), 2.95 (t, J = 6.7 Hz, 2H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H).
    565
    Figure US20190292176A1-20190926-C01419
         		I-72 I-98 579.18 Ortho- gonal HPLC method B Injection 2 Injection 2, 2.298 45- 90% 25 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 8.78-8.67 (m, 3H), 8.55 (s, 1H), 8.04-7.89 (m, 2H), 7.83 (s, 1H), 5.19-5.05 (m, 1H), 4.85- 4.77 (m, 1H), 3.79 (d, J = 5.8 Hz, 2H), 2.93 (t, J = 6.7 Hz, 2H), 1.39 (t, J = 6.9 Hz, 6H).
    566
    Figure US20190292176A1-20190926-C01420
         		I-80 I-98 593.24 Ortho- gonal HPLC method B Injection 2, 2.359 50- 100% 20 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.75 (br. s., 2H), 8.63 (s, 1H), 8.51 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 11.3 Hz, 1H), 7.76 (s, 1H), 5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.79 (d, J = 4.0 Hz, 1H), 4.66 (t, J = 5.5 Hz, 1H), 4.51 (q, J = 7.0 Hz, 2H), 3.87-3.62 (m, 2H), 2.94 (t, J = 6.7 Hz, 2H), 2.56 (s, 3H), 1.54-1.28 (m, 9H).
    567
    Figure US20190292176A1-20190926-C01421
         		I-67 I-108 622.2 Ortho- gonal HPLC method B Injection 2, 2.087 50- 100% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.09-7.91 (m, 3H), 7.81 (s, 1H), 7.01 (d, J = 5.8 Hz, 1H), 6.90 (s, 1H), 5.26 (br. s., 1H), 4.45-4.14 (m, 4H), 4.08 (s, 3H), 2.62 (s, 3H), 1.79 (t, J = 7.2 Hz, 2H), 1.42 (d, J = 6.4 Hz, 3H), 1.14 (s, 6H).
    568
    Figure US20190292176A1-20190926-C01422
         		I-80 I-97 609.19 Ortho- gonal HPLC method B Injection 2, 2.408 30- 100% 15 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.57 (s, 3H), 8.06-7.92 (m, 2H), 7.82 (s, 1H), 5.14-5.03 (m, 1H), 4.94-4.89 (m, 1H), 4.85-4.75 (m, 1H), 4.55 (d, J = 7.0 Hz, 2H), 4.23 (br. s., 2H), 3.74-3.63 (m, J = 4.9 Hz, 2H), 2.63 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.42-1.31 (m, 6H).
    569
    Figure US20190292176A1-20190926-C01423
         		I-67 I-100 623.15 Ortho- gonal HPLC method B Injection 2, 2.345 45- 100% 21 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.88 (br. s., 1H), 8.71-8.56 (m, 3H), 8.50 (s, 1H), 8.02-7.86 (m, 2H), 7.76 (s, 1H), 5.24 (br. s., 1H), 4.41-4.18 (m, 4H), 3.97 (s, 3H), 2.59 (s, 3H), 1.81 (br. s., 2H), 1.41 (d, J = 6.1 Hz, 3H), 1.14 (br. s., 6H).
    570
    Figure US20190292176A1-20190926-C01424
         		I-72 I-100 637.2 Ortho- gonal HPLC method B Injection 2, 2.436 50- 100% 6 min, 100% 22 min 1H NMR (500 MHz, DMSO-d6) δ 9.77 (br. s., 1H), 8.70-8.42 (m, 4H), 8.09-7.86 (m, 2H), 7.77 (s, 1H), 5.16-5.03 (m, 1H), 4.91-4.72 (m, J = 6.4 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 4.05 (s, 3H), 2.59 (s, 3H), 1.79 (t, J = 7.1 Hz, 2H), 1.45-1.31 (m, J = 6.7 Hz, 6H), 1.19-1.01 (m, 6H).
    571
    Figure US20190292176A1-20190926-C01425
         		I-72 I-93 594.15 Ortho- gonal HPLC method B Injection 2, 2.303 35- 100% 15 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.57 (br. s., 1H), 8.65 (s, 1H), 8.50 (s, 1H), 8.16 (br. s., 1H), 8.01-7.86 (m, 2H), 7.77 (s, 2H), 6.75 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 6.1 Hz, 1H), 4.77 (d, J = 6.1 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 4.06 (s, 3H), 3.67 (d, J = 4.9 Hz, 1H), 3.59-3.55 (m, 2H), 2.60 (s, 3H), 1.38 (dd, J = 12.1, 6.3 Hz, 6H).
    572
    Figure US20190292176A1-20190926-C01426
         		I-67 I-93 580.17 Ortho- gonal HPLC method B Injection 2, 2.215 35- 100% 10 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.80-9.39 (m, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.19 (br. s., 1H), 7.97-7.87 (m, 2H), 7.78 (br. s., 2H), 6.77 (d, J = 8.5 Hz, 1H), 5.23 (br. s., 1H), 4.36-4.23 (m, 2H), 4.19 (d, J = 4.9 Hz, 2H), 4.06 (s, 3H), 3.68 (d, J = 4.9 Hz, 1H), 3.59 (br. s., 1H), 2.60 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    573
    Figure US20190292176A1-20190926-C01427
         		I-72 I-99 644.18 Ortho- gonal HPLC method B Injection 2, 2.541 45- 100% 15 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.65 (br. s., 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.20 (br. s., 1H), 8.02-7.88 (m, 2H), 7.79 (br. s., 2H), 6.86 d, J = 8.2 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H), 4.78 (d, J = 4.0 Hz, 1H), 4.51 (t, J = 13.4 Hz, 2H), 4.06 (s, 3H), 3.78-3.65 (m, 2H), 2.61 (s, 3H), 1.38 (dd, J = 11.0, 6.4 Hz, 6H).
    574
    Figure US20190292176A1-20190926-C01428
         		I-67 I-99 630.16 Ortho- gonal HPLC method B Injection 2, 2.460 35- 100% 15 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.85-9.51 (m, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.20 (br. s., 1H), 7.93-7.68 (m, 4H), 6.86 (d, J = 8.9 Hz, 1H), 5.22 (br. s., 1H), 4.51 (t, J = 13.4 Hz, 2H), 4.37-4.18 (m, 2H), 4.04 (s, 3H), 3.75-3.73 (m, 2H), 2.56 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    575
    Figure US20190292176A1-20190926-C01429
         		I-72 I-101 623.2 Ortho- gonal HPLC method B Injection 2, 2.418 40- 80% 30 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 9.72 (br. s., 1H), 8.61 (s, 1H), 8.53 (br. s., 2H), 8.46 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 11.3 Hz, 1H), 7.73 (s, 1H), 5.02 (d, J = 6.4 Hz, 1H), 4.73 (d, J = 4.0 Hz, 1H), 4.63 (s, 1H), 4.00 (s, 3H), 3.95-3.89 (m, 2H), 2.54 (s, 3H), 1.38- 1.26 (m, 6H), 1.10 (s, 6H).
    576
    Figure US20190292176A1-20190926-C01430
         		I-67 I-101 609.19 Ortho- gonal HPLC method B Injection 2, 2.340 50- 83% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.62 (br. s., 2H), 8.52 (s, 1H), 8.00-7.90 (m, 2H), 7.79 (s, 1H), 5.35-5.03 (m, 1H), 4.44-4.22 (m, 2H), 4.07 (s, 3H), 2.61 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.18 (s, 6H).
    577
    Figure US20190292176A1-20190926-C01431
         		I-72 I-102 607.21 Ortho- gonal HPLC method B Injection 2, 2.366 40- 80% 25 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 10.14-9.80 (m, 1H), 8.84-8.76 (m, 2H), 8.75-8.71 (m, 1H), 8.61-8.55 (m, 1H), 8.08-8.03 (m, 1H), 7.99-7.93 (m, 1H), 7.87-7.83 (m, 1H), 5.19-5.03 (m, 1H), 4.91-4.73 (m, 1H), 4.13-4.06 (m, 3H), 2.66-2.59 (m, 3H), 1.45-1.32 (m, 6H), 1.11-1.04 (m, 6H).
    578
    Figure US20190292176A1-20190926-C01432
         		I-72 I-103 609.19 Ortho- gonal HPLC method B Injection 2, 2.333 35- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.85-9.67 (m, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.62-8.51 (m, 3H), 8.06-7.90 (m, 2H), 7.81 (s, 1H), 5.16-5.04 (m, J = 6.7 Hz, 1H), 4.90 (br. s., 1H), 4.84-4.73 (m, J = 6.1, 2.4 Hz, 1H), 4.07 (s, 4H), 4.04-3.83 (m, 2H), 3.44-3.34 (m, 3H), 2.62 (s, 3H), 1.38 (t, J = 6.1 Hz, 6H), 1.10 (d, J = 6.4 Hz, 3H).
    579
    Figure US20190292176A1-20190926-C01433
         		I-91 I-98 598.13 Ortho- gonal HPLC method B Injection 2, 2.232 45- 90% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.11-9.73 (m, 1H), 8.88 (br. s., 1H), 8.76 (br. s., 2H), 8.64 (br. s., 1H), 8.20 (br. s., 1H), 8.06 (d, J = 7.3 Hz, 1H), 8.01- 7.90 (m, 2H), 5.20-5.04 (m, 1H), 4.87-4.73 (m, 1H), 4.00 (br. s., 3H), 3.83-3.65 (m, 2H), 2.97-2.84 (m, 2H), 1.47-1.35 (m, 6H).
    580
    Figure US20190292176A1-20190926-C01434
         		I-80 I-103 623.21 Ortho- gonal HPLC method B Injection 2, 2.466 50- 100% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br. s., 1H), 8.76-8.32 (m, 4H), 8.05-7.88 (m, 2H), 7.78 (s, 1H), 5.18-5.03 (m, 1H), 4.87-4.73 (m, 1H), 4.52 (q, J = 7.0 Hz, 2H), 4.14-3.76 (m, 3H), 2.61 (s, 3H), 1.52-1.33 (m, 10H), 1.11 (d, J = 6.1 Hz, 3H).
    581
    Figure US20190292176A1-20190926-C01435
         		I-72 I-104 609.1 Ortho- gonal HPLC method B Injection 2, 2.35 50- 100% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br. s., 1H), 8.76-8.45 (m, 4H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.82 (s, 1H), 5.17-5.06 (m, J = 4.0 Hz, 1H), 4.86-4.74 (m, J = 3.4 Hz, 1H), 4.17-4.05 (m, 4H), 4.04-3.86 (m, 2H), 2.63 (s, 3H), 1.45-1.35 (m, 6H), 1.12 (d, J = 6.1 Hz, 3H).
    582
    Figure US20190292176A1-20190926-C01436
         		I-80 I-104 623.0 Ortho- gonal HPLC method B Injection 2, 2.51 45- 90% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.74-8.43 (m, 4H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.79 (s, 1H), 5.17-5.05 (m, J = 6.1 Hz, 1H), 4.88-4.73 (m, 1H), 4.54 (q, J = 6.9 Hz, 2H), 4.18- 3.86 (m, 3H), 2.62 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.40-1.36 (m, J = 6.7 Hz, 6H), 1.12 (d, J = 6.1 Hz, 3H).
    583
    Figure US20190292176A1-20190926-C01437
         		I-80 I-114 639.2 Ortho- gonal HPLC method B Injection 2, 2.402 45- 90% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.93-9.60 (m, 1H), 8.68 (s, 1H), 8.62 (br. s., 2H), 8.55 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.79 (s, 1H), 5.10 (dd, J = 6.6, 2.6 Hz, 1H), 4.80 (dd, J = 6.4, 2.7 Hz, 1H), 4.66 (s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.26 (dd, J = 11.0, 4.3 Hz, 1H), 4.13 (dd, J = 10.8, 6.6 Hz, 1H), 3.79 (d, J = 4.9 Hz, 1H), 3.43 (t, J = 5.6 Hz, 1H), 3.39-3.28 (m, 1H), 2.62 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.42-1.36 (m, 6H).
    584
    Figure US20190292176A1-20190926-C01438
         		612 I-98 579.2 Ortho- gonal HPLC method B Injection 2, 2.24 45- 90% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.03 (br. s., 1H), 8.79 (br. s., 2H), 8.73 (s, 1H), 8.57 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.6 Hz, 1H), 7.70 (dd, J = 6.9, 2.3 Hz, 2H), 5.19-5.05 (m, 1H), 4.79-4.68 (m, 1H), 4.61 (t, J = 5.5 Hz, 1H), 4.09 (s, 3H), 3.81 (q, J = 6.2 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H), 2.63 (s, 3H), 1.45-1.45 (m, 1H), 1.39 (dd, J = 11.9, 6.4 Hz, 6H).
    585
    Figure US20190292176A1-20190926-C01439
         		I-72 I-113 625.3 Ortho- gonal HPLC method B Injection 2, 2.25 45- 90% 18 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.71 (s, 1H), 8.62 (br. s., 2H), 8.56 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.11 (dd, J = 6.4, 2.7 Hz, 1H), 4.81 (dd, J = 6.1, 2.7 Hz, 1H), 4.29-4.23 (m, 1H), 4.14 (ddd, J = 10.5, 6.6, 3.7 Hz, 1H), 4.08 (s, 3H), 3.84-3.71 (m, 1H), 3.46-3.40 (m, 1H), 3.52-3.13 (m, 2H), 2.63 (s, 3H), 1.46-1.21 (m, 6H).
    586
    Figure US20190292176A1-20190926-C01440
         		I-69 I-98 600.1 Ortho- gonal HPLC method B Injection 2, 2.24 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.07 (br. s., 1H), 8.78 (br. s., 2H), 8.67 (s, 1H), 8.52 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 5.36-5.17 (m, J = 2.7 Hz, 1H), 4.44-4.36 (m, 1H), 4.33-4.27 (m, J = 10.8, 6.0 Hz, 1H), 4.08 (s, 3H), 3.87-3.74 (m, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.63 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H).
    587
    Figure US20190292176A1-20190926-C01441
         		I-72 I-114 625.0 Ortho- gonal HPLC method B Injection 2, 2.17 45- 90% 18 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.71 (s, 1H), 8.62 (br. s., 2H), 8.55 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.81 (s, 1H), 5.10 (dd, J = 6.4, 2.4 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.85-4.74 (m, 1H), 4.68 (t, J = 5.5 Hz, 1H), 4.26 (dd, J = 11.0, 4.0 Hz, 1H), 4.13 (dd, J = 10.8, 6.6 Hz, 1H), 3.84-3.74 (m, 1H), 3.68-3.54 (m, 1H), 3.46-3.31 (m, 1H), 2.63 (s, 3H), 1.46-1.17 (m, 6H).
    588
    Figure US20190292176A1-20190926-C01442
         		I-80 I-113 639.1 Ortho- gonal HPLC method B Injection 2, 2.337 55- 90% 25 min, 100% 4 min 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.70 (s, 1H), 8.62 (br. s., 2H), 8.57 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.81 (s, 1H), 5.10 (d, J = 6.7 Hz, 1H), 4.95 (d, J = 5.2 Hz, 1H), 4.80 (br. s., 1H), 4.66 (t, J = 5.6 Hz, 1H), 4.54 (q, J = 7.0 Hz, 2H), 4.32-4.23 (m, 1H), 4.19-4.10 (m, 1H), 3.83-3.68 (m, 1H), 3.43 (t, J = 5.6 Hz, 1H), 3.39- 3.31 (m, 1H), 2.63 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 1.42-1.36 (m, 6H).
    589
    Figure US20190292176A1-20190926-C01443
         		I-69 — 569.05 Ortho- gonal HPLC method B Injection 2, 2.218 45- 85% 22 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 8.74 (br. s., 2H), 8.66 (s, 1H), 8.51 (s, 1H), 7.95 (d, J = 7.32 Hz, 1H), 7.78 (s, 1H), 5.25 (br. s., 1H), 4.35-4.46 (m, 1H), 4.22-4.32 (m, 1H), 4.06 (s, 3H), 2.62 (s, 3H), 2.52 (s, 3H), 1.42 (d, J = 6.41 Hz, 3H).
    590
    Figure US20190292176A1-20190926-C01444
         		I-69 — 569.05 Ortho- gonal HPLC method B Injection 2, 2.229 40- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.15 (br. s., 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.20 (d, J = 4.27 Hz, 1H), 7.97 (d, J = 7.32 Hz, 1H), 7.81 (s, 1H), 7.71 (d, J = 7.93 Hz, 1H), 6.98-7.25 (m, 1H), 5.24 (br. s., 1H), 4.36 (br. s., 1H), 4.27 (br. s., 1H), 4.06 (s, 3H), 2.63 (s, 3H), 2.37 (s, 3H), 1.39 (d, J = 6.41 Hz, 3H.
    591
    Figure US20190292176A1-20190926-C01445
         		I-69 — 555.10 Ortho- gonal HPLC method B Injection 2, 2.452 30- 90% 21 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.05-10.37 (m, 1H), 8.88 (s, 2H), 8.84 (s, 1H), 8.72 (s, 1H), 8.56 (d, J = 1.38 Hz, 1H), 8.01 (d, J = 7.70 Hz, 1H), 7.83 (s, 1H), 5.29 (dd, J = 3.03, 6.33 Hz, 1H), 4.41 (dd, J = 3.03, 10.73 Hz, 1H), 4.31 (dd, J = 5.91, 10.87 Hz, 1H), 4.07-4.11 (m, 3H), 2.64 (s, 4H), 1.44 (d, J = 6.60 Hz, 4H).
    592
    Figure US20190292176A1-20190926-C01446
         		I-67 — 534.2 Ortho- gonal HPLC method B Injection 2, 2.063 40- 80% 22 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.84 (br. s., 1H), 8.70 (s, 1H), 8.55-8.42 (m, 2H), 8.01-7.91 (m, 2H), 7.82-7.67 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 5.36- 5.02 (m, 1H), 4.41-4.17 (m, 2H), 4.06 (s, 3H), 2.60 (s, 3H), 2.40-2.23 (m, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    593
    Figure US20190292176A1-20190926-C01447
         		I-80 I-117 634.9 Ortho- gonal HPLC method B Injection 2, 2.63 60- 100% 15 min, 100% 10 min 1H NMR (500 MHz, DMSO-d6) δ 9.92 (br. s., 1H), 8.70 (br. s., 2H), 8.61 (s, 1H), 8.49 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 5.18-5.02 (m, J = 6.6, 2.6 Hz, 1H), 4.87-4.71 (m, J = 4.0 Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 3.54 (s, 2H), 3.03 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1.53- 1.12 (m, 9H).
    594
    Figure US20190292176A1-20190926-C01448
         		612 — 533.9 Ortho- gonal HPLC method B Injection 2, 2.15 45- 90% 22 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.03 (br. s., 1H), 8.75 (s, 1H), 8.69 (br. s., 1H), 8.59 (s, 1H), 8.26 (d, J = 4.0 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 2H), 7.84 (s, 1H), 7.44-7.33 (m, 1H), 5.18- 4.96 (m, 1H), 4.79-4.64 (m, 1H), 4.10 (s, 3H), 2.56 (s, 3H), 1.39 (dd, J = 12.8, 6.4 Hz, 6H).
    595
    Figure US20190292176A1-20190926-C01449
         		612 — 549.0 Ortho- gonal HPLC method B Injection 2, 2.40 50- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.02 (br. s., 1H), 8.90-8.68 (m, 3H), 8.56 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.27-4.96 (m, 1H), 4.81-4.55 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 2.56 (s, 3H), 1.39 (dd, J = 11.9, 6.4 Hz, 6H).
    596
    Figure US20190292176A1-20190926-C01450
         		I-69 I-385A 584.1 Ortho- gonal HPLC method B Injection 2, 2.13 35- 68% 25 min 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 9.88 (br. s., 1H), 8.34-8.65 (m, 3H), 7.82-7.98 (m, 2H), 7.73 (s, 1H), 7.37 (d, J = 8.54 Hz, 1H), 5.16-5.33 (m, 1H), 4.47 (br. s., 2H), 4.20-4.38 (m, 2H), 4.04 (s, 3H), 2.59 (s, 3H), 1.41 (d, J = 6.71 Hz, 3H).
    597
    Figure US20190292176A1-20190926-C01451
         		I-67 I-115 564.2 Ortho- gonal HPLC method B Injection 2, 2.25 25- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.44 (br. s., 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.37 (br. s., 1H), 7.96 (d, J = 11.0 Hz, 2H), 7.82 (s, 1H), 5.29-5.07 (m, 1H), 4.32 (br. s., 2H), 4.07 (s, 3H), 3.05 (br. s., 6H), 2.62 (s, 3H), 1.38 (d, J = 5.8 Hz, 3H).
    598
    Figure US20190292176A1-20190926-C01452
         		I-72 I-115 578.2 Ortho- gonal HPLC method B Injection 2, 2.308 40- 80% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.34 (br. s., 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.33 (br. s., 2H), 8.07-7.87 (m, 2H), 7.78 (s, 1H), 5.03 (d, J = 4.3 Hz, 1H), 4.76 (br. s., 1H), 4.05 (s, 3H), 3.02 (s, 6H), 2.59 (s, 3H), 1.43-1.27 (m, 6H).
    599
    Figure US20190292176A1-20190926-C01453
         		I-72 — 577.20 Ortho- gonal HPLC method B Injection 2, 2.762 70- 100% 12 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.32 (br. s., 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.11 (br. s., 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 11.6 Hz, 1H), 7.79 (s, 1H), 7.57 (br. s., 1H), 6.58 (d, J = 8.5 Hz, 1H), 5.04 (d, J = 4.3 Hz, 1H), 4.75 (br. s., 1H), 4.06 (s, 3H), 2.93 (s, 6H), 2.60 (s, 3H), 1.36 (dd, J = 13.4, 5.8 Hz, 6H).
    600
    Figure US20190292176A1-20190926-C01454
         		I-72 — 619.15 Ortho- gonal HPLC method B Injection 2, 2.41 50- 100% 10 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.78 (br. s., 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.37 (br. s., 1H), 8.06-7.83 (m, 4H), 7.79 (s, 1H), 5.08 (dd, J = 6.6, 2.6 Hz, 1H), 4.80 (dd, J = 6.3, 2.6 Hz, 1H), 4.51-4.30 (m, 2H), 4.12- 3.97 (m, 5H), 2.60 (s, 3H), 1.38 (t, J = 6.9 Hz, 6H).
    601
    Figure US20190292176A1-20190926-C01455
         		I-72 — 591.20 Ortho- gonal HPLC method B Injection 2, 2.104 50- 100% 12 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.75 (br. s., 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.35 (br. s., 1H), 8.09-7.89 (m, 2H), 7.79 (s, 1H), 5.08 (dd, J = 6.4, 2.4 Hz, 1H), 4.79 (dd, J = 6.1, 2.7 Hz, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 2.03 (s, 3H), 1.38 (t, J = 6.6 Hz, 6H).
    602
    Figure US20190292176A1-20190926-C01456
         		I-72 — 549.20 Ortho- gonal HPLC method B Injection 2, 2.034 45- 90% 25 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.25 (br. s., 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.3 Hz, 2H), 7.80 (s, 1H), 7.43 (br. s., 1H), 6.40 (d, J = 8.5 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.73 (br. s., 1H), 4.06 (s, 3H), 2.61 (s, 3H), 1.44-1.30 (m, 6H).
    603
    Figure US20190292176A1-20190926-C01457
         		I-72 — 619.21 Ortho- gonal HPLC method B Injection 2, 2.267 30- 100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.51-9.30 (m, 1H), 8.77-8.72 (m, 1H), 8.63-8.52 (m, 1H), 8.25-8.13 (m, 1H), 8.07-8.01 (m, 1H), 8.00-7.93 (m, 1H), 7.88-7.82 (m, 1H), 7.73-7.58 (m, 1H), 6.90-6.70 (m, 1H), 5.13-4.99 (m, 1H), 4.86-4.59 (m, 1H), 4.09 (s, 3H), 3.75-3.61 (m, 8H), 2.64 (s, 3H), 1.42-1.31 (m, 6H).
    604
    Figure US20190292176A1-20190926-C01458
         		I-72 — 706.05 Ortho- gonal HPLC method B Injection 2, 2.525 30- 70% 20 min, 100% 5 min 1H NMR (400MHz, DMSO-d6) δ 11.06 (br. s., 1H), 10.12-9.78 (m, 1H), 8.79 (br. s., 2H), 8.72 (s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.19 (dd, J = 7.3, 2.2 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.03-7.92 (m, 2H), 7.87-7.76 (m, 1H), 7.57 (t, J = 9.0 Hz, 1H), 5.14 (dd, J = 6.6, 2.6 Hz, 1H), 4.86 (dd, J = 6.4, 2.6 Hz, 1H), 4.15-4.02 (m, 3H), 2.64 (s, 3H), 1.51-1.37 (m, 6H).
    605
    Figure US20190292176A1-20190926-C01459
         		I-72 — 602.55 Ortho- gonal HPLC method B Injection 2, 2.196 40- 80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.25 (br. s., 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.11-7.88 (m, 4H), 7.78 (s, 1H), 7.53 (br. s., 1H), 6.35 (br. s., 1H), 5.03 (d, J = 4.3 Hz, 1H), 4.75 (br. s., 1H), 4.11-4.02 (m, 3H), 3.27 (br. s., 2H), 2.60 (s, 3H), 1.88 (br. s., 4H), 1.36 (dd, J = 14.5, 5.3 Hz, 8H).
    606
    Figure US20190292176A1-20190926-C01460
         		I-72 — 622.0 Ortho- gonal HPLC method B Injection 2, 2.219 30- 70% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.33 (br. s., 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.27 (br. s., 2H), 8.03-7.88 (m, 2H), 7.78 (s, 1H), 5.03 (d, J = 6.4 Hz, 1H), 4.75 (br. s., 1H), 4.05 (s, 3H), 3.22 (d, J = 5.8 Hz, 2H), 2.60 (s, 3H), 1.47-1.24 (m, 6H), 1.06 (s, 6H).
    607
    Figure US20190292176A1-20190926-C01461
         		I-72 I-116 642.16 Ortho- gonal HPLC method B Injection 2, 2.517 30- 70% 20 min, 100% 5 min 1H NMR (400 MHz, MeOH-d4) δ 8.76-8.61 (m, 2H), 8.56-8.45 (m, 2H), 7.79-7.68 (m, 3H), 5.18-5.05 (m, 1H), 4.12 (s, 3H), 3.36 (d, J = 1.5 Hz, 6H), 2.63 (s, 3H), 1.45 (d, J = 6.4 Hz, 6H).
    608
    Figure US20190292176A1-20190926-C01462
         		I-72 — 620.12 Ortho- gonal HPLC method B Injection 2, 2.438 40- 80% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.46 (br. s., 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.40 (br. s., 2H), 8.07-7.89 (m, 2H), 7.80 (s, 1H), 5.04 (d, J = 4.9 Hz, 1H), 4.79 (br. s., 1H), 4.06 (s, 4H), 3.68- 3.50 (m, 8H), 2.61 (s, 3H), 1.75-1.75 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H).
    609
    Figure US20190292176A1-20190926-C01463
         		I-67 — 605.16 Ortho- gonal HPLC method B Injection 2, 2.362 20- 100% 15 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.88 (br. s., 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.41 (br. s., 1H), 8.01-7.86 (m, 4H), 7.78 (s, 1H), 5.25 (br. s., 1H), 4.55-4.19 (m, 4H), 4.16-3.99 (m, 5H), 3.62- 3.52 (m, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.1 Hz, 3H).
    610
    Figure US20190292176A1-20190926-C01464
         		I-67 — 577.17 Ortho- gonal HPLC method B Injection 2, 2.056 20- 100% 20 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.72 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.38 (br. s., 1H), 8.06-7.91 (m, 3H), 7.87-7.78 (m, 2H), 5.24 (td, J = 6.3, 3.4 Hz, 1H), 4.43-4.22 (m, 2H), 4.08 (s, 3H), 3.90 (s, 3H), 1.42 (d, J = 6.3 Hz, 3H).
    611
    Figure US20190292176A1-20190926-C01465
         		I-67 I-119 550.20 2.155 45- 95% 13 min, 100% 6 min 1H NMR (500 MHz, DMSO-d6) δ 9.96-9.57 (m, 1H), 8.75 (s, 1H), 8.62-8.49 (m, 2H), 8.10- 7.94 (m, 2H), 7.84 (s, 1H), 7.81-7.74 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.32-5.15 (m, 1H), 4.67-4.53 (m, 1H), 4.41-4.23 (m, 2H), 4.13-4.05 (m, 3H), 3.69 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 2.66-2.59 (m, 3H), 1.42 (d, J = 6.6 Hz, 3H).
    • Example 612 (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C01466
  • This intermediate was prepared from (2R,3S)-butane-2,3-diol using the same synthetic sequence as described for Intermediate I-72. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 414.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.70-8.62 (m, 1H), 8.58 (s, 1H), 7.90-7.83 (m, 1H), 7.82-7.77 (m, 1H), 7.60-7.45 (m, 1H), 4.36-4.19 (m, 1H), 4.16 (s, 3H), 4.05-3.87 (m, 1H), 2.68 (s, 3H), 2.65-2.58 (m, 1H), 1.38 (d, J=6.4 Hz, 3H), 1.34 (d, J=6.4 Hz, 3H).
    • Example 613 (2R,3S)-3-((2-(2-carbamoyl-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01467
  • Intermediate I-75 was dissolved in a 7 M ammonia solution in MeOH (2 mL, 92 mmol) and the resulting mixture stirred for 12 h at 65° C. The reaction mixture was then concentrated and purified by reverse phase HPLC (Method D, 30-70% 20 min, 100% 5 min) to yield Example 613 (8.4 mg, 0.014 mmol, 74% yield). LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 562.20 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.87 (s, 1H), 8.73 (br. s., 2H), 8.44 (s, 1H), 8.19-7.73 (m, 4H), 5.12 (dd, J=6.4, 2.4 Hz, 1H), 4.83 (dd, J=6.3, 2.6 Hz, 1H), 3.48-3.26 (m, 2H), 2.71 (s, 3H), 1.41 (t, J=6.4 Hz, 7H).
    • Example 614 (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01468
  • Example 614 was prepared from methylamine (33% in EtOH) using the method described for Example 613. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 576.18 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.07 (d, J=4.9 Hz, 1H), 8.83 (s, 1H), 8.73 (br. s., 2H), 8.11-8.01 (m, 2H), 7.94 (d, J=11.6 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.3 Hz, 1H), 2.98-2.90 (m, 3H), 2.70 (s, 3H), 2.52 (br. s., 3H), 1.40 (t, J=6.9 Hz, 6H).
    • Example 615 (2R,3S)-3-((2-(2-(dimethylcarbamoyl)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01469
  • Example 615 was prepared from dimethylamine (2M in THF) using the method as described for Example 613. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z: 590.20 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s., 1H), 9.19 (s, 1H), 8.84 (s, 1H), 8.72 (br. s., 2H), 8.09-8.03 (m, 2H), 7.96 (d, J=11.3 Hz, 1H), 5.12 (d, J=6.1 Hz, 1H), 4.82 (d, J=5.5 Hz, 1H), 3.26-3.07 (m, 6H), 2.69 (s, 3H), 1.40 (t, J=6.4 Hz, 6H).
    • Example 616 (2R,3S)-3-((5-fluoro-2-(2-((2-hydroxyethyl)carbamoyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01470
  • Example 616 was prepared from 2-aminoethanol using the same method as described for Example 613. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z: 606.0 (M+H)+.
    • Preparation of Alcohol Examples
  • The alcohols in the accompanying table were prepared according to the following three general procedures.
  • Primary Alcohols
  • The appropriately substituted hetero-aryl ester was subjected to conditions described in Procedure G. Purification by Prep HPLC (Method D) afforded the desired example.
  • Secondary Alcohols
  • The appropriately substituted hetero-aryl aldehyde was subjected to conditions described in Procedure H. Purification by Prep HPLC (Method D) afforded the desired example.
  • Tertiary Alcohols
  • The appropriately substituted hetero-aryl ester was subjected to conditions described in Procedure H. Purification by Prep HPLC (Method D) afforded the desired example.
  • Orthog-
    onal
    HPLC HPLC
    Ester/ LCMS method B Prep
    Ex. Alde- [M + H]+ Injection Method
    No. Structure hyde m/z 2 D NMR
    617
    Figure US20190292176A1-20190926-C01471
         		I-118 564.0 2.037 45-90% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 9.89 (br. s., 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.51 (br. s., 1H), 8.15 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.89 (br. s., 1H), 7.82 (s, 1H), 5.33 (t, J = 5.6 Hz, 1H), 5.19-5.03 (m, J = 6.6, 2.6 Hz, 1H), 4.83- 4.73 (m, 1H), 4.49 (d, J = 5.5 Hz, 2H), 4.09 (s, 3H), 2.63 (s, 3H), 1.41 (t, J = 6.3 Hz, 6H)
    618
    Figure US20190292176A1-20190926-C01472
         		I-74 592.1 2.126 45-90% 12 min, 100% 5 min 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.69 (s, 1H), 8.56-8.48 (m, 2H), 8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.83 (br. s., 1H), 7.79 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 5.5 Hz, 1H), 4.79 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 2.61 (s, 3H), 1.43-1.37 (m, 12H)
    619
    Figure US20190292176A1-20190926-C01473
         		I-85 564.1 2.092 55-85% 25 min, 85% 4 min 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.27 (d, J = 5.5 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.34 (d, J = 4.0 Hz, 1H), 5.14 (dd, J = 6.4, 2.7 Hz, 1H), 4.80 (dd, J = 6.4, 2.7 Hz, 1H), 4.49 (d, J = 4.6 Hz, 2H), 4.08 (s, 3H), 2.63 (s, 3H), 1.41 (t, J = 6.0 Hz, 6H)
    620
    Figure US20190292176A1-20190926-C01474
         		I-120 579.2 2.384 45-90% 20 min, 100% 7 min 1H NMR (500 MHz, DMSO-d6) δ 10.04 (br. s., 1H), 8.83 (br. s., 2H), 8.72 (s, 1H), 8.56 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.14 (d, J = 5.2 Hz, 1H), 4.82 (d, J = 3.7 Hz, 1H), 4.76-4.66 (m, 1H), 4.09 (s, 3H), 3.40-3.37 (m, 1H), 2.63 (s, 3H), 1.41 (dd, J = 6.0, 4.1 Hz, 6H), 1.36 (d, J = 6.4 Hz, 3H)
    • Example 621 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl isothiazol-5-ylcarbamate
  • Figure US20190292176A1-20190926-C01475
  • Example 318 (12 mg, 0.029 mmol), isothiazole-5-carboxylic acid (7.38 mg, 0.057 mmol) and triethylamine (7.97 μl, 0.057 mmol) were suspended in toluene (1 mL) in a pressure rated 1 dram vial. Diphenylphosphoryl azide (15.73 mg, 0.057 mmol) was added to the mixture which was heated to 110° C. for 3 hours. The crude reaction mixture was purified by reverse phase HPLC (Method D, 65-100% 20 min, 100% 5 min) to yield Example 621 (1.3 mg, 2.38 mmol, 8% yield). LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 546.10 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.62 (s, 1H), 8.21 (s, 1H), 8.02-8.12 (m, 1H), 7.88 (s, 1H), 6.81 (s, 1H), 4.61-4.69 (m, 2H), 4.46-4.56 (m, 2H), 4.10 (s, 3H), 3.19 (s, 3H).
    • Example 622 (R)-5-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazolidin-2-one
  • Figure US20190292176A1-20190926-C01476
    • Intermediate 622A: (R)-5-(chloromethyl)oxazolidin-2-one
  • Figure US20190292176A1-20190926-C01477
  • (R)-2-(chloromethyl)oxirane (285 mg, 3.08 mmol), potassium cyanate (500 mg, 6.16 mmol) and magnesium sulfate (742 mg, 6.16 mmol) were dissolved in water (10 mL) and the mixture was heated to 100° C. under a reflux condenser for 18 h. The reaction mixture was then diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated to yield Intermediate 622A (210 mg, 1.549 mmol, 50.3% yield). The product was brought forward without further purification. 1H NMR (400 MHz, CDCl3) δ 5.81 (br. s., 1H), 4.98-4.75 (m, 1H), 3.84-3.65 (m, 3H), 3.57 (ddd, J=9.0, 5.9, 1.0 Hz, 1H).
    • Example 622
  • Intermediate I-65 (30 mg, 0.080 mmol) was dissolved in DMF (2 mL) along with potassium carbonate (33.1 mg, 0.239 mmol), Intermediate 622A (21.64 mg, 0.160 mmol) and potassium iodide (13.25 mg, 0.080 mmol). The reaction mixture was then stirred at 80° C. for 18 h before being diluted with EtOAc. The organic layer was washed with 10% aq. LiCl (3×), brine, dried with sodium sulfate, filtered, and concentrated. The crude residue was purified by reverse phase HPLC (Method D, 30-75% 30 min, 100% 5 min) to yield Example 622 (4 mg, 8.00 μmol, 10.02% yield). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 475.05 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.60 (s, 1H), 7.99-8.08 (m, 1H), 7.87 (s, 1H), 7.59-7.69 (m, 1H), 4.93-5.09 (m, 1H), 4.27-4.49 (m, 2H), 4.09 (s, 3H), 3.48-3.72 (m, 1H), 3.36-3.45 (m, 1H), 2.65 (s, 3H).
    • Example 623 4-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazol-2-amine
  • Figure US20190292176A1-20190926-C01478
    • Intermediate 623A: 1-bromo-3-((tert-butyldimethylsilyl)oxy)propan-2-one
  • Figure US20190292176A1-20190926-C01479
  • 1-bromo-3-((tert-butyldimethylsilyl)oxy)propan-2-ol (500 mg, 1.857 mmol) was dissolved in DCM (10 mL). Dess-Martin Periodinane (1181 mg, 2.79 mmol) was added to the reaction mixture which stirred at room temperature for 2 hours. The reaction mixture was concentrated and the resulting residue was dissolved in a small amount of methylene chloride before being charged to a 12 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractions containing the desired product were collected and concentrated to yield Intermediate 623A (300 mg, 1.123 mmol, 60.5% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 4.25 (s, 2H), 3.94-4.05 (m, 2H), 0.75-0.89 (m, 9H), −0.10-0.09 (m, 6H).
    • Example 623
  • Intermediate 623A (20 mg, 0.053 mmol) was dissolved in DMF (2 mL). Potassium carbonate (22.07 mg, 0.160 mmol) was added to the mixture followed by I-65 (20 mg, 0.053 mmol). The reaction mixture was stirred for 1 h at room temperature after which additional Intermediate 623A (20 mg, 0.053 mmol) was added to the mixture. The reaction mixture was allowed to stir for 2 hours at room temperature and then quenched with a few drops of AcOH. The mixture was diluted with EtOAc and the organic layer was washed with 10% aq. LiCl (3×), brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in THF (5 mL)/water (0.500 mL)/acetic acid (0.500 mL). 1M TBAF in THF (0.064 mL, 0.064 mmol) was added to the mixture which was allowed to stir for 1 hour at room temperature after which additional 1M TBAF in THF (0.064 mL, 0.064 mmol) was added. The mixture was then diluted 1.5 M dipotassium phosphate solution and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in THF (1 mL) along with cyanamide (21.59 mg, 0.514 mmol), 1N aqueous sodium acetate (0.051 mL, 0.051 mmol), tetrabutylammonium hydroxide (13.33 mg, 0.051 mmol) and 1M aq. NaOH (0.051 mL, 0.051 mmol). The reaction mixture was allowed to stir at room temperature for 3 h then a few drops of AcOH added and the reaction mixture was concentrated and purified by reverse phase HPLC (Method D, 40-73% 22 min, 100% 7 min) to yield Example 623 (0.6 mg, 0.001 mmol, 2% yield) over the three step sequence. LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 472.10 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.61 (s, 1H), 8.10-8.14 (m, 1H), 7.81-7.90 (m, 1H), 7.56 (s, 1H), 6.66 (s, 2H), 5.02 (s, 2H), 4.10 (s, 3H), 2.66 (s, 3H).
    • Example 624 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-(phosphonooxy)ethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01480
    • Intermediate 624A: (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-((bis(2-(trimethylsilyl)ethoxy)phosphoryl)oxy)ethyl) pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01481
  • To a suspension of Example 566 (313 mg, 0.528 mmol) in DCM (40 mL) was added bis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (0.7 mL, 1.704 mmol) followed by 1H-tetrazole (137 mg, 1.956 mmol) and the resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was then cooled to 0° C. and hydrogen peroxide (35% wt. in H2O) (0.3 mL, 3.43 mmol) was added dropwise over 2 minutes. After stirring for 30 minutes at rt, the reaction mixture was diluted with 30 mL of DCM and the organic layer was washed with saturated aqueous sodium sulfite (2×), brine (1×), dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a small amount of DCM and purified by silica gel chromatography (gradient of 0-100% EtOAc/DCM). The fractions containing desired product were concentrated to yield Intermediate 624A (349 mg, 0.4 mmol, 76% yield). LC-MS: Method H, MS (ESI) m/z: 873.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.79 (br. s., 2H), 8.53 (d, J=2.0 Hz, 1H), 8.46 (s, 1H), 7.77 (d, J=11.4 Hz, 1H), 7.69 (dd, J=2.0, 0.9 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.39-7.30 (m, 1H), 5.21-4.99 (m, 1H), 4.60-4.44 (m, 5H), 4.16-3.98 (m, 4H), 3.28 (t, J=6.8 Hz, 2H), 1.48 (t, J=7.0 Hz, 3H), 1.42 (dd, J=16.3, 6.4 Hz, 6H), 1.10-0.98 (m, J=8.6, 8.6, 0.7 Hz, 4H), 0.03-0.04 (m, 18H).
    • Example 624
  • Intermediate 624A (226 mg, 0.259 mmol) was dissolved in DCM (10 mL). TFA (0.140 mL, 1.812 mmol) and water (0.033 mL, 1.812 mmol) were added to the solution which was stirred at room temperature. After 5 minutes of stirring, additional TFA (0.140 mL, 1.812 mmol) was added dropwise and the reaction mixture was allowed to stir for 50 minutes at room temperature. Concentration of the reaction mixture followed by trituration from ether yielded a particulate solid. The mother liquor was removed by filtration, and the remaining solid was redissolved in dioxane and concentrated to afford 624 in quantitative yield. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 673.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (br. s., 1H), 8.78 (br. s., 2H), 8.68 (s, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.94 (d, J=11.7 Hz, 1H), 7.78 (dd, J=2.0, 0.9 Hz, 1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.78 (dd, J=6.4, 2.9 Hz, 1H), 4.51 (q, J=7.0 Hz, 2H), 4.23 (q, J=6.8 Hz, 2H), 3.10 (t, J=6.7 Hz, 2H), 2.60 (s, 3H), 1.46-1.29 (m, 9H).
    • Example 625 2-(6-chloro-3-(methoxymethyl)quinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01482
    • Intermediate 625A: 8-bromo-6-chloro-3-(methoxymethyl)quinoline
  • Figure US20190292176A1-20190926-C01483
  • Intermediate I-123 (33.5 mg, 0.143 mmol), 3-methoxypropanal (13.8 mg, 0.157 mmol), and sodium methoxide (0.5 M in MeOH, 314 μl, 0.157 mmol) were dissolved in MeOH (1.43 mL) and heated to reflux. After 3 hours, the reaction mixture was diluted with saturated NH4Cl and EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 625A (23.5 mg, 0.082 mmol, 57%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.99 (d, J=2.2 Hz, 1H), 8.09-8.07 (m, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 4.71 (s, 2H), 3.51 (s, 3H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 286/288 (M+H)+.
    • Intermediate 625B: (6-chloro-3-(methoxymethyl)quinolin-8-yl)boronic acid
  • Figure US20190292176A1-20190926-C01484
  • Intermediate 625A (73.2 mg, 0.255 mmol), bispinacolatodiboron (97 mg, 0.383 mmol), and potassium acetate (62.7 mg, 0.639 mmol) were dissolved in 1,4-dioxane (2.56 mL) and degassed for 5 minutes by bubbling with argon. PdCl2(dppf)-CH2Cl2Adduct (16.7 mg, 0.020 mmol) was added and the reaction degassed for an additional 10 minutes. The reaction mixture was heated to 130° C. in the microwave for 45 minutes. The reaction mixture was diluted with EtOAc and water. The aqueous layer was further extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A, 30-100% B in 15 minutes) to give Intermediate 625B (31.4 mg, 0.125 mmol, 49%) was a brown solid: LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 252.1 (M+H)+.
    • Example 625
  • Intermediate 625B (10 mg, 0.040 mmol), Intermediate I-3 (12.32 mg, 0.048 mmol), and PdCl2(dppf)-CH2Cl2 adduct (1.95 mg, 2.39 μmol) were dissolved in 1,4-dioxane (306 μL) and Na2CO3 (2 M, 179 μL, 0.358 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 60-100% B in 20 minutes) to give Example 625 (7.0 mg, 0.018 mmol, 46%): 1H NMR (500 MHz, DMSO-d6) δ 9.09 (br. s., 1H), 8.84 (br. s., 1H), 8.45 (br. s., 1H), 8.33 (br. s., 1H), 7.56 (br. s., 1H), 7.02 (br. s., 1H), 4.74 (s, 2H), 3.87 (s, 3H), 3.44 (s, 3H), 2.76 (s, 3H); LC-MS: Method H, RT=1.44 min, MS (ESI) m/z: 385.1 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 626 2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01485
    • Intermediate 626A: 6-methoxy-4-methyl-2-(tributylstannyl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01486
  • Intermediate I-3 (300 mg, 1.162 mmol) was dissolved in Et2O (4.65 mL) and cooled to −78° C. BuLi (2.5 M in hexanes, 511 μL, 1.278 mmol) was then added. After 45 minutes, tributylchlorostannane (315 μL, 1.16 mmol) was added. After 15 minutes, the reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude material was suspended in hexanes and filtered through dry celite. The residue was concentrated in vacuo to give Intermediate 626A, which was used directly in the subsequent step.
    • Intermediate 626B: 2-(3-(benzyloxy)-6-chloroquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01487
  • Intermediate I-122A (270 mg, 0.774 mmol), Intermediate 626A (526 mg, 1.12 mmol), and potassium acetate (152 mg, 1.55 mmol) were dissolved in 1,4-dioxane (7.74 mL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (44.7 mg, 0.039 mmol) was added and the reaction vessel was sealed and heated to 120° C. in the microwave for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) then repurified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% DCM in hexanes) to give Intermediate 626B (201 mg, 0.45 mmol, 58%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=2.9 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.56-7.38 (m, 6H), 7.28 (s, 1H), 6.96 (dd, J=2.6, 0.9 Hz, 1H), 5.27 (s, 2H), 3.92 (s, 3H), 2.85 (s, 3H); LC-MS: Method H, RT=1.58 min, MS (ESI) m/z: 447.1 (M+H)+.
    • Intermediate 626C: 6-chloro-8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)quinolin-3-ol
  • Figure US20190292176A1-20190926-C01488
  • Intermediate 626B (25 mg, 0.056 mmol) and pentamethylbenzene (58.0 mg, 0.392 mmol) were dissolved in DCM (2.8 mL) and cooled to −78° C. Boron trichloride (1 M in heptane, 145 μL, 0.145 mmol) was added and the reaction mixture was allowed to slowly warm to ambient temperature. After stirring overnight, the reaction was quenched with 1 N HCl and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 4 g silica gel column, 15 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 626C (17.1 mg, 0.048 mmol, 86%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=2.4 Hz, 1H), 8.82 (d, J=2.9 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.48 (d, J=2.9 Hz, 1H), 6.96 (dd, J=2.6, 0.9 Hz, 1H), 3.92 (s, 3H), 2.86 (s, 3H); LC-MS: Method H, RT=1.39 min, MS (ESI) m/z: 357.1 (M+H)+.
    • Example 626
  • Intermediate 626C (17 mg, 0.048 mmol), K2CO3 (13.2 mg, 0.095 mmol), and MeI (11.9 μL, 0.191 mmol) were dissolved in acetone (1.91 mL). After stirring overnight, the reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method D, 55-95% B in 10 minutes) to give Example 626 (5.5 mg, 0.015 mmol, 31%): 1H NMR (500 MHz, DMSO-d6) δ 8.89 (br. s., 1H), 8.67 (s, 1H), 8.18 (s, 1H), 7.95 (br. s., 1H), 7.54 (s, 1H), 7.01 (br. s., 1H), 4.00 (s, 3H), 3.86 (s, 3H), 2.75 (s, 3H); LC-MS: Method H, RT=1.51 min, MS (ESI) m/z: 371.1 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 627 2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-2-ol
  • Figure US20190292176A1-20190926-C01489
    • Intermediate 627A: 2-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)propan-2-ol
  • Figure US20190292176A1-20190926-C01490
  • Intermediate I-20C (50 mg, 0.165 mmol) was dissolved in THF (331 μL) and cooled to −78° C. Methylmagnesium bromide (3 M in Et2O, 124 μL, 0.372 mmol) was added and the reaction mixture was allowed to slowly warm to 0° C. in the freezer. After stirring overnight, the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 627A (13.6 mg, 0.045 mmol, 27%) as a clear oil: LC-MS: Method H, RT=1.00 min, MS (ESI) m/z: 302/304 (M+H)+.
    • Example 627
  • Intermediate I-9 (11.6 mg, 0.039 mmol), Intermediate 627A (14 mg, 0.046 mmol), and potassium phosphate, tribasic (16.4 mg, 0.077 mmol) were dissolved in DMF (386 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (4.46 mg, 3.86 μmol) was added and degassing continued for 5 minutes. The reaction was then sealed and heated to 85° C. After stirring overnight, the crude material was purified by preparative HPLC (Method D, 50-100% B in 14 minutes) to give Example 627 (6.6 mg, 0.016 mmol, 42%): 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.51 (d, J=1.7 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 5.42 (s, 1H), 4.10 (s, 3H), 3.88 (s, 3H), 2.66 (s, 3H), 1.83 (s, 6H); LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 396.2 (M+H)+; Analytical HPLC Method B, 97% purity.
    • Example 628 1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01491
    • Intermediate 628A: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01492
  • Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) and cooled to −78° C. tert-Butylmagnesium chloride (1 M in THF, 184 μL, 0.184 mmol) was then added and the reaction mixture was allowed to slowly warm to 0° C. in the freezer. After stirring overnight, the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 628A (29 mg, 0.088 mmol, 60%) as a white solid: LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 330/332 (M+H)+.
    • Example 628
  • Intermediate I-2 (16.6 mg, 0.053 mmol), Intermediate 628A (14.5 mg, 0.044 mmol), and potassium phosphate, tribasic (18.6 mg, 0.088 mmol) were dissolved in DMF (439 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (5.07 mg, 4.39 μmol) was added and degassing continued for 5 minutes. The reaction vessel was then sealed and heated to 85° C. After heating overnight, the crude material was purified by preparative HPLC (Method D, 45-85% B in 20 minutes) to give Example 628 (6.4 mg, 0.015 mmol, 33%): 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.45 (d, J=4.7 Hz, 1H), 5.34 (d, J=4.7 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H), 0.97 (s, 9H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 437.8 (M+H)+; Analytical HPLC Method B, 98% purity.
    • Example 629 (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl) (phenyl)methanol
  • Figure US20190292176A1-20190926-C01493
    • Intermediate 629A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)(phenyl)methanol
  • Figure US20190292176A1-20190926-C01494
  • Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) and cooled to −78° C. Phenylmagnesium bromide (3 M in Et2O, 61.2 μl, 0.184 mmol) was added and the reaction mixture was allowed to slowly warm to 0° C. in the freezer. After stirring overnight, the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 629A (33.6 mg, 0.096 mmol, 65%) as a white solid: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 350/352 (M+H)+.
    • Example 629
  • Intermediate I-9 (14.1 mg, 0.047 mmol), Intermediate 629A (16.5 mg, 0.047 mmol), and potassium phosphate, tribasic (20 mg, 0.094 mmol) were dissolved in DMF (471 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (5.44 mg, 4.71 μmol) was added and degassing continued for 5 minutes. The reaction vessel was then sealed and heated to 85° C. After heating overnight, the crude material was purified by preparative HPLC (Method D, 40-75% B in 15 minutes) then repurified by preparative HPLC (Method D, 60-100% B in 12 minutes) to give Example 629 (7.4 mg, 0.017 mmol, 35%): 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.61 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.62-7.55 (m, 3H), 7.35-7.26 (m, 3H), 7.23-7.15 (m, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.10 (d, J=4.1 Hz, 1H), 4.09 (s, 3H), 3.86 (s, 3H), 2.67 (s, 3H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 443.8 (M+H)+; Analytical HPLC Method B, 99% purity.
    • Example 630 1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01495
  • Intermediate I-9 (15.8 mg, 0.053 mmol), Intermediate 628A (14.5 mg, 0.044 mmol), and potassium phosphate, tribasic (18.6 mg, 0.088 mmol) were dissolved in DMF (439 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (5.07 mg, 4.39 μmol) was added and degassing continued for 5 minutes. The reaction vessel was then sealed and heated to 85° C. After heating overnight, the crude material was purified by preparative HPLC (Method D, 50-85% B in 15 minutes) then repurified by preparative HPLC (Method D, 60-100% B in 20 minutes) to give Example 630 (3.8 mg, 0.0087 mmol, 20%): 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.55 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 5.43 (s, 1H), 5.34 (br. s., 1H), 4.09 (s, 3H), 3.88 (s, 3H), 2.66 (s, 3H), 0.96 (s, 9H); LC-MS: Method H, RT=1.32 min, MS (ESI) m/z: 423.8 (M+H)+; Analytical HPLC Method B, 97% purity.
    • Example 631 1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2-phenylethanol
  • Figure US20190292176A1-20190926-C01496
    • Intermediate 631A: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2-phenylethanol
  • Figure US20190292176A1-20190926-C01497
  • Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) and cooled to −78° C. Benzylmagnesium chloride (2 M in Et2O, 92 μL, 0.184 mmol) was added and the reaction mixture was allowed to slowly warm to 0° C. in the freezer. After stirring overnight, the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 631A (18.9 mg, 0.052 mmol, 35%) as a yellow oil: LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 364/366 (M+H)+.
    • Example 631
  • Intermediate I-9 (9.39 mg, 0.031 mmol), Intermediate 631A (9.5 mg, 0.026 mmol), and potassium phosphate, tribasic (11.1 mg, 0.052 mmol) were dissolved in DMF (261 μL) and degassed by bubbling with argon for 15 minutes. Palladium tetrakistriphenylphosphine (3.01 mg, 2.61 μmol) was added and degassing continued for 5 minutes. The reaction was then sealed and heated to 85° C. After heating overnight, the crude material was purified by preparative HPLC (Method D, 45-80% B in 20 minutes) then repurified by preparative HPLC (Method D, 70-100% B in 15 minutes) to give Example 631 (1.2 mg, 0.0026 mmol, 10%): 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.61 (d, J=1.4 Hz, 1H), 7.85 (s, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.38-7.33 (m, 2H), 7.33-7.27 (m, 2H), 7.23-7.16 (m, 2H), 5.71 (dt, J=8.3, 4.4 Hz, 1H), 5.49 (d, J=5.2 Hz, 1H), 4.10 (s, 3H), 3.87 (s, 3H), 3.29 (dd, J=13.5, 3.6 Hz, 1H), 2.97 (dd, J=13.6, 8.4 Hz, 1H), 2.69 (s, 3H); LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 457.8 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 632 1-(5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01498
    • Intermediate 632A: 1-(2-amino-5-fluoro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01499
  • Intermediate I-43C (100 mg, 0.430 mmol) was dissolved in THF (4.3 mL).
  • Sodium hydride (18.9 mg, 0.473 mmol) was then added. After 30 minutes, the reaction mixture was cooled to −78° C. and tert-butyllithium (1 M, 430 μL, 0.516 mmol) was added. After 45 minutes, pivalaldehyde (96 μL, 0.86 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After the reaction mixture achieved ambient temperature, it was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 632A, which was used immediately in the subsequent reaction: LC-MS: Method H, RT=0.74 min, MS (ESI) m/z: 285.2 (M+H)+.
    • Intermediate 632B: 1-(2-chloro-5-fluoro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01500
  • Copper(II) chloride (81 mg, 0.601 mmol) and t-butyl nitrite (77 μL, 0.644 mmol) were dissolved in MeCN (1.72 mL) and allowed to stir 10 minutes. Intermediate 632A (122 mg, 0.429 mmol) was dissolved in MeCN (2.57 mL) and the copper solution was added and heated to 60° C. After 1.5 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 632B (21 mg, 0.021 mmol, 4.8%) as a brown solid: LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 304.1 (M+H)+.
    • Example 632
  • Intermediate I-9 (24.9 mg, 0.083 mmol) and Intermediate 632B (21 mg, 0.069 mmol) were dissolved in DMF (691 μL). PdCl2(dppf)-CH2Cl2 adduct (3.39 mg, 4.15 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 41.5 μl, 0.083 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The material was heated in the microwave for an additional 30 minutes at 120° C. The crude material was purified by preparative HPLC (Method D, 70-100% B in 20 minutes) then repurified by preparative HPLC (Method D, 60-100% B in 20 minutes) to give Example 632 (0.7 mg, 0.0015 mmol, 2.2%): 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.50 (d, J=1.7 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.83-7.80 (m, 1H), 5.57 (br. s., 1H), 5.25 (br. s., 1H), 4.08 (s, 3H), 3.94 (s, 3H), 2.64 (s, 3H), 1.00 (s, 9H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 442.2 (M+H)+; Analytical HPLC Method B, 97% purity.
    • Example 633 2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C01501
    • Intermediate 633A: 1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2,2-trifluoroethanol
  • Figure US20190292176A1-20190926-C01502
  • Intermediate I-21 (207 mg, 0.909 mmol) was dissolved in THF (18.2 mL). (Trifluoromethyl)trimethylsilane (161 μL, 1.09 mmol) then TBAF (1 M in THF, 1.09 mL, 1.09 mmol) were added to the reaction. After stirring overnight, the reaction mixture was diluted with EtOAc and washed with water, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 633A (70.8 mg, 0.238 mmol, 26%) as a white solid: LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 298.1 (M+H)+.
    • Intermediate 633B: 2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol (racemic)
  • Figure US20190292176A1-20190926-C01503
  • Intermediate I-9 (70.6 mg, 0.235 mmol) and Intermediate 633A (70 mg, 0.235 mmol) were dissolved in DMF (2.35 mL). PdCl2(dppf)-CH2Cl2 adduct (11.5 mg, 0.014 mmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 141 μL, 0.282 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The reaction mixture was diluted with water and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 633B (racemic) (49.9 mg, 0.115 mmol, 49%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 7.78 (d, J=0.9 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.35 (d, J=9.9 Hz, 1H), 7.06 (s, 1H), 5.35 (dd, J=9.8, 7.4 Hz, 1H), 4.13 (s, 3H), 3.93 (s, 3H), 2.66 (s, 3H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 436.1 (M+H)+.
    • Example 633
  • Intermediate 633B (49.9 mg, 0.115 mmol) was purified by chiral SFC (Chiralpak OJ-H, 21×250 mm, 5 micron, 25% IPA/75% CO2, 2 mL/min) to give Example 633 (Peak 2, Enantiomer 2, 20.4 mg, 0.044 mmol, 38%, >99% ee) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.48 (d, J=1.5 Hz, 1H), 7.78 (dd, J=1.9, 1.0 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.35 (d, J=9.9 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 5.40-5.30 (m, 1H), 4.13 (s, 3H), 3.93 (s, 3H), 2.66 (s, 3H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 436.1 (M+H)+.
    • Example 634 4-(1-fluoro-2,2-dimethylpropyl)-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01504
    • Intermediate 634A: 2-bromo-4-(1-fluoro-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01505
  • Intermediate 628A (20 mg, 0.061 mmol) and Deoxofluor (14 μL, 0.076 mmol) were dissolved in DCM (606 μL). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 634A (24 mg, 0.072 mmol, 100%), which was used immediately in the subsequent reaction: LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 332/334 (M+H)+.
    • Example 634
  • Intermediate I-9 (10.8 mg, 0.036 mmol) and Intermediate 634A (10 mg, 0.030 mmol) were dissolved in DMF (301 μL). PdCl2(dppf)-CH2Cl2 adduct (1.48 mg, 1.81 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (18.1 μL, 0.036 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 80-100% B in 15 minutes) to give Example 634 (3.5 mg, 0.0079 mmol, 26%): 1H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H), 8.48 (s, 1H), 7.67 (s, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.37-6.25 (m, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.60 (s, 3H), 1.03 (s, 9H); LC-MS: Method H, RT=1.47 min, MS (ESI) m/z: 426.2 (M+H)+; Analytical HPLC Method B, 96% purity.
    • Example 635 4-(benzyloxy)-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01506
    • Intermediate 635A: 2-(benzyloxy)-4-methoxy-1-nitrobenzene
  • Figure US20190292176A1-20190926-C01507
  • 5-Methoxy-2-nitrophenol (1 g, 5.91 mmol), potassium carbonate (2.45 g, 17.7 mmol), and benzyl bromide (1.06 ml, 8.87 mmol) were dissolved in DMF (11.8 mL). After stirring overnight, the reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 120 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 635A (1.51 g, 5.81 mmol, 98%) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.30 (m, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.1, 2.5 Hz, 1H), 5.22 (s, 2H), 3.84 (s, 3H); LC-MS: Method H, The compound did not ionize.
    • Intermediate 635B: 2-(benzyloxy)-4-methoxyaniline
  • Figure US20190292176A1-20190926-C01508
  • Intermediate 635A (1.51 g, 5.81 mmol) was dissolved in MeOH (39.7 mL) and THF (4.96 mL). Ammonium chloride (6.21 g, 116 mmol) and zinc (3.80 g, 58.1 mmol) were added and the reaction mixture was heated to 40° C. After 3.5 hours, the reaction mixture was concentrated in vacuo. The crude material was redissolved in EtOAc/saturated Na2CO3 and allowed to stir vigorously for 15 minutes. The mixture was filtered through a sintered glass funnel. The organic layer was washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 635B (511 mg, 2.23 mmol, 38%) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.46-7.31 (m, 5H), 6.68 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.6 Hz, 1H), 6.38 (dd, J=8.6, 2.6 Hz, 1H), 5.06 (s, 2H), 3.74 (s, 3H), 3.56 (br. s., 2H); LC-MS: Method H, RT=0.69 min, MS (ESI) m/z: 230.2 (M+H)+.
    • Intermediate 635C: 4-(benzyloxy)-6-methoxybenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01509
  • Intermediate 635B (0.5 g, 2.18 mmol) was dissolved in MeCN (10.9 mL). Ammonium thiocyanate (0.249 g, 3.27 mmol) was added, followed by benzyltrimethylammonium tribromide (0.850 g, 2.18 mmol). After stirring for 2 days, the reaction mixture was diluted with saturated NaHCO3 and the solid collected by suction filtration and washed with water to give Intermediate 635C (574 mg, 2 mmol, 92%) as a purple solid: LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 287.2 (M+H)+.
    • Intermediate 635D: 4-(benzyloxy)-2-chloro-6-methoxybenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01510
  • Copper(II) chloride (0.377 g, 2.80 mmol) and t-butyl nitrite (0.357 mL, 3.00 mmol) were dissolved in MeCN (8 mL) and allowed to stir 10 minutes. Intermediate 635C (0.573 g, 2.001 mmol) was dissolved in MeCN (12 mL) and the copper solution was added and the reaction mixture was heated to 60° C. After 2 hours, the reaction mixture was concentrated in vacuo to remove the majority of the MeCN. The reaction was then diluted with EtOAc, washed twice with 1 N HCl, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 635D (147 mg, 0.481 mmol, 24%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=7.3 Hz, 2H), 7.40-7.34 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 6.54 (d, J=2.2 Hz, 1H), 5.32 (s, 2H), 3.80 (s, 3H); LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 306.1 (M+H)+.
    • Example 635
  • Intermediate I-2 (13.2 mg, 0.042 mmol) and Intermediate 635D (10 mg, 0.035 mmol) were dissolved in DMF (350 μL). PdCl2(dppf)-CH2Cl2 adduct (1.72 mg, 2.1 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 21 μL, 0.042 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 40-80% B in 22 minutes) to give Example 635 (7.6 mg, 0.015 mmol, 44%): 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.85 (br. s., 1H), 7.85 (br. s., 1H), 7.50 (d, J=6.9 Hz, 2H), 7.39-7.22 (m, 3H), 6.95 (br. s., 1H), 6.52 (br. s., 1H), 5.38 (s, 2H), 4.77 (s, 2H), 3.79 (s, 3H), 3.50 (d, J=1.4 Hz, 3H), 2.61 (br. s., 3H); LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 458.2 (M+H)+; Analytical HPLC Method B, 93% purity.
    • Example 636 1-(2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01511
  • Intermediate I-28 (10.4 mg, 0.044 mmol) and Intermediate 628A (12 mg, 0.036 mmol) were dissolved in DMF (363 μL). PdCl2(dppf)-CH2Cl2 adduct (1.78 mg, 2.18 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 21.8 μL, 0.044 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 40-100% B in 15 minutes) then repurified by preparative HPLC (Method D, 45-85% B in 22 minutes) to give Example 636 (1.2 mg, 0.0025 mmol, 6.8%): 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 5.41 (br. s., 1H), 5.32 (br. s., 1H), 4.10 (s, 3H), 3.88 (s, 3H), 0.95 (s, 9H); LC-MS: Method H, RT=1.43 min, MS (ESI) m/z: 444.2 (M+H)+; Analytical HPLC Method B, 91% purity.
    • Example 637 1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01512
    • Intermediate 637A: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01513
  • Intermediate 628A (110 mg, 0.333 mmol) was purified by chiral preparative HPLC (Chiralpak AD, 90% heptane/10% EtOH:MeOH (50:50)) to give Intermediate 637A (33.8 mg, 0.102 mmol, 31%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=2.6 Hz, 1H), 6.98-6.91 (m, 1H), 4.84 (d, J=8.4 Hz, 1H), 4.02 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 0.96 (s, 9H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 330/332 (M+H)+.
    • Example 637
  • Intermediate I-9 (5.45 mg, 0.018 mmol) and Intermediate 637A (5 mg, 0.015 mmol) were dissolved in DMF (151 μL). PdCl2(dppf)-CH2Cl2 adduct (0.742 mg, 0.908 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 9.08 μL, 0.018 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 70-100% B in 15 minutes) to give Example 637 (4.6 mg, 0.011 mmol, 70%): 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.59 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.20 (s, 1H), 5.48 (d, J=4.6 Hz, 1H), 5.38 (d, J=4.6 Hz, 1H), 4.14 (s, 3H), 3.93 (s, 3H), 2.70 (s, 3H), 1.01 (s, 9H); LC-MS: Method H, RT=1.36 min, MS (ESI) m/z: 424.1 (M+H)+; Analytical HPLC Method B, 97% purity.
    • Example 638 2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl (5-cyanopyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01514
    • Intermediate 638A: 1-(2-amino-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
  • Figure US20190292176A1-20190926-C01515
  • Intermediate I-22 (0.5 g, 1.93 mmol) was dissolved in THF (19.3 mL). Sodium hydride (0.085 g, 2.12 mmol) was added. After 30 minutes, the reaction mixture was cooled to −78° C. and BuLi (1.68 ml, 3.86 mmol) was added. After 1 hour, methyl pivalate (0.77 mL, 5.79 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After achieving ambient temperature, the reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 20% MeOH in DCM) to give Intermediate 638A (382 mg, 1.45 mmol, 75%) as a brown solid: 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 5.09 (br. s., 2H), 3.82 (s, 3H), 1.29 (s, 9H); LC-MS: Method H, RT=0.76 min, MS (ESI) m/z: 265.2 (M+H)+.
    • Intermediate 638B: 1-(2-amino-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
  • Figure US20190292176A1-20190926-C01516
  • Intermediate 638A (380 mg, 1.44 mmol) was dissolved in AcOH (5.75 mL) and HBr (976 μL, 8.63 mmol) and heated to reflux. After heating for 2 days, the reaction mixture was concentrated in vacuo to give Intermediate 638B, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.64 min, MS (ESI) m/z: 251.1 (M+H)+.
    • Intermediate 638C: 2-((2-amino-4-pivaloylbenzo[d]thiazol-6-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01517
  • Intermediate 638B (360 mg, 1.44 mmol), Cs2CO3 (2.81 g, 8.63 mmol), and 2-bromoethyl acetate (397 μL, 3.60 mmol) were dissolved in DMF (5.75 mL). After stirring overnight, the reaction mixture was diluted with water and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A, 30-100% B in 12 minutes) to give Intermediate 638C (139 mg, 0.412 mmol, 29%) as a white solid: LC-MS: Method H, RT=0.76 min, MS (ESI) m/z: 337.2 (M+H)+.
    • Intermediate 638D: 2-((2-chloro-4-pivaloylbenzo[d]thiazol-6-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01518
  • Copper(II) chloride (78 mg, 0.577 mmol) and t-butyl nitrite (73.5 μL, 0.618 mmol) were dissolved in MeCN (1.65 mL) and allowed to stir 10 minutes. Intermediate 638C (139 mg, 0.412 mmol) was dissolved in MeCN (2.47 mL) and the copper solution was added and the reaction mixture was heated to 60° C. After 2.5 hours, the reaction mixture was concentrated in vacuo to remove the majority of the MeCN. The reaction was then diluted with EtOAc, washed twice with 1 N HCl, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 638D (134 mg, 0.377 mmol, 91%) as an orange oil: LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 356.1 (M+H)+.
    • Intermediate 638E: 1-(2-chloro-6-(2-hydroxyethoxy)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01519
  • Intermediate 638D (134 mg, 0.377 mmol) was dissolved in toluene (2.51 mL) and THF (1.26 mL) and cooled to −78° C. DIBAL-H (1 M in toluene, 1.13 mL, 1.13 mmol) was added and the reaction was warmed to ambient temperature. After 5 hours, more DIBAL-H (1130 μl, 1.130 mmol) was added. After 45 minutes, the reaction was quenched with a saturated solution of Rochelle's salt. After stirring overnight, the reaction mixture was extracted with EtOAc. The organic layer was further washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes). The resulting product was purified by chiral preparative HPLC (Chiralpak AD, 16% MeOH/EtOH (50/50) in heptane) to give Intermediate 638E (7.2 mg, 0.023 mmol, 6.1%) as a clear oil: LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 316.1 (M+H)+.
    • Intermediate 638F: 2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C01520
  • Intermediate 638E (7.2 mg, 0.023 mmol) and phosgene solution (15% in toluene, 0.114 mmol) were dissolved in THF (228 μL). After 1.5 hours, the reaction mixture was concentrated in vacuo to give Intermediate 638F, which was used directly in the subsequent reaction.
    • Intermediate 638G: 2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethyl (5-cyanopyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01521
  • Intermediate 638F (8.6 mg, 0.023 mmol), 5-aminonicotinonitrile (9.48 mg, 0.080 mmol), and pyridine (18.4 μl, 0.227 mmol) were dissolved in DCM (455 μL). After 45 minutes, the reaction mixture was concentrated in vacuo to give Intermediate 638G, which was used directly in the subsequent reaction: LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 461.1 (M+H)+.
    • Example 638
  • Intermediate I-9 (8.21 mg, 0.027 mmol) and Intermediate 638G (10.5 mg, 0.023 mmol) were dissolved in DMF (228 μL). PdCl2(dppf)-CH2Cl2 adduct (1.12 mg, 1.37 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 13.7 μL, 0.027 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 65-100% B in 20 minutes) to give Example 638 (2.0 mg, 0.0033 mmol, 15%): 1H NMR (500 MHz, DMSO-d6) δ 8.79 (br. s., 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.23 (br. s., 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.58 (br. s., 1H), 7.09 (br. s., 1H), 5.35 (d, J=4.9 Hz, 1H), 5.24 (d, J=4.6 Hz, 1H), 4.49 (br. s., 2H), 4.30 (d, J=11.3 Hz, 2H), 4.01 (s, 3H), 2.58 (s, 3H), 0.88 (s, 9H); LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 599.2 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 639 8-(4-(1-hydroxy-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile
  • Figure US20190292176A1-20190926-C01522
  • Intermediate I-38 (4.16 mg, 0.018 mmol) and Intermediate 637A (5 mg, 0.015 mmol) were dissolved in DMF (151 μL). PdCl2(dppf)-CH2Cl2 adduct (0.742 mg, 0.908 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 9.08 μL, 0.018 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example 639 (2.1 mg, 0.0046 mmol, 30%): 1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 7.69 (br. s., 1H), 7.23 (br. s., 1H), 5.49 (br. s., 1H), 5.38 (d, J=4.0 Hz, 1H), 4.19 (s, 3H), 3.94 (s, 3H), 1.02 (s, 9H); LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 435.2 (M+H)+; Analytical HPLC Method B, 95% purity.
    • Example 640 1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01523
    • Intermediate 640A: 1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
  • Figure US20190292176A1-20190926-C01524
  • Copper(II) chloride (0.363 g, 2.70 mmol) and t-butyl nitrite (0.344 mL, 2.89 mmol) were dissolved in MeCN (7.72 mL) and allowed to stir 10 minutes. Intermediate 638A (0.51 g, 1.93 mmol) was dissolved in MeCN (11.6 mL) and the copper solution was added and the reaction mixture was heated to 60° C. After 2 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 640A (211 mg, 0.743 mmol, 39%) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=2.6 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 3.87 (s, 3H), 1.30 (s, 9H); LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 284.2 (M+H)+.
    • Intermediate 640B: 1-(2-chloro-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
  • Figure US20190292176A1-20190926-C01525
  • Intermediate 640A (190 mg, 0.670 mmol) and borontribromide (1 M in THF, 2.01 mL, 2.01 mmol) were dissolved in DCM (6.7 mL). After 2 hours, the reaction mixture was diluted with DCM, washed with 1 N HCl, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 640B, which was used directly in the subsequent step: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 270.1 (M+H)+.
    • Intermediate 640C: 1-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
  • Figure US20190292176A1-20190926-C01526
  • Intermediate I-1 (221 mg, 0.872 mmol) and Intermediate 640B (196 mg, 0.727 mmol) were dissolved in DMF (7.27 mL). PdCl2(dppf)-CH2Cl2 adduct (35.6 mg, 0.044 mmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2M, 436 μL, 0.872 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 40 minutes. More PdCl2(dppf)-CH2Cl2Adduct (35.6 mg, 0.044 mmol) was added and the reaction mixture was heated for an additional 30 minutes in the microwave at 100° C. The reaction mixture was diluted with water and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 640C (182 mg, 0.411 mmol, 57%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J=1.8 Hz, 1H), 8.66 (s, 1H), 7.77 (dd, J=1.8, 0.9 Hz, 1H), 7.85-7.44 (m, 1H), 7.38 (d, J=2.4 Hz, 1H), 6.84 (d, J=2.6 Hz, 1H), 5.18 (s, 1H), 2.66 (s, 3H), 1.39 (s, 9H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 444.2 (M+H)+.
    • Intermediate 640D: 1-(6-hydroxy-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
  • Figure US20190292176A1-20190926-C01527
  • Intermediate 640C (180 mg, 0.406 mmol) was azeotroped with toluene and stored on HIVAC overnight. The starting material was dissolved in THF (8.12 mL). Sodium methoxide (0.5 M in MeOH, 554 μL, 2.03 mmol) was then added. After 1 hour, the reaction mixture was diluted with 1 N HCl and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 640D (167 mg, 0.411 mmol, 100%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 7.74 (dd, J=1.8, 0.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 5.08 (s, 1H), 4.12 (s, 3H), 2.62 (s, 3H), 1.39 (s, 9H); LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 408.2 (M+H)+.
    • Intermediate 640E: 1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one
  • Figure US20190292176A1-20190926-C01528
  • Intermediate 640D (20 mg, 0.049 mmol) was dissolved in THF (982 μL). Cesium carbonate (16 mg, 0.049 mmol) then ethyl iodide (5.95 μL, 0.074 mmol) were added. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 640E, which was used directly in the subsequent reaction: LC-MS: Method H, RT=1.43 min, MS (ESI) m/z: 436.2 (M+H)+.
    • Example 640
  • Intermediate 640E (21 mg, 0.048 mmol) was dissolved in MeOH (964 μL) and cooled to 0° C. Sodium borohydride (5.47 mg, 0.145 mmol) was then added. After 1.5 hours, the reaction was warmed to ambient temperature. After 1.5 hours, the reaction mixture was diluted with EtOAc, washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 60-100% B in 30 minutes) to give Example 640 (5.7 mg, 0.013 mmol, 27%): 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.59 (s, 1H), 7.88 (s, 1H), 7.63 (br. s., 1H), 7.19 (br. s., 1H), 5.47 (br. s., 1H), 5.38 (br. s., 1H), 4.23-4.16 (m, 2H), 4.15 (s, 3H), 2.71 (s, 3H), 1.46 (t, J=6.7 Hz, 3H), 1.01 (s, 9H); LC-MS: Method H, RT=1.40 min, MS (ESI) m/z: 438.2 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 641 2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C01529
    • Intermediate 641A: ethyl 2-(5-methoxy-2-nitrophenyl)acetate
  • Figure US20190292176A1-20190926-C01530
  • Ethyl 2-(5-hydroxy-2-nitrophenyl)acetate (100 mg, 0.444 mmol), potassium carbonate (123 mg, 0.888 mmol), and iodomethane (41.6 μL, 0.666 mmol) were dissolved in acetone (4.44 mL). After stirring overnight, the reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with aqueous HCl, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 641A (102 mg, 0.427 mmol, 96%) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=9.0 Hz, 1H), 6.93 (dd, J=9.1, 2.8 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.02 (s, 2H), 3.92 (s, 3H), 1.29 (t, J=7.0 Hz, 3H); LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 240.0 (M+H)+.
    • Intermediate 641B: 2-(5-methoxy-2-nitrophenyl)ethanol
  • Figure US20190292176A1-20190926-C01531
  • Intermediate 641A (100 mg, 0.418 mmol) was dissolved in toluene (2.79 mL) and THF (1.39 mL) and cooled to −78° C. DIBAL-H (1 M in toluene, 920 μL, 0.920 mmol) was added and the reaction mixture was allowed to warm slowly to ambient temperature. After 1.5 hours, the reaction was quenched with saturated Rochelle's salt. After stirring overnight, the reaction mixture was extracted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 641B (65 mg, 0.33 mmol, 79%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 1H), 6.91-6.84 (m, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.91 (s, 3H), 3.25 (t, J=6.3 Hz, 2H); LC-MS: Method H, Did not ionize well.
    • Intermediate 641C: 2-(2-amino-5-methoxyphenyl)ethanol
  • Figure US20190292176A1-20190926-C01532
  • Intermediate 641B (65 mg, 0.330 mmol) was dissolved in EtOH (471 μL). Palladium on carbon (7.02 mg, 6.59 μmol) then ammonium formate (104 mg, 1.65 mmol) were added and the reaction mixture was heated to reflux. After 1 hour, the reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate 641C (54.8 mg, 0.328 mmol, 99%) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.69 (s, 2H), 3.94 (t, J=6.1 Hz, 2H), 3.77 (s, 3H), 2.82 (t, J=6.2 Hz, 2H); LC-MS: Method H, RT=0.51 min, MS (ESI) m/z: 168.0 (M+H)+.
    • Intermediate 641D: 2-(2-amino-6-methoxybenzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C01533
  • Intermediate 641C (55 mg, 0.329 mmol) was dissolved in MeCN (1.64 mL). Ammonium thiocyanate (37.6 mg, 0.493 mmol) was added, followed by benzyltrimethylammonium tribromide (128 mg, 0.329 mmol). After stirring for 5 days, the reaction mixture was diluted with saturated NaHCO3. The reaction mixture was extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 641D (59.9 mg, 0.267 mmol, 81%) as a brown solid: LC-MS: Method H, RT=0.59 min, MS (ESI) m/z: 225.0 (M+H)+.
    • Intermediate 641E: 2-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)ethanol
  • Figure US20190292176A1-20190926-C01534
  • Copper(II) chloride (50.4 mg, 0.375 mmol) and t-butyl nitrite (47.7 μL, 0.401 mmol) were dissolved in MeCN (1.07 mL) and allowed to stir 10 minutes. Intermediate 641D (60 mg, 0.268 mmol) was dissolved in MeCN (1.6 mL) and the copper solution was added and the reaction mixture was heated to 60° C. After 1.5 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 641E (51.6 mg, 0.212 mmol, 79%) as a red oil: 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 4.02 (br. s., 2H), 3.88 (s, 3H), 3.29 (t, J=6.1 Hz, 2H), 2.34 (br. s., 1H); LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 244.0 (M+H)+.
    • Example 641
  • Intermediate I-9 (14.8 mg, 0.049 mmol) and Intermediate 641E (10 mg, 0.041 mmol) were dissolved in DMF (410 μL). PdCl2(dppf)-CH2Cl2 adduct (2.01 mg, 2.46 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 24.6 μL, 0.049 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 40-90% B in 15 minutes) to give Example 641 (6.4 mg, 0.016 mmol, 40%): 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.53 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.00 (s, 1H), 4.81 (t, J=5.2 Hz, 1H), 4.06 (s, 3H), 3.88-3.73 (m, 5H), 3.30 (t, J=7.0 Hz, 2H), 2.62 (s, 3H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 382.1 (M+H)+; Analytical HPLC Method B, 97% purity.
    • Example 642 (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(3-(trifluoromethyl)phenyl)methanol
  • Figure US20190292176A1-20190926-C01535
    • Intermediate 642A: (2-amino-6-methoxybenzo[d]thiazol-4-yl)(3-(trifluoromethyl) phenyl)methanol
  • Figure US20190292176A1-20190926-C01536
  • Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1.93 mL). Sodium hydride (17 mg, 0.425 mmol) was added. After 30 minutes, the reaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes, 101 μL, 0.232 mmol) was added. After 30 minutes, 3-(trifluromethyl)benzaldehyde (50.4 mg, 0.289 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After achieving ambient temperature, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 642A, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 355.0 (M+H)+.
    • Intermediate 642B: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(3-(trifluoromethyl) phenyl)methanol
  • Figure US20190292176A1-20190926-C01537
  • Intermediate 642A (68 mg, 0.192 mmol), lithium chloride (8.14 mg, 0.192 mmol), copper(II) chloride (25.8 mg, 0.192 mmol), and tert-butyl nitrite (22.9 μL, 0.192 mmol) were dissolved in MeCN (1.92 mL). After 2 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 642B (73.5 mg, 0.197 mmol, 100%) as a red oil: LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 374.0 (M+H)+.
    • Example 642
  • Intermediate I-9 (15 mg, 0.050 mmol) and Intermediate 642B (22.4 mg, 0.060 mmol) were dissolved in DMF (250 μL). PdCl2(dppf)-CH2Cl2 adduct (2.45 mg, 3.00 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 30.0 μL, 0.060 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 45-90% B in 20 minutes) then repurified by preparative HPLC (Method D, 60-100% B in 15 minutes) to give Example 642 (7.5 mg, 0.015 mmol, 29%): 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.64-7.55 (m, 2H), 7.41 (d, J=2.1 Hz, 1H), 6.76 (d, J=4.3 Hz, 1H), 6.44 (d, J=4.3 Hz, 1H), 4.14 (s, 3H), 3.94 (s, 3H), 2.72 (s, 3H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 512.1 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 643 (2-isopropylphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol
  • Figure US20190292176A1-20190926-C01538
    • Intermediate 643A: (2-amino-6-methoxybenzo[d]thiazol-4-yl)(2-isopropylphenyl)methanol
  • Figure US20190292176A1-20190926-C01539
  • Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1.93 mL). Sodium hydride (17 mg, 0.425 mmol) was then added. After 30 minutes, the reaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes, 101 μL, 0.232 mmol) was added. After 30 minutes, 2-isopropylbenzaldehyde (42.9 mg, 0.289 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After achieving ambient temperature, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 643A, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.87 min, MS (ESI) m/z: 329.1 (M+H)+.
    • Intermediate 643B: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(2-isopropylphenyl)methanol
  • Figure US20190292176A1-20190926-C01540
  • Intermediate 643A (63 mg, 0.192 mmol), lithium chloride (8.13 mg, 0.192 mmol), copper(II) chloride (25.8 mg, 0.192 mmol), and tert-butyl nitrite (22.9 μL, 0.192 mmol) were dissolved in MeCN (1.92 mL). After 2 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 643B, which was used directly in the subsequent reaction: LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 348 (M+H)+.
    • Example 643
  • Intermediate I-9 (15 mg, 0.050 mmol) and Intermediate 643B (20.9 mg, 0.060 mmol) were dissolved in DMF (250 μL). PdCl2(dppf)-CH2Cl2 adduct (2.45 mg, 3.00 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 30.0 μL, 0.060 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 50-100% B in 20 minutes) then repurified by preparative HPLC (Method D, 60-100% B in 20 minutes) to give Example 643 (1.7 mg, 0.0034 mmol, 6.7%): 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.45 (s, 1H), 7.80 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.36-7.26 (m, 3H), 7.20 (t, J=7.6 Hz, 1H), 7.14-7.08 (m, 1H), 6.98 (d, J=4.9 Hz, 1H), 5.92 (d, J=5.2 Hz, 1H), 4.07 (s, 3H), 3.96-3.85 (m, 4H), 2.60 (s, 3H), 1.32 (d, J=7.0 Hz, 3H), 1.21 (d, J=6.7 Hz, 3H); LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 486.1 (M+H)+; Analytical HPLC Method B, 96% purity.
    • Example 644 Ethyl 1-(hydroxy(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methyl)cyclobutanecarboxylate
  • Figure US20190292176A1-20190926-C01541
    • Intermediate 644A: Ethyl 1-(2-amino-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate
  • Figure US20190292176A1-20190926-C01542
  • Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1.93 mL). Sodium hydride (17 mg, 0.425 mmol) was then added. After 15 minutes, the reaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes, 101 μL, 0.232 mmol) was added. After 30 minutes, diethyl cyclobutane-1,1-dicarboxylate (58.0 mg, 0.289 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After achieving ambient temperature, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 644A, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 335.0 (M+H)+.
    • Intermediate 644B: Ethyl 1-(2-chloro-6-methoxybenzo[d]thiazole-4-carbonyl) cyclobutane-1-carboxylate
  • Figure US20190292176A1-20190926-C01543
  • Intermediate 644A (64.5 mg, 0.193 mmol), lithium chloride (8.18 mg, 0.193 mmol), copper(II) chloride (25.9 mg, 0.193 mmol), and tert-butyl nitrite (23 μL, 0.193 mmol) were dissolved in MeCN (1.93 mL). After 2 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 644B (12 mg, 0.034 mmol, 18%) as a white solid: LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 354.1 (M+H)+.
    • Intermediate 644C: Ethyl 1-((2-chloro-6-methoxybenzo[d]thiazol-4-yl)(hydroxy)methyl) cyclobutane-1-carboxylate
  • Figure US20190292176A1-20190926-C01544
  • Intermediate 644B (12 mg, 0.034 mmol) was dissolved in MeOH (339 μL) at 0° C. Sodium borohydride (2.57 mg, 0.068 mmol). After 45 minutes, the reaction mixture was diluted with EtOAc, washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 644C, which was used directly in the subsequent reaction: LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 356.0 (M+H)+.
    • Example 644
  • Intermediate I-9 (12.2 mg, 0.040 mmol) and Intermediate 644C (12 mg, 0.034 mmol) were dissolved in DMF (169 μL). PdCl2(dppf)-CH2Cl2 adduct (1.65 mg, 2.02 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes.
  • Sodium carbonate (20.2 μL, 0.040 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 60-100% B in 22 minutes) to give Example 644 (3.1 mg, 0.0062 mmol, 18%): 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.47 (s, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 7.08 (d, J=1.7 Hz, 1H), 5.83 (d, J=5.4 Hz, 1H), 5.78 (d, J=5.7 Hz, 1H), 4.01 (s, 3H), 3.88-3.78 (m, 3H), 3.76 (dd, J=7.1, 4.4 Hz, 2H), 2.57 (s, 3H), 2.53-2.35 (m, 2H), 2.19 (br. s., 1H), 2.08 (br. s., 1H), 1.67-1.58 (m, 1H), 1.54 (br. s., 1H), 0.87 (t, J=7.1 Hz, 3H); LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 494.1 (M+H)+; Analytical HPLC Method B, 99% purity.
    • Example 645 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01545
  • Intermediate I-121 (12 mg, 0.038 mmol), Intermediate I-130 (18.5 mg, 0.045 mmol) and PdCl2(dppf) (1.65 mg, 2.25 μmol) were dissolved in 1,4-dioxane (375 μL) and Na2CO3 (2 M, 169 μL, 0.338 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 50-100% B in 20 minutes) to give Example 645 (6.6 mg, 0.011 mmol, 30%): 1H NMR (500 MHz, DMSO-d6) δ 9.92 (br. s., 1H), 8.82 (br. s., 1H), 8.71 (br. s., 2H), 8.58 (s, 1H), 8.15 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.93 (d, J=11.9 Hz, 1H), 7.90 (br. s., 1H), 5.11 (d, J=6.1 Hz, 1H), 4.82 (d, J=6.1 Hz, 1H), 3.98 (s, 3H), 2.50 (s, 3H), 1.39 (t, J=6.7 Hz, 6H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 568.1 (M+H)+; Analytical HPLC Method B, 96% purity.
    • Example 646 (1-(hydroxymethyl)cyclobutyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl) benzo[d]thiazol-4-yl)methanol
  • Figure US20190292176A1-20190926-C01546
    • Intermediate 646A: Methyl 1-(2-amino-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate
  • Figure US20190292176A1-20190926-C01547
  • Intermediate I-22 (1 g, 3.86 mmol) was dissolved in THF (38.6 mL). Sodium hydride (0.340 g, 8.49 mmol) was then added. After 15 minutes, the reaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes, 2.01 mL, 4.63 mmol) was added. After 45 minutes, dimethyl cyclobutane-1,1-dicarboxylate (0.892 mL, 5.79 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After the reaction reached ambient temperature, it was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 646A, which was used directly in the subsequent step: LC-MS: Method H, RT=0.75 min, MS (ESI) m/z: 321.1 (M+H)+.
    • Intermediate 646B: Methyl 1-(2-chloro-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate
  • Figure US20190292176A1-20190926-C01548
  • Intermediate 646A (1.24 g, 3.86 mmol), lithium chloride (0.164 g, 3.86 mmol), copper(II) chloride (0.519 g, 3.86 mmol), and tert-butyl nitrite (0.460 mL, 3.86 mmol) were dissolved in MeCN (38.6 mL). After 2 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 646B (124 mg, 0.365 mmol, 9.5% over 2 steps) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=2.6 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 3.68 (s, 3H), 2.80-2.65 (m, 2H), 2.64-2.50 (m, 2H), 2.25-2.11 (m, 1H), 1.94-1.80 (m, 1H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 340.1 (M+H)+.
    • Intermediate 646C: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(hydroxymethyl) cyclobutyl)methanol
  • Figure US20190292176A1-20190926-C01549
  • Intermediate 646B (124 mg, 0.365 mmol) and NaBH4 (13.8 mg, 0.365 mmol) were dissolved in MeOH (1.82 mL) at 0° C. After 4 hours, the reaction mixture was diluted with EtOAc, washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 646C (23.8 mg, 0.076 mmol, 21%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 7.19 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.41 (d, J=5.8 Hz, 1H), 3.88 (s, 3H), 3.74-3.67 (m, 1H), 3.46-3.36 (m, 2H), 3.26 (d, J=5.8 Hz, 1H), 2.38-2.22 (m, 2H), 1.89 (dd, J=9.2, 3.2 Hz, 1H), 1.82-1.72 (m, 2H), 1.53-1.49 (m, 1H); LC-MS: Method H, RT=0.95 min, MS (ESI) m/z: 314.1 (M+H)+.
    • Example 646
  • Intermediate I-9 (20.1 mg, 0.067 mmol) and Intermediate 646C (20 mg, 0.064 mmol) were dissolved in DMF (319 μL). PdCl2(dppf)-CH2Cl2 adduct (3.12 mg, 3.82 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 38.2 μL, 0.076 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. More PdCl2(dppf)-CH2Cl2 adduct (3.12 mg, 3.82 μmol) was added and the reaction mixture was heated in the microwave for an additional 30 minutes at 100° C. The crude material was purified by preparative HPLC (Method D, 45-95% B in 20 minutes) to give Example 646 (12.4 mg, 0.026 mmol, 41%): 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.47 (br. s., 1H), 7.82 (br. s., 1H), 7.60 (br. s., 1H), 7.20 (br. s., 1H), 5.64 (br. s., 1H), 5.51 (br. s., 1H), 4.80 (br. s., 1H), 4.08 (s, 3H), 3.47 (br. s., 1H), 3.26 (d, J=5.5 Hz, 1H), 2.63 (br. s., 3H), 2.35 (br. s., 1H), 2.17 (br. s., 1H), 1.79-1.55 (m, 4H); LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 452.1 (M+H)+; Analytical HPLC Method B, 96% purity.
    • Example 647 (2R,3S)-3-((2-(6-chloro-3-ethyl quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01550
    • Intermediate 647A: 8-bromo-6-chloro-3-ethylquinoline
  • Figure US20190292176A1-20190926-C01551
  • Intermediate I-123 (185 mg, 0.789 mmol), butyraldehyde (71.1 μL, 0.789 mmol), and sodium methoxide (0.5 M in MeOH, 1.74 mL, 0.868 mmol) were dissolved in MeOH (1.58 mL) and heated to reflux. After heating overnight, the reaction mixture was diluted with saturated NH4Cl, partially concentrated in vacuo and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 50% EtOAc in hexanes) to give Intermediate 647A (192 mg, 0.710 mmol, 90%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=2.2 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.87-7.82 (m, 1H), 7.74 (d, J=2.2 Hz, 1H), 2.88 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H); LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 270/272 (M+H)+.
    • Intermediate 647B: 6-chloro-3-ethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline
  • Figure US20190292176A1-20190926-C01552
  • Intermediate 647A (192 mg, 0.710 mmol), bispinacolatodiboron (216 mg, 0.852 mmol), and potassium acetate (174 mg, 1.78 mmol) were dissolved in 1,4-dioxane (7.1 mL) and degassed for 5 minutes by bubbling with argon. PdCl2(dppf)-CH2Cl2 adduct (46.4 mg, 0.057 mmol) was added and the reaction degassed for an additional 10 minutes. The reaction mixture was heated to 130° C. in the microwave for 2 hours. The reaction mixture was diluted with EtOAc and water. The reaction was further extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 647B, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 236.1 (boronic acid mass observed, M+H)+.
    • Example 647
  • Intermediate 647B (15 mg, 0.047 mmol), I-130 (19.4 mg, 0.047 mmol) and PdCl2(dppf) (2.07 mg, 2.83 μmol) were dissolved in 1,4-dioxane (472 μL) and Na2CO3 (2 M, 213 μL, 0.425 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 65-100% B in 25 minutes) to give Example 647 (4.3 mg, 0.0074 mmol, 15%): 1H NMR (500 MHz, DMSO-d6) δ 9.93 (br. s., 1H), 9.06 (d, J=2.1 Hz, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.73 (br. s., 2H), 8.34 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.99 (d, J=11.6 Hz, 1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.84 (dd, J=6.4, 2.7 Hz, 1H), 2.92 (q, J=7.4 Hz, 2H), 2.55 (s, 3H), 1.40 (dd, J=6.3, 4.4 Hz, 6H), 1.35 (t, J=7.6 Hz, 3H); LC-MS: Method H, RT=1.30 min, MS (ESI) m/z: 566.1 (M+H)+; Analytical HPLC Method B, 98% purity.
    • Example 648 (2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01553
  • Intermediate I-124 (15 mg, 0.050 mmol), Intermediate I-130 (20.6 mg, 0.050 mmol) and PdCl2(dppf) (2.2 mg, 3.01 μmol) were dissolved in 1,4-dioxane (501 μL) and Na2CO3 (2 M, 226 μL, 0.451 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-100% B in 15 minutes) to give Example 648 (8.4 mg, 0.015 mmol, 30%): 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.79 (d, J=2.7 Hz, 1H), 8.74 (br. s., 2H), 8.61 (d, J=1.5 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.89-7.82 (m, 2H), 5.16-5.05 (m, 1H), 4.80 (dd, J=6.1, 2.7 Hz, 1H), 3.99 (s, 3H), 2.61 (s, 3H), 1.40 (dd, J=6.4, 2.4 Hz, 6H) (1 methyl group under solvent); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 548.1 (M+H)+; Analytical HPLC Method B, 99% purity.
    • Example 649 (2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01554
  • Intermediate I-126 (15 mg, 0.045 mmol), Intermediate I-130 (18.5 mg, 0.045 mmol) and PdCl2(dppf) (1.97 mg, 2.70 μmol) were dissolved in 1,4-dioxane (450 μL) and Na2CO3 (2 M, 202 μL, 0.405 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature. The reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 50-100% B in 20 minutes) then repurified by preparative HPLC (Method D, 50-100% B in 20 minutes) to give Example 649 (2.5 mg, 0.0041 mmol, 9.2%): 1H NMR (500 MHz, DMSO-d6) δ 9.94 (br. s., 1H), 8.85 (d, J=2.7 Hz, 1H), 8.73 (br. s., 2H), 8.62 (d, J=2.1 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 7.93 (d, J=2.7 Hz, 1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.82 (dd, J=6.4, 2.4 Hz, 1H), 4.27 (q, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.46 (t, J=6.9 Hz, 3H), 1.40 (t, J=5.5 Hz, 6H); LC-MS: Method H, RT=1.30 min, MS (ESI) m/z: 582.1 (M+H)+; Analytical HPLC Method B, 96% purity.
    • Example 650 (2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01555
  • Intermediate I-127 (22 mg, 0.062 mmol), Intermediate I-130 (25.4 mg, 0.062 mmol) and PdCl2(dppf) (2.72 mg, 3.71 μmol) were dissolved in 1,4-dioxane (619 μL) and Na2CO3 (2 M, 278 μL, 0.557 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example 650 (3.9 mg, 0.0063 mmol, 10%): 1H NMR (500 MHz, DMSO-d6) δ 9.93 (br. s., 1H), 9.06 (d, J=2.4 Hz, 1H), 8.78 (s, 1H), 8.72 (br. s., 2H), 8.36 (br. s., 2H), 8.07 (d, J=7.9 Hz, 1H), 7.99 (d, J=11.3 Hz, 1H), 7.67-7.34 (m, 1H), 5.11 (dd, J=6.4, 2.1 Hz, 1H), 4.88-4.79 (m, 1H), 2.55 (s, 3H), 1.40 (t, J=5.8 Hz, 6H); LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 604.1 (M+H)+; Analytical HPLC Method B, 98% purity.
    • Example 651 (2R,3S)-3-((2-(6-chloro-3-(2,2-difluoroethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01556
    • Intermediate 651A: 8-bromo-6-chloro-3-(2,2-difluoroethoxy)quinoline
  • Figure US20190292176A1-20190926-C01557
  • Intermediate I-122 (82 mg, 0.317 mmol), K2CO3 (132 mg, 0.952 mmol), and 2-bromo-1,1-difluoroethane (92 mg, 0.634 mmol) were dissolved in Acetone (3.17 mL) and heated to 50° C. in a sealed tube. After heating overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 651A (60.4 mg, 0.187 mmol, 59%) as an orange solid: 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=2.9 Hz, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.33 (d, J=2.9 Hz, 1H), 6.36-6.02 (m, 1H), 4.34 (td, J=12.8, 4.0 Hz, 2H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 322/324 (M+H)+.
    • Intermediate 651B: 6-chloro-3-(2,2-difluoroethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C01558
  • Intermediate 651A (60.4 mg, 0.187 mmol), bispinacolatodiboron (57.1 mg, 0.225 mmol), and potassium acetate (45.9 mg, 0.468 mmol) were dissolved in 1,4-dioxane (1.87 mL) and degassed for 5 minutes by bubbling with argon. PdCl2(dppf)-CH2Cl2 adduct (12.2 mg, 0.015 mmol) was added and the reaction degassed for an additional 10 minutes. The reaction mixture was heated to 130° C. in the microwave for 2 hours. The reaction mixture was diluted with EtOAc and water. The reaction was further extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 651B, which was used directly in the subsequent reaction: LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 287.9 (M+H)+.
    • Example 651
  • Intermediate 651B (17 mg, 0.046 mmol), Intermediate I-130 (18.9 mg, 0.046 mmol) and PdCl2(dppf) (2.02 mg, 2.76 μmol) were dissolved in 1,4-dioxane (460 μL) and Na2CO3 (2 M, 207 μL, 0.414 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 50-100% B in 20 minutes) then repurified by preparative HPLC (Method D, 45-90% in 20 minutes) to give Example 651 (3.6 mg, 0.0058 mmol, 13%): 1H NMR (500 MHz, DMSO-d6) δ 9.94 (br. s., 1H), 8.95 (br. s., 1H), 8.73 (br. s., 2H), 8.67 (s, 1H), 8.18 (s, 1H), 8.11-8.03 (m, 2H), 7.98 (d, J=11.3 Hz, 1H), 6.67-6.42 (m, 1H), 5.11 (d, J=6.4 Hz, 1H), 4.82 (d, J=6.1 Hz, 1H), 4.60 (t, J=13.6 Hz, 2H), 2.55 (s, 3H), 1.40 (t, J=5.3 Hz, 6H); LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 604.1 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 652 (2R,3S)-3-((2-(6-chloro-3-(methylamino)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01559
    • Intermediate 652A: tert-butyl (8-bromo-6-chloroquinolin-3-yl)(methyl)carbamate
  • Figure US20190292176A1-20190926-C01560
  • Intermediate I-123 (100 mg, 0.426 mmol), tert-butyl methyl(2-oxoethyl) carbamate (73.9 mg, 0.426 mmol), and sodium methoxide (0.5 M in MeOH, 938 μL, 0.469 mmol) were dissolved in MeOH (1.71 mL) and heated to reflux. After heating overnight, the reaction mixture was diluted with saturated NH4Cl, partially concentrated in vacuo and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 21 minute gradient from 0 to 50% EtOAc in hexanes) to give Intermediate 652A (64 mg, 0.172 mmol, 40%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.02 (d, J=2.5 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 3.42 (s, 3H), 1.51 (s, 9H); LC-MS: Method H, RT=1.39 min, MS (ESI) m/z: 371/373 (M+H)+.
    • Intermediate 652B: 8-bromo-6-chloro-N-methylquinolin-3-amine
  • Figure US20190292176A1-20190926-C01561
  • Intermediate 652A (64 mg, 0.172 mmol) was dissolved in DCM (1.72 mL) and TFA (66.3 μL, 0.861 mmol). After stirring for 4 days, the reaction mixture was diluted with DCM, washed with 1N NaOH, water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 652B (43.4 mg, 0.160 mmol, 93%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=2.9 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.9 Hz, 1H), 4.27 (br. s., 1H), 2.96 (d, J=5.1 Hz, 3H); LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 271/273 (M+H)+.
    • Intermediate 652C: 6-chloro-N-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinolin-3-amine
  • Figure US20190292176A1-20190926-C01562
  • Intermediate 652B (20 mg, 0.074 mmol), bispinacolatodiboron (37.4 mg, 0.147 mmol), potassium acetate (18.1 mg, 0.184 mmol), and PdCl2(dppf)-CH2Cl2 adduct (4.81 mg, 5.89 μmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (368 μL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 652C, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 237.0 (boronic acid mass observed, M+H)+.
    • Example 652
  • Intermediate 652C (8 mg, 0.025 mmol), Intermediate I-130 (10.3 mg, 0.025 mmol) and PdCl2(dppf) (1.1 mg, 1.51 μmol) were dissolved in 1,4-dioxane (251 μL) and Na2CO3 (2 M, 113 μL, 0.226 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 40-80% in 20 minutes) to give Example 652 (3.3 mg, 0.0057 mmol, 23%): 1H NMR (500 MHz, DMSO-d6) δ 9.94 (br. s., 1H), 8.73 (br. s., 2H), 8.67 (br. s., 1H), 8.39 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.64-7.48 (m, 1H), 7.14 (br. s., 1H), 5.11 (d, J=6.1 Hz, 1H), 4.81 (d, J=6.1 Hz, 1H), 2.85 (br. s., 3H), 2.55 (s, 3H), 1.40 (d, J=6.1 Hz, 6H); LC-MS: Method H, compound did not ionize; Analytical HPLC Method B, 98% purity.
    • Example 653 (2R,3S)-3-((2-(6-(difluoromethyl)-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01563
  • Intermediate I-128 (15 mg, 0.045 mmol), Intermediate I-130 (18.4 mg, 0.045 mmol) and PdCl2(dppf) (1.96 mg, 2.69 μmol) were dissolved in 1,4-dioxane (448 μL) and Na2CO3 (2 M, 201 μL, 0.403 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-90% B in 22 minutes) to give Example 653 (5.1 mg, 0.0087 mmol, 19%): 1H NMR (500 MHz, DMSO-d6) δ 9.91 (br. s., 1H), 8.90 (d, J=2.4 Hz, 1H), 8.82 (s, 1H), 8.70 (br. s., 2H), 8.30 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.95 (d, J=11.6 Hz, 1H), 7.33 (t, J=44 Hz, 1H), 5.15-5.06 (m, 1H), 4.81 (d, J=4.0 Hz, 1H), 3.99 (s, 3H), 2.49 (s, 3H), 1.38 (t, J=7.2 Hz, 6H); LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 584.1 (M+H)+; Analytical HPLC Method B, 99% purity.
    • Example 654 (2R,3S)-3-((5-fluoro-2-(6-(fluoromethyl)-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01564
  • Intermediate I-129 (15 mg, 0.047 mmol), Intermediate I-130 (19.4 mg, 0.047 mmol) and PdCl2(dppf) (2.08 mg, 2.84 μmol) were dissolved in 1,4-dioxane (473 μL) and Na2CO3 (2 M, 213 μL, 0.426 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example 654 (2.5 mg, 0.0043 mmol, 9.1%): 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s., 1H), 8.89 (d, J=2.7 Hz, 1H), 8.75 (d, J=14.0 Hz, 3H), 8.13 (s, 1H), 8.07-8.00 (m, 2H), 7.96 (d, J=11.6 Hz, 1H), 5.76 (d, J=20 Hz, 2H), 5.12 (dd, J=6.4, 2.7 Hz, 1H), 4.82 (d, J=3.7 Hz, 1H), 4.01 (s, 3H), 3.45 (s, 3H), 1.46-1.34 (m, 6H); LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 566.1 (M+H)+; Analytical HPLC Method B, 97% purity.
    • Example 655 (2R,3S)-3-((2-(6-cyano-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01565
    • Intermediate 655A: methyl 2-amino-3-bromo-5-cyanobenzoate
  • Figure US20190292176A1-20190926-C01566
  • Methyl 2-amino-5-cyanobenzoate (0.25 g, 1.42 mmol) and NBS (0.253 g, 1.42 mmol) were dissolved in AcOH (2.84 mL) and heated to 120° C. After 2 hours, the reaction mixture was cooled to ambient temperature and diluted with EtOAc. The reaction was then quenched with vigorous stirring with saturated NaHCO3. The layers were separated and the organic layer further washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 655A (356 mg, 1.4 mmol, 98%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=1.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 3.95 (s, 3H); LC-MS: Method H, compound did not ionize
    • Intermediate 655B: 4-amino-3-bromo-5-(hydroxymethyl)benzonitrile
  • Figure US20190292176A1-20190926-C01567
  • Intermediate 655A (356 mg, 1.4 mmol) was dissolved in THF (4.65 mL). Lithium borohydride (60.8 mg, 2.79 mmol) was added and the reaction mixture was heated to 50° C. After 1 hour, the reaction mixture was diluted with water. The reaction mixture was then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, dry load, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes, polar weighted) to give Intermediate 655B (106 mg, 0.465 mmol, 33%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=1.8 Hz, 1H), 7.32 (d, J=1.8 Hz, 1H), 5.35 (br. s., 2H), 4.73 (s, 2H), 1.79 (br. s., 1H); LC-MS: Method H, compound did not ionize
    • Intermediate 655C: 4-amino-3-bromo-5-formylbenzonitrile
  • Figure US20190292176A1-20190926-C01568
  • Intermediate 655B (106 mg, 0.465 mmol) was dissolved in CHCl3 (3.1 mL). Manganese dioxide (243 mg, 2.79 mmol) was added and the reaction mixture was heated to 40° C. After heating overnight, the reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate 655C (88.3 mg, 0.392 mmol, 84%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 7.88-7.86 (m, 1H), 7.86-7.83 (m, 1H); LC-MS: Method H, compound did not ionize.
    • Intermediate 655D: 3-(benzyloxy)-8-bromoquinoline-6-carbonitrile
  • Figure US20190292176A1-20190926-C01569
  • Intermediate 655C (88.3 mg, 0.392 mmol), 2-(benzyloxy)acetaldehyde (58.9 mg, 0.392 mmol), and sodium methoxide (0.5 M, 863 μL, 0.432 mmol) were dissolved in MeOH (1.57 mL) and heated to reflux. After heating overnight, the reaction mixture was diluted with saturated NH4Cl, partially concentrated in vacuo and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 655D (59.5 mg, 0.175 mmol, 45%) as a yellow solid: LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 339/341 (M+H)+.
    • Intermediate 655E: 8-bromo-3-hydroxyquinoline-6-carbonitrile, HCl
  • Figure US20190292176A1-20190926-C01570
  • Intermediate 655D (59 mg, 0.174 mmol) and pentamethylbenzene (181 mg, 1.218 mmol) were dissolved in DCM (3.48 mL) and cooled to −78° C. Boron trichloride (1 M in heptane, 452 μL, 0.452 mmol) was added and the reaction mixture was allowed to slowly warm to ambient temperature. After stirring overnight, the reaction mixture was diluted with hexanes and 1 N HCl and allowed to stir for 1 hour. The solid was collected by suction filtration to give Intermediate 655E (24.5 mg, 0.086 mmol, 49%) as a white solid: 1H NMR (400 MHz, MeOH4) δ 8.73 (d, J=2.9 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.59 (d, J=2.6 Hz, 1H); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 249/251 (M+H)+.
    • Intermediate 655F: 8-bromo-3-methoxyquinoline-6-carbonitrile
  • Figure US20190292176A1-20190926-C01571
  • Intermediate 655E (24.5 mg, 0.086 mmol), K2CO3 (35.6 mg, 0.257 mmol), and methyl iodide (10.7 μL, 0.172 mmol) were dissolved in acetone (858 μL) and heated to 50° C. in a sealed tube. After heating overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 655F (21.5 mg, 0.082 mmol, 95%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J=2.9 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.43 (d, J=2.9 Hz, 1H), 4.03 (s, 3H); LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 263/265 (M+H)+.
    • Intermediate 655G: 3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline-6-carbonitrile
  • Figure US20190292176A1-20190926-C01572
  • Intermediate 655F (21 mg, 0.080 mmol), bispinacolatodiboron (40.5 mg, 0.160 mmol), potassium acetate (19.6 mg, 0.200 mmol), and PdCl2(dppf)-CH2Cl2 adduct (5.21 mg, 6.39 μmol) were stored on HIVAC for 15 minutes then were dissolved in 1,4-dioxane (399 μL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 655G, which was used directly in the subsequent reaction.
    • Example 655
  • Intermediate 655G (20 mg, 0.064 mmol), Intermediate I-130 (26.5 mg, 0.064 mmol) and PdCl2(dppf) (2.83 mg, 3.87 μmol) were dissolved in 1,4-dioxane (645 μL) and Na2CO3 (2 M, 290 μL, 0.580 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-90% B in 20 minutes) then repurified by preparative HPLC (Method D, 40-80% B in 20 minutes) to give Example 655 (1.3 mg, 0.0023 mmol, 3.6%): 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.95 (d, J=2.4 Hz, 1H), 8.80-8.69 (m, 3H), 8.60 (s, 1H), 8.05-7.98 (m, 2H), 7.93 (d, J=11.6 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.82 (d, J=4.0 Hz, 1H), 4.01 (s, 3H), 3.41 (br. s., 3H), 1.41 (t, J=6.6 Hz, 6H); LC-MS: Method H, compound did not ionize; Analytical HPLC Method B, 100% purity.
    • Example 656 (2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol
  • Figure US20190292176A1-20190926-C01573
    • Intermediate 656A: (2-amino-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl) cyclobutyl)methanone
  • Figure US20190292176A1-20190926-C01574
  • Intermediate I-22 (1 g, 3.86 mmol) was dissolved in THF (38.6 mL). NaH (0.170 g, 4.25 mmol) was added. After 15 minutes, the reaction mixture was cooled to −78° C. and BuLi (1.93 mL, 4.82 mmol) was added. After 30 minutes, ethyl 1-(trifluoromethyl) cyclobutanecarboxylate (2.27 g, 11.6 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After achieving ambient temperature, the reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 656A, which was used directly in the subsequent step: LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 331.1 (M+H)+.
    • Intermediate 656B: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl) cyclobutyl)methanone
  • Figure US20190292176A1-20190926-C01575
  • Intermediate 656A (1.28 g, 3.86 mmol), lithium chloride (0.164 g, 3.86 mmol), copper(II) chloride (0.519 g, 3.86 mmol), and tert-butyl nitrite (0.461 mL, 3.86 mmol) were dissolved in MeCN (38.6 mL). After 3 hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 656B (386 mg, 1.1 mmol, 29% over 2 steps): 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=2.4 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 3.91 (s, 3H), 3.01-2.89 (m, 2H), 2.66-2.56 (m, 2H), 2.23-2.09 (m, 1H), 2.06-1.92 (m, 1H); LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 350.1 (M+H)+.
    • Intermediate 656C: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl) cyclobutyl)methanol
  • Figure US20190292176A1-20190926-C01576
  • Intermediate 656B (386 mg, 1.104 mmol) was suspended in MeOH (5.52 mL) and cooled to 0° C. Sodium borohydride (84 mg, 2.21 mmol) was then added. After 45 minutes, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 656C (314 mg, 0.891 mmol, 81%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 5.31 (d, J=8.6 Hz, 1H), 4.28 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 2.69-2.59 (m, 1H), 2.39-2.25 (m, 2H), 2.24-2.14 (m, 1H), 1.99-1.86 (m, 1H), 1.69-1.59 (m, 1H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 352.1 (M+H)+.
    • Intermediate 656D: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl) cyclobutyl)methanol
  • Figure US20190292176A1-20190926-C01577
  • Intermediate 656C (314 mg, 0.891 mmol) was purified by chiral SFC (Chiralpak OJ-H, 30×250 mm, 5 micron, 5% MeOH/95% CO2, 70 mL/min, 150 bar, 40° C.) to give Intermediate 656D (136 mg, 0.386 mmol, 43%, 87.8% ee): 1H NMR and LCMS data was identical to Intermediate 656C.
    • Example 656
  • Intermediate I-121 (20 mg, 0.063 mmol), Intermediate 656D (22 mg, 0.063 mmol) and PdCl2(dppf) (2.75 mg, 3.75 μmol) were dissolved in 1,4-dioxane (626 μL) and Na2CO3 (2 M, 282 μL, 0.563 mmol) and heated to 100° C. After 2 hours, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 60-100% B in 20 minutes) to give Example 656 (6.7 mg, 0.013 mmol, 21%): 1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J=2.4 Hz, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.69 (s, 1H), 7.33 (s, 1H), 5.94 (s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.42-3.36 (m, 1H), 2.70 (d, J=8.5 Hz, 1H), 2.21-2.12 (m, 2H), 2.09 (d, J=5.8 Hz, 1H), 1.83 (d, J=9.8 Hz, 1H), 1.56 (dd, J=10.5, 5.3 Hz, 1H); LC-MS: Method H, RT=1.32 min, MS (ESI) m/z: 509.0 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 657 (2R,3S)-3-((2-(3,6-dimethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01578
    • Intermediate 657A: 5-methoxy-2-nitrobenzoyl chloride
  • Figure US20190292176A1-20190926-C01579
  • 5-methoxy-2-nitrobenzoic acid (3.9 g, 19.78 mmol) was dissolved in DCM (39.6 mL). Oxalyl chloride (13.8 mL, 27.7 mmol) and then DMF (0.153 mL, 1.98 mmol) were added at ambient temperature. After 1.5 hours, the reaction mixture was concentrated in vacuo to give Intermediate 657A, which was used directly in the subsequent step.
    • Intermediate 657B: ethyl 5-methoxy-2-nitrobenzoate
  • Figure US20190292176A1-20190926-C01580
  • Intermediate 657A (4.26 g, 19.8 mmol) was dissolved in sodium methoxide (0.5 M in MeOH, 59.3 mL, 29.6 mmol). THF (60 mL) was added to aid solubility. After stirring overnight, the reaction mixture was concentrated in vacuo, diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 657B (3.43 g, 15.2 mmol, 77%) as a yellow oil (Note, final extraction solution was allowed to sit overnight and the methyl ester swapped to the ethyl ester at that point): 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=9.0 Hz, 1H), 7.06-7.04 (m, 1H), 7.04-6.99 (m, 1H), 4.41 (q, J=7.0 Hz, 2H), 3.92 (s, 3H), 1.37 (t, J=7.2 Hz, 3H)
    • Intermediate 657C: Ethyl 2-amino-5-methoxybenzoate
  • Figure US20190292176A1-20190926-C01581
  • Intermediate 657B (3.43 g, 15.2 mmol) was dissolved in EtOH (21.8 mL). Palladium on carbon (0.324 g, 0.305 mmol) and then ammonium formate (4.80 g, 76 mmol) were added and the reaction mixture was heated to reflux. After 3 hours, the reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate 657C (2.85 g, 14.6 mmol, 96%) as an orange oil: 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=3.1 Hz, 1H), 6.95 (dd, J=8.9, 3.0 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.40 (br. s., 2H), 4.34 (q, J=7.3 Hz, 2H), 3.77 (s, 3H), 1.39 (t, J=7.2 Hz, 3H); LC-MS: Method H, RT=0.76 min, MS (ESI) m/z: 196 (M+H)+.
    • Intermediate 657D: ethyl 2-amino-3-bromo-5-methoxybenzoate
  • Figure US20190292176A1-20190926-C01582
  • Intermediate 657C (0.5 g, 2.56 mmol) and NBS (0.456 g, 2.56 mmol) were dissolved in AcOH (5.12 mL). After 3 hours, the reaction was quenched with vigorous stirring with saturated NaHCO3. The layers were separated and the organic layer was further washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 40 g silica gel column, 27 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 657D (236 mg, 0.861 mmol, 34%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J=2.8 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 5.98 (br. s., 2H), 4.38 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 274/276 (M+H)+.
    • Intermediate 657E: (2-amino-3-bromo-5-methoxyphenyl)methanol
  • Figure US20190292176A1-20190926-C01583
  • Intermediate 657D (236 mg, 0.861 mmol) was dissolved in THF (2.87 mL). Lithium borohydride (37.5 mg, 1.72 mmol) was added and the reaction mixture was heated to 50° C. After 2 hours, the reaction mixture was diluted with water and stirred for 30 minutes. All of the lithium borohydride had not dissolved, so concentrated HCl was added carefully to speed up the quenching process. The reaction mixture was then extracted three times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 657E (188 mg, 0.808 mmol, 94%) as an orange solid: 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=2.9 Hz, 1H), 6.71 (d, J=2.9 Hz, 1H), 4.68 (s, 2H), 4.35 (br. s., 2H), 3.76 (s, 3H), 1.72 (br. s., 1H); LC-MS: Method H, RT=0.68 min, MS (ESI) m/z: 232/234 (M+H)+.
    • Intermediate 657F: 2-amino-3-bromo-5-methoxybenzaldehyde
  • Figure US20190292176A1-20190926-C01584
  • Intermediate 657E (186 mg, 0.801 mmol) was dissolved in CHCl3 (5.34 mL). Manganese dioxide (418 mg, 4.81 mmol) was added and the reaction mixture was heated to 40° C. After heating overnight, the reaction mixture was filtered through celite and concentrated in vacuo to give Intermediate 657F (167 mg, 0.724 mmol, 90%) as a red solid: 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.36 (d, J=2.9 Hz, 1H), 7.04 (d, J=2.9 Hz, 1H), 6.35 (br. s., 2H), 3.82 (s, 3H); LC-MS: Method H, RT=0.90 min, MS (ESI) m/z: 230/232 (M+H)+.
    • Intermediate 657G: 3-(benzyloxy)-8-bromo-6-methoxyquinoline
  • Figure US20190292176A1-20190926-C01585
  • Intermediate 657F (165 mg, 0.717 mmol), 2-(benzyloxy)acetaldehyde (108 mg, 0.717 mmol), and sodium methoxide (0.5 M in MeOH, 1.58 mL, 0.789 mmol) were dissolved in MeOH (2.87 mL) and heated to reflux. After heating overnight, the reaction mixture was diluted with saturated NH4Cl, partially concentrated in vacuo and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate 657G (210 mg, 0.610 mmol, 85%): LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 344/346 (M+H)+.
    • Intermediate 657H: 8-bromo-6-methoxyquinolin-3-ol, HCl
  • Figure US20190292176A1-20190926-C01586
  • Intermediate 657G (210 mg, 0.610 mmol) and pentamethylbenzene (633 mg, 4.27 mmol) were dissolved in DCM (12.2 mL) and cooled to −78° C. Boron trichloride (1 M in heptane, 1.59 mL, 1.59 mmol) was then added and the reaction mixture was allowed to warm slowly to ambient temperature. After stirring overnight, the reaction mixture was diluted with hexanes and 1 N HCl and allowed to stir for 1 hour. The solid was collected by suction filtration to give Intermediate 657H (38.9 mg, 0.134 mmol, 22%) as a brown solid: 1H NMR (400 MHz, MeOH4) δ 8.54 (d, J=2.6 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 3.97 (s, 3H); LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 254/256 (M+H)+.
    • Intermediate 657I: 8-bromo-3,6-dimethoxyquinoline
  • Figure US20190292176A1-20190926-C01587
  • Intermediate 657H (38.9 mg, 0.134 mmol), K2CO3 (55.5 mg, 0.402 mmol), and methyl iodide (16.7 μL, 0.268 mmol) were dissolved in acetone (1.34 mL) and heated to 50° C. in a sealed tube. After heating overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 657I (32 mg, 0.119 mmol, 89%) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.6 Hz, 1H), 7.51 (d, J=2.6 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 6.93 (d, J=2.6 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H); LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 268/270 (M+H)+.
    • Intermediate 657J: 3,6-dimethoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline
  • Figure US20190292176A1-20190926-C01588
  • Intermediate 657I (32 mg, 0.119 mmol), bispinacolatodiboron (60.6 mg, 0.239 mmol), potassium acetate (29.3 mg, 0.298 mmol), and PdCl2(dppf)-CH2Cl2 adduct (7.80 mg, 9.55 μmol) were stored on HIVAC for 15 minutes, then were dissolved in 1,4-dioxane (597 μL), and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 657J, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.66 min, MS (ESI) m/z: 234.2 (boronic acid mass observed, M+H)+.
    • Example 657
  • Intermediate 657J (18 mg, 0.057 mmol), Intermediate I-130 (23.5 mg, 0.057 mmol) and PdCl2(dppf) (2.51 mg, 3.43 μmol) were dissolved in 1,4-dioxane (571 μL) and Na2CO3 (2 M, 257 μL, 0.514 mmol) and heated to 100° C. After 2 hours, the reaction mixture was cooled to ambient temperature. The reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example 657 (6.2 mg, 0.011 mmol, 19%): 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s., 1H), 8.82-8.64 (m, 3H), 8.33 (br. s., 1H), 8.04 (d, J=7.9 Hz, 1H), 7.96 (d, J=11.6 Hz, 1H), 7.87 (br. s., 1H), 7.55 (br. s., 1H), 5.12 (d, J=4.9 Hz, 1H), 4.81 (br. s., 1H), 3.99 (s, 6H), 2.56 (s, 3H), 1.40 (d, J=5.8 Hz, 6H); LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 565.9 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 658 2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-4-ylcarbamate
  • Figure US20190292176A1-20190926-C01589
    • Intermediate 658A: 1-(2-chloro-6-(2-hydroxyethoxy)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01590
  • Intermediate 638D (19.4 mg, 0.055 mmol) was dissolved in toluene (363 μL) and THF (182 μL) and cooled to −78° C. DIBAL-H (1 M in toluene, 164 μL, 0.164 mmol) was then added and the reaction mixture was allowed to warm slowly to ambient temperature. After stirring overnight, another 50 μL of DIBAL was then added. After 2.5 hours, the reaction was quenched with a saturated solution of Rochelle's salt. The reaction mixture was extracted with EtOAc. The organic layer was further washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 658A (28.3 mg, 0.090 mmol, 100%) as an orange oil, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 316.2 (M+H)+.
    • Intermediate 658B: 2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C01591
  • Intermediate 658A (24 mg, 0.076 mmol) and phosgene solution (15% in toluene, 268 μL, 0.380 mmol) were dissolved in THF (760 μL). After 30 minutes, the reaction mixture was concentrated in vacuo to give Intermediate 658B, which was used directly in the subsequent reaction: LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 378.0 (M+H)+.
    • Intermediate 658C: 2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethyl pyridin-4-ylcarbamate
  • Figure US20190292176A1-20190926-C01592
  • Intermediate 658B (14 mg, 0.037 mmol), pyridin-4-amine (12.2 mg, 0.130 mmol), and diisopropylethylamine (64.6 μL, 0.370 mmol) were dissolved in DCM (740 μL.) After 30 minutes, the reaction mixture was concentrated in vacuo to give Intermediate 658C, which was used directly in the subsequent step: LC-MS: Method H, RT=0.87 min, MS (ESI) m/z: 436.1 (M+H)+.
    • Example 658
  • Intermediate I-9 (13.2 mg, 0.044 mmol) and Intermediate 658C (16 mg, 0.037 mmol) were dissolved in DMF (367 μL). PdCl2(dppf)-CH2Cl2 adduct (1.8 mg, 2.2 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 22 μL, 0.044 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100° C. in the microwave for 30 minutes. The crude material was purified by preparative HPLC (Method D, 55-100% B in 20 minutes) to give Example 658 (3.3 mg, 0.0057 mmol, 16%): 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.38 (d, J=5.8 Hz, 2H), 7.81 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.45 (d, J=6.1 Hz, 2H), 7.15 (d, J=2.1 Hz, 1H), 5.42 (d, J=4.6 Hz, 1H), 5.31 (d, J=4.9 Hz, 1H), 4.53 (br. s., 2H), 4.42-4.23 (m, 2H), 4.07 (s, 3H), 3.35 (s, 1H), 2.64 (s, 3H), 0.94 (s, 9H); LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 574.2 (M+H)+; Analytical HPLC Method B, 99% purity.
    • Example 659 (2R,3S)-3-((2-(3-(difluoromethoxy)-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01593
    • Intermediate 659A: 8-bromo-3-(difluoromethoxy)-6-methylquinoline
  • Figure US20190292176A1-20190926-C01594
  • Intermediate I-125E (100 mg, 0.42 mmol) and K2CO3 (290 mg, 2.1 mmol) were suspended in DMF (4.2 mL) and heated to 100° C. Sodium 2-chloro-2,2-difluoroacetate (256 mg, 1.68 mmol) was then added. After 1.5 hours, the reaction mixture was cooled to ambient temperature, diluted with water, and thrice extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to 50% EtOAc in hexanes) to give Intermediate 659A (58 mg, 0.201 mmol, 48%): 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=2.5 Hz, 1H), 7.93 (d, J=1.7 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.56 (s, 1H), 6.88-6.47 (m, 1H), 2.56 (s, 3H); LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 288/290 (M+H)+.
    • Intermediate 659B: 3-(difluoromethoxy)-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  • Figure US20190292176A1-20190926-C01595
  • Intermediate 659A (58 mg, 0.201 mmol), bispinacolatodiboron (102 mg, 0.403 mmol), potassium acetate (49.4 mg, 0.503 mmol), and PdCl2(dppf)-CH2Cl2 adduct (13.2 mg, 0.016 mmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (1.01 mL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 659B, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.82 min, MS (ESI) m/z: 254.0 (boronic acid mass observed, M+H)+.
    • Example 659
  • Intermediate 659B (15 mg, 0.045 mmol), Intermediate I-130 (18.4 mg, 0.045 mmol) and PdCl2(dppf) (1.96 mg, 2.69 μmol) were dissolved in 1,4-dioxane (448 μL) and Na2CO3 (2 M, 201 μL, 0.403 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example 659 (8.7 mg, 0.015 mmol, 33%): 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.98 (br. s., 1H), 8.77 (br. s., 1H), 8.74 (br. s., 2H), 8.29 (br. s., 1H), 8.06 (d, J=7.6 Hz, 1H), 8.00 (br. s., 1H), 7.96 (d, J=11.3 Hz, 1H), 7.66-7.32 (m, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.82 (d, J=5.8 Hz, 1H), 2.64 (s, 3H), 2.55 (s, 3H), 1.40 (br. s., 6H); LC-MS: Method H, compound did not ionize; Analytical HPLC Method B, 100% purity.
    • Example 660 (2R,3S)-3-((2-(3-ethoxy-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01596
    • Intermediate 660A: 8-bromo-3-ethoxy-6-methylquinoline
  • Figure US20190292176A1-20190926-C01597
  • Intermediate I-125E (100 mg, 0.364 mmol), K2CO3 (151 mg, 1.09 mmol), and iodoethane (114 mg, 0.728 mmol) were dissolved in acetone (3.64 mL) and heated to 50° C. in a sealed tube. After heating overnight, the reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 660A (105 mg, 0.394 mmol, 100%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J=2.9 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J=2.9 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 2.52 (s, 3H), 1.54 (t, J=6.9 Hz, 3H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 266/268 (M+H)+.
    • Intermediate 660B: 3-ethoxy-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline
  • Figure US20190292176A1-20190926-C01598
  • Intermediate 660A (100 mg, 0.376 mmol), bispinacolatodiboron (191 mg, 0.752 mmol), potassium acetate (92 mg, 0.939 mmol), and PdCl2(dppf)-CH2Cl2 adduct (24.6 mg, 0.030 mmol) were stored on HIVAC for 15 minutes then were dissolved in dry 1,4-dioxane (1.88 mL) and degassed for 15 minutes by bubbling with argon. The reaction mixture was heated to 130° C. in the microwave for 40 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4), filtered, and concentrated in vacuo to give Intermediate 660B, which was used directly in the subsequent reaction: LC-MS: Method H, RT=0.70 min, MS (ESI) m/z: 232.0 (boronic acid mass observed, M+H)+.
    • Example 660
  • Intermediate 660B (15 mg, 0.048 mmol), Intermediate I-130 (19.7 mg, 0.048 mmol) and PdCl2(dppf) (2.1 mg, 2.87 μmol) were dissolved in 1,4-dioxane (479 μL) and Na2CO3 (2 M, 216 μL, 0.431 mmol) and heated to 100° C. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by preparative HPLC (Method D, 50-100% B in 15 minutes) to give Example 660 (7.2 mg, 0.013 mmol, 27%): 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.77 (br. s., 1H), 8.74 (br. s., 2H), 8.60 (br. s., 1H), 8.04 (d, J=7.9 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.85 (br. s., 2H), 5.11 (d, J=6.1 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.33-4.20 (m, 2H), 2.61 (s, 3H), 2.55 (s, 3H), 1.46 (t, J=6.6 Hz, 3H), 1.40 (d, J=5.5 Hz, 6H); LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 562.2 (M+H)+; Analytical HPLC Method B, 100% purity.
    • Example 661 5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C01599
    • Intermediate 661A: tert-butyl N-(2-bromo-4-methyl-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate
  • Figure US20190292176A1-20190926-C01600
  • 2-Bromo-4-methyl-6-nitroaniline (3 g, 12.98 mmol), DMAP (0.159 g, 1.298 mmol), and Boc2O (7.54 ml, 32.5 mmol) were dissolved in THF (21.64 ml) and allowed to stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0 to 50% EtOAc in hexanes) to yield Intermediate 661A (5.41 g, 12.54 mmol, 97% yield) as a yellow solid. 1H NMR (400 MHz, MeOH4) δ 7.90 (s, 2H), 2.47 (s, 3H), 1.36 (s, 18H). LC-MS: method H, RT=1.10 min, compound does not ionize.
    • Intermediate 661B: methyl 2-((2-bromo-4-methyl-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate
  • Figure US20190292176A1-20190926-C01601
  • Intermediate 661A (5.41 g, 12.54 mmol) was dissolved in DCM (20.91 ml) and TFA (1.933 ml, 25.09 mmol) was added. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with DCM, quenched with saturated NaHCO3, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was redissolved in DMF (20.91 ml). Cs2CO3 (10.22 g, 31.4 mmol) was added and stirred for 15 minutes. Methyl bromoacetate (1.387 ml, 15.05 mmol) was added and stirred for an additional 15 min. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (ISCO, 120 g silica gel column, 29 minute gradient from 0 to 50% EtOAc in hexanes) to yield Intermediate 661B (4.58 g, 11.36 mmol, 91% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.79-7.54 (m, 2H), 4.55 (d, J=17.3 Hz, 1H), 4.00 (s, 1H), 3.68 (s, 3H), 2.43 (s, 3H), 1.56-1.53 (m, 3H), 1.42-1.33 (m, 9H). LC-MS: method H, RT=1.02 min, compound does not ionize.
    • Intermediate 661C: methyl 2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate
  • Figure US20190292176A1-20190926-C01602
  • Intermediate 661B (4.58 g, 11.36 mmol) was dissolved in HCl in dioxanes (14.20 ml, 56.8 mmol) and stirred at room temperature for 5h. The reaction mixture was concentrated to yield Intermediate 661C (3.55 g, 11.71 mmol, 100% yield) as a yellow solid. Used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=2.8 Hz, 2H), 4.56 (d, J=17.3 Hz, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.69 (s, 3H), 2.43 (s, 3H). LC-MS: method H, RT=0.97 min, MS (ESI) m/z: 303.1 (M+H)+.
    • Intermediate 661D: 5-bromo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C01603
  • Intermediate 661C (3.55 g, 11.71 mmol) was dissolved in MeOH (42.6 ml). Concentrated HCl (3.90 ml, 46.8 mmol) then tin(II) chloride dihydrate (10.57 g, 46.8 mmol) were added and the reaction heated to 65° C. for 2.5 h. The reaction mixture was cooled to ambient temperature, neutralized with 10 N NaOH and diluted with brine and EtOAc. The mixture was filtered through celite and the layers separated. The organic layer was washed with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate 661D (2.30 g, 9.54 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ 8.75 (br. s., 1H), 6.95 (s, 1H), 6.52 (s, 1H), 4.29 (br. s., 1H), 4.04 (d, J=1.3 Hz, 2H), 2.22 (s, 3H). LC-MS: method H, RT=0.78 min, MS (ESI) m/z: 241.1 (M+H)+.
    • Intermediate 661E: 5-bromo-7-methylquinoxalin-2(1H)-one
  • Figure US20190292176A1-20190926-C01604
  • Intermediate 661D (2.30 g, 9.54 mmol) was suspended in MeOH (27.7 ml). NaOH (28.6 ml, 28.6 mmol) then H2O2 (5.01 ml, 57.2 mmol) were added and the reaction mixture was allowed to stir at room temperature for 48 h. The reaction was quenched with saturated Na2SO3. The reaction was then diluted with saturated NaHCO3 and extracted thrice with EtOAc. The combined organic layers were filtered through celite, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Compound was then triturated with EtOAc to yield Intermediate 661E (1.32 g, 5.52 mmol, 57.9% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.49 (s, 1H), 7.09 (s, 1H), 2.40 (s, 3H). LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 239.0 (M+H)+.
    • Intermediate 661F: 5-bromo-2-ethoxy-7-methylquinoxaline
  • Figure US20190292176A1-20190926-C01605
  • Intermediate 661E (0.050 g, 0.209 mmol) was dissolved in DMF (1 mL). To this solution was added Cs2CO3 (0.341 g, 1.046 mmol), and the reaction mixture was allowed to stir for 5 min. Iodoethane (0.017 mL, 0.209 mmol) was then added, and the reaction mixture was allowed to room temperature for 48 hours. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. Purified on Prep HPLC using Solvent A: 10% MeOH/90% H2O/0.1% TFA and Solvent B 90% MeOH/10% H2O/0.1% TFA on Phenomenex AXIA C18 30×100 mm with a 10 min gradient and 5 min hold time with a flow rate of 40 mL/min to yield Intermediate 661F (0.012 g, 0.045 mmol, 21.48% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.52-7.47 (m, 1H), 7.11 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 2.51 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). LC-MS: method H, RT=0.87 min, MS (ESI) m/z: 267.0 (M+H)+.
    • Example 661
  • Intermediate 661F (0.012 g, 0.045 mmol) and benzofuran-2-ylboronic acid (10.91 mg, 0.067 mmol) were dissolved in toluene (0.674 ml) and EtOH (0.225 ml). PdCl2(dppf)-CH2Cl2 adduct (2.201 mg, 2.70 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Na2CO3 (0.027 ml, 0.054 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 120° C. in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc, filtered through a micron filter, and concentrated in vacuo. The crude material was purified by Prep LC (Axia Luna 5 u C18 30×100 mm column, 10 minute gradient from 20 to 100% B in A, A=10:90:0.1 MeOH:H2O:TFA, B=90:10:0.1 MeOH:H2O:TFA) to yield Example 661 (0.88 mg, 2.75 μmol, 6.11% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.07 (d, J=0.8 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.60 (d, J=1.0 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.35-7.29 (m, 1H), 7.28-7.22 (m, 1H), 4.56 (q, J=7.0 Hz, 2H), 2.62 (s, 3H), 1.50 (t, J=7.2 Hz, 3H). LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 305.1 (M+H)+.
    • Example 662 4-methoxyphenyl (2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C01606
    • Intermediate 662A: tert-butyl (2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C01607
  • Intermediate I-138A (0.250 g, 0.729 mmol) was dissolved in DMF (7.29 ml). tert-Butyl (2-bromoethyl)carbamate (0.196 g, 0.875 mmol) and Cs2CO3 (1.187 g, 3.64 mmol) were added and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction was purified on ISCO using a 40 g column with a 0-100% EtOAc in hexanes gradient to yield Intermediate 662A (0.074 g, 0.228 mmol, 31.3% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.54 (s, 1H), 5.01 (br. s., 2H), 4.33 (t, J=5.2 Hz, 2H), 3.52 (d, J=4.8 Hz, 2H), 2.49 (d, J=0.7 Hz, 3H), 1.45 (s, 9H), 1.28-1.24 (m, 1H). LC-MS: method H, RT=0.83 min, MS (ESI) m/z: 325.2 (M+H)+.
    • Intermediate 662B: tert-butyl (2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C01608
  • Copper(II) bromide (0.087 g, 0.388 mmol) and t-butyl nitrite (0.046 ml, 0.388 mmol) were dissolved in MeCN (0.912 ml) and allowed to stir 10 minutes. Intermediate 662A (0.074 g, 0.228 mmol) was dissolved in MeCN (1.369 ml) and the copper solution was added. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na+SO4), filtered, and concentrated in vacuo to yield Intermediate 662B (0.080 g, 0.206 mmol, 90% yield). 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J=0.9 Hz, 1H), 4.39 (t, J=5.3 Hz, 2H), 3.54 (d, J=5.1 Hz, 2H), 2.63 (d, J=0.9 Hz, 3H), 1.45 (s, 9H). LC-MS: method H, RT=1.13 min, MS (ESI) m/z: 388.1 (M+H)+.
    • Intermediate 662C: tert-butyl (2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate
  • Figure US20190292176A1-20190926-C01609
  • Intermediate I-9 (0.062 g, 0.206 mmol) and Intermediate 662B (0.080 g, 0.206 mmol) were dissolved in DMF (1 ml). PdCl2(dppf)-CH2Cl2 adduct (10.10 mg, 0.012 mmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and purified on 24 g ISCO column with 0-100% EtOAc in hexanes gradient to yield Intermediate 662C (0.048 g, 0.100 mmol, 48.4% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 7.77-7.72 (m, 1H), 6.70 (d, J=0.7 Hz, 1H), 4.47 (t, J=5.2 Hz, 2H), 4.12 (s, 3H), 3.58 (d, J=4.8 Hz, 2H), 2.79 (d, J=0.7 Hz, 3H), 2.66 (s, 3H), 1.53 (s, 9H). LC-MS: method H, RT=1.36 min, MS (ESI) m/z: 482.1 (M+H)+.
    • Intermediate 662D: 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanamine
  • Figure US20190292176A1-20190926-C01610
  • To a mixture of Intermediate 662C (0.048 g, 0.100 mmol) in DCM (1) was added 2,6-lutidine (0.035 ml, 0.299 mmol) followed by TMS-OTf (0.072 ml, 0.399 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with NaHCO3 and extracted by EtOAc. The combined organic layer was washed by brine, dried by sodium sulfate and concentrated to yield Intermediate 662D (0.036 g, 0.094 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=1.5 Hz, 1H), 8.53 (s, 1H), 7.74 (d, J=0.9 Hz, 1H), 6.72 (d, J=0.9 Hz, 1H), 4.44 (t, J=5.3 Hz, 2H), 4.12 (s, 3H), 3.12 (t, J=5.3 Hz, 2H), 2.79 (d, J=0.9 Hz, 3H), 2.66 (s, 3H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 382.1 (M+H)+.
    • Example 662
  • Intermediate 662D (0.020 g, 0.052 mmol) was dissolved in DCM (0.350 ml) and THF (0.175 ml). To the solution was added 4-methoxyphenyl carbonochloridate (0.029 g, 0.157 mmol) followed by DIEA (0.092 ml, 0.524 mmol). The solution was allowed to stir at room temperature overnight. The reaction mixture was concentrated and suspended in 2 mL of hot DMSO, filtered, and purified by preparative HPLC (Method D, 70% to 100% B in 20 minutes) to yield Example 662 (0.0027 g, 5.08 mol, 9.69% yield): MS (ESI) m/z: 532.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (br. s., 1H), 8.59 (br. s., 1H), 7.94-7.85 (m, 2H), 7.03 (d, J=8.0 Hz, 2H), 6.79-6.67 (m, 2H), 4.47 (br. s., 2H), 4.11 (br. s., 3H), 3.76 (br. s., 4H), 3.67 (br. s., 2H), 2.77 (br. s., 3H), 2.67 (br. s., 3H). LC-MS: method H, RT=1.45 min, MS (ESI) m/z: 532.1 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 663 (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol
  • Figure US20190292176A1-20190926-C01611
    • Intermediate 663A: (2-amino-6-methoxybenzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl) methanol
  • Figure US20190292176A1-20190926-C01612
  • Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μl). NaH (8.49 mg, 0.212 mmol) was added and the reaction mixture was stirred for 5 min. The reaction mixture was cooled to −78° C. and BuLi (101 μl, 0.232 mmol) was added and allowed to stir for 30 min. Tetrahydro-2H-pyran-4-carbaldehyde (44.0 mg, 0.386 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with EtOAc and washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate 663A (0.05 g, 0.170 mmol, 88%). Used without further purification. LC-MS: method H, RT=0.56 min, MS (ESI) m/z: 295.2 (M+H)+.
    • Intermediate 663B: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol
  • Figure US20190292176A1-20190926-C01613
  • Copper(II) chloride (0.044 g, 0.329 mmol) and t-butyl nitrite (0.039 ml, 0.329 mmol) were dissolved in MeCN (0.775 ml) and allowed to stir 10 minutes. Intermediate 663A (0.057 g, 0.194 mmol) was dissolved in MeCN (1.162 ml) and the copper solution was added. The reaction mixture was stirred for 2.5h at 60° C. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using 0-100% EtOAc in hexanes gradient on a 24 g column to yield Intermediate 663B (0.020 g, 0.064 mmol, 32.9% yield). 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 4.72 (t, J=7.6 Hz, 1H), 3.97 (d, J=6.6 Hz, 2H), 3.87 (s, 3H), 3.46-3.34 (m, 3H), 3.27 (td, J=11.8, 2.2 Hz, 1H), 1.28-1.23 (m, 2H), 0.94-0.81 (m, 2H). LC-MS: method H, RT=0.56 min, MS (ESI) m/z: 314.1 (M+H)+.
    • Example 663
  • Intermediate I-9 (9.57 mg, 0.032 mmol) and Intermediate 663B (0.010, 0.032 mmol) were dissolved in DMF (1 ml). PdCl2(dppf)-CH2Cl2 adduct (1.561 mg, 1.912 μmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was concentrated and suspended in 2 mL of hot DMSO, filtered, and purified by preparative HPLC (Method D, 30% to 70% B in 25 minutes) to yield Example 663 (0.0044 g, 9.45 μmol, 29.7% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.73 (br. s., 1H), 8.54 (br. s., 1H), 7.82 (br. s., 1H), 7.59 (br. s., 1H), 7.16 (br. s., 1H), 5.48-5.31 (m, 2H), 4.08 (br. s., 3H), 3.88-3.86 (m, 3H), 3.78 (d, J=9.8 Hz, 1H), 3.27-3.16 (m, 2H), 2.64 (br. s., 3H), 2.00 (br. s., 1H), 1.71 (d, J=11.8 Hz, 1H), 1.45 (t, J=12.6 Hz, 3H), 1.19 (d, J=12.5 Hz, 2H). LC-MS: method H, RT=1.45 min, MS (ESI) m/z: 452.2 (M+H)+. Analytical HPLC Method B: 97% purity.
    • Example 664 (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol
  • Figure US20190292176A1-20190926-C01614
    • Intermediate 664A: (2-amino-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanone
  • Figure US20190292176A1-20190926-C01615
  • Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μl). NaH (8.49 mg, 0.212 mmol) was added and the reaction mixture was stirred for 30 min. The reaction mixture was cooled to −78° C. and BuLi (101 μl, 0.232 mmol) was added and the reaction mixture was allowed to stir for 30 min. Methyl 1-(trifluoromethyl) cyclobutanecarboxylate (35.1 mg, 0.193 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was stirred for 10 min and diluted with water and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layer was washed with water, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 664A (0.023 g, 0.191 mmol, 33%). LC-MS: method H, RT=0.77 min, MS (ESI) m/z: 331.2 (M+H)+.
    • Intermediate 664B: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl) cyclobutyl)methanone
  • Figure US20190292176A1-20190926-C01616
  • Copper(II) chloride (0.042 g, 0.309 mmol) and t-butyl nitrite (0.037 ml, 0.309 mmol) were dissolved in MeCN (0.727 ml) and allowed to stir 10 minutes. Intermediate 664A (0.060 g, 0.182 mmol) was dissolved in MeCN (1.090 ml) and the copper solution was added. The reaction mixture was stirred for 2.5 h at 60° C. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using a 12 g column with 0-100% gradient of EtOAc in hexanes to yield Intermediate 664B (0.025 g, 0.036 mmol, 19.68% yield). LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 350.1 (M+H)+.
    • Intermediate 664C: (2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl) cyclobutyl)methanol
  • Figure US20190292176A1-20190926-C01617
  • Intermediate 664B (0.035 g, 0.100 mmol) was dissolved in MeOH (1.00 ml) and cooled to 0° C. Sodium borohydride (3.79 mg, 0.100 mmol) was added to the flask, and the reaction mixture was allowed to stir for 2h. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was back extracted with EtOAc×3. The combined organic layer was washed with water, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 664C (0.030 g, 0.085 mmol, 85% yield) as a white solid. Used without further purification. LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 352.1 (M+H)+.
    • Example 664
  • Intermediate I-9 (0.065 g, 0.216 mmol) and Intermediate 664B (0.076 g, 0.216 mmol) were dissolved in DMF (2.160 ml). PdCl2(dppf)-CH2Cl2 adduct (10.59 mg, 0.013 mmol) was added and the reaction degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added and the reaction degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. Enantiomers were separated using Lux 5 u Cellulose-4, 21×250 mm, 5 micron column with 35% EtOH/65% CO2, UV 220 nm to afford Example 664 (10.7 mg, 0.021 mmol, 9.61% yield) as a single enantiomer (99% enantiomeric excess). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.77 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 5.81 (d, J=9.2 Hz, 1H), 5.34 (d, J=9.2 Hz, 1H), 4.13 (s, 3H), 3.92 (s, 3H), 2.73 (s, 2H), 2.65 (s, 3H), 2.35 (s, 4H), 1.88 (s, 1H). LC-MS: method H, RT=1.34 min, MS (ESI) m/z: 490.1 (M+H)+. Analytical HPLC Method B: 97% purity
    • Examples 665 to 677
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 663 or Example 664 and the examples above.
  • LCMS LCMS
    Ex. [M + H]+ RT(Min)/
    No. Structure m/z Method NMR
    665
    Figure US20190292176A1-20190926-C01618
         		498.2 1.37/H 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 7.11-7.07 (m, 2H), 6.99-6.94 (m, 1H), 6.90 (d, J = 7.3 Hz, 2H), 6.48 (s, 1H), 5.94 (d, J = 4.9 Hz, 1H), 5.59 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 3.66 (s, 3H), 2.75 (d, J = 7.3 Hz, 1H), 2.65 (s, 4H), 2.25 (d, J = 9.2 Hz, 1H), 2.18-2.03 (m, 2H), 1.75 (br. s., 1H).
    666
    Figure US20190292176A1-20190926-C01619
         		466.2 1.35/H 1H NMR (500 MHz, DMSO-d6) δ 8.72 (br. s., 1H), 8.56 (br. s., 1H), 7.81 (br. s., 1H), 7.59 (br. s., 1H), 7.15 (br. s., 1H), 5.67 (br. s., 1H), 5.36 (br. s., 1H), 4.07 (br. s., 3H), 3.86 (br. s., 3H), 3.43-3.38 (m, 2H), 3.17 (br. s., 3H), 2.63 (br. s., 3H), 2.35 (br. s., 1H), 2.23-2.13 (m, 1H), 1.74 (br. s., 4H).
    667
    Figure US20190292176A1-20190926-C01620
         		476.1 1.29/H 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.53 (s, 1H), 7.79 (s, 1H), 7.62 (s, 1H), 7.19 (s, 1H), 5.93-5.90 (m, 1H), 5.89-5.86 (m, 1H), 4.06 (s, 3H), 3.86 (s, 3H), 2.60 (s, 3H), 1.22 (br. s., 1H), 0.92 (br. s., 2H), 0.49 (d, J = 9.5 Hz, 1H).
    668
    Figure US20190292176A1-20190926-C01621
         		484.2 1.27/H 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.45 (s, 1H), 7.78 (s, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.20-7.00 (m, 5H), 6.73 (s, 1H), 5.58 (d, J = 4.4 Hz, 1H), 5.51 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 3.71 (s, 3H), 2.65 (s, 3H), 1.37 (d, J = 4.4 Hz, 1H), 1.00 (d, J = 4.0 Hz, 1H), 0.78- 0.65 (m, 2H).
    669
    Figure US20190292176A1-20190926-C01622
         		490.1 1.34/H 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.45 (s, 1H), 7.78 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 5.98 (d, J = 5.2 Hz, 1H), 5.92 (d, J = 5.2 Hz, 1H), 4.05 (s, 3H), 3.86 (s, 3H), 2.58 (s, 3H), 2.21-2.01 (m, 2H), 1.80 (d, J = 10.4 Hz, 1H), 1.67-1.53 (m, 1H), 1.20 (br. s., 1H), 0.80 (br. s., 1H).
    671
    Figure US20190292176A1-20190926-C01623
         		476.1 1.29/H 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.49 (s, 1H), 7.77 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.72-5.64 (m, 1H), 5.53 (s, 1H), 4.13 (s, 3H), 3.92 (s, 3H), 2.66 (s, 3H), 1.17 (br. s., 1H), 1.02 (dt, J = 18.2, 5.7 Hz, 2H), 0.58 (d, J = 8.8 Hz, 1H)
    672
    Figure US20190292176A1-20190926-C01624
         		464.2 1.43   1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.47 (d, J = 1.5 Hz, 1H), 7.75 (dd, J = 1.8, 0.9 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 5.84 (d, J = 9.1 Hz, 1H), 4.79 (d, J = 9.5 Hz, 1H), 4.13 (s, 3H), 3.91 (s, 3H), 2.66 (s, 3H), 1.61 (br. s., 10H), 0.96 (s, 3H).
    673
    Figure US20190292176A1-20190926-C01625
         		451.0 1.15/H 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.50 (s, 1H), 7.78 (s, 1H), 7.70-7.60 (m, 3H), 7.13 (s, 1H), 6.96 (br. s., 1H), 6.91 (br. s., 1H), 4.06 (s, 3H), 3.84 (s, 3H), 2.61 (s, 3H).
    674
    Figure US20190292176A1-20190926-C01626
         		466.2 1.23/H 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.49 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 5.58-5.42 (m, 2H), 4.05 (s, 3H), 3.85 (s, 3H), 3.77-3.59 (m, 3H), 3.42 (br. s., 1H), 2.61 (s, 3H), 1.93-1.73 (m, 2H), 1.44 (br. s., 1H), 0.98 (s, 3H), 0.89-0.82 (m, 1H).
    675
    Figure US20190292176A1-20190926-C01627
         		492.1 1.29/H 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.66 (s, 1H), 7.84 (s, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 7.01 (d, J = 9.8 Hz, 1H), 6.72-6.64 (m, 2H), 6.32 (d, J = 4.3 Hz, 1H), 4.12 (s, 3H), 3.91 (s, 3H), 3.78 (s, 3H), 2.68 (s, 3H).
    676
    Figure US20190292176A1-20190926-C01628
         		464.2 1.39/H 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.52 (s, 1H), 7.80 (s, 1H), 7.58 (br. s., 1H), 7.14 (br. s., 1H), 5.46 (br. s., 1H), 5.32 (d, J = 4.0 Hz, 1H), 4.08 (s, 3H), 3.87 (s, 3H), 3.48 (br. s., 3H), 2.63 (s, 3H), 1.69-1.49 (m, 6H), 1.43-1.29 (m, 2H), 1.24-1.13 (m, 1H), 1.05 (d, J = 12.5 Hz, 1H).
    677
    Figure US20190292176A1-20190926-C01629
         		382.1 1.19/H 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.55 (s, 1H), 7.80 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 5.72-5.59 (m, 1H), 4.08 (s, 3H), 3.88 (s, 3H), 3.39 (br. s., 1H), 2.64 (s, 3H), 2.56 (s, 3H).
    • Example 678 (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01630
  • To a solution of Intermediate I-132 (17 mg, 0.037 mmol) in DCM (1 mL) and THF (0.5 mL) was added 2-methylpyrimidin-5-amine (8.02 mg, 0.073 mmol) followed by pyridine (0.030 mL, 0.367 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with 0.2 mL of MeOH. The reaction mixture was concentrated and redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 25 to 100% B in 20 minutes) to yield Example 678 (5.9 mg, 10.58 μmol, 28.8% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.97 (br. s., 1H), 8.71 (br. s., 2H), 8.63-8.59 (m, 1H), 8.44 (s, 1H), 8.37 (d, J=10.7 Hz, 1H), 7.77 (s, 1H), 5.26 (br. s., 1H), 4.79 (d, J=10.7 Hz, 1H), 4.57-4.44 (m, 1H), 4.05 (s, 3H), 3.44 (br. s., 3H), 2.58 (s, 3H), 1.40 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.45 min, MS (ESI) m/z: 536.2 (M+H)+. Analytical HPLC Method B: 96% purity.
    • Examples 679 to 702
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 678 and the examples above. If necessary, removal of silyl protecting groups was accomplished by treatment of the protected compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to afford the desired compound.
  • LCMS
    RT
    LCMS (Min)
    Ex. [M + H]+ Method
    No. Structure Amine m/z H NMR
    679
    Figure US20190292176A1-20190926-C01631
    Figure US20190292176A1-20190926-C01632
         		552.1 1.27 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.62-8.54 (m, 2H), 8.40 (br. s., 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.73 (s, 1H), 5.24 (br. s., 1H), 4.79 (d, J = 11.3 Hz, 1H), 4.48 (t, J = 11.6 Hz, 1H), 4.04 (s, 3H), 3.45 (br. s., 1H), 2.57 (s, 3H), 2.54 (s, 3H), 1.46-1.37 (m, 3H).
    680
    Figure US20190292176A1-20190926-C01633
    Figure US20190292176A1-20190926-C01634
         		521.1 1.07 1H NMR (500 MHz, DMSO-d6) δ 8.60- 8.56 (m, 1H), 8.42 (s, 1H), 8.35 (d, J = 9.5 Hz, 3H), 7.75 (s, 1H), 7.43 (d, J = 5.2 Hz, 2H), 5.28 (br. s., 1H), 4.78 (d, J = 10.1 Hz, 1H), 4.56-4.47 (m, 1H), 4.04 (s, 3H), 2.57 (s, 3H), 1.54-1.31 (m, 3H).
    681
    Figure US20190292176A1-20190926-C01635
    Figure US20190292176A1-20190926-C01636
         		535.1 1.06 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.62 (s, 1H), 8.45 (br. s., 2H), 8.37 (d, J = 10.7 Hz, 1H), 7.77 (s, 2H), 7.16 (d, J = 7.9 Hz, 1H), 5.26 (br. s., 1H), 4.75 (d, J = 9.5 Hz, 1H), 4.50 (dd, J = 11.7, 6.0 Hz, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 2.35 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    682
    Figure US20190292176A1-20190926-C01637
    Figure US20190292176A1-20190926-C01638
         		539.1 1.27 1H NMR (500 MHz, DMSO-d6) δ 10.21 (br. s., 1H), 8.60 (s, 1H), 8.46-8.34 (m, 3H), 8.17 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 5.28 (br. s., 1H), 4.78 (d, J = 10.4 Hz, 1H), 4.51 (dd, J = 11.7, 5.6 Hz, 1H), 4.05 (s, 3H), 3.42 (br. s., 3H), 2.58 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H).
    683
    Figure US20190292176A1-20190926-C01639
    Figure US20190292176A1-20190926-C01640
         		577.1 1.23 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.51 (d, J = 1.7 Hz, 1H), 8.43 (d, J = 10.7 Hz, 1H), 7.82 (s, 1H), 7.39- 7.33 (m, 1H), 7.09-7.04 (m, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.26 (td, J = 6.3, 3.0 Hz, 1H), 4.74 (dd, J = 11.7, 2.9 Hz, 1H), 4.54 (dd, J = 11.7, 6.2 Hz, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 1.40 (d, J = 6.6 Hz, 3H).
    684
    Figure US20190292176A1-20190926-C01641
    Figure US20190292176A1-20190926-C01642
         		521.2 1.07 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 2H), 8.44 (s, 1H), 8.37 (d, J = 10.7 Hz, 1H), 8.19 (br. s., 1H), 7.89 (br. s., 1H), 7.76 (s, 1H), 7.32 (br. s., 1H), 5.28 (br. s., 1H), 4.75 (d, J = 9.8 Hz, 1H), 4.52 (dd, J = 11.4, 6.0 Hz, 1H), 4.05 (s, 3H), 2.58 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H).
    685
    Figure US20190292176A1-20190926-C01643
         		I-97 582.2 1.15 1H NMR (400 MHz, CDCl3) δ 8.73- 8.51 (m, 4H), 8.01 (d, J = 9.7 Hz, 1H), 7.79 (br. s., 1H), 6.64 (br. s., 1H), 5.80 (br. s., 1H), 5.41 (br. s., 1H), 4.83 (br. s., 1H), 4.50 (br. s., 2H), 4.15 (s, 3H), 4.00 (br. s., 2H), 2.67 (s, 3H), 1.52 (t, J = 6.1 Hz, 3H).
    686
    Figure US20190292176A1-20190926-C01644
         		I-98 566.2 1.13 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s., 1H), 8.76-8.65 (m, 3H), 8.51 (s, 2H), 8.42 (d, J = 10.7 Hz, 2H), 7.83 (s, 2H), 5.75-5.64 (m, 1H), 5.27 (br. s., 1H), 4.81 (d, J = 11.6 Hz, 1H), 4.58-4.46 (m, 1H), 4.07 (s, 3H), 3.77 (br. s., 2H), 2.91 (d, J = 6.7 Hz, 2H), 2.61 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    687
    Figure US20190292176A1-20190926-C01645
         		I-99 631.2 1.27 1H NMR (500 MHz, DMSO-d6) δ 9.69 (br. s., 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.33 (d, J = 10.7 Hz, 1H), 8.20 (br. s., 1H), 7.85-7.78 (m, 1H), 7.74 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.72-5.59 (m, 1H), 5.26 (br. s., 1H), 4.75 (d, J = 9.8 Hz, 1H), 4.56-4.43 (m, 3H), 4.05 (s, 3H), 3.82-3.65 (m, 2H), 2.58 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H).
    688
    Figure US20190292176A1-20190926-C01646
         		I-103 596.1 1.26 1H NMR (500 MHz, DMSO-d6) δ 9.87- 9.76 (m, 1H), 8.65 (s, 1H), 8.60 (br. s., 2H), 8.48 (s, 1H), 8.41 (d, J = 10.7 Hz, 1H), 7.80 (s, 1H), 5.69 (d, J = 6.4 Hz, 1H), 5.31-5.23 (m, 1H), 4.86-4.76 (m, 1H), 4.53 (dd, J = 11.6, 6.1 Hz, 1H), 4.07 (s, 3H), 4.05-3.99 (m, 1H), 3.93 (br. s., 1H), 3.54 (d, J = 4.9 Hz, 1H), 2.61 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H).
    689
    Figure US20190292176A1-20190926-C01647
         		I-107 580.2 1.20 1H NMR (500 MHz, DMSO-d6) δ 9.39 (br. s., 1H), 8.23 (br. s., 1H), 7.97-7.84 (m, 3H), 7.63 (d, J = 7.6 Hz, 2H), 7.34- 7.05 (m, 2H), 6.57 (d, J = 9.5 Hz, 1H), 5.75 (d, J = 6.1 Hz, 1H), 2.54 (s, 3H), 2.50 (br. s., 3H), 2.13 (br. s., 3H), 1.54 (d, J = 4.9 Hz, 3H).
    690
    Figure US20190292176A1-20190926-C01648
    Figure US20190292176A1-20190926-C01649
         		579.2 1.23 1H NMR (500 MHz, DMSO-d6) δ 8.65 (br. s., 2H), 8.54 (s, 1H), 8.46 (d, J = 10.7 Hz, 1H), 8.05 (br. s., 1H), 8.00 (s, 1H), 7.86 (s, 1H), 5.29 (br. s., 1H), 4.96 (d, J = 11.9 Hz, 1H), 4.53 (dd, J = 11.6, 5.2 Hz, 1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H).
    691
    Figure US20190292176A1-20190926-C01650
         		I-109 565.1 1.00 1H NMR (500 MHz, DMSO-d6) δ 9.78 (br. s., 1H), 8.65 (s, 1H), 8.57-8.47 (m, 2H), 8.39 (d, J = 10.7 Hz, 1H), 7.90- 7.68 (m, 2H), 7.18 (d, J = 8.5 Hz, 1H), 5.66 (br. s., 1H), 5.28 (dt, J = 6.3, 3.3 Hz, 1H), 4.76 (dd, J = 11.7, 2.9 Hz, 1H), 4.53 (dd, J = 11.7, 6.3 Hz, 1H), 4.07 (s, 3H), 3.68 (d, J = 5.2 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.61 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H).
    692
    Figure US20190292176A1-20190926-C01651
         		I-106 596.1 1.20 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.64-8.62 (m, 1H), 8.60 (br. s., 2H), 8.47 (s, 1H), 8.39 (d, J = 10.7 Hz, 1H), 7.79 (s, 1H), 5.68 (br. s., 1H), 5.31-5.23 (m, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.89-4.84 (m, 1H), 4.82-4.76 (m, 1H), 4.53 (dd, J = 11.7, 6.0 Hz, 2H), 4.07 (s, 3H), 2.60 (s, 3H), 1.48-1.39 (m, 3H), 1.25-1.18 (m, 3H).
    693
    Figure US20190292176A1-20190926-C01652
         		I-105 596.2 1.20 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.67-8.54 (m, 2H), 8.45 (s, 2H), 8.37 (d, J = 10.7 Hz, 1H), 7.77 (s, 1H), 5.68 (br. s., 1H), 5.27 (br. s., 2H), 5.00 (d, J = 5.2 Hz, 2H), 4.91-4.85 (m, 1H), 4.80 (d, J = 9.5 Hz, 1H), 4.52 (dd, J = 11.6, 5.8 Hz, 2H), 4.07 (s, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H).
    694
    Figure US20190292176A1-20190926-C01653
         		385B 551.1 1.01 1H NMR (500 MHz, DMSO-d6) δ 9.87 (br. s., 1H), 8.65-8.60 (m, 1H), 8.55- 8.49 (m, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.37 (d, J = 10.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 5.67 (br. s., 1H), 5.29 (dt, J = 6.4, 3.2 Hz, 1H), 4.76 (dd, J = 11.6, 2.7 Hz, 1H), 4.54 (dd, J = 11.9, 6.1 Hz, 1H), 4.49 (s, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 1.51-1.35 (m, 3H).
    695
    Figure US20190292176A1-20190926-C01654
         		I-92 593.2 1.03 1H NMR (500 MHz, DMSO-d6) δ 9.72 (br. s., 1H), 8.55 (s, 1H), 8.42 (br. s., 1H), 8.37 (s, 1H), 8.29 (d, J = 10.7 Hz, 1H), 7.69 (s, 2H), 7.12 (d, J = 8.5 Hz, 1H), 5.25-5.15 (m, 1H), 4.68 (dd, J = 11.6, 2.4 Hz, 1H), 4.59 (s, 1H), 4.46 (dd, J = 11.7, 6.3 Hz, 1H), 3.99 (s, 3H), 2.52 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 2.4 Hz, 6H).
    696
    Figure US20190292176A1-20190926-C01655
         		I-94 565.2 1.02 1H NMR (500 MHz, DMSO-d6) δ 8.63- 8.58 (m, 1H), 8.45 (s, 1H), 8.39-8.34 (m, 1H), 8.28-8.22 (m, 1H), 7.77 (s, 1H), 7.32 (s, 1H), 7.28 (d, J = 3.7 Hz, 2H), 5.72-5.61 (m, 1H), 5.33-5.26 (m, 1H), 4.78 (d, J = 9.2 Hz, 1H), 4.53 (dd, J = 11.7, 6.3 Hz, 1H), 4.07 (s, 3H), 3.68 (br. s., 2H), 2.79-2.70 (m, 2H), 2.60 (s, 3H), 1.49-1.39 (m, 3H).
    697
    Figure US20190292176A1-20190926-C01656
         		I-110 581.1 1.03 1H NMR (500 MHz, DMSO-d6) δ 10.09 (br. s., 1H), 8.61 (s, 1H), 8.47 (s, 1H), 8.38 (d, J = 11.0 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 7.79 (s, 1H), 7.04 (d, J = 5.8 Hz, 1H), 6.88 (s, 1H), 5.29 (br. s., 1H), 4.80 (d, J = 11.9 Hz, 1H), 4.55- 4.50 (m, 2H), 4.22-4.14 (m, 4H), 4.07 (s, 3H), 2.61 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H).
    698
    Figure US20190292176A1-20190926-C01657
    Figure US20190292176A1-20190926-C01658
         		522.1 1.03 1H NMR (500 MHz, DMSO-d6) δ 10.43 (br. s., 1H), 9.16-9.11 (m, 1H), 8.98 (d, J = 5.8 Hz, 1H), 8.68-8.63 (m, 1H), 8.52 (br. s., 1H), 8.47-8.39 (m, 1H), 7.85 (br. s., 1H), 7.76 (br. s., 1H), 5.37-5.24 (m, 1H), 4.98-4.88 (m, 1H), 4.54 (s, 1H), 4.39-4.28 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.53-1.41 (m, 3H).
    699
    Figure US20190292176A1-20190926-C01659
         		I-108 623.2 1.10 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.94 (d, J = 5.8 Hz, 1H), 7.75 (s, 1H), 7.01 (d, J = 5.8 Hz, 1H), 6.85 (s, 1H), 5.28 (br. s., 1H), 4.80 (d, J = 9.8 Hz, 1H), 4.50 (dd, J = 11.7, 5.6 Hz, 1H), 4.34-4.19 (m, 2H), 4.06 (s, 3H), 3.46 (br. s., 2H), 2.59 (s, 3H), 1.76 (t, J = 7.3 Hz, 2H), 1.42 (d, J = 6.4 Hz, 3H), 1.14-1.08 (m, 6H).
    700
    Figure US20190292176A1-20190926-C01660
         		I-93 581.1 1.18 1H NMR (500 MHz, DMSO-d6) δ 9.60 (br. s., 1H), 8.59 (s, 1H), 8.43 (br. s., 1H), 8.34 (d, J = 10.7 Hz, 1H), 8.16 (br. s., 1H), 7.75 (br. s., 2H), 6.75 (d, J = 8.9 Hz, 1H), 5.74-5.59 (m, 1H), 5.25 (br. s., 1H), 4.76 (d, J = 10.1 Hz, 1H), 4.57- 4.44 (m, 1H), 4.16 (d, J = 4.3 Hz, 2H), 4.06 (s, 3H), 3.67 (br. s., 2H), 2.59 (s, 3H), 1.51-1.37 (m, 3H).
    701
    Figure US20190292176A1-20190926-C01661
         		I-104 596.1 1.26 1H NMR (500 MHz, DMSO-d6) δ 9.82 (br. s., 1H), 8.70-8.65 (m, 1H), 8.63- 8.55 (m, 2H), 8.51 (s, 1H), 8.43 (d, J = 11.0 Hz, 1H), 7.82 (s, 1H), 5.70 (br. s., 1H), 5.27 (t, J = 6.1 Hz, 1H), 4.89-4.77 (m, 2H), 4.53 (dd, J = 11.6, 5.8 Hz, 1H), 4.08 (s, 3H), 4.03-3.89 (m, 1H), 3.58-3.34 (m, 1H), 2.62 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.11 (d, J = 5.8 Hz, 3H).
    702
    Figure US20190292176A1-20190926-C01662
         		I-100 624.2 1.30 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br. s., 1H), 8.69 (s, 1H), 8.59 (br. s., 2H), 8.53 (s, 1H), 8.44 (d, J = 10.7 Hz, 1H), 7.84 (s, 1H), 5.25 (br. s., 1H), 4.85 (br. s., 1H), 4.58-4.48 (m, 1H), 4.38 (s, 1H), 4.30 (d, J = 7.6 Hz, 2H), 4.09 (s, 3H), 3.43-3.33 (m, 2H), 2.63 (s, 3H), 1.41 (d, J = 6.7 Hz, 3H), 1.14 (s, 6H).
    • Example 708 (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate
  • Figure US20190292176A1-20190926-C01663
  • To a solution of Intermediate I-134 (17 mg, 0.036 mmol) in DCM (1 mL) and THF (0.5 mL), was added 6-aminobenzo[d]oxazol-2(3H)-one (10.70 mg, 0.071 mmol) followed by pyridine (0.029 mL, 0.356 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with 0.2 mL of MeOH. The reaction mixture was concentrated and redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% B in 20 minutes) to yield Example 708 (6 mg, 9.96 μmol, 27.9% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.56 (br. s., 1H), 8.53 (s, 1H), 8.44 (s, 1H), 8.35 (d, J=10.4 Hz, 1H), 7.75 (s, 1H), 7.39 (br. s., 1H), 7.09 (br. s., 1H), 6.91 (d, J=7.6 Hz, 1H), 5.64 (d, J=6.4 Hz, 1H), 5.13 (d, J=6.4 Hz, 1H), 4.06 (s, 3H), 3.54-3.38 (m, 1H), 2.59 (s, 3H), 1.45 (d, J=6.4 Hz, 3H), 1.40-1.35 (m, 3H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 591.1 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Examples 709 to 731
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 708 and the examples above. If necessary, removal of silyl protecting groups was accomplished by treatment of the protected compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to afford the desired compound.
  • LCMS
    LCMS RT
    [M + (Min)
    Ex. H]+ Method
    No. Structure Amine m/z H NMR
    709
    Figure US20190292176A1-20190926-C01664
    Figure US20190292176A1-20190926-C01665
         		535.2 1.01 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.61- 8.50 (m, 2H), 8.39 (br. s., 1H), 8.31 (d, J = 10.7 Hz, 1H), 8.16 (br. s., 1H), 7.87 (br. s., 1H), 7.72 (br. s., 1H), 7.30 (br. s., 1H), 5.62 (d, J = 5.2 Hz, 1H), 5.16 (d, J = 6.1 Hz, 1H), 4.05 (s, 3H), 3.56 (br. s., 3H), 1.45 (d, J = 5.8 Hz, 3H), 1.39 (d, J = 5.8 Hz, 3H).
    710
    Figure US20190292176A1-20190926-C01666
    Figure US20190292176A1-20190926-C01667
         		549.1 1.11 1H NMR (500 MHz, DMSO-d6) δ 9.76 (br. s., 1H), 8.60 (s, 1H), 8.46 (br. s., 2H), 8.38 (d, J = 10.7 Hz, 1H), 7.78 (br. s., 2H), 7.21 (br. s., 1H), 5.66 (d, J = 6.7 Hz, 1H), 5.14 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 2.35 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    711
    Figure US20190292176A1-20190926-C01668
    Figure US20190292176A1-20190926-C01669
         		566.0 1.31 1H NMR (500 MHz, DMSO-d6) δ 9.70 (br. s., 1H), 8.60 (d, J = 9.2 Hz, 3H), 8.48 (s, 1H), 8.40 (d, J = 10.4 Hz, 1H), 7.80 (s, 1H), 5.73 (d, J = 5.2 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 4.08 (s, 3H), 3.79 (s, 3H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H).
    712
    Figure US20190292176A1-20190926-C01670
         		I-107 594.2 1.18 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.91 (br. s., 2H), 8.49-8.41 (m, 2H), 8.37 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 5.82 (d, J = 6.7 Hz, 1H), 5.14 (d, J = 5.2 Hz, 1H), 4.07 (s, 3H), 3.83 (s, 3H), 2.58 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    713
    Figure US20190292176A1-20190926-C01671
    Figure US20190292176A1-20190926-C01672
         		535.2 1.01 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.34-8.29 (m, 3H), 7.72 (s, 1H), 7.39 (d, J = 5.2 Hz, 2H), 5.66 (d, J = 6.7 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.05 (s, 3H), 2.56 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    714
    Figure US20190292176A1-20190926-C01673
    Figure US20190292176A1-20190926-C01674
         		553.2 1.25 1H NMR (500 MHz, DMSO-d6) δ 10.07 (br. s., 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.36 (br. s., 1H), 8.32 (d, J = 10.7 Hz, 1H), 8.13 (br. s., 1H), 7.83-7.76 (m, 1H), 7.72 (s, 1H), 5.67 (d, J = 6.4 Hz, 1H), 5.15 (d, J = 6.4 Hz, 1H), 4.05 (s, 3H), 2.58-2.56 (m, 3H), 1.44 (d, J = 6.1 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    715
    Figure US20190292176A1-20190926-C01675
    Figure US20190292176A1-20190926-C01676
         		593.2 1.21 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.54 (br. s., 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.33 (d, J = 10.7 Hz, 1H), 8.00 (br. s., 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 5.81 (d, J = 6.4 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 4.06 (s, 3H), 3.77 (s, 3H), 2.58 (br. s., 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H).
    716
    Figure US20190292176A1-20190926-C01677
    Figure US20190292176A1-20190926-C01678
         		536.3 1.23 1H NMR (500 MHz, DMSO-d6) δ 10.12-9.93 (m, 1H), 8.83 (br. s., 2H), 8.79 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 10.7 Hz, 1H), 7.85 (s, 1H), 5.70 (dd, J = 6.7, 2.6 Hz, 1H), 5.16 (dd, J = 6.6, 2.5 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H), 1.40 (d, J = 6.6 Hz, 3H).
    717
    Figure US20190292176A1-20190926-C01679
         		I-94  579.3 1.00 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.40 (d, J = 11.0 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H), 7.80 (s, 1H), 7.29 (br. s., 2H), 5.67 (d, J = 6.4 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.08 (s, 3H), 3.64 (t, J = 6.6 Hz, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.61 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    718
    Figure US20190292176A1-20190926-C01680
         		I-92  607.2 1.06 1H NMR (500 MHz, DMSO-d6) δ 9.64 (br. s., 1H), 8.54 (s, 1H), 8.40 (s, 2H), 8.29 (d, J = 10.7 Hz, 1H), 7.74 (s, 2H), 7.22-7.13 (m, 1H), 5.65 (dd, J = 6.7, 2.4 Hz, 1H), 5.12 (dd, J = 6.7, 2.4 Hz, 1H), 4.05 (s, 3H), 3.71-3.70 (m, 1H), 2.67 (d, J = 9.2 Hz, 2H), 2.57 (s, 3H), 1.43 (d, J = 6.7 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 8.9 Hz, 6H).
    719
    Figure US20190292176A1-20190926-C01681
         		I-110 595.1 1.07 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.55 (s, 1H), 8.46 (s, 1H), 8.36 (d, J = 10.7 Hz, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.77 (s, 1H), 7.00 (d, J = 5.5 Hz, 1H), 6.81 (s, 1H), 5.68 (dd, J = 6.6, 2.3 Hz, 1H), 5.14 (dd, J = 6.7, 2.1 Hz, 1H), 4.19-4.09 (m, 3H), 4.07 (s, 3H), 3.65-3.58 (m, 1H), 3.46 (br. s., 1H), 2.60 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H).
    720
    Figure US20190292176A1-20190926-C01682
         		I-109 579.1 1.04 MS (ESI) m/z: 579.1 (M + H)+. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (br. s., 1H), 8.58 (s, 1H), 8.44 (s, 2H), 8.33 (d, J = 10.7 Hz, 1H), 7.76 (s, 2H), 7.16 (d, J = 7.9 Hz, 1H), 5.62 (dd, J = 6.4, 2.4 Hz, 1H), 5.14 (dd, J = 6.4, 2.4 Hz, 1H), 4.06 (s, 3H), 3.65 (t, J = 6.9 Hz, 1H), 3.48 (br. s., 1H), 2.76 (d, J = 4.0 Hz, 2H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H).
    721
    Figure US20190292176A1-20190926-C01683
         		I-97  596.1 1.21 1H NMR (500 MHz, DMSO-d6) δ 9.71 (br. s., 1H), 8.62 (br. s., 1H), 8.50 (s, 1H), 8.40 (d, J = 10.7 Hz, 1H), 7.82 (s, 1H), 5.75 (d, J = 6.4 Hz, 1H), 5.17 (d, J = 6.7 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.28-4.16 (m, 2H), 4.12 (s, 3H), 3.72 (d, J = 5.2 Hz, 2H), 2.65 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H).
    722
    Figure US20190292176A1-20190926-C01684
         		I-106 610.1 1.24 1H NMR (500 MHz, DMSO-d6) δ 9.78-9.71 (m, 1H), 8.70-8.60 (m, 2H), 8.52 (s, 1H), 8.43 (d, J = 10.4 Hz, 1H), 7.84 (s, 1H), 5.73 (dd, J = 6.4, 2.4 Hz, 1H), 5.18 (dd, J = 6.6, 2.3 Hz, 1H), 5.02 (br. s., 1H), 4.93-4.86 (m, 1H), 4.13 (s, 3H), 3.65-3.38 (m, 3H), 2.66 (s, 3H), 1.49 (d, J = 6.1 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H).
    723
    Figure US20190292176A1-20190926-C01685
         		I-94  565.1 1.05 1H NMR (500 MHz, DMSO-d6) δ 9.82-9.74 (m, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.53-8.46 (m, 2H), 8.39 (d, J = 11.0 Hz, 1H), 7.92-7.83 (m, 1H), 7.80 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 5.64 (dd, J = 6.6, 2.6 Hz, 1H), 5.16 (dd, J = 6.6, 2.3 Hz, 1H), 4.47 (s, 2H), 4.08 (s, 3H), 2.61 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H).
    724
    Figure US20190292176A1-20190926-C01686
         		I-105 610.1 1.23 1H NMR (500 MHz, DMSO-d6) δ 9.68-9.57 (m, 1H), 8.57 (s, 1H), 8.52 (br. s., 1H), 8.43 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.75 (s, 1H), 5.65 (dd, J = 6.7, 2.4 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H), 4.91 (d, J = 5.5 Hz, 1H), 4.80 (t, J = 5.6 Hz, 1H), 4.03 (s, 3H), 3.54-3.38 (m, 3H), 2.56 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.7 Hz, 3H), 1.10 (d, J = 6.1 Hz, 3H).
    725
    Figure US20190292176A1-20190926-C01687
         		I-93  595.2 1.22 1H NMR (500 MHz, DMSO-d6) δ 9.42 (br. s., 1H), 8.52 (br. s., 1H), 8.40 (br. s., 1H), 8.34-8.24 (m, 1H), 8.14- 8.01 (m, 1H), 7.73 (br. s., 2H), 6.80-6.59 (m, 1H), 5.66 (br. s., 1H), 5.09 (d, J = 6.1 Hz, 1H), 4.92 (s, 1H), 4.15- 4.08 (m, 1H), 4.05 (s, 3H), 3.72-3.57 (m, 4H), 2.59-2.55 (m, 3H), 1.42 (d, J = 6.1 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H).
    726
    Figure US20190292176A1-20190926-C01688
         		I-99  645.2 1.30 1H NMR (500 MHz, DMSO-d6) δ 9.57 (br. s., 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.31 (d, J = 10.4 Hz, 1H), 8.17 (br. s., 1H), 7.85 (br. s., 1H), 7.75 (s, 1H), 6.88 (br. s., 1H), 5.79 (t, J = 6.1 Hz, 1H), 5.71 (d, J = 5.8 Hz, 1H), 5.17 (d, J = 5.8 Hz, 1H), 4.60-4.39 (m, 2H), 4.10 (s, 3H), 3.77 (br. s., 2H), 2.61 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H), 1.42 (d, J = 6.4 Hz, 3H).
    727
    Figure US20190292176A1-20190926-C01689
         		I-108 637.2 1.13 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.77 (s, 1H), 6.99 (d, J = 5.2 Hz, 1H), 6.76 (s, 1H), 5.70 (d, J = 4.9 Hz, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.27-4.13 (m, 2H), 4.06 (s, 3H), 3.48 (s, 1H), 2.59 (s, 3H), 2.52 (br. s., 6H), 1.72 (t, J = 6.4 Hz, 2H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H).
    728
    Figure US20190292176A1-20190926-C01690
         		I-103 610.2 1.29 1H NMR (500 MHz, DMSO-d6) δ 9.72-9.62 (m, 1H), 8.63 (br. s., 1H), 8.57 (br. s., 2H), 8.50 (s, 1H), 8.41 (d, J = 10.4 Hz, 1H), 7.81 (s, 1H), 5.71 (d, J = 6.7 Hz, 1H), 5.12 (dd, J = 6.4, 2.1 Hz, 1H), 4.97 (d, J = 5.5 Hz, 1H), 4.84 (d, J = 4.9 Hz, 1H), 4.08 (s, 3H), 4.06-3.96 (m, 1H), 3.94-3.89 (m, 2H), 2.62 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.10 (t, J = 5.8 Hz, 3H).
    729
    Figure US20190292176A1-20190926-C01691
         		I-104 610.2 1.29 1H NMR (500 MHz, DMSO-d6) δ 9.72-9.65 (m, 1H), 8.64 (br. s., 1H), 8.57 (br. s., 2H), 8.51 (s, 1H), 8.41 (d, J = 10.7 Hz, 1H), 7.82 (s, 1H), 5.71 (d, J = 6.4 Hz, 1H), 5.16-5.09 (m, 1H), 4.84 (d, J = 4.9 Hz, 1H), 4.08 (s, 3H), 4.06-3.97 (m, 1H), 3.91 (s, 2H), 2.62 (s, 3H), 1.44 (d, J = 6.1 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.10 (s, 3H).
    730
    Figure US20190292176A1-20190926-C01692
         		I-100 638.2 1.32 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.56 (br. s., 2H), 8.50 (s, 1H), 8.40 (d, J = 10.7 Hz, 1H), 7.81 (s, 1H), 5.73 (d, J = 4.9 Hz, 1H), 5.11 (dd, J = 6.4, 1.8 Hz, 1H), 4.34-4.16 (m, 2H), 4.08 (s, 3H), 2.61 (s, 3H), 1.78 (t, J = 7.3 Hz, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 2.7 Hz, 6H).
    731
    Figure US20190292176A1-20190926-C01693
    Figure US20190292176A1-20190926-C01694
         		550.2 1.23 1H NMR (500 MHz, DMSO-d6) δ 8.68 (br. s., 2H), 8.62 (s, 1H), 8.49 (s, 1H), 8.40 (d, J = 11.0 Hz, 1H), 7.81 (s, 1H), 5.69 (d, J = 6.4 Hz, 1H), 5.12 (d, J = 6.4 Hz, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 2.46 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H).
    • Example 733 (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl pyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C01695
  • To a solution of Intermediate I-138 (10 mg, 0.022 mmol) in DCM (1 mL) and THF (0.5 mL) was added pyridin-3-amine (7.18 mg, 0.076 mmol) followed by DIEA (0.038 mL, 0.218 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched with 0.2 mL of MeOH. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 25 to 100% B in 15 minutes) to yield Example 733 (3.5 mg, 6.57 μmol, 30.2% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.62 (br. s., 1H), 8.54 (s, 1H), 8.19 (br. s., 1H), 7.89 (br. s., 1H), 7.82 (s, 1H), 7.30 (d, J=7.9 Hz, 1H), 6.90 (s, 1H), 5.24 (br. s., 1H), 4.65-4.41 (m, 2H), 4.08 (s, 3H), 2.72 (s, 3H), 2.63 (s, 3H), 1.39 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.07 min, MS (ESI) m/z: 517.2 (M+H)+. Analytical HPLC Method B: 97% purity.
    • Examples 734 to 740
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 733 and the examples above
  • LCMS
    LCMS RT
    [M + (Min)
    Ex. H]+ Method
    No. Structure Amine m/z H NMR
    734
    Figure US20190292176A1-20190926-C01696
    Figure US20190292176A1-20190926-C01697
         		549.2 1.36 1H NMR (500 MHz, DMSO-d6) δ 9.88 (br. s., 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.05 (br. s., 1H), 7.81 (s, 1H), 6.90 (s, 1H), 5.22 (br. s., 1H), 4.68-4.38 (m, 2H), 4.08 (s, 3H), 2.72 (s, 3H), 2.63 (s, 3H), 2.18 (s, 3H), 1.38 (d, J = 6.1 Hz, 4H).
    735
    Figure US20190292176A1-20190926-C01698
    Figure US20190292176A1-20190926-C01699
         		542.2 1.30 1H NMR (500 MHz, DMSO-d6) δ 10.30 (br. s., 1H), 8.81 (br. s., 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 8.26 (br. s., 1H), 7.80 (s, 1H), 6.89 (s, 1H), 5.26 (br. s., 1H), 4.74-4.34 (m, 2H), 4.07 (s, 3H), 2.71 (s, 3H), 2.62 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    736
    Figure US20190292176A1-20190926-C01700
    Figure US20190292176A1-20190926-C01701
         		553.1 1.35 1H NMR (500 MHz, DMSO-d6) δ 8.77 (br. s., 2H), 8.59 (s, 1H), 8.44 (s, 1H), 7.73 (s, 1H), 6.85 (s, 1H), 5.22 (br. s., 1H), 4.68 (d, J = 9.5 Hz, 1H), 4.38 (dd, J = 11.9, 6.1 Hz, 1H), 4.04 (s, 3H), 2.67 (s, 3H), 2.58 (s, 3H), 1.39 (d, J = 6.7 Hz, 3H).
    737
    Figure US20190292176A1-20190926-C01702
    Figure US20190292176A1-20190926-C01703
         		532.2 1.25 1H NMR (500 MHz, DMSO-d6) δ 8.73 (br. s., 2H), 8.59 (s, 1H), 8.43 (s, 1H), 7.73 (s, 1H), 6.84 (s, 1H), 5.22 (dd, J = 6.4, 3.4 Hz, 1H), 4.61 (dd, J = 11.7, 2.6 Hz, 1H), 4.39 (dd, J = 11.7, 6.3 Hz, 1H), 4.04 (s, 3H), 2.66 (s, 3H), 2.58 (s, 3H), 2.51 (br. s., 3H), 1.38 (d, J = 6.4 Hz, 3H).
    738
    Figure US20190292176A1-20190926-C01704
    Figure US20190292176A1-20190926-C01705
         		548.2 1.30 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.61 (br. s., 2H), 8.52 (s, 1H), 7.80 (s, 1H), 6.89 (s, 1H), 5.19 (br. s., 1H), 4.66 (d, J = 9.5 Hz, 1H), 4.39 (dd, J = 11.7, 6.0 Hz, 1H), 4 06 (s, 3H), 3.86-3.79 (m, 3H), 2.70 (s, 3H), 2.62 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H).
    740
    Figure US20190292176A1-20190926-C01706
    Figure US20190292176A1-20190926-C01707
         		530.2 1.12 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.62-8.57 (m, 1H), 8.55 (s, 1H), 8.42 (s, 1H), 8.18 (br. s., 1H), 7.88 (br. s., 1H), 7.72 (s, 1H), 7.38- 7.22 (m, 1H), 6.80 (s, 1H), 5.56-5.46 (m, 1H), 5.10 (dd, J = 6.4, 2.4 Hz, 1H), 4.04 (s, 3H), 2.66 (s, 3H), 2.58 (s, 3H), 1.37 (dd, J = 11.6, 6.4 Hz, 6H).
    • Example 741 (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01708
  • To a suspension of Example 689 (0.012 g, 0.021 mmol) in THF (0.207 ml) was added 1-amino-2-methylpropan-2-ol (0.029 ml, 0.622 mmol) followed by magnesium chloride (0.020 g, 0.207 mmol). The reaction vial was sealed and heated to 65° C. overnight. The reaction mixture was diluted with EtOAc and filtered through Celite. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 50 to 100% B in 21 minutes) to yield Example 741 (0.0011 g, 1.713 mol, 8.26% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.15 (br. s., 1H), 8.60 (br. s., 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.35 (d, J=11.0 Hz, 1H), 8.26 (br. s., 1H), 8.04 (d, J=7.9 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.78 (s, 1H), 5.28 (br. s., 1H), 4.89 (d, J=10.1 Hz, 1H), 4.50 (dd, J=11.7, 5.6 Hz, 1H), 4.06 (s, 3H), 3.23 (dd, J=11.1, 6.3 Hz, 2H), 2.59 (s, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.08 (d, J=5.8 Hz, 6H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 636.2 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Examples 742 to 749
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 741 and the examples above.
  • LCMS LCMS
    [M + RT
    Ex. H]+ (Min)/
    No. Structure ester m/z Method NMR
    742
    Figure US20190292176A1-20190926-C01709
         		689 632.2 2.17/B 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br. s., 2H), 8.61 (br. s., 2H), 8.50 (br. s., 1H), 8.41 (d, J = 9.8 Hz, 1H), 8.03 (br. s., 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.82 (br. s., 1H), 5.83- 5.67 (m, 1H), 5.29 (br. s., 2H), 4.95-4.83 (m, 3H), 4.53 (br. s., 2H), 4.08 (br. s., 3H), 3.38 (br. s., 3H), 2.62 (br. s., 3H), 1.85-1.66 (m, 6H).
    743
    Figure US20190292176A1-20190926-C01710
         		689 648.2 2.25/B 1H NMR (500 MHz, DMSO-d6) δ 10.11 (d, J = 12.2 Hz, 1H), 8.58 (br. s., 2H), 8.42 (br. s., 1H), 8.33 (d, J = 10.1 Hz, 1H), 7.99 (br. s., 1H), 7.74 (br. s., 1H), 7.51 (t, J = 10.2 Hz, 1H), 5.31 (br. s., 1H), 5.06 (br. s., 1H), 4.78 (d, J = 10.1 Hz, 2H), 4.06 (s, 3H), 3.51 (s, 2H), 3.14 (br. s., 2H), 3.01-2.91 (m, 2H), 2.58 (s, 3H), 1.92-1.72 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H).
    744
    Figure US20190292176A1-20190926-C01711
         		689 634.2 2.20/B 1H NMR (500 MHz, DMSO-d6) δ 10.15-10.04 (m, 1H), 8.56 (d, J = 10.1 Hz, 2H), 8.42 (br. s., 1H), 8.33 (d, J = 10.4 Hz, 1H), 8.02 (br. s., 1H), 7.75 (br. s., 2H), 5.30 (br. s., 1H), 5.09-4.97 (m, 1H), 4.92-4.74 (m, 1H), 4.52 (br. s., 1H), 4.28 (br. s., 1H), 4.05 (s, 3H), 3.80-3.67 (m, 1H), 3.52-3.36 (m, 2H), 2.58 (br. s., 3H), 1.95-1.84 (m, 1H), 1.77 (br. s., 2H), 1.43 (d, J = 6.1 Hz, 3H).
    745
    Figure US20190292176A1-20190926-C01712
         		689 634.2 2.20/B 1H NMR (500 MHz, DMSO-d6) δ 10.15-10.04 (m, 1H), 8.56 (d, J = 10.1 Hz, 2H), 8.42 (br. s., 1H), 8.33 (d, J = 10.4 Hz, 1H), 8.02 (br. s., 1H), 7.75 (br. s., 2H), 5.30 (br. s., 1H), 5.09-4.97 (m, 1H), 4.92-4.74 (m, 1H), 4.52 (br. s., 1H), 4.28 (br. s., 1H), 4.05 (s, 3H), 3.80-3.67 (m, 1H), 3.52-3.36 (m, 2H), 2.58 (br. s., 3H), 1.95-1.84 (m, 1H), 1.77 (br. s., 2H), 1.43 (d, J = 6.1 Hz, 3H).
    746
    Figure US20190292176A1-20190926-C01713
         		689 648.2 2.19/B 1H NMR (500 MHz, DMSO-d6) δ 10.11 (br. s., 2H), 8.63- 8.53 (m, 2H), 8.45 (s, 1H), 8.36 (d, J = 10.7 Hz, 1H), 7.98 (br. s., 1H), 7.77 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 5.31 (br. s., 1H), 4.87-4.75 (m, 2H), 4.61-4.48 (m, 1H), 4.06 (s, 3H), 4.01 (br. s., 1H), 3.72 (br. s., 1H), 3.60 (br. s., 1H), 3.22- 3.10 (m, 2H), 2.60 (s, 3H), 1.79 (br. s., 1H), 1.67 (br. s., 1H), 1.43 (d, J = 6.1 Hz, 3H), 1.40-1.24 (m, 2H).
    747
    Figure US20190292176A1-20190926-C01714
         		689 622.1 1.17/H 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br. s., 2H), 8.62 (br. s., 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.41-8.34 (m, 2H), 8.03 (br. s., 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 5.29 (br. s., 1H), 4.89 (d, J = 10.1 Hz, 1H), 4.52 (dd, J = 11.7, 5.3 Hz, 1H), 4.07 (s, 3H), 3.75 (br. s., 1H), 3.53 (s, 1H), 3.32- 3.25 (m, 1H), 3.18-3.10 (m, 1H), 2.61 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.10-0.99 (m, 3H).
    748
    Figure US20190292176A1-20190926-C01715
         		689 622.2 1.17/H 1H NMR (500 MHz, DMSO-d6) δ 10.17 (br. s., 2H), 8.63 (br. s., 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.43-8.33 (m, 2H), 8.03 (br. s., 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 5.29 (br. s., 1H), 4.88 (d, J = 10.1 Hz, 1H), 4.52 (dd, J = 11.3, 5.5 Hz, 1H), 4.07 (s, 3H), 3.77 (br. s., 1H), 3.50-3.44 (m, 1H), 3.30 (br. s., 1H), 3.13 (d, J = 7.0 Hz, 1H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 5.8 Hz, 3H).
    749
    Figure US20190292176A1-20190926-C01716
         		690 565.1 1.10/H 1H NMR (500 MHz, DMSO-d6) δ 8.95 (br. s., 2H), 8.58 (s, 1H), 8.43 (s, 1H), 8.36 (d, J = 10.8 Hz, 1H), 8.19-8.01 (m, 2H), 7.75 (s, 1H), 7.65 (br. s., 1H), 5.35-5.26 (m, 1H), 4.84 (d, J = 9.8 Hz, 1H), 4.59-4.48 (m, 1H), 4.05 (s, 3H), 2.58 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H).
    • Example 750 (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01717
  • To a suspension of Example 715 (0.030 g, 0.051 mmol) in THF (0.506 ml) was added (S)-1-aminopropan-2-ol (0.114 g, 1.519 mmol) followed by magnesium chloride (0.047 g, 0.510 mmol). The reaction vial was sealed and heated to 65° C. overnight. The reaction mixture was diluted with EtOAc and filtered through Celite. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 35 to 100% B in 20 minutes) to yield Example 750 (0.0129 g, 0.020 mmol, 40.1% yield 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.51 (d, J=8.2 Hz, 1H), 8.41 (s, 2H), 8.31 (d, J=10.7 Hz, 2H), 7.99 (br. s., 1H), 7.89 (t, J=7.3 Hz, 1H), 7.73 (s, 1H), 5.77 (d, J=6.7 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.91 (s, 1H), 4.05 (s, 3H), 3.77-3.69 (m, 1H), 3.38-2.96 (m, 2H), 2.57 (s, 3H), 1.44 (d, J=6.4 Hz, 3H), 1.38 (d, J=6.4 Hz, 3H), 1.08-0.98 (m, 3H). LC-MS: method H, RT=1.23 min,): MS (ESI) m/z: 636.1 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Examples 751 to 761
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 741 and the examples above.
  • LCMS
    LCMS RT
    Ex. [M + H]+ (Min)/
    No. Structure ester m/z Method NMR
    751
    Figure US20190292176A1-20190926-C01718
         		712 650.2 2.37/B 1H NMR (500 MHz, DMSO-d6) δ 10.23-10.17 (m, 1H), 8.90 (br. s., 2H), 8.48 (s, 1H), 8.43 (s, 1H), 8.37-8.30 (m, 2H), 7.75 (s, 1H), 5.78 (dd, J = 6.6, 2.3 Hz, 1H), 5.22-5.08 (m, 1H), 4.72 (s, 1H), 4.05 (s, 3H), 3.51-3.45 (m, 2H), 3.30-3.14 (m, 2H), 2.58 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 10.4 Hz, 6H).
    752
    Figure US20190292176A1-20190926-C01719
         		712 637.2 1.14/H 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br. s., 1H), 8.87 (br. s., 2H), 8.47 (s, 2H), 8.43 (s, 1H), 8.34 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 5.78 (d, J = 6.7 Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.86 (d, J = 4.9 Hz, 1H), 4.04 (s, 3H), 3.81-3.71 (m, 1H), 3.47 (s, 3H), 3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.57 (s, 3H), 1.43 (d, J = 6.4 Hz, 2H), 1.38 (d, J = 6.4 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H).
    753
    Figure US20190292176A1-20190926-C01720
         		712 637.2 1.14/H 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br. s., 1H), 8.87 (br. s., 2H), 8.47 (s, 2H), 8.43 (s, 1H), 8.34 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 5.78 (d, J = 6.7 Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.86 (d, J = 4.9 Hz, 1H), 4.04 (s, 3H), 3.81-3.71 (m, 1H), 3.47 (s, 3H), 3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.57 (s, 3H), 1.43 (d, J = 6.4 Hz, 2H), 1.38 (d, J = 6.4 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H).
    754
    Figure US20190292176A1-20190926-C01721
         		715 578.2 1.23/H 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.60 (br. s., 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.38 (d, J = 10.8 Hz, 1H), 8.02-7.97 (m, 1H), 7.95-7.88 (m, 2H), 7.76 (s, 1H), 7.42 (br. s., 1H), 5.69 (dd, J = 6.4, 2.4 Hz, 1H), 5.20-5.11 (m, 1H), 4.06 (s, 3H), 2.59 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    755
    Figure US20190292176A1-20190926-C01722
         		712 579.0 1.14/H 1H NMR (500 MHz, DMSO-d6) δ 10.27 (br. s., 1H), 8.92 (br. s., 2H), 8.59 (s, 1H), 8.48 (s, 1H), 8.41 (d, J = 10.8 Hz, 1H), 8.06 (br. s., 1H), 7.79 (s, 1H), 7.64 (br. s., 1H), 5.73 (d, J = 6.4 Hz, 1H), 5.18 (d, J = 4.4 Hz, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 1.46 (d, J = 6.7 Hz, 3H), 1.41 (d, J = 6.7 Hz, 3H).
    756
    Figure US20190292176A1-20190926-C01723
         		715 678.2 2.56/B 1H NMR (500MHz, DMSO-d6) δ 10.01 (br. s., 1H), 8.64 (s, 1H), 8.59-8.53 (m, 1H), 8.51 (s, 1H), 8.41 (d, J = 11.0 Hz, 1H), 8.05- 7.93 (m, 1H), 7.82 (s, 1H), 7.59- 7.52 (m, 1H), 5.67 (br. s., 1H), 5.17 (d, J = 6.1 Hz, 1H), 4.36- 4.15 (m, 1H), 4.08 (s, 3H), 4.05- 3.99 (m, 1H), 3.91 (s, 2H), 3.75 (br. s., 2H), 3.66-3.31 (m, 3H), 3.33-2.97 (m, 1H), 2.62 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H).
    757
    Figure US20190292176A1-20190926-C01724
         		715 648.2 2.41/B 1H NMR (500 MHz, DMSO-d6) δ 9.99-9.88 (m, 1H), 8.52-8.48 (m, 1H), 8.42 (br. s., 1H), 8.38- 8.28 (m, 2H), 8.12-7.87 (m, 1H), 7.74 (br. s., 1H), 7.69 (d, J = 7.9 Hz, 1H), 5.81-5.65 (m, 1H), 5.14 (br. s., 1H), 5.05-4.92 (m, 1H), 4.24 (br. s., 1H), 4.05 (s, 3H), 3.58 (d, J = 5.8 Hz, 3H), 3.51- 3.32 (m, 1H), 2.58 (s, 3H), 1.93- 1.65 (m, 2H), 1.45 (br. s., 3H), 1.39 (d, J = 6.1 Hz, 3H).
    758
    Figure US20190292176A1-20190926-C01725
         		715 662.2 2.47/B 1H NMR (500 MHz, DMSO-d6) δ 9.96 (d, J = 18.9 Hz, 1H), 8.54 (br. s., 2H), 8.41 (br. s., 1H), 8.32 (d, J = 10.7 Hz, 1H), 7.96 (br. s., 1H), 7.74 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 5.67 (br. s., 2H), 5.18-5.09 (m, 2H), 4.90 (d, J = 4.9 Hz, 1H), 4.05 (s, 3H), 3.84 (br. s., 1H), 3.47 (br. s., 1H), 3.14 (br. s., 1H), 2.90 (s, 1H), 2.82-2.64 (m, 1H), 2.56 (s, 3H), 1.90-1.70 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    759
    Figure US20190292176A1-20190926-C01726
         		715 662.0 2.97/B 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.53 (s, 2H), 8.40 (s, 1H), 8.30 (d, J = 10.7 Hz, 1H), 8.04-7.90 (m, 1H), 7.72 (s, 1H), 7.49 (br. s., 1H), 5.67 (br. s., 1H), 5.15 (d, J = 6.4 Hz, 1H), 4.90 (br. s., 1H), 4.04 (s, 3H), 3.74-3.55 (m, 4H), 3.24-2.95 (m, 2H), 2.57 (br. s., 3H), 1.78 (br. s., 1H), 1.68-1.54 (m, 1H), 1.44 (d, J = 6.1 Hz, 3H), 1.39 (d, J = 6.1 Hz, 3H), 1.27 (br. s., 1H).
    760
    Figure US20190292176A1-20190926-C01727
         		715 648.0 2.98/B 1H NMR (500 MHz, DMSO-d6) δ 9.99-9.88 (m, 1H), 8.52-8.48 (m, 1H), 8.42 (br. s., 1H), 8.38- 8.28 (m, 2H), 8.12-7.87 (m, 1H), 7.74 (br. s., 1H), 7.69 (d, J = 7.9 Hz, 1H), 5.81-5.65 (m, 1H), 5.14 (br. s., 1H), 5.05-4.92 (m, 1H), 4.24 (br. s., 1H), 4.05 (s, 3H), 3.58 (d, J = 5.8 Hz, 3H), 3.51-3.32 (m, 1H), 2.58 (s, 3H), 1.93- 1.65 (m, 2H), 1.45 (br. s., 3H), 1.39 (d, J = 6.1 Hz, 3H).
    761
    Figure US20190292176A1-20190926-C01728
         		712 676.0 3.43/B 1H NMR (500 MHz, DMSO-d6) δ 9.98 (br. s., 1H), 8.51 (d, J = 7.0 Hz, 2H), 8.45 (d, J = 11.6 Hz, 2H), 8.33 (d, J = 10.7 Hz, 1H), 7.99 (br. s., 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 5.76 (d, J = 6.4 Hz, 1H), 5.14 (br. s., 1H), 4.83 (br. s., 1H), 4.06 (s, 3H), 3.36 (d, J = 4.9 Hz, 2H), 2.58 (s, 3H), 1.83-1.62 (m, 8H), 1.45 (d, J = 6.1 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    • Example 762 N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)-4-methylbenzenesulfonamide
  • Figure US20190292176A1-20190926-C01729
  • To a solution of Intermediate 662D (15 mg, 0.039 mmol) in DMF (1 mL) was added DIEA (0.069 mL, 0.393 mmol) and 4-methylbenzene-1-sulfonyl chloride (9.00 mg, 0.047 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched by 0.2 ml of MeOH. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 65 to 100% B in 22 minutes) to yield Example 762 (7.52 mg, 0.014 mmol, 35.7% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.52 (s, 1H), 7.89 (t, J=5.4 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.72 (s, 1H), 4.31 (t, J=5.5 Hz, 2H), 4.08 (s, 3H), 3.21 (d, J=5.5 Hz, 2H), 2.71 (s, 3H), 2.63 (s, 3H), 2.35 (s, 3H). LC-MS: method H, RT=1.23 min,): MS (ESI) m/z: 536.1 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 763 6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C01730
    • Intermediate 763A: 5-bromo-3-fluoro-2-methoxy-4-methylpyridine
  • Figure US20190292176A1-20190926-C01731
  • 3-fluoro-2-methoxy-4-methylpyridine (0.500 g, 3.54 mmol) was dissolved in AcOH (17.71 ml). Next, bromine (0.219 ml, 4.25 mmol) and sodium acetate (0.581 g, 7.09 mmol) were added, and the reaction mixture was heated to 80° C. overnight. The reaction was carefully quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with 1 N NaOH, water, then brine, then dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate 763A (0.450 g, 2.045 mmol, 57.7% yield) as a white solid. LC-MS: Method H, RT=1.02 min, MS (ESI) m/z: 220.1 (M+H)+.
    • Intermediate 763B: N-benzyl-5-fluoro-6-methoxy-4-methylpyridin-3-amine
  • Figure US20190292176A1-20190926-C01732
  • Intermediate 763A (0.450 g, 2.045 mmol), copper(I) iodide (0.078 g, 0.409 mmol), potassium carbonate (0.424 g, 3.07 mmol), and L-proline (0.094 g, 0.818 mmol) was added. The reaction mixture was placed under vacuum and backfilled with argon. The solids were dissolved in DMSO (20.45 ml) and stirred for 5 min. To the reaction was added benzylamine (0.268 ml, 2.454 mmol) and the reaction mixture was heated to 80° C. overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with water, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. Purified on ISCO using a 40 g column with 0-100% EtOAc in hexanes gradient to yield Intermediate 763B (0.123 g, 0.499 mmol, 24.42% yield): 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 6H), 4.33 (d, J=5.1 Hz, 2H), 3.93 (s, 3H), 3.48 (br. s., 1H), 2.12 (d, J=2.2 Hz, 3H). LC-MS: method H, RT=0.99 min, MS (ESI) m/z: 247.2 (M+H)+.
    • Intermediate 763C: 5-fluoro-6-methoxy-4-methylpyridin-3-amine
  • Figure US20190292176A1-20190926-C01733
  • Intermediate 763B (0.150 g, 0.609 mmol) was dissolved in MeOH (6.09 ml) and palladium on carbon (0.130 g, 0.122 mmol) was added. The reaction mixture was placed under vacuum and back filled with argon three times. The reaction mixture was placed under vacuum and back filled with hydrogen (1.228 mg, 0.609 mmol) three times. The reaction mixture was allowed to stir at room temperature for 3h. The reaction mixture was filtered and concentrated to yield Intermediate 763C (0.074 g, 0.474 mmol, 78% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 3.94 (s, 3H), 3.33 (br. s., 1H), 2.13 (d, J=2.0 Hz, 3H). LC-MS: method H, RT=0.55 min, MS (ESI) m/z: MS (ESI) m/z: 157.0 (M+H)+.
    • Intermediate 763D: 6-fluoro-5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-amine
  • Figure US20190292176A1-20190926-C01734
  • Potassium thiocyanate (0.046 g, 0.474 mmol) was dissolved in acetic acid (1.137 ml) and cooled to 0° C. Intermediate 763C (0.074 g, 0.474 mmol) was dissolved in acetic acid (0.379 ml) and added dropwise. Bromine (0.049 ml, 0.948 mmol) was dissolved in acetic acid (0.379 ml) and added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was diluted with water and neutralized with 1 N NaOH. The aqueous solution was extracted with EtOAc×3. The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 763D (0.099 g, 0.464 mmol, 98% yield). LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: MS (ESI) m/z: 214.1 (M+H)+.
    • Intermediate 763E: 2-bromo-6-fluoro-5-methoxy-7-methylthiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C01735
  • Copper(II)bromide (0.178 g, 0.797 mmol) and t-butyl nitrite (0.095 ml, 0.797 mmol) were dissolved in MeCN (1.876 ml) and allowed to stir 10 minutes. Intermediate 763D (0.100 g, 0.469 mmol) was dissolved in MeCN (2.81 ml) and the copper solution was added. The reaction mixture was stirred for 2.5h at 60° C. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using a 12 g column with 0-100% gradient of EtOAc in hexanes to yield Intermediate 763E (0.098 g, 0.354 mmol, 75% yield). 1H NMR (400 MHz, CDCl3) δ 4.06 (s, 1H), 2.60 (d, J=2.2 Hz, 1H). LC-MS: method H, RT=1.13 min, MS (ESI) m/z: MS (ESI) m/z: 277.1 (M+H)+.
    • Example 763
  • Intermediate I-2 (0.017 g, 0.054 mmol) and Intermediate 763E (0.015 g, 0.054 mmol) were dissolved in DMF (1 ml). PdCl2(dppf)-CH2Cl2 adduct (2.65 mg, 3.25 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Next, Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in a microwave for 30 minutes. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 60 to 100% B in 20 minutes) to yield Example 763 (0.0008 g, 1.831 μmol, 3.38% yield): LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 385.2 (M+H)+. Analytical HPLC Method B: 88% purity.
    • Example 764 (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01736
  • Example 712 (50 mg, 0.084 mmol) was solvated in THF (1 mL) and cooled to −78° C. To this mixture was added diisobutylaluminum hydride (1 M in toluene) (0.253 mL, 0.253 mmol) and the reaction mixture was stirred for 30 min. The reaction was quenched with 1 mL of a 1 M HCl solution at −78° C. The reaction mixture was allowed to thaw to room temperature and stirred for a total of 30 min. The mixture was diluted with EtOAc and washed with saturated NH4Cl before being dried over MgSO4 and filtered over a pad of SiO2 gel. The filtrate was concentrated and resubjected to identical reaction conditions. The reaction mixture was diluted with sat′d Rochelle's salt and allowed to stir overnight. The reaction mixture was diluted with EtOAc and the layers were separated. The aqueous layer was back extracted with EtOAc×3 and the combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Example 764 (24.2 mg, 0.042 mmol, 49.8% yield): 1H NMR (400 MHz, CDCl3) δ 8.91-8.84 (m, 2H), 8.58 (d, J=1.8 Hz, 1H), 8.55 (s, 1H), 8.01 (d, J=10.3 Hz, 1H), 7.85-7.74 (m, 1H), 6.69-6.53 (m, 1H), 5.75 (dd, 2.5 Hz, 1H), 5.27 (dd, 2.6 Hz, 1H), 4.82 (d, J=4.8 Hz, 2H), 4.16 (s, 3H), 3.49 (s, 1H), 2.67 (s, 3H), 1.50 (t, J=6.9 Hz, 6H). LC-MS: method H, RT=1.23 min,): MS (ESI) m/z: 566.2 (M+H)+. Analytical HPLC Method B: 95% purity.
    • Example 765 (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01737
  • A solution of Example 715 (0.045 g, 0.076 mmol) in THF (1 mL) was cooled to −78° C. Methylmagnesium bromide (0.101 mL, 0.304 mmol) was added and the mixture was allowed to warm to room temperature. The mixture was stirred for 1 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. Purified by ISCO using a 24 g column eluting with 0-70% EtOAc in DCM to yield Example 765 (0.015 g, 0.025 mmol, 33.3% yield). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=1.8 Hz, 2H), 8.37 (s, 1H), 7.98 (d, J=10.3 Hz, 1H), 7.77 (s, 1H), 7.31 (s, 2H), 6.59 (br. s., 1H), 5.66 (br. s., 1H), 5.23 (dd, J=6.5, 3.0 Hz, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 1.48 (d, J=6.6 Hz, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.25 (s, 6H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 593.2 (M+H)+.
  • The methyl ketone (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl) thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-acetylpyridin-3-yl)carbamate was also isolated from the reaction as Intermediate 765A (0.020 g, 0.035 mmol 35% yield), which will be used below. LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 577.2 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 766 (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(1-hydroxyethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01738
  • Intermediate 765A (0.020 g, 0.035 mmol) was dissolved in THF (0.347 ml) and cooled to −78° C. To the cooled reaction mixture was added DIBAL-H in toluene (0.087 ml, 0.087 mmol), and the reaction mixture was allowed to stir for 1 h. The reaction mixture was allowed to warm to room temperature and saturated solution of Rochelle's salt was added. The resulting mixture was allowed to stir overnight. The reaction mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 60 to 100% B in 15 minutes, then a 6 minute hold time) to yield the racemic product. The reaction was further purified 35% EtOH/65% CO2 in a 15 min run, Lux 5 u Cellulose-4, 21×250 mm, 5 micron column, flow rate 45 mL/min, 150 Bar, 40° C. and UV detection was set to 220 nm to yield Example 766 (3.3 mg, 5.48 μmol, 15.78% yield) as the first eluting isomer: 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br. s., 1H), 8.63 (br. s., 1H), 8.48 (s, 2H), 8.37 (d, J=10.7 Hz, 1H), 7.80 (s, 2H), 5.64 (d, J=4.9 Hz, 1H), 5.15 (d, J=5.8 Hz, 1H), 4.07 (s, 3H), 3.56-3.48 (m, 3H), 2.61 (s, 3H), 1.44 (d, J=6.4 Hz, 3H), 1.38 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 579.2 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 767 (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (6-(1-hydroxyethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01739
  • Intermediate 765A (0.020 g, 0.035 mmol) was dissolved in THF (0.347 ml) and cooled to −78° C. To the cooled reaction, was added DIBAL-H in toluene (0.087 ml, 0.087 mmol), and the reaction mixture was allowed to stir for 1 h. The reaction mixture was allowed to warm to room temperature and sat′d solution of Rochelle's salt was added. The reaction mixture was allowed to stir overnight. The reaction mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 60 to 100% B in 15 minutes, then a 6 minute hold time) to yield the racemic product. The reaction was further purified as above 35% EtOH/65% CO2 in a 15 min run, Lux 5 u Cellulose-4, 21×250 mm, 5 micron column, flow rate 45 mL/min, 150 Bar, 40° C. and UV detection was set to 220 nm to yield Example 767 (2.9 mg, 4.66 μmol, 13.4% yield) as the second eluting isomer: 1H NMR (500 MHz, DMSO-d6) δ 9.80-9.64 (m, 1H), 8.63 (s, 1H), 8.48 (s, 2H), 8.37 (d, J=10.7 Hz, 1H), 7.80 (s, 2H), 7.43-7.35 (m, 1H), 5.69-5.60 (m, 1H), 5.22-5.10 (m, 1H), 4.64 (d, J=6.4 Hz, 1H), 4.07 (s, 3H), 3.55 (br. s., 4H), 2.61 (s, 3H), 1.45 (d, J=6.7 Hz, 3H), 1.38 (d, J=6.7 Hz, 3H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 579.2 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 768 (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01740
  • Example 689 (50 mg, 0.086 mmol) was solvated in THF (1 mL) and cooled to −78° C. To this mixture was added diisobutylaluminum hydride (1 M in toluene) (0.259 mL, 0.259 mmol) and stirred for 30 min. The reaction was quenched with 1 mL of a 1 M HCl solution at −78° C. The reaction mixture was allowed to thaw to room temperature and stirred for a total of 30 min. The mixture was diluted with EtOAc and washed with saturated NH4Cl before being dried over MgSO4 and filtered over a pad of SiO2 gel to remove aluminates. The filtrate was concentrated and resubjected to identical reaction conditions. The reaction mixture was diluted with sat'd Rochelle's salt and allowed to stir overnight. The reaction mixture was diluted with EtOAc and the layers were separated. The aqueous layer was back extracted with EtOAc×3 and the combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The reaction was purified on ISCO using a 12 g column eluting with 0-100% EtOAc in hexanes to yield Example 768 (19.60 mg, 0.034 mmol, 39.1% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.88 (br. s., 2H), 8.59 (s, 1H), 8.57 (s, 1H), 8.03 (d, J=10.3 Hz, 1H), 7.81 (s, 1H), 6.67 (br. s., 1H), 5.44 (dt, J=6.3, 3.0 Hz, 1H), 4.89-4.78 (m, 3H), 4.57 (d, J=6.2 Hz, 1H), 4.16 (s, 3H), 3.50 (br. s., 1H), 2.68 (s, 3H), 1.53 (d, J=6.4 Hz, 3H). MS (ESI) m/z: 552.1 (M+H)+. LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 552.1 (M+H)+. Analytical HPLC Method B: 95% purity.
    • Example 769 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01741
  • Intermediate I-121 (15 mg, 0.047 mmol), Intermediate I-135 (21.26 mg, 0.052 mmol) and PdCl2(dppf) (2.061 mg, 2.82 μmol) were dissolved in dioxane (469 μl) and Na2CO3 (211 μl, 0.422 mmol) and heated to 100° C. in an oil bath for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 25 to 100% B in 15 minutes) to yield Example 769 (7.2, 12.65 mmol, 2.70E+04% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.77 (br. s., 1H), 8.68 (br. s., 2H), 8.55 (s, 1H), 8.41 (d, J=10.7 Hz, 1H), 8.19 (s, 1H), 7.93 (br. s., 1H), 5.73 (d, J=6.4 Hz, 1H), 5.13 (d, J=6.1 Hz, 1H), 4.00 (s, 3H), 2.46 (s, 3H), 1.44 (d, J=6.4 Hz, 3H), 1.38 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.42, MS (ESI) m/z: 569.1 (M+H)+. Analytical HPLC Method B: 100%
    • Examples 770 to 775
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 769 and the examples above. If necessary, removal of silyl protecting groups was accomplished by treatment of the protected compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to afford the desired compound.
  • LCMS LCMS
    Ex. Boronic [M + H]+ RT (Min)
    No. Structure acid Chloride m/z Method H NMR
    770
    Figure US20190292176A1-20190926-C01742
         		I-121 I-139 555.1 1.40 1H NMR (500 MHz, DMSO-d6) δ 10.03-9.92 (m, 1H), 8.82 (br. s., 1H), 8.73 (br. s., 2H), 8.56 (s, 1H), 8.44 (d, J = 10.7 Hz, 1H), 8.19 (s, 1H), 7.93 (br. s., 1H), 5.28 (br. s., 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.55 (dd, J = 11.7, 6.3 Hz, 1H), 4.00 (s, 3H), 2.50-2.50 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H).
    771
    Figure US20190292176A1-20190926-C01743
         		I-124 I-139 535.2 1.03 1H NMR (500 MHz, DMSO-d6) δ 8.73 (br. s., 2H), 8.58 (br. s., 1H), 8.47-8.38 (m, 1H), 7.89 (d, J = 9.8 Hz, 1H), 7.21- 6.97 (m, 2H), 5.28 (br. s., 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.62-4.50 (m, 1H), 4.00 (s, 3H), 2.61 (s, 3H), 1 48-1.40 (m, 3H).
    772
    Figure US20190292176A1-20190926-C01744
         		I-136 I-130 552.2 1.09 1H NMR (500 MHz, DMSO-d6) δ 8.77 (br. s., 1H), 8.66 (br. s., 2H), 8.41 (d, J = 9.5 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.93-7.82 (m, 3H), 5.04 (d, J = 6.4 Hz, 1H), 4.75 (d, J = 6.1 Hz, 1H), 3.93 (s, 3H), 2.48 (br. s., 3H), 1.33 (br. s., 6H).
    773
    Figure US20190292176A1-20190926-C01745
         		I-140 I-130 564.3 0.92 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s, 1H), 8.83 (br. s., 1H), 8.75 (br. s., 2H), 8.06- 7.99 (m, 2H), 7.98-7.93 (m, 2H), 5.22-5.05 (m, 1H), 4.81 (br. s., 2H), 4.00 (br. s., 3H), 2.55 (br. s., 5H), 1.40 (br. s., 6H).
    774
    Figure US20190292176A1-20190926-C01746
         		I-121 I-137 615.1 1.18 1H NMR (500 MHz, DMSO-d6) δ 9.66 (br. s., 1H), 8.76 (br. s., 1H), 8.59-8.56 (m, 2H), 8.54 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 10.7 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 2.7 Hz, 1H), 5.72 (dd, J = 6.6, 2.3 Hz, 1H), 5.11 (dd, J = 6.4, 2.1 Hz, 1H), 4.87 (s, 1H), 4.22-4.10 (m, 2H), 3.99 (s, 3H), 3.66 (d, J = 5.5 Hz, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.7 Hz, 3H).
    775
    Figure US20190292176A1-20190926-C01747
         		I-124 I-137 595.0 1.08 1H NMR (500 MHz, DMSO-d6) δ 9.71-9.54 (m, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.56-8.46 (m, 3H), 8.33 (d, J = 10.7 Hz, 1H), 7.83-7.72 (m, 2H), 5.63 (dd, J = 6.6, 2.3 Hz, 1H), 5.14-4.99 (m, 1H), 4.76 (s, 1H), 4.19-4.03 (m, 2H), 3.92 (s, 3H), 3.60 (d, J = 5.5 Hz, 2H), 2.53 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.7 Hz, 3H).
    • Example 776 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (5-fluoropyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01748
    • Intermediate 776A: (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C01749
  • Intermediate I-121 (75 mg, 0.235 mmol), Intermediate I-133 (64.7 mg, 0.235 mmol) and PdCl2(dppf) (10.30 mg, 0.014 mmol) were dissolved in dioxane (2347 μl) and Na2CO3 (1056 μl, 2.112 mmol) and heated to 100° C. in an oil bath for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using 0-100% EtOAc in DCM on a 24 g column to yield Intermediate 776A (0.054 g, 0.124 mmol, 53.0% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.80 (dd, J=16.2, 2.5 Hz, 2H), 8.02 (d, J=10.3 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.9 Hz, 1H), 5.48-5.35 (m, 1H), 4.22-4.10 (m, 1H), 4.03 (s, 3H), 2.56-2.47 (m, 1H), 1.46 (d, J=6.4 Hz, 3H), 1.33 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 433.9 (M+H)+.
    • Intermediate 776B: (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C01750
  • To a solution of Intermediate 776A (0.054 g, 0.124 mmol) in THF (5 mL) at room temperature was added 15% phosgene in toluene (0.439 mL, 0.622 mmol), and the mixture was stirred at room temperature overnight. Solvent was completely removed to give Intermediate 776B (0.062 g, 0.112 mmol, 90% yield) as a yellow solid. LC-MS: method H, RT=1.39 min MS (ESI) m/z: 495.9 (M+H)+.
    • Example 776
  • 5-fluoropyridin-3-amine (3.39 mg, 0.030 mmol) and pyridine (0.016 mL, 0.201 mmol) were dissolved in DCM (2 mL). To this solution was added Intermediate 776B (0.010 g, 0.020 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure, redissolved in DMF, filtered, and purified by preparative HPLC (Method D, 25 to 100% B in 15 minutes) to yield Example 776 (0.0072 g, 0.013 mmol, 62.5% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.07 (br. s., 1H), 8.76 (s, 1H), 8.54 (s, 1H), 8.44-8.37 (m, 2H), 8.18 (s, 1H), 8.14 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.81 (br. s., 1H), 5.71 (d, J=6.1 Hz, 1H), 5.17 (d, J=5.2 Hz, 1H), 4.00 (s, 3H), 1.46 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 572.0 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Examples 777 to 791
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 776 and the examples above. If necessary, removal of silyl protecting groups was accomplished by treatment of the protected compound with a solution of 90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to afford the desired compound.
  • LCMS LCMS
    Ex. [M + H]+ RT (Min)
    No. Structure Amine m/z Method H NMR
    777
    Figure US20190292176A1-20190926-C01751
    Figure US20190292176A1-20190926-C01752
         		610.0 1.50 1H NMR (500 MHz, DMSO- d6) δ 11.39 (s, 1H), 9.53 (br. s., 1H), 8.70 (br. s., 1H), 8.52 (s, 1H), 8.37 (d, J = 11.0 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.37 (br. s, 1H), 7.09 (br. s., 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.66 (d, J = 4.6 Hz, 1H), 5.13 (d, J = 4.3 Hz, 1H), 3.98 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H).
    778
    Figure US20190292176A1-20190926-C01753
    Figure US20190292176A1-20190926-C01754
         		656.0 1.08 1H NMR (500 MHz, DMSO- d6) δ 9.90 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.35 (d, J = 10.7 Hz, 1H), 8.13 (s, 1H), 7.94-7.84 (m, 2H), 7.00-6.95 (m, 1H), 6.76 (br. s, 1H), 5.77-5.64 (m, 1H), 5.23-5.09 (m, 1H), 4.19 (dt, J = 19.8, 7.4 Hz, 2H), 3.97 (s, 3H), 3.49 (s, 1H), 1.74-1.68 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.10 (s, 6H).
    779
    Figure US20190292176A1-20190926-C01755
    Figure US20190292176A1-20190926-C01756
         		614.1 1.06 1H NMR (500 MHz, DMSO- d6) δ 9.49 (br. s., 1H), 8.79 (br. s., 1H), 8.56 (s, 1H), 8.42 (d, J = 10.7 Hz, 1H), 8.19 (s, 1H), 8.12 (br. s., 1H), 7.93 (br. s., 1H), 7.76 (br. s., 1H), 6.72 (br. s., 1H), 5.68 (d, J = 6.7 Hz, 1H), 5.12 (d, J = 6.7 Hz, 1H), 4.18-4.06 (m, 2H), 4.00 (s, 3H), 3.65 (t, J = 4.9 Hz, 2H), 3.36 (br. s., 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H).
    780
    Figure US20190292176A1-20190926-C01757
    Figure US20190292176A1-20190926-C01758
         		614.1 1.06 1H NMR (500 MHz, DMSO- d6) δ 9.95 (s, 1H), 8.74 (d, J = 2.7 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 11.0 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 7.94-7.88 (m, 2H), 7.02 (d, J = 5.5 Hz, 1H), 6.82 (s, 1H), 5.70 (d, J = 6.7 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.14 (dq, J = 19.5, 5.5 Hz, 2H), 4.00 (s, 3H), 3.61 (d, J = 4.0 Hz, 2H), 3.39 (s, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    781
    Figure US20190292176A1-20190926-C01759
    Figure US20190292176A1-20190926-C01760
         		598.1 1.06 1H NMR (500 MHz, DMSO- d6) δ 9.74 (br. s., 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.49 (br. s., 1H), 8.42 (d, J = 11.0 Hz, 1H), 8.19 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.79 (br. s., 1H), 7.26-7.18 (m, 1H), 5.66 (d, J = 6.4 Hz, 1H), 5.16 (d, J = 7.3 Hz, 1H), 4.00 (s, 3H), 3.66 (t, J = 6.9 Hz, 2H), 3.38 (br. s., 1H), 2.77 (q, J = 6.1 Hz, 2H), 1.46 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    782
    Figure US20190292176A1-20190926-C01761
    Figure US20190292176A1-20190926-C01762
         		570.9 1.25 1H NMR (500 MHz, DMSO- d6) δ 10.21-10.16 (m, 1H), 8.87 (d, J = 2.7 Hz, 1H), 8.63 (s, 1H), 8.47 (br. s., 1H), 8.20 (br. s., 2H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 11.3 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 12.2 Hz, 1H), 5.13 (br. s., 1H), 4.82 (br. s., 1H), 4.00 (s, 3H), 1.49-1.34 (m, 6H).
    783
    Figure US20190292176A1-20190926-C01763
    Figure US20190292176A1-20190926-C01764
         		622.9 1.31 1H NMR (500 MHz, DMSO- d6) δ 10.32 (s, 1H), 8.83 (d, J = 2.7 Hz, 1H), 8.77 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.14-8.10 (m, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.6 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 5.15 (dd, J = 6.6, 2.3 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 1.42 (dd, J = 6.0, 3.8 Hz, 6H).
    784
    Figure US20190292176A1-20190926-C01765
    Figure US20190292176A1-20190926-C01766
         		582.9 1.26 1H NMR (500 MHz, DMSO- d6) δ 9.65-9.57 (m, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.61 (s, 1H), 8.23-8.20 (m, 1H), 8.18 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.93 (br. s., 1H), 7.82-7.73 (m, 1H), 6.76 (d, J = 8.2 Hz, 1H), 5.09 (d, J = 4.6 Hz, 1H), 4.80 (d, J = 5.5 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 1.39 (dd, J = 9.9, 6.6 Hz, 6H).
    785
    Figure US20190292176A1-20190926-C01767
    Figure US20190292176A1-20190926-C01768
         		583.0 1.05 1H NMR (500 MHz, DMSO- d6) d 9.91 (br. s., 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.61 (s, 1H), 8.24 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.99-7.91 (m, 3H), 7.55 (br. s., 1H), 5.12 (d, J = 4.6 Hz, 1H), 4.81 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 1.41 (t, J = 6.6 Hz, 6H).
    786
    Figure US20190292176A1-20190926-C01769
    Figure US20190292176A1-20190926-C01770
         		577.9 1.25 1H NMR (500 MHz, DMSO- d6) d 10.28 (br. s., 1H), 8.87-8.81 (m, 2H), 8.60 (s, 2H), 8.25 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.3 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 5.14 (d, J = 4.3 Hz, 1H), 4.85 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 1.42 (d, J = 4.9 Hz, 6H).
    787
    Figure US20190292176A1-20190926-C01771
    Figure US20190292176A1-20190926-C01772
         		582.8 1.02 1H NMR (500 MHz, DMSO- d6) d 9.71 (br. s., 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.62 (s, 1H), 8.33 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.93 (br. s., 1H), 7.63 (br. s., 1H), 5.10 (d, J = 4.0 Hz, 1H), 4.81 (d, J = 4.3 Hz, 1H), 4.00 (s, 3H), 2.33 (s, 3H), 2.18 (s, 3H), 1.40 (t, J = 7.3 Hz, 6H).
    788
    Figure US20190292176A1-20190926-C01773
    Figure US20190292176A1-20190926-C01774
         		552.9 1.02 1H NMR (500 MHz, DMSO- d6) δ 9.91 (br. s., 1H), 8.86 (d, J = 2.7 Hz, 1H), 8.65 (br. s., 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 4.3 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.92-7.88 (m, 1H), 7.33 (dd, J = 8.2, 4.6 Hz, 1H), 5.22-5.08 (m, 1H), 4.81 (d, J = 3.7 Hz, 1H), 4.00 (s, 3H), 1.41 (t, J = 6.7 Hz, 6H).
    789
    Figure US20190292176A1-20190926-C01775
    Figure US20190292176A1-20190926-C01776
         		571.0 1.27 1H NMR (500 MHz, DMSO- d6) d 10.01-9.90 (m, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.27 (br. s., 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 11.6 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 6.4 Hz, 1H), 5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.81 (d, J = 3.7 Hz, 1H), 4.00 (s, 3H), 1.41 (t, J = 6.4 Hz, 6H).
    790
    Figure US20190292176A1-20190926-C01777
    Figure US20190292176A1-20190926-C01778
         		552.9 1.02 1H NMR (500 MHz, DMSO- d6) δ 10.31 (s, 1H), 8.86 (d, J = 2.7 Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 5.5 Hz, 2H), 8.19 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.3 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 5.8 Hz, 2H), 5.16 (d, J = 4.0 Hz, 1H), 4.82 (d, J = 3.7 Hz, 1H), 4.00 (s, 3H), 1.48-1.36 (m, 6H).
    791
    Figure US20190292176A1-20190926-C01779
    Figure US20190292176A1-20190926-C01780
         		549.2 1.06 1H NMR (500 MHz, DMSO- d6) δ 9.76 (br. s., 1H), 8.65 (br. s., 2H), 8.49 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.80 (d, J = 9.8 Hz, 2H), 7.61-7.33 (m, 1H), 7.18-6.88 (m, 1H), 5.65 (d, J = 6.4 Hz, 1H), 5.06 (d, J = 6.4 Hz, 1H), 3.92 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H), 1.37 (d, J = 6.1 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H).
    • Example 792 (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01781
    • Intermediate 792A: methyl 5-(((((2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C01782
  • Intermediate I-124 (6.56 mg, 0.022 mmol), Intermediate I-141 (10 mg, 0.022 mmol), and PdCl2(dppf) (0.963 mg, 1.316 μmol) were dissolved in dioxane (219 μl) and 3 M aqueous Na2CO3 (99 μl, 0.197 mmol) was added. The reaction mixture was heated to 100° C. in an oil bath for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The reaction material was dissolved in DCM and filtered. Purified on ISCO using 0-100% EtOAc in DCM on a 4 g column to yield Intermediate 792A (7.5 mg, 0.013 mmol, 57.7% yield) as a yellow solid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 593.1 (M+H)+.
    • Example 792
  • Intermediate 792A (7.5 mg, 0.013 mmol) was dissolved in THF (127 μl) and lithium borohydride (0.276 mg, 0.013 mmol) was added in one portion. The reaction mixture was allowed to stir at room temperature for 3 h. Residue was dissolved in THF and air was bubbled through the reaction until the solvent was evaporated. The reaction material was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% B in 15 minutes) to yield Example 792 (1.7 mg, 2.95 μmol, 23.32% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br. s., 1H), 8.80 (br. s., 2H), 8.74 (br. s., 1H), 8.57 (br. s., 1H), 8.41 (d, J=10.7 Hz, 1H), 7.88 (d, J=10.4 Hz, 2H), 5.70 (br. s., 1H), 5.17 (br. s., 1H), 4.49 (br. s., 2H), 4.00 (br. s., 3H), 3.84-3.34 (m, 1H), 2.61 (br. s., 3H), 1.54-1.34 (m, 6H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 565.2 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Example 793 (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01783
    • Intermediate 793A: methyl 5-(((((2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C01784
  • Intermediate I-121 (7.01 mg, 0.022 mmol), Intermediate I-141 (10 mg, 0.022 mmol), and PdCl2(dppf) (0.963 mg, 1.316 μmol) were dissolved in dioxane (219 μl) and 3 M aqueous Na2CO3 (99 μl, 0.197 mmol) was added. The reaction mixture was heated to 100° C. in an oil bath for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The reaction material was dissolved in DCM and filtered. Purified on ISCO using 0-100% EtOAc in DCM on a 4 g column to yield Intermediate 793A (5.9 mg, 0.0096 mmol, 44% yield) as a yellow solid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 613.1 (M+H)+.
    • Example 793
  • Intermediate 793A (5.9 mg, 0.009 mmol) was dissolved in THF (127 μl) and lithium borohydride (0.276 mg, 0.013 mmol) was added in one portion. The reaction mixture was allowed to stir at room temperature for 3 h. Residue was dissolved in THF and air was bubbled through the reaction until the solvent was evaporated. The reaction material was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% B in 15 minutes) to yield Example 793 (1.1 mg, 1.79 μmol, 19% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.94 (br. s., 1H), 8.91-8.71 (m, 2H), 8.58 (br. s., 1H), 8.45 (d, J=10.1 Hz, 1H), 8.21 (br. s., 1H), 7.95 (br. s., 1H), 7.70 (d, J=14.3 Hz, 1H), 5.71 (br. s., 1H), 5.17 (br. s., 1H), 4.48 (br. s., 2H), 4.00 (br. s., 3H), 3.43-3.28 (m, 1H), 1.52-1.36 (m, 6H). LC-MS: method H, RT=0.95 min, MS (ESI) m/z: 585.1 (M+H)+. Analytical HPLC Method B: 95% purity.
    • Example 794 (R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01785
    • Intermediate 794A: (R)-methyl 5-((((1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C01786
  • Intermediate I-121 (7.23 mg, 0.022 mmol), Intermediate I-142 (10 mg, 0.022 mmol) and PdCl2(dppf) (0.963 mg, 1.316 μmol) were dissolved in dioxane (219 μl) and 3M aqueous Na2CO3 (99 μl, 0.197 mmol) was added. The reaction mixture was heated to 100° C. in an oil bath for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The material was dissolved in DCM and filtered. Purified on ISCO using 0-100% EtOAc in DCM on a 4 g column to yield Intermediate 792A (4.5 mg, 0.0075 mmol, 33% yield) as a yellow solid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 599.1 (M+H)+.
    • Example 794
  • Intermediate 794A (4.5 mg, 0.008 mmol) was dissolved in THF (127 μl) and lithium borohydride (0.276 mg, 0.013 mmol) was added in one portion. The reaction mixture was allowed to stir at room temperature for 3 h. Residue was dissolved in THF and air was bubbled through the reaction mixture until the solvent was evaporated. The mixture was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% B in 15 minutes) to yield Example 794 (0.8 mg, 1.33 μmol, 18% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.08 (br. s., 1H), 8.84 (d, J=18.0 Hz, 3H), 8.59 (br. s., 1H), 8.48 (d, J=9.8 Hz, 1H), 8.22 (br. s., 1H), 7.96 (br. s., 1H), 5.30 (br. s., 1H), 4.84 (d, J=11.9 Hz, 1H), 4.60-4.54 (m, 1H), 4.51 (br. s., 2H), 4.01 (br. s., 3H), 3.41-3.23 (m, 1H), 1.43 (br. s., 3H). LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 571.1 (M+H)+. Analytical HPLC Method B: 95% purity.
    • Example 795 (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01787
  • Intermediate I-97 (10.83 mg, 0.035 mmol) and pyridine (0.019 mL, 0.236 mmol) were dissolved in DCM (2 mL). To this solution was added Intermediate I-143 (0.0125 g, 0.024 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 30 min. The reaction mixture was concentrated under reduced pressure and dissolved in 2 mL of 1:1 THF:MeOH solution and CSA (5.48 mg, 0.024 mmol) was added. The reaction mixture was allowed to stir at room temperature for 2 h. TEA (0.033 mL, 0.236 mmol) was added to quench the CSA, and the reaction mixture was concentrated and dissolved in 2 mL of DMF, filtered, and purified by preparative HPLC (Method D, 50 to 100% B in 20 minutes) to yield Example 795 (0.0075 g, 0.012 mmol, 49.0% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.82 (d, J=2.1 Hz, 1H), 8.59 (br. s., 3H), 8.18 (s, 1H), 8.05 (d, J=7.3 Hz, 1H), 7.92 (br. s., 1H), 5.11 (d, J=4.9 Hz, 1H), 4.86 (br. s., 1H), 4.23 (br. s., 2H), 3.99 (s, 3H), 3.68 (d, J=4.9 Hz, 2H), 3.34 (br. s., 1H), 1.41 (dd, J=15.3, 6.1 Hz, 6H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 647.9 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Examples 796 to 804
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 795 and the examples above.
  • LCMS LCMS
    Ex. [M + H]+ RT (Min)
    No. Structure Amine m/z Method H NMR
    796
    Figure US20190292176A1-20190926-C01788
    Figure US20190292176A1-20190926-C01789
         		663.9 1.26 1H NMR (500 MHz, DMSO-d6) δ 9.80 (br. s., 1H), 8.80 (br. s., 1H), 8.63- 8.54 (m, 3H), 8.16 (s, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.90 (br. s., 1H), 5.11 (d, J = 7.0 Hz, 1H), 4.85 (d, J = 7.0 Hz, 1H), 4.07 (d, J = 6.4 Hz, 1H), 4.02 (br. s., 1H), 3.99 (s, 3H), 3.96- 3.89 (m, 1H), 3.36 (d, J = 4.6 Hz, 1H), 1.41 (dd, J = 15.6, 6.1 Hz, 6H), 1.11 (d, J = 6.1 Hz, 3H).
    797
    Figure US20190292176A1-20190926-C01790
    Figure US20190292176A1-20190926-C01791
         		605.1 1.33 1H NMR (500 MHz, DMSO-d6) δ 9.94 (br. s., 1H), 8.78 (d, J = 2.7 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.30-8.24 (m, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 7.3 Hz, 2H), 7.88 (d, J = 2.7 Hz, 1H), 7.11 (d, J = 7.0 Hz, 1H), 5.13 (dd, J = 6.4, 2.4 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 3.98 (s, 3H), 1.42 (dd, J = 16.2, 6.4 Hz, 6H).
    798
    Figure US20190292176A1-20190926-C01792
    Figure US20190292176A1-20190926-C01793
         		588.8 1.10 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.82 (d, J = 2.7 Hz, 1H), 8.59 (d, J = 2.4 Hz, 3H), 8.18 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.79 (d,J = 6.4 Hz, 2H), 5.22 (dd, J = 6.7, 2.4 Hz, 1H), 4.95-4.77 (m, 1H), 3.99 (s, 3H), 1.44 (t, J = 7.0 Hz, 6H).
    799
    Figure US20190292176A1-20190926-C01794
    Figure US20190292176A1-20190926-C01795
         		588.8 1.11 1H NMR (500 MHz, DMSO-d6) δ 9.91 (br. s., 1H), 8.83 (d, J = 3.1 Hz, 1H), 8.65 (br. s., 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.23- 8.17 (m, 2H), 8.07 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 2.7 Hz, 2H), 7.33 (dd, J = 8.1, 4.7 Hz, 1H), 5.15 (dd, J = 6.4, 2.7 Hz, 1H), 4.92-4.77 (m, 1H), 4.00 (s, 3H), 1.42 (dd, J = 15.3, 6.4 Hz, 6H).
    800
    Figure US20190292176A1-20190926-C01796
    Figure US20190292176A1-20190926-C01797
         		616.8 1.12 1H NMR (500 MHz, DMSO-d6) δ 10.15 (br. s., 1H), 8.83 (d, J = 2.7 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.50 (br. s., 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.97- 7.85 (m, 2H), 5.14 (d, J = 6.4 Hz, 1H), 4.87 (d, J = 4.0 Hz, 1H), 4.00 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H), 1.42 (dd, J = 14.2, 6.6 Hz, 6H).
    801
    Figure US20190292176A1-20190926-C01798
    Figure US20190292176A1-20190926-C01799
         		618.8 1.33 1H NMR (500 MHz, DMSO-d6) δ 9.60 (br. s., 1H), 8.82 (d, J = 2.7 Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.1 Hz, 2H), 8.04 (d, J = 7.3 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.76 (br. s., 1H), 6.75 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 6.6, 2.6 Hz, 1H), 4.83 (dd, J = 6.4, 2.7 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 1.42 (d, J = 6.1 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).
    802
    Figure US20190292176A1-20190926-C01800
    Figure US20190292176A1-20190926-C01801
         		613.8 1.32 1H NMR (500 MHz, DMSO-d6) δ 10.27 (br. s., 1H), 8.81 (d, J = 2.7 Hz, 2H), 8.62-8.56 (m, 2H), 8.25 (br. s., 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 5.15 (dd, J = 6.6, 2.3 Hz, 1H), 4.88 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 1.43 (dd, J = 12.2, 6.4 Hz, 6H).
    803
    Figure US20190292176A1-20190926-C01802
    Figure US20190292176A1-20190926-C01803
         		618.9 1.13 1H NMR (500 MHz, DMSO-d6) δ 9.86 (br. s., 1H), 8.76 (d, J = 2.7 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.19 (br. s., 1H), 8.12 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.50 (br. s., 1H), 5.09 (dd, J = 6.6, 2.6 Hz, 1H), 4.89-4.68 (m, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.7 Hz, 3H).
    804
    Figure US20190292176A1-20190926-C01804
    Figure US20190292176A1-20190926-C01805
         		605.1 1.32 1H NMR (500 MHz, DMSO-d6) δ 10.18 (br. s., 1H), 8.79 (d, J = 2.7 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.46 (br. s., 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.89 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 10.4 Hz, 1H), 5.15 (dd, J = 6.6, 2.6 Hz, 1H), 4.85 (d, J = 3.7 Hz, 1H), 3.98 (s, 3H), 1.42 (dd, J = 14.2, 6.6 Hz, 6H).
    • Example 806 1-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01806
    • Intermediate 806A: 4-bromo-6-fluorobenzo[d]thiazol-2-amine
  • Figure US20190292176A1-20190926-C01807
  • 2-Bromo-4-fluoroaniline (0.54 g, 2.84 mmol) was dissolved in MeCN (14.21 ml). Ammonium thiocyanate (0.324 g, 4.26 mmol) was added to the reaction mixture followed by benzyltrimethylammonium tribromide (1.108 g, 2.84 mmol), and the reaction mixture was allowed to stir for 12 hours. The reaction mixture was diluted with saturated aqueous NaHCO3, and the solids were collected by suction filtration and washed with water to yield Intermediate 806A (0.700 g, 2.84 mmol, 100%). 1H NMR (400 MHz, MeOH4) δ 7.41 (dd, J=8.0, 2.5 Hz, 1H), 7.26 (dd, 2.5 Hz, 1H). LC-MS: method H, RT=0.81 min, MS (ESI) m/z: 247/249 (M+H)+.
    • Intermediate 806B: 1-(2-amino-6-fluorobenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01808
  • Intermediate 806A (50 mg, 0.202 mmol) was dissolved in THF (2024 μl). NaH (8.90 mg, 0.223 mmol) was added and the reaction mixture was stirred for 30 min. The reaction mixture was cooled to −78° C. and BuLi (106 μl, 0.243 mmol) was added. The reaction mixture was allowed to stir for 30 min. Pivalaldehyde (17.43 mg, 0.202 mmol) was added, and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was stirred for 10 min then diluted with water and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layer was washed with water, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 806B (0.064 g, 0.151 mmol, 75% yield). Used without further purification as a 60% pure mixture. LC-MS: method H, RT=0.56 min, MS (ESI) m/z: 255.2 (M+H)+.
    • Intermediate 806C: 1-(2-chloro-6-fluorobenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01809
  • Copper(II) chloride (0.058 g, 0.434 mmol) and t-butyl nitrite (0.052 ml, 0.434 mmol) were dissolved in MeCN (1.022 ml) and allowed to stir 10 minutes. Intermediate 806B (0.065 g, 0.256 mmol) was dissolved in MeCN (1.533 ml), and the copper solution was added. The reaction mixture was stirred for 2.5 h at 60° C. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with 1 N HCl, washed with saturated aqueous NaHCO3, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified on ISCO using a 12 g column with 0-100% gradient of EtOAc in hexanes to yield Intermediate 806C (0.008 g, 0.029 mmol, 11.43% yield) as a white solid. LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 274.1 (M+H)+.
    • Example 806
  • Intermediate I-9 (8.77 mg, 0.029 mmol) and Intermediate 806C (0.008 g, 0.029 mmol) were dissolved in DMF (0.292 ml). PdCl2(dppf)-CH2Cl2 adduct (1.432 mg, 1.753 μmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and purified by preparative HPLC (Method D, 20 to 100% B in 20 minutes) to yield Example 806 (0.0032 g, 0.007 mmol, 24% % yield): 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.55 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.32 (d, J=10.4 Hz, 1H), 5.46 (br. s., 1H), 4.07 (s, 3H), 2.64 (s, 3H), 0.95 (s, 9H). LC-MS: method H, RT=1.39 min, MS (ESI) m/z: 412.2 (M+H)+. Analytical HPLC Method B: 92% purity.
    • Example 807 1-(5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01810
    • Intermediate 807A: 2-bromo-7-(dibromomethyl)-5-methoxythiazolo[5,4-b]pyridine
  • Figure US20190292176A1-20190926-C01811
  • Intermediate I-16 (0.250 g, 0.965 mmol) was dissolved in CCl4 (3 mL) and NBS (0.859 g, 4.82 mmol) was added followed by AIBN (0.048 g, 0.289 mmol). The reaction mixture was allowed to stir at reflux for 12 hours. The reaction mixture was cooled and diluted with water and EtOAc. The layers were separated and the organic layer was washed with 1 N HCl, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 807A (0.125 g, 0.300 mmol, 31%) which was used without purification. LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 416.9 (M+H)+.
    • Intermediate 807B: 1-(2-bromo-5-methoxythiazolo[5,4-b]pyridin-7-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01812
  • Intermediate 807A (0.125 g, 0.458 mmol) was dissolved in THF (4.58 ml) and t-butyl magnesium chloride (0.267 g, 2.288 mmol) was added at −78° C. The reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched with saturated aqueous NH4Cl and the reaction mixture was diluted with EtOAc. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 807B (0.034 g, 0.103 mmol, 22.43% yield): 1H NMR (400 MHz, CDCl3) δ 6.72 (s, 1H), 4.78 (d, J=8.1 Hz, 1H), 3.98 (s, 3H), 3.79 (d, J=8.4 Hz, 1H), 0.96 (s, 9H). LC-MS: method H, RT=1.18 min, MS (ESI) m/z: 331.0 (M+H)+.
    • Example 807
  • Intermediate I-9 (0.034 g, 0.115 mmol) and Intermediate 806B (0.038 g, 0.115 mmol) were dissolved in DMF (1.147 ml). PdCl2(dppf)-CH2Cl2 adduct (5.62 mg, 6.88 μmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and purified by preparative HPLC (Method D, 60 to 100% B in 17 minutes) to yield Example 807 (13.7 mg, 0.032 mmol, 27.8% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 7.84 (s, 1H), 6.95 (s, 1H), 5.53 (d, J=4.6 Hz, 1H), 5.32 (d, J=4.6 Hz, 1H), 4.09 (s, 3H), 3.99 (s, 3H), 2.65 (s, 3H), 0.97 (s, 9H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 425.1 (M+H)+. Analytical HPLC Method B: 99% purity.
    • Example 808 6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(methoxymethyl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01813
    • Intermediate 808A: 2-bromo-6-methoxy-4-(methoxymethyl)benzo[d]thiazole
  • Figure US20190292176A1-20190926-C01814
  • Intermediate I-20D (0.100 g, 0.365 mmol) was dissolved in THF (3.65 ml) and sodium hydride (0.022 g, 0.547 mmol) was added. The reaction mixture was allowed to stir for 10 min and MeI (0.034 ml, 0.547 mmol) was added. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The crude reaction mixture was purified on ISCO using a 12 g column eluting with 0-100% EtOAc in hexanes to yield Intermediate 808A (0.037 g, 0.129 mmol, 35.5% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.20 (s, 2H), 4.96 (s, 2H), 3.90 (s, 3H), 3.53 (s, 3H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 287.9 (M+H)+.
    • Example 808
  • Intermediate I-9 (10 mg, 0.033 mmol) and Intermediate 808A (8.12 mg, 0.033 mmol) were dissolved in DMF (0.333 ml). PdCl2(dppf)-CH2Cl2 adduct (1.632 mg, 1.999 μmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and purified by preparative HPLC (Method D, 70 to 100% B in 25 minutes) to yield Example 808 (0.0046 g, 0.012 mmol, 36% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.58 (s, 1H), 7.83 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.14 (s, 1H), 5.04 (s, 2H), 4.09 (s, 3H), 3.89 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H). LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 382.12 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 809 2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine
  • Figure US20190292176A1-20190926-C01815
    • Intermediate 809A: 2-chlorothiazolo[4,5-c]pyridine
  • Figure US20190292176A1-20190926-C01816
  • Copper(II) chloride (0.445 g, 3.31 mmol) and t-butyl nitrite (0.669 ml, 5.62 mmol) were dissolved in MeCN (13.23 ml) and allowed to stir 10 minutes. Thiazolo[4,5-c]pyridin-2-amine (0.500 g, 3.31 mmol) was dissolved in MeCN (19.84 ml) and the copper solution was added. The reaction mixture was stirred for 1.5 h at 60° C. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using a 40 g column with 0-100% gradient of EtOAc in hexanes to yield Intermediate 809A (0.125 g, 0.733 mmol, 22.15% yield). LC-MS: method H, RT=0.51 min, MS (ESI) m/z: 170.9 (M+H)+.
    • Example 809
  • Intermediate I-9 (17.59 mg, 0.059 mmol) and Intermediate 809A (10 mg, 0.059 mmol) were dissolved in DMF (0.586 ml). PdCl2(dppf)-CH2Cl2 adduct (2.87 mg, 3.52 μmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and purified by preparative HPLC (Method D, 20 to 25% B in 25 minutes) to yield Example 809 (1.3 mg, 4.22 μmol, 7.19% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.51 (br. s., 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.61 (br. s., 1H), 8.41 (br. s., 1H), 7.95 (s, 1H), 4.10 (s, 3H), 2.67 (s, 3H). LC-MS: method H, RT=0.86 min, MS (ESI) m/z: 309.1 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 810 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl pyridin-3-ylcarbamate
  • Figure US20190292176A1-20190926-C01817
    • Intermediate 810A: 2-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01818
  • Intermediate I-131A (1.394 g, 4.02 mmol) was dissolved in DMF (40.2 ml) and Cs2CO3 (7.85 g, 24.10 mmol) was added followed by 2-bromoethyl acetate (0.805 g, 4.82 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then heated to 40° C. and allow to stir for 12 hours. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 810A (0.540 g, 1.991 mmol, 49.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=10.6 Hz, 1H), 5.16 (br. s., 2H), 4.64-4.57 (m, 2H), 4.50-4.42 (m, 2H), 2.09 (s, 3H). LC-MS: method H, RT=0.69 min, MS (ESI) m/z: 272.1 (M+H)+.
    • Intermediate 810B: 2-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01819
  • Copper(II) chloride (0.455 g, 3.38 mmol) and t-butyl nitrite (0.403 ml, 3.38 mmol) were dissolved in MeCN (7.96 ml) and the mixture was allowed to stir for 10 minutes. Intermediate 810A (0.540 g, 1.991 mmol) was dissolved in MeCN (11.94 ml), and the copper solution was added. The reaction mixture was stirred for 2.5 hours at 60° C. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with 1 N HCl, washed with saturated aqueous NaHCO3, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purified on ISCO using a 12 g column with 0-100% gradient of EtOAc in hexanes to yield Intermediate 810B (0.306 g, 1.053 mmol, 52.9% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=9.7 Hz, 1H), 4.71-4.64 (m, 2H), 4.52-4.45 (m, 2H), 2.10 (s, 3H). LC-MS: method H, RT=1.01 min, MS (ESI) m/z: 291.0 (M+H)+.
    • Intermediate 810C: 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01820
  • Intermediate I-9 (20.65 mg, 0.069 mmol) and Intermediate 810B (20 mg, 0.069 mmol) were dissolved in DMF (0.688 ml). PdCl2(dppf)-CH2Cl2 adduct (3.37 mg, 4.13 μmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. Purified on ISCO using a 12 g column eluting with 0-100% EtOAc in DCM to yield Intermediate 810C (0.039 g, 0.055 mmol, 79% yield) as a yellow solid. LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 428.9 (M+H)+.
    • Intermediate 810D: 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01821
  • To a suspension of Intermediate 810C (0.039 g, 0.091 mmol) in THF (1 mL) and MeOH (0.333 mL) was added NaOH (0.273 mL, 0.273 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was diluted by EtOAc and 1N HCl. The layers were separated, and the organic layer was washed with water, washed with brine, dried with sodium sulfate, and concentrated to yield Intermediate 810D (0.050 g, 0.129 mmol, 100% yield) as a white solid. Used without further purification in the next step. LC-MS: method H, RT=1.14 min, MS (ESI) m/z: 386.9 (M+H)+.
    • Intermediate 810E: 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C01822
  • To a solution of Intermediate 810D (0.050 g, 0.129 mmol) in THF (5 mL) at room temperature was added 15% phosgene in toluene (0.456 mL, 0.647 mmol), and the mixture was stirred for 3 h. Solvent was completely removed to yield Intermediate 810E (0.058 g, 0.129 mmol, 100% yield) as a yellow solid. The material was used immediately in the next step without purification. LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 448.8 (M+H)+.
    • Example 810
  • Pyridin-3-amine (0.012 g, 0.129 mmol) and pyridine (0.105 mL, 1.292 mmol) were dissolved in DCM (2 mL). Intermediate 810E (0.058 g, 0.129 mmol) was added as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 30 min. The reaction mixture was concentrated under reduced pressure and purified on ISCO using 0-100% EtOAc in hexanes on a 12 g column. The reaction mixture was further purified by preparative HPLC (Method D, 35 to 75% B in 25 minutes, 4 min hold time at 75%) to yield Example 810 (0.0052 g, 10.06 μmol, 7.79% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.73 (s, 1H), 8.62 (br. s., 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.20 (br. s., 1H), 7.88 (br. s., 2H), 7.33 (br. s., 1H), 4.79 (br. s., 2H), 4.57 (br. s., 2H), 4.10 (s, 3H), 2.64 (br. s., 3H). LC-MS: method H, RT=0.98 min, MS (ESI) m/z: 507.1 (M+H)+. Analytical HPLC Method B: 98% purity.
    • Example 811 2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy) ethyl (6-fluoro-5-methylpyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01823
  • To a solution of Intermediate 810E (7.5 mg, 0.017 mmol) in DCM (1 mL) and THF (0.5 mL) was added 6-fluoro-5-methylpyridin-3-amine (7.38 mg, 0.058 mmol) followed by DIPEA (0.029 mL, 0.167 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with 0.2 mL of MeOH. The reaction mixture was concentrated, dissolved in DMF, and filtered. The reaction was purified by preparative HPLC (Method D, 50 to 100% B in 20 minutes, 5 min hold time at 100%) to yield Example 811 (0.0052 g, 9.37 μmol, 56.1% yield): LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 539.2 (M+H)+. Analytical HPLC Method B: 97% purity.
    • Example 812 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy) ethyl (6-(thiophen-2-yl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01824
    • Intermediate 812A: 2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01825
  • 2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate (0.050 g, 0.146 mmol) was dissolved in DMF. 2-Bromomethyl acetate (0.058 g, 0.350 mmol) and Cs2CO3 (0.237 g, 0.729 mmol) were added and the reaction mixture was stirred at 40° C. for 18 h. The reaction mixture was diluted with EtOAc and water. The layers were separated. The organic layer was washed with brine dried with sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified on ISCO using a 24 g column with a 0-100% EtOAc in hexanes gradient to yield Intermediate 812A (0.044 g, 0.165 mmol, 56.5% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.53-6.53 (m, 1H), 5.01 (br. s., 2H), 4.52-4.48 (m, 2H), 4.44-4.39 (m, 2H), 2.49 (d, J=0.7 Hz, 3H), 2.09 (s, 3H). LC-MS: method H, RT=0.72 min, MS (ESI) m/z: 268.2 (M+H)+.
    • Intermediate 812B: 2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01826
  • Copper(II) bromide (0.063 g, 0.280 mmol) and t-butyl nitrite (0.033 mL, 0.280 mmol) were dissolved in MeCN (0.658 mL) and allowed to stir 10 minutes. Intermediate 812A (0.044 g, 0.165 mmol) was dissolved in MeCN (0.988 mL) and the copper solution was added. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with 1 N HCl, washed with saturated aqueous NaHCO3, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield Intermediate 812B (0.046 g, 0.139 mmol, 84% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J=0.9 Hz, 1H), 4.57-4.53 (m, 2H), 4.44-4.41 (m, 2H), 2.63 (d, J=0.9 Hz, 3H), 2.09 (s, 3H). LC-MS: method H, RT=1.07 min, MS (ESI) m/z: 331.0 (M+H)+.
    • Intermediate 812C: 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate
  • Figure US20190292176A1-20190926-C01827
  • Intermediate I-9 (0.042 g, 0.140 mmol) and Intermediate 812B (0.046 g, 0.140 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2Adduct (6.86 mg, 8.40 μmol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction was purified on ISCO using 24 g column with a 0-100% EtOAc in hexanes gradient to yield Intermediate 812C (0.021 g, 0.049 mmol, 35.4% yield) as an off white solid. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 7.75 (s, 1H), 6.74 (s, 1H), 4.63 (dd, J=5.8, 3.6 Hz, 2H), 4.51-4.43 (m, 2H), 4.13 (s, 3H), 2.79 (s, 3H), 2.66 (s, 3H), 2.11 (s, 3H). LC-MS: method H, RT=1.34 min, MS (ESI) m/z: 425.1 (M+H)+.
    • Intermediate 812D: 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanol
  • Figure US20190292176A1-20190926-C01828
  • To a suspension of Intermediate 812C (0.143 g, 0.337 mmol) in THF (3 mL) and MeOH (1 mL) was added NaOH (1.011 mL, 1.011 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and 1N HCl. The organic layer was washed with water, washed with brine, dried with sodium sulfate, and concentrated to yield Intermediate 812D (0.120 g, 0.314 mmol, 93% yield) as a tan solid. 1H NMR (400 MHz, MeOH-d4) δ 8.61 (s, 1H), 8.58 (s, 1H), 7.78 (s, 1H), 6.82 (s, 1H), 4.48-4.45 (m, 2H), 4.40-4.36 (m, 1H), 4.13 (s, 3H), 3.94-3.90 (m, 2H), 2.77 (s, 3H), 2.66 (s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 383.9 (M+H)+.
    • Intermediate 812E: 2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl carbonochloridate
  • Figure US20190292176A1-20190926-C01829
  • To a solution of Intermediate 812D (0.025 g, 0.065 mmol) in THF (3 mL) at was added 15% phosgene in toluene (0.231 mL, 0.327 mmol) and the mixture was stirred at for 1 h. The reaction mixture was concentrated under vacuum to give Intermediate 812E (0.030 g, 0.067 mmol, 100% yield) as a yellow solid. It was used for the next step without any purification. LC-MS: method H, RT=1.35 min, MS (ESI) m/z: 444.7 (M+H)+.
    • Example 812
  • To a solution of Intermediate 812E (20 mg, 0.045 mmol) in DCM (1 mL) and THF (0.5 mL) was added 6-(thiophen-2-yl)pyridin-3-amine (14.81 mg, 0.157 mmol) followed by DIEA (0.079 mL, 0.450 mmol). The mixture was stirred at for 1 hour. The reaction mixture was diluted with EtOAc and water. The combined organic layer was washed with brine and concentrated under vacuum. The reaction mixture was diluted with DMSO, filtered, and purified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) to yield Example 812 (0.0057 g, 5.61 μmol, 12.48% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.63 (s, 1H), 8.56 (br. s., 1H), 8.50 (s, 1H), 7.92 (br. s., 1H), 7.83 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.63 (d, J=3.3 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.12 (t, J=3.9 Hz, 1H), 6.90 (s, 1H), 4.66 (br. s., 2H), 4.52 (br. s., 2H), 4.06 (s, 3H), 2.72 (s, 3H), 2.62 (s, 3H). LC-MS: method H, RT=1.21 min, MS (ESI) m/z: 585.5 (M+H)+. Analytical HPLC Method B: 97% purity.
    • Example 813 (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01830
    • Intermediate 813A: (R)-1-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C01831
  • Intermediate I-1(0.483 g, 1.903 mmol) and Intermediate I-131 (0.500 g, 1.903 mmol) were dissolved in DMF (19.03 ml). PdCl2(dppf)-CH2Cl2 adduct (0.093 g, 0.114 mmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield a brown oil. Purified by ISCO using 0-70% gradient of EtOAc in hexanes on a 120 g column over 15 min to yield Intermediate 813A (0.591 g, 1.354 mmol, 71.1% yield): 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J=1.7 Hz, 1H), 8.71 (s, 1H), 8.04 (d, J=10.2 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.83-7.53 (m, 1H), 4.58 (dd, J=10.7, 2.8 Hz, 1H), 4.47-4.37 (m, 1H), 4.34 (br. s., 1H), 2.71 (s, 3H), 1.61-1.53 (m, 1H), 1.38 (d, J=6.3 Hz, 3H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 437.1 (M+H)+.
    • Intermediate 813B: (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C01832
  • Intermediate 813A (0.035 g, 0.080 mmol) was dissolved in THF (2 ml) and sodium ethoxide (0.040 ml, 0.080 mmol, 2 M in EtOH) was added. The reaction mixture was allowed to stir at for 2 hours. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 813B (0.030 g, 0.058 mmol, 80% yield). Used without further purification in the next step. LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 415.1 (M+H)+.
    • Intermediate 813C: (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C01833
  • To a solution of Intermediate 813B (0.030 g, 0.058 mmol) in THF (3 mL) at was added 15% phosgene in toluene (0.511 mL, 0.724 mmol), and the mixture was stirred at for 12 hours. Solvent was completely removed, and the sample was stored under vacuum overnight to yield Intermediate 813C (0.035 g, 0.066 mmol, 91% yield) as a yellow solid. LC-MS: method H, RT=1.42 min, MS (ESI) m/z: 477.1 (M+H)+.
    • Example 813
  • 2-Methylpyrimidin-5-amine (13.73 mg, 0.126 mmol) and pyridine (0.068 mL, 0.839 mmol) were dissolved in DCM (3 mL). Intermediate 813C (40 mg, 0.084 mmol) was added as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by ISCO using a 12 g column with a 0-100% EtOAc in hexanes gradient to yield Example 813 (0.0203 g, 0.035 mmol, 41.8% yield) as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 8.74 (br. s., 2H), 8.55 (t, J=2.3 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.01 (s, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.74 (s, 1H), 6.55 (br. s., 1H), 5.75 (dd, J=6.5, 3.4 Hz, 1H), 5.39 (dd, J=6.5, 3.4 Hz, 1H), 4.57 (d, J=7.0 Hz, 3H), 2.64 (s, 3H), 1.52 (d, J=1.5 Hz, 3H), 1.50 (s, 3H), 1.48 (d, J=1.5 Hz, 3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 550.1 (M+H)+. Analytical HPLC Method B: 95% purity.
    • Example 814 (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01834
    • Intermediate 814A: (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01835
  • Intermediate I-97 (16.95 mg, 0.063 mmol) and pyridine (0.034 mL, 0.419 mmol) were dissolved in DCM (3 mL). Intermediate 813C (20 mg, 0.042 mmol) was added as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was concentrated under reduced pressure. Used without further purification in the next step. LC-MS: method H, RT=1.56 min, MS (ESI) m/z: 710.3 (M+H)+.
    • Example 814
  • Intermediate 814A (0.009 g, 0.013 mmol) was dissolved in THF (2 mL) and 2 mL of 90% MeOH, 10% water, 0.1% TFA was added. The reaction mixture was allowed to stir for 12 hours. The reaction mixture was concentrated, dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 50% to 100% B in 19 minutes, 6 min hold time) to yield Example 814 (7.7 mg, 0.013 mmol, 100% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.81-9.74 (m, 1H), 8.61-8.52 (m, 3H), 8.41 (br. s., 1H), 8.33 (d, J=10.7 Hz, 1H), 7.71 (s, 1H), 5.67 (br. s., 1H), 5.24 (br. s., 1H), 4.93-4.87 (m, 1H), 4.80 (d, J=9.8 Hz, 1H), 4.48 (q, J=6.8 Hz, 5H), 4.20 (d, J=5.2 Hz, 3H), 2.57 (s, 3H), 1.45-1.38 (m, 6H). LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 596.2 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 815 (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01836
    • Intermediate 815A: (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-(((R)-2-((tert-butyldimethylsilyl)oxy)propoxy) pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01837
  • Intermediate I-103 (0.020 g, 0.069 mmol) and pyridine (0.051 mL, 0.629 mmol) were dissolved in DCM (2 mL) Intermediate 813C (0.030 g, 0.063 mmol) was added as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was concentrated under reduced pressure and purified on ISCO using 24 g column eluting with 0-100% EtOAc in hexanes over 15 min to yield Intermediate 815A (28.3 mg, 0.039 mmol, 62.1% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.08-9.05 (m, 2H), 8.56 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.01 (d, J=10.3 Hz, 1H), 7.77 (s, 1H), 6.80 (s, 1H), 5.87-5.73 (m, 1H), 5.28 (dd, J=6.6, 2.9 Hz, 1H), 4.68-4.54 (m, 1H), 4.09 (s, 2H), 2.67 (s, 3H), 1.54-1.48 (m, 9H). LC-MS: method H, RT=1.58 min, MS (ESI) m/z: 724.0 (M+H)+.
    • Example 815
  • Intermediate 815A (0.0283 g, 0.039 mmol) was dissolved in THF (1 mL) and EtOH (1 mL). To the solution was added 4 M HCl in dioxane (1 mL, 110 mmol), and the reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 50% to 100% B in 20 minutes, 10 min hold time) to yield Example 815 (0.0145 g, 0.024 mmol, 60.8% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.86-9.73 (m, 1H), 8.62-8.53 (m, 3H), 8.44 (br. s., 1H), 8.36 (d, J=10.7 Hz, 1H), 7.74 (s, 1H), 5.69 (br. s., 1H), 5.26 (br. s., 2H), 4.83 (d, J=10.1 Hz, 1H), 4.50 (q, J=7.0 Hz, 4H), 4.29 (d, J=7.6 Hz, 1H), 4.04 (d, J=12.8 Hz, 1H), 3.93 (br. s., 1H), 3.52-3.46 (m, 3H), 2.59 (s, 3H), 1.47-1.40 (m, 6H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 610.1 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 816 (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01838
    • Intermediate 816A: (2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C01839
  • Intermediate I-1(0.075 g, 0.285 mmol) and Intermediate I-133 (0.082 g, 0.285 mmol) were dissolved in DMF (2.95 ml). PdCl2(dppf)-CH2Cl2 adduct (0.012 g, 0.018 mmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield a brown oil. Purified by ISCO using 0-100% gradient of EtOAc in hexanes on a 24 g column over 15 min to yield Intermediate 816A (0.050 g, 0.111 mmol, 37.6% yield): 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=1.8 Hz, 1H), 8.71 (s, 1H), 8.03 (d, J=10.1 Hz, 1H), 7.89-7.49 (m, 2H), 5.41 (dd, J=6.5, 3.0 Hz, 1H), 4.26-4.08 (m, 1H), 2.49 (d, J=4.6 Hz, 1H), 1.46 (d, J=6.4 Hz, 3H), 1.33 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 451.1 (M+H)+.
    • Intermediate 816B: (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C01840
  • Intermediate 816A (0.100 g, 0.222 mmol) was dissolved in THF (2 ml) and sodium ethoxide (0.111 ml, 0.222 mmol, 2 M in EtOH) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to yield Intermediate 816B (0.090 g, 0.210 mmol, 95% yield). Used without further purification in the next step. LC-MS: method H, RT=1.25 min, MS (ESI) m/z: 429.1 (M+H)+.
    • Intermediate 816C: (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C01841
  • To a solution of Intermediate 816B (0.025 g, 0.058 mmol) in THF (5 mL) at room temperature was added 15% phosgene in toluene (0.206 mL, 0.292 mmol), and the mixture was stirred at room temperature for 12 hours. Solvent was completely removed, and the sample was stored under vacuum overnight to yield Intermediate 816C (0.029 g, 0.053 mmol, 90% yield) as a yellow solid. LC-MS: method H, RT=1.43 min, MS (ESI) m/z: 490.0 (M+H)+.
    • Intermediate 816D: methyl 5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate
  • Figure US20190292176A1-20190926-C01842
  • Methyl 5-aminopyrimidine-2-carboxylate (10.29 mg, 0.067 mmol) and pyridine (0.049 mL, 0.611 mmol) were dissolved in DCM (2 mL) Intermediate 816C (0.030 g, 0.061 mmol) was added as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was concentrated under reduced pressure and purified on ISCO using 24 g column eluting with 0-100% EtOAc over 15 min to yield Intermediate 816D (24.6 mg, 0.040 mmol, 66.3% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=1.8 Hz, 3H), 8.44 (s, 1H), 7.91 (d, J=10.3 Hz, 1H), 7.66 (s, 1H), 7.13 (s, 1H), 5.70-5.60 (m, 1H), 5.31 (br. s., 1H), 2.56 (s, 3H), 1.41 (d, J=6.8 Hz, 5H), 1.17 (s, 3H), 0.07-0.11 (m, 6H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 608.0 (M+H)+.
    • Example 816
  • Intermediate 816D (39 mg, 0.064 mmol) was solvated in THF (1 mL) and cooled to −78° C. Diisobutylaluminum hydride (1 M in toluene) (0.193 mL, 0.193 mmol) was added to the cooled mixture, and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with 1 mL of a 1 M HCl solution at −78° C. The resulting thick, orange sludge was allowed to thaw to room temperature and stirred for a total of 30 min until the solution became fluid and bright yellow. The mixture was diluted with EtOAc and washed with saturated NH4Cl before being dried over sodium sulfate and filtered over a pad of SiO2 gel to remove aluminates. The filtrate was concentrated and resubjected to identical reaction conditions to those described above. This second reaction mixture was quenched with saturated Rochelle's salt and allowed to stir at room temperature for 1 hour. The resulting mixture was diluted with EtOAc and the layers were separated. The aqueous layer was back extracted with EtOAc 3×, and the combined organic layer was washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The crude material was dissolved in DMF, filtered, and purified by preparative HPLC (Method D, 50% to 100% B in 22 minutes, 5 min hold time) to yield Example 816 (0.0078 g, 0.013 mmol, 20.97% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.79 (br. s., 2H), 8.61 (s, 1H), 8.49 (s, 1H), 8.41 (d, J=10.7 Hz, 1H), 7.79 (s, 1H), 5.68 (d, J=6.4 Hz, 1H), 5.17 (d, J=5.2 Hz, 1H), 4.53 (q, J=7.0 Hz, 2H), 4.49 (s, 2H), 2.61 (s, 3H), 1.47-1.43 (m, 6H), 1.40 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=0.98 min, MS (ESI) m/z: 580.0 (M+H)+. Analytical HPLC Method B: 100% purity.
    • Example 817 1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol
  • Figure US20190292176A1-20190926-C01843
    • Intermediate 817A: 2-ethoxy-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline
  • Figure US20190292176A1-20190926-C01844
  • In a sealed tube, Intermediate 661F (290 mg, 1.086 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (551 mg, 2.171 mmol), and potassium acetate (213 mg, 2.171 mmol) were mixed in 1,4-dioxane (5 mL). After degassing with bubbling argon for 10 minutes, Pd(dppf)Cl2.CH2Cl2 (44.3 mg, 0.054 mmol) was added. The vial was sealed and heated at 120° C. for 60 minutes in the microwave. The reaction mixture was cooled to room temperature, loaded on celite and was purified on ISCO (40 g column, 0-50% EtOAc/Hexane in 18 minutes) to yield Intermediate 817A (0.311 g, 0.990 mmol, 91% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.91 (s, 1H), 7.68 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.26 (br. s., 3H), 1.41 (t, J=7.0 Hz, 3H), 1.34 (s, 12H). LC-MS: method H, RT=0.94 min, MS (ESI) m/z: 233.0 (M+H)+ (mass of the boronic acid).
    • Example 817
  • Intermediate 817A (10 mg, 0.032 mmol) and Intermediate 628A (9.10 mg, 0.032 mmol) were dissolved in DMF (1 ml). PdCl2(dppf)-CH2Cl2 adduct (1.560 mg, 1.910 μmol) was added, and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90° C. in the microwave for 30 minutes. The reaction mixture was filtered and purified by preparative HPLC (Method D, 45% to 80% B in 25 minutes, 7 min hold time) to yield Example 817 (4.5 mg, 9.87 μmol, 31.0% yield): 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.51 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 5.41 (d, J=4.6 Hz, 1H), 5.36 (br. s., 1H), 4.53 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 2.63 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 0.94 (s, 9H). LC-MS: method H, RT=1.39 min, MS (ESI) m/z: 438.2 (M+H)+. Analytical HPLC Method B: 96% purity.
    • Example 818 (R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl (6-cyanopyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01845
    • Intermediate 818A (R)-1-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-ol
  • Figure US20190292176A1-20190926-C01846
  • In a flask charged with a stirring bar, Intermediate I-60 (215 mg, 0.867 mmol) was suspended in (R)-2-methyloxirane (1 mL, 0.867 mmol). Potassium carbonate (144 mg, 1.040 mmol) was added, followed by tetrabutylammonium bromide (335 mg, 1.040 mmol). The mixture was allowed to stir at 60° C. for 18 hours. On the next day, the reaction mixture was diluted by adding 20 mL of DCM and silica gel was added. The solvent was removed on the rotavapor and sample was dry loaded on ISCO (24 g silica gel column, 0-60% EtOAc/Hexane). Collection of the desired fraction and removal of solvent gave Intermediate 818A (245.4 mg, 0.802 mmol, 92% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J=1.3 Hz, 1H), 7.97-7.89 (m, 1H), 4.96 (d, J=4.8 Hz, 1H), 4.07-3.98 (m, 1H), 3.98-3.89 (m, 2H), 1.18 (d, J=6.2 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −133.79 (s, 1F); LC-MS: method E, RT=0.85 min, MS (ESI) m/z: 306.0, 308.0 (M+H)+.
    • Intermediate 818B: (R)-1-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C01847
  • Intermediate 818A (110 mg, 0.359 mmol) was dissolved in THF (5 mL) under N2. Phosgene (2.56 mL, 3.59 mmol, 15% by wt.) in toluene solution was added. The resulting mixture was stirred at room temperature for 5 hours, then the solvent was removed on rotavapor and residue was dried on HVAC for 30 minutes. The crude product was used in the next step without purification. LC-MS: method E, RT=1.08 min, MS (ESI) m/z: 365.0, 366.9 (M+H)+.
    • Intermediate 818C: (R)-1-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl (6-cyanopyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01848
  • Intermediate 818B (66 mg, 0.179 mmol) was dissolved in DCM (3 mL) and mixed with 5-aminopicolinonitrile (85 mg, 0.716 mmol). Anhydrous pyridine (0.072 mL, 0.895 mmol) was added. The mixture was allowed to stir at room temperature for 2 hours. The solvent was removed on rotavapor and the residue was purified on ISCO column (24 g silica gel, 0-100% EtOAc/Hexane). The desired fractions were collected and removing solvent gave Intermediate 818C (59 mg, 0.145 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.75 (d, J=2.6 Hz, 1H), 8.08 (dd, 2.5 Hz, 1H), 8.01-7.87 (m, 3H), 5.26 (td, J=6.4, 3.1 Hz, 1H), 4.37-4.32 (m, 1H), 4.23 (dd, J=11.0, 6.2 Hz, 1H), 1.41 (d, J=6.6 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −133.72 (s, 1F); LC-MS: method E, RT=0.97 min, MS (ESI) m/z: 407.0 (M+H)+.
    • Example 818
  • In a vial charged with a stirring bar, Intermediate 818C (14 mg, 0.034 mmol) was mixed with Intermediate I-38 (12.7 mg, 0.041 mmol) in 1,4-dioxane (1 mL). PdCl2(dppf)-DCM (2.81 mg, 3.44 μmol) was added, followed by Na2CO3 (0.5 ml, 1.0 mmol). The reaction mixture was allowed to stir at 100° C. for 30 minutes. After cooling down to room temperature, the layers were separated and the aqueous layer was extracted by EtOAc (2 mL×2). Then organic phases were combined and concentrated on Rotavapor. The residue was dissolved in DMF and purified by prep-HPLC, Method B to afford Example 818 (3.8 mg, 0.007 mmol, 20% yield) as the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 8.03-7.90 (m, 3H), 5.29 (br. s., 1H), 4.40 (d, J=8.5 Hz, 1H), 4.29 (dd, J=10.7, 5.8 Hz, 1H), 4.11 (s, 3H), 3.35 (s, 1H), 1.44 (d, J=6.4 Hz, 3H); LC-MS: method L, RT=2.26 min, MS (ESI) m/z: 556.15 (M+H)+.
    • Example 819 (R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01849
    • Intermediate 819A: (R)-1-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl (2-methylpyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01850
  • Intermediate 819A was synthesized by the method described in Intermediate 818C, using 2-methylpyrimidin-5-amine instead of 5-aminopicolinonitrile. LC-MS: method E, RT=0.86 min, MS (ESI) m/z: 397.1 (M+H)+.
    • Example 819
  • Example 819 (2.2 mg, 0.004 mmol, 16% yield) was made from Intermediate 819A (9.0 mg, 0.023 mmol) by the method described for Example 818. LC-MS: method L, RT=2.03 min, MS (ESI) m/z: 546.10 (M+H)+.
    • Example 820 (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-methoxypyrimidin-5-yl)carbamate
  • Figure US20190292176A1-20190926-C01851
    • Intermediate 820A: (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol
  • Figure US20190292176A1-20190926-C01852
  • In a vial charged with a stirring bar, Intermediate I-72A (228 mg, 0.713 mmol) was mixed with Intermediate I-28 (170 mg, 0.713 mmol) in 1,4-dioxane (5 mL). Na2CO3 (2 mL, 4.00 mmol) was added, followed by Pd(dppf)Cl2-DCM (29.1 mg, 0.036 mmol). The mixture was stirred at 100° C. for 30 min. After cooling down to room temperature, the reaction mixture was diluted by adding 30 mL of EtOAc and 20 mL of water. After separation, the aqueous layer was extracted by EtOAc (20 mL×2). Then the organic phases were combined and washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified on CombiFlash (40 g silica gel column, 0-100% EtOAc/Hexane). Removing solvent gave Intermediate 820A (296 mg, 0.682 mmol, 96% yield) as a yellow solid. LC-MS: method E, RT=1.09 min, MS (ESI) m/z: 434.1 (M+H)+.
    • Intermediate 820B: (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl carbonochloridate
  • Figure US20190292176A1-20190926-C01853
  • Intermediate 820A (0.290 g, 0.668 mmol) was dissolved in anhydrous THF (7 mL) and was treated with phosgene (4.77 mL, 6.68 mmol, 15% by wt. in toluene) at room temperature overnight. On the next day, LCMS showed a clean reaction. Then solvent was removed on the rotavapor and the residue was dried on high vacuum for 1 hour. The crude product was used in the next step as is. LC-MS: method E, RT=1.34 min, MS (ESI) m/z: 496.1 (M+H)+.
    • Example 820
  • In a round bottom flask charged with a stirring bar, Intermediate 820B (60 mg, 0.121 mmol) was dissolved in DCM (2 mL) and mixed with 2-methoxypyrimidin-5-amine (60.5 mg, 0.484 mmol). Pyridine (0.049 mL, 0.604 mmol) was added and the mixture was stirred at room temperature for 4 hours. Solvent was removed on a rotavapor and the residue was loaded on silica gel and purified by CC (40 g silica gel, 0-100% EtOAc/Hexane gradient). The desired fractions were removed and freeze-dried to give Example 820 (55.8 mg, 0.093 mmol, 77% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.69-9.87 (1H, m), 8.82 (1H, s), 8.63 (1H, d, J=2.42 Hz), 8.61 (1H, br. s.), 8.08 (1H, d, J=2.42 Hz), 8.06 (1H, d, J=8.14 Hz), 8.00 (1H, d, J=11.44 Hz), 5.09 (1H, dd, J=6.60, 2.64 Hz), 4.82 (1H, dd, J=6.38, 2.86 Hz), 4.10 (3H, s), 3.83 (3H, s), 3.57 (1H, s), 1.36-1.42 (6H, m); 19F NMR (376 MHz, DMSO-d6) δ ppm −132.98 (1F, s); LC-MS: method G, RT=1.14 min, MS (ESI) m/z: 585.1 (M+H)+.
    • Examples 821 to 830
  • The following additional examples have been prepared, isolated and characterized using the methods described for Example 820 and the examples above, from corresponded quinoxaline boronic acids and aniline intermediates.
  • LCMS LCMS
    [M + RT
    Ex. H]+ (Min)/
    No. Structure m/z Method NMR
    821
    Figure US20190292176A1-20190926-C01854
         		584.15 2.66/L 1H NMR (500 MHz, DMSO-d6) δ ppm 9.61 (1 H, br. s.), 8.79 (1 H, s), 8.58 (1 H, d, J = 1.83 Hz), 8.19 (1 H, br. s.), 8.01-8.06 (2 H, m), 7.97 (1 H, d, J = 11.29 Hz), 7.74 (1 H, br. s.), 6.74 (1 H, d, J = 7.63 Hz), 5.07 (1 H, d, J = 4.27 Hz), 4.79 (1 H, d, J = 3.97 Hz), 4.08 (3 H, s), 3.76 (3 H, s), 1.38 (6 H, dd, J = 11.14, 6.26 Hz)
    822
    Figure US20190292176A1-20190926-C01855
         		568.15 2.22/L 1H NMR (500 MHz, DMSO-d6) δ ppm 9.82 (1 H, br. s.), 8.82 (1 H, s), 8.62 (1 H, d, J = 2.44 Hz), 8.50 (1 H, br. s.), 8.04-8.10 (2 H, m), 8.00 (1 H, d, J = 11.29 Hz), 7.77 (1 H, br. s.), 7.20 (1 H, br. s.), 5.09 (1 H, d, J = 6.71 Hz), 4.80 (1 H, br. s.), 4.10 (3 H, s), 2.37 (3 H, s), 1.33-1.46 (6 H, m))
    823
    Figure US20190292176A1-20190926-C01856
         		559.2 1.90/L 1H NMR (500 MHz, DMSO-d6) δ ppm 9.78 (1 H, br. s.), 8.85 (1 H, s), 8.73 (1 H, s), 8.48 (1 H, br. s.), 8.45 (1 H, s), 8.02 (1 H, d, J = 7.93 Hz), 7.92 (1 H, d, J = 11.29 Hz), 7.75 (1 H, br. s.), 7.15 (1 H, d, J = 8.24 Hz), 5.10 (1 H, d, J = 6.41 Hz), 4.79 (1 H, d, J = 3.97 Hz), 4.09 (3 H, s), 2.36 (3 H, s), 1.39 (6 H, dd, J = 11.29, 6.41 Hz)
    824
    Figure US20190292176A1-20190926-C01857
         		569.0 1.26/E 1H NMR (400 MHz, DMSO-d6) δ ppm 9.93 (1 H, br. s.), 8.84 (1 H, s), 8.72 (2 H, br. s.), 8.64 (1 H, d, J = 2.42 Hz), 8.09 (1 H, d, J = 2.42 Hz), 8.07 (1 H, d, J = 8.36 Hz), 8.01 (1 H, d, J = 11.44 Hz), 5.11 (1 H, dd, J = 6.49, 2.75 Hz), 4.77- 4.93 (1 H, m), 4.10 (3 H, s), 2.51-2.52 (3 H, m), 1.39 (6 H, dd, J = 6.49, 3.41 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −132.97 (1 F, s)
    825
    Figure US20190292176A1-20190926-C01858
         		560.2 2.11/L 1H NMR (500 MHz, DMSO-d6) δ ppm 9.95 (1 H, br. s.), 8.94 (1 H, s), 8.84 (1 H, s), 8.71 (2 H, br. s.), 8.53 (1 H, s), 8.06 (1 H, d, J = 8.24 Hz), 7.99 (1 H, d, J = 11.60 Hz), 5.10 (1 H, d, J = 6.41 Hz), 4.83 (1 H, d, J = 5.19 Hz), 4.11 (3 H, s), 2.50 (3 H, s), 1.39 (6 H, t, J = 6.26 Hz)
    826
    Figure US20190292176A1-20190926-C01859
         		579.1 1.15/E 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (1 H, s), 8.83 (1 H, s), 8.81 (1 H, s), 8.64 (1 H, d, J = 2.20 Hz), 8.60 (1 H, s), 8.23 (1 H, br. s.), 8.06-8.12 (2 H, m), 8.01 (1 H, d, J = 11.44 Hz), 5.12 (1 H, d, J = 6.82 Hz), 4.85 (1 H, s), 4.11 (3 H, s), 1.40 (6 H, d, J = 6.60 Hz) 19F NMR (376 MHz, DMSO-d6) δ ppm −132.95 (1 F, s)
    827
    Figure US20190292176A1-20190926-C01860
         		599.1 0.90/J 1H NMR (500 MHz, DMSO-d6) δ ppm 9.85-10.06 (1 H, m), 8.80 (1 H, s), 8.72 (2 H, br. s.), 8.57 (1 H, s), 8.02 (1 H, d, J = 8.24 Hz), 7.93 (1 H, d, J = 11.29 Hz), 7.81 (1 H, s), 6.39- 6.65 (1 H, m), 5.10 (1 H, dd, J = 6.56, 2.29 Hz), 4.68-4.89 (3 H, m), 2.61 (3 H, s), 2.54 (3 H, s), 1.38 (6 H, t, J = 5.65 Hz)
    828
    Figure US20190292176A1-20190926-C01861
         		570.20 2.36/L 1H NMR (500 MHz, DMSO-d6) δ ppm 8.85 (1 H, s), 8.73 (1 H, s), 8.66 (1 H, br. s.), 8.45 (1 H, s), 8.00 (2 H, d, J = 7.93 Hz), 7.82-7.95 (2 H, m), 5.09 (1 H, d, J = 6.41 Hz), 4.81 (1 H, d, J = 4.27 Hz), 4.06 (3 H, s), 1.37 (7 H, t, J = 5.34 Hz)
    829
    Figure US20190292176A1-20190926-C01862
         		579.15 2.69/M 1H NMR (500 MHz, DMSO-d6) δ ppm 10.40 (1 H, s), 8.66- 8.77 (2 H, m), 8.51 (1 H, d, J = 2.14 Hz), 7.85-8.12 (5 H, m), 5.13 (1 H, dd, J = 6.41, 2.14 Hz), 4.84 (1 H, d, J = 3.97 Hz), 4.06 (3 H, s), 1.35-1.45 (6H, m)
    830
    Figure US20190292176A1-20190926-C01863
         		612.2 2.69/G 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.82 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.3 Hz, 1H), 8.16-7.83 (m, 5H), 5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.86 (d, J = 6.6 Hz, 1H), 4.10 (s, 3H), 3.80 (s, 3H), 1.41 (dd, J = 6.5, 2.8 Hz, 6H)
    • Example 831 (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(hydroxymethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01864
  • Example 830 (10 mg, 0.016 mmol) was dissolved in anhydrous THF (1 mL) and cooled to −78° C. under an atmosphere of N2. DIBAL-H (0.082 mL, 0.082 mmol) was then added drop wise. After 2 min of stirring at −78° C., the reddish solution was allowed to thaw to room temperature. Next, 1 mL of saturated Rochelle's Salt solution was added to quench the reaction, causing the solution to return to a yellow color. The reaction mixture was stirred vigorously for 3 h before being diluted with EtOAc and washed with saturated NH4Cl (aq.). The organic phase was dried over Na2SO4, filtered, concentrated. The crude product was purified by prep-HPLC, Method D to afford Example 831 (2.4 mg, 0.004 mmol, 24% yield) as the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.81 (1H, br. s.), 8.64 (1H, s), 8.50 (1H, br. s.), 8.44 (1H, s), 7.77-8.03 (4H, m), 7.34 (1H, d, J=8.54 Hz), 5.36-5.45 (1H, m), 5.10 (1H, d, J=5.19 Hz), 4.76 (1H, br. s.), 4.45 (2H, d, J=5.19 Hz), 4.03 (3H, s), 1.38 (6H, dd, J=12.36, 6.26 Hz); 19F NMR (471 MHz, DMSO-d6) δ ppm −132.94 (1F, s.); LC-MS: method L, RT=2.24 min, MS (ESI) m/z: 584.25 (M+H)+.
    • Example 832 (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(methylcarbamoyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01865
  • To a vial charged with Example 830 (8 mg, 0.013 mmol) were added THF (0.4 mL), followed by methylamine (0.6 mL, 0.013 mmol). The reaction mixture was sealed and heated at 60° C. for 30 minutes. The solvent was removed and the residue was redissolved in DMF, before being purified by prep-HPLC, Method D to afford Example 832 (4.9 mg, 0.008 mmol, 59% yield) as the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.11 (1H, br. s.), 8.61 (1H, br. s.), 8.54 (1H, d, J=4.58 Hz), 8.43 (1H, s), 7.61-8.11 (6H, m), 5.11 (1H, d, J=6.10 Hz), 4.83 (1H, d, J=6.10 Hz), 4.03 (3H, s), 2.75 (3H, d, J=4.58 Hz), 1.40 (6H, dd, J=8.85, 7.02 Hz); 19F NMR (471 MHz, DMSO-d6) δ ppm −132.95 (1F, br. s.); LC-MS: method L, RT=2.57 min, MS (ESI) m/z: 611.15 (M+H)+.
    • Example 833 (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy) butan-2-yl (6-carbamoylpyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01866
  • Example 830 (8 mg, 0.013 mmol) was dissolved in THF (0.5 mL). NH3 (2 mL, 14.00 mmol) in methanol (7N) was added. The reaction mixture was sealed and heated at 60° C. for 20 hours. On the next day, solvent was removed and the residue was purified by prep-HPLC, Method D to afford Example 833 (4.5 mg, 0.007 mmol, 55% yield) as the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.16 (1H, br. s.), 8.50-8.70 (2H, m), 8.39 (1H, br. s.), 7.75-8.09 (6H, m), 7.43 (1H, br. s.), 5.12 (1H, d, J=6.10 Hz), 4.78 (1H, d, J=4.58 Hz), 4.01 (3H, s), 1.33-1.46 (6H, m); 19F NMR (471 MHz, DMSO-d6) δ ppm −132.98 (1F, br. s.); LC-MS: method L, RT=2.50 min, MS (ESI) m/z: 597.10 (M+H)+.
    • Example 834 (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(dimethylcarbamoyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01867
  • To a vial charged with Example 830 (8 mg, 0.013 mmol) was added THF (0.5 mL). The resulting solution was cooled to 0° C. and magnesium chloride (6.22 mg, 0.065 mmol) was added. The mixture was allowed to stir for 30 min before dimethylamine (0.196 mL, 0.392 mmol) was added. The ice bath was allowed to expire and the reaction mixture was stirred at 60° C. for 2 hours. After cooling down to room temperature, solvent was removed and the residue was dissolved in DMF. The remaining solids were removed by filtration and the resulting solution was purified by prep-HPLC, Method D to afford Example 834 (0.8 mg, 0.001 mmol, 10% yield) as the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.07 (1H, br. s.), 8.80 (1H, s), 8.60 (2H, d, J=2.48 Hz), 8.03-8.10 (2H, m), 7.92-8.02 (2H, m), 7.52 (1H, d, J=8.53 Hz), 5.13 (1H, dd, J=6.60, 2.75 Hz), 4.83 (1H, dd, J=6.33, 2.75 Hz), 4.09 (3H, s), 2.96 (6H, d, J=6.33 Hz), 1.40 (6H, dd, J=6.33, 5.23 Hz); 19F NMR (471 MHz, DMSO-d6) δ ppm −138.05 (1F, br. s.); LC-MS: method L, RT=2.52 min, MS (ESI) m/z: 625.15 (M+H)+.
    • Example 835 (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01868
  • 1-(5-aminopyridin-2-yl)-2-methylpropan-2-ol (2.95 mg, 0.018 mmol) was dissolved in DCM (0.5 mL) and pyridine (1.955 μl, 0.024 mmol) was added. A solution of Intermediate 820B (8 mg, 0.016 mmol) in DCM (0.5 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. On the next day, solvent was removed and the residue was purified by prep-HPLC, Method D to afford Example 835 (6.8 mg, 0.010 mmol, 63% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.76 (1H, br. s.), 8.65 (1H, s), 8.49 (1H, br. s.), 8.46 (1H, d, J=2.14 Hz), 7.94 (1H, d, J=8.24 Hz), 7.92 (1H, d, J=2.14 Hz), 7.87 (1H, d, J=11.60 Hz), 7.75 (1H, br. s.), 7.19 (1H, d, J=8.24 Hz), 5.09 (1H, dd, J=6.41, 2.75 Hz), 4.77 (1H, dd, J=6.26, 2.59 Hz), 4.04 (3H, s), 3.53 (1H, s), 2.72 (2H, s), 1.38 (6H, dd, J=12.66, 6.56 Hz), 1.02 (6H, s); NMR (471 MHz, DMSO-d6) δ ppm −132.92 (1F, br. s.); LC-MS: method L, RT=2.29 min, MS (ESI) m/z: 626.15 (M+H)+.
    • Example 836 (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate
  • Figure US20190292176A1-20190926-C01869
  • Intermediate I-93 (7.83 mg, 0.031 mmol) was dissolved in DCM (0.5 mL) and pyridine (3.42 μl, 0.042 mmol) was added. Then Intermediate 820B (14 mg, 0.028 mmol) in DCM (0.5 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. On the next day, TBAF (0.282 mL, 0.282 mmol) solution was added. After stirring for 3 hours, HCl (0.071 mL, 0.282 mmol) was added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Then solvent was removed on the rotavapor and the residue was purified by prep-HPLC, Method D to afford Example 836 (4.8 mg, 0.008 mmol, 27% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.75 (1H, br. s.), 8.64 (1H, s), 8.49 (1H, br. s.), 8.45 (1H, s), 7.93 (1H, d, J=8.24 Hz), 7.91 (1H, s), 7.85 (1H, d, J=11.60 Hz), 7.71-7.79 (1H, m), 7.18 (1H, d, J=8.54 Hz), 5.09 (1H, d, J=6.41 Hz), 4.76 (1H, d, J=5.80 Hz), 4.03 (3H, s), 3.66 (1H, t, J=6.71 Hz), 3.56 (1H, d, J=2.75 Hz), 2.77 (2H, t, J=6.71 Hz), 1.37 (7H, dd, J=13.43, 6.41 Hz); 19F NMR (471 MHz, DMSO-d6) δ ppm −132.95 (1F, br. s.); LC-MS: method L, RT=2.19 min, MS (ESI) m/z: 598.15 (M+H)+.
    • Example 837 2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole
  • Figure US20190292176A1-20190926-C01870
  • In a vial charged with a stirring bar, Intermediate I-28 (17 mg, 0.053 mmol) was dissolved in 1,4-dioxane (1 mL), mixed with 2-bromo-6-methoxy-4-methylbenzo[d]thiazole (17.80 mg, 0.069 mmol). Na2CO3 (1 mL, 2.0 mmol) was added, followed by PdCl2(dppf)-DCM (4.33 mg, 5.30 μmol). The reaction mixture was stirred at 100° C. for 1 hour. After cooling down to room temperature, the reaction mixture was diluted by adding 20 ml of EtOAc and 20 mL of water. After shaking and separation, the organic phase was passed through Na2SO4 and concentrated on rotavapor. The residue was purified by prep-HPLC, Method D to afford Example 837 (2.0 mg, 0.005 mmol, 10% yield). 1H NMR (500 MHz, CDCl3-d) δ 8.80 (d, J=2.5 Hz, 1H), 8.59 (s, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 6.95 (s, 1H), 4.14 (s, 3H), 3.90 (s, 3H), 2.83 (s, 3H); LC-MS: method L, RT=2.934 min, MS (ESI) m/z: 372.10 (M+H)+.

Claims (14)

What is claimed is:
1. A compound of Formula (I) to (VIII):
Figure US20190292176A1-20190926-C01871
or a salt thereof; wherein:
R1 is F, Cl, —OH, C1-4 alkyl, C1-4 fluoroalkyl, C2-4alkenyl, C2-4alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, C2-4 hydroxyalkoxy, C3-6 cycloalkoxy, (C1-3 alkoxy)-(C1-3 alkylene), (C1-3 alkoxy)-(C1-3 fluoroalkylene), (C1-3 deuteroalkoxy)-(C1-3 deuteroalkylene), (C1-3 fluoroalkoxy)-(C1-3 alkylene), (C1-3 fluoroalkoxy)-(C1-3 fluoroalkylene), —(CH2)1-3O(phenyl), —(CH2)1-3NRaRa, —C(O)O(C1-6 alkyl), —C(O)NRaRa, —C(O)NRbRb, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —NH(C1-6 hydroxyalkyl), azetidinyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, piperazinyl, —S(O)2(C1-3 alkyl), —S(O)2NRaRa, C1-3 alkylthio, or C1-3 fluoroalkylthio;
R2, at each occurrence, is independently H, F, Cl, Br, —OH, —CN, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 aminoalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, C1-6 alkoxy, C1-3 fluoroalkoxy, C1-3 alkylthio, C1-3 fluoroalkylthio, (C1-3 alkoxy)-(C1-3 alkylene), (C1-3 fluoroalkoxy)-(C1-3 alkylene), —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —C(O)O(C1-6 alkyl), —C(O)NH(CH2CH2O(C1-3 alkyl)), —C(O)NRbRb, —C(O)(piperidinyl), —CH(OH)(C3-6 cycloalkyl), —CH(OH)(phenyl), —CH(OH)(pyridyl), —S(O)2(C1-3 alkyl), —S(O)2NRaRa, or a cyclic group selected from phenyl, 5-to 6-membered heteroaryl, and 5-to 7-membered heterocyclyl, wherein said cyclic group is substituted with zero to 5 substituents independently selected from F, Cl, hydroxy, C1-3 alkyl, C1-3 alkoxy, cyclopropyl, and —CN;
R3 is a bicyclic group selected from indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzofuranyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, 6,7-dihydrothiazolo[5,4-c]pyridinyl, 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazinyl, 4,5,6,7-tetrahydrobenzothiophenyl, furo[3,2-b]pyridinyl, and furo[2,3-b]pyridinyl, each bicyclic group substituted with zero to 3 R3a;
R3a, at each occurrence, is independently:
(i) F, Cl, —CN, —OH, C1-3 alkyl, C1-6 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxy-fluoroalkyl, C1-6 alkoxy, C1-3 fluoroalkoxy, C3-6 cycloalkyl, C3-6 fluorocycloalkyl, 4-to 7-membered heterocyclyl, —CH(OH)Ry wherein Ry is C3-6 cycloalkyl, aryl, heteroaryl, or 4-to 7-membered heterocyclyl; (C1-3 alkoxy)-(C1-3 alkylene), —(CH2)1-3NRaRa, —(CH2)1-3NHS(O)2(aryl), —O(CH2)1-3(aryl), —O(CH2)1-3(thiazolyl), —O(CH2)1-3(oxazolidinonyl), —O(CH2)1-3(amino isoxazolyl), —O(CH2)1-3(imidazolyl substituted with phenyl), C1-6 hydroxyalkoxy, (C1-3 alkoxy)-(C1-6 alkoxy), —O(CH2)1-4O(aryl), —O(CH2)1-4O(CH2)1-3(aryl), —O(CH2)1-4NRaRa, —O(CH2)1-3CHRaNRa(methoxy pyrimidinyl), —O(CH2)1-4NHS(O)2(C1-3 alkyl), —O(CH2)1-4NHS(O)2(aryl), —O(CH2)1-4C(O)OH, —O(CH2)1-4C(O)O(C1-6 alkyl), —O(CH2)1-4C(O)NRa(CH2)0-3(aryl), —O(CH2)1-4C(O)NRa(CH2)0-3(heteroaryl), —O(CH2)1-4C(O)(morpholinyl), —O(CH2)1-4OC(O)O(C1-3 alkyl), —O(CH2)1-3CHRaOC(O)NRa(CH2)1-4C(O)NRaRa, —CH2CHRdOC(O)NRa(heteroaryl), —O(CH2)1-4OC(O)NRa(heteroaryl), —O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C1-6 alkyl), —NRaC(O)(furanyl), —NRaC(O)(pyranyl), —NRaC(O)O(C1-6 alkyl), —NRaC(O)O(CH2)1-4(aryl), —O(CH2)1-4NRaC(O)O(C1-6 alkyl), —O(CH2)1-4NRaC(O)O(CH2)0-4(tetrahydropyranyl), —O(CH2)1-4NRaC(O)O(CH2)0-4(aryl), —O(CH2)1-4NRaC(O)O(CH2)0-4(heteroaryl), or —O(CH2)1-4NRaC(O)O(CH2)0-4(tetrahydrofuranyl), wherein each of said aryl, heteroaryl, and 3- to 6-membered heterocyclyl is substituted with zero to 5 substituents independently selected from F, Cl, —CN, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy, —OCF3, —OCHF2, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —C(O)O(C1-3 alkyl), C1-3 hydroxyalkoxy, phenyl, —CONRcRc, and —S(O)2NRcRc;
(ii) —CH(OH)CRhRiRj wherein Rh and Ri are independently H, F, C1-4 alkyl, C1-4 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, or taken together with the carbon atom to which they are attached, form C3-8 cycloalkyl or 4- to 7-membered heterocyclyl ring; and Rj is H, C1-6 alkyl, C1-5 fluoroalkyl, (C1-3 alkoxy)-(C1-3 alkylene), C3-8 cycloalkyl, C3-8 heterocyclyl, aryl, or heteroaryl;
(iii) —O(CH2)1-4NRaS(O)2(C1-4 alkyl) or —O(CH2)1-4NRaS(O)2Rw, wherein Rw is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, Cl, cyano, C1-3 alkyl, C1-3 alkoxy, —OCF3, —OCHF2, and C1-3 fluoroalkyl; or
(iv) —O(CH2)1-4OC(O)NRaRx, —OCH(Rd)(CH2)1-3OC(O)NRaRx, —OCRdRd(CH2)1-3OC(O)NRaRx, —O(CH2)1-3CH(Rd)OC(O)NRaRx, —O(CH2)1-3CRdRdOC(O)NRaRx, —OCH(Rd)CH(Rd)(CH2)0-2OC(O)NRaRx, or —OCRdRdCRdRd(CH2)0-2OC(O)NRaRx, wherein Rx is selected from H, C1-4 alkyl, C1-4 fluoroalkyl, aryl, heteroaryl, and —CH2(heteroaryl), each aryl and heteroaryl substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxyalkoxy, C1-6 hydroxy-fluoroalkoxy, C1-3 alkoxy, —C(O)OH, —(CH2)0-3C(O)O(C1-3 alkyl), —(CH2)1-3OP(O)(OH)2, —CH2(morpholinyl), —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —C(O)NRa(C1-6 hydroxyalkyl), —C(O)NRbRb, —S(O)2NRaRa, —NH2, —NH(C1-6 alkyl), —NRa(C1-6 hydroxyalkyl), —N(C1-6 alkyl)2, —NRaC(O)(C1-6 alkyl), —NRaC(O)(chloro, fluorophenyl), —NRaS(O)2(C1-3 alkyl), —C(O)NRa(CH2)0-1 (hydroxymethyloxetanyl), —C(O)NRa(CH2)0-1 (hydroxymethyl C3-6 cycloalkyl), —C(O)NRa(CH2)0-1 (hydroxy C3-6 cycloalkyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl;
R4 is H, F, Cl, or —CH3;
Ra, at each occurrence, is independently H, C1-4alkyl, or C1-4 fluoroalkyl;
two Rb along with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo ring having 1 to 2 nitrogen atoms and 0-1 oxygen or sulfur atoms;
Rc, at each occurrence, is independently C1-3 alkyl or C1-3 hydroxyalkyl, or two Rc along with the nitrogen atom to which they are attached form a heterocyclyl or bicyclic heterocyclyl;
Rd, at each occurrence, is independently C1-6 alkyl, C1-4 fluoroalkyl, C1-6 hydroxyalkyl, (C1-4 alkoxy)-(C1-3 alkylene), (C1-2 fluoroalkoxy)-(C1-2 alkylene), (C3-6 cycloalkyl)-(C0-2 alkylene), aryl-(C1-2 alkylene), heteroaryl-(C1-2 alkylene), aryloxy-(C1-2 alkylene), aryl-CH2O—(C1-2 alkylene), or heteroaryloxy-(C1-2 alkylene); and
n is zero, 1, or 2.
2. The compound according to claim 1 having the structure of Formula (I) to Formula (IV):
Figure US20190292176A1-20190926-C01872
3. The compound according to claim 1 or a salt thereof; wherein:
R1 is —OH, C1-2 alkyl, —CHFCH3, —CH═CH2, C1-3 alkoxy, C1-2 fluoroalkoxy, —OCH2CH2OH, —CH2O(C1-2 alkyl), —CD2OCD3, —CH2OCHF2, —CF2OCH3, —CH2O(phenyl), —CH(CH3)OCH3, —NH(CH3), —N(CH3)2, —CH2N(CH3)2, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)OCH3, —CH(CH3)OCH3, cyclopropyl, furanyl, or —O(cyclopropyl);
R2, at each occurrence, is independently H, F, Cl, —CN, —CH3, —CH2F, —CHF2, —CF3, —OCH3, —OCF3, —CH2OH, —CH2CH2OH, —CH(CH3)OH, —C(CH3)2OH, —CH(OH)CH2OH, —CH2NH2, —C(O)NH2, —C(O)N(CH3)2, —C(O)(piperidinyl), —C(O)OCH3, —C(O)NH(CH2CH2OCH3), —CH(OH)(cyclopropyl), —CH(OH)(phenyl), —CH═CH2, —C(CH3)═CH2, or —C≡CH;
R3 is:
Figure US20190292176A1-20190926-C01873
R3a, at each occurrence, is independently:
(i) F, Cl, —CN, —OH, —CH3, —CF3, —CHFC(CH3)3, cyclopropyl, —CH2OH, —CD2OH, —CH2CH2OH, —CH(OH)CH3, —C(CH3)2OH, —CH(OH)C(CH3)3, —CD(OH)C(CH3)3, —CH(OH)CF3, —CH(OH)CH2CF3, —CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substituted with phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl), —CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl), —CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted with phenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl), —CH(OH)(phenyl), —CH(OH)(isopropylphenyl), —CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl), —CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl), —CH(OH)(methyltetrahydropyranyl), —CH2OCH3, —CH2N(CH3)2, —CH2NHS(O)2(phenyl), or —CH(OH)CH2(phenyl);
(ii) —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCHF2, —OCH2(phenyl), —OCH2(thiazolyl), —OCH2(oxazolidinonyl), —OCH2(amino isoxazolyl), —OCH2(imidazolyl substituted with phenyl), —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2CH2OCH3, —OCH(CH3)CH2OH, —OCH2CH(OH)CH3, —OCH(CH3)CH(OH)CH3, —OCH2C(CH3)2OH, —OCH2CH2O(phenyl), —OCH2CH2OCH2(phenyl), —OCH2CH2NH(CH3), —OCH2CH(CH3)NH(methoxy pyrimidinyl), —OCH2C(O)OH, —OCH2C(O)OCH3, —OCH2C(O)OCH2CH3, —OCH2C(O)OC(CH3)3, —OCH2C(O)NH(phenyl), —OCH2C(O)NHCH2(phenyl), —OCH2C(O)(morpholinyl), —OCH2CH2CH2C(O)NH(pyridinyl), —OCH2CH2OC(O)OCH3, —OCH2CH(CH3)OC(O)NHCH2CH2C(O)NH2, —OCH2CH(CH2CH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH3)OC(O)NH(pyridinyl), —OCH2CH(CH2OC(CH3)3)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2(phenyl))OC(O)NH(pyridinyl), —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(pyrimidinyl), or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NH(methyl pyrimidinyl);
(iii) —C(O)OH, —C(O)OCH3, or —C(O)OC(CH3)3;
(iv) —NHC(O)OCH3, —NHC(O)OC(CH3)3, —NHC(O)OCH2(phenyl), —NHC(O)OCH2(tetrahydrofuranyl), or —NHC(O)O(tetrahydropyranyl);
(v) —OCH2CH2NHC(O)OCH3, —OCH2CH2NHC(O)O(tetrahydropyranyl), —OCH2CH2NHC(O)OCH2(phenyl), —OCH2CH2NHC(O)O(methoxyphenyl), —OCH2CH2NHC(O)O(tetrahydrofuranyl), —OCH2CH2NHC(O)OCH2(tetrahydrofuranyl), —OCH2CH2NHC(O)NH(pyridinyl), —OCH2CH2N(CH3)C(O)NH(methylpyrimidinyl), or —OCH2CH(CH3)OC(O)OCH2(aminopyridinyl);
(vi) —OCH2CH2NHS(O)2CH3 or —OCH2CH2NHS(O)2Rw wherein Rw is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, Cl, and —CH3; or
(vii) —OCH2CH2OC(O)NHRz, —OCH(CH3)CH2OC(O)NHRz, —OCH2CH(CH3)OC(O)NHRz, —OCH(CH3)CH(CH3)OC(O)NHRz, —OCH2CH(CH2O(isobutyl))OC(O)NHRz, —OCH2CH(CH2CH3)OC(O)NHRz, —OCH2CH(CH2OCH3)OC(O)NHRz, or —OCH2CH(CH2OCH2CH(CH3)2)OC(O)NHRz wherein Rz is H, —CH2CF3, phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH2(pyrazolyl), —CH2(imidazolyl), or —CH2(pyridinyl), each substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, —CH3, —CH2CH2CH3, —CF3, —CH2OH, —CD2OH, —CH(CH3)OH, —CH2CH2OH, —CH2CH2CH2OH, —C(CH3)2OH, —CH2CH(CH3)OH, —CH2C(CH3)2OH, —CH2CH2C(O)OCH3, —CH2OP(O)(OH)2, —CH2CH2OP(O)(OH)2, —CH2(morpholinyl), —OCH3, —OCH2CH2OH, —OCH2CH(CH3)OH, —OCH2C(CH3)2OH, —OCH2CH2C(CH3)2OH, —OCH(CH3)CH2OH, —OCH2CH(OH)CH2OH, —OCH2CF2OH, —OCH2CF2CH2OH, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2, —C(O)NH(CH2CH2OH), —C(O)NH(CH2CH(CH3)OH), —C(O)NH(CH2C(CH3)2OH), —C(O)NH(CH2C(CH3)2CH2OH), —C(O)NH(CH2CH2C(CH3)2OH), —C(O)N(CH3)CH2CH2OH, —C(O)N(CH3)CH2C(CH3)2OH, —C(O)NHCH2(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl), —C(O)NHCH2(hydroxycyclobutyl), —C(O)NHCH2(hydroxymethylcyclobutyl), —C(O)NHCH2C(CH3)2OP(O)(OH)2, —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH2, —N(CH3)2, —NHC(O)CH3, —NHC(O)(chloro, fluorophenyl), —NH(CH2C(CH3)2OH), —N(CH3)S(O)2CH3, pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl;
R4 is H, F, or —CH3; and
p is zero, 1, 2, or 3.
4. The compound according to claim 1 or a salt thereof, wherein:
R3 is:
Figure US20190292176A1-20190926-C01874
5. The compound according to claim 1 having the structure of Formula (I):
Figure US20190292176A1-20190926-C01875
or a salt thereof.
6. The compound according to claim 5 or a salt thereof, wherein:
R1 is —OCH3, —OCHF2, —OCH2CH3, or —CH2OCH3;
R2, at each occurrence, is independently H, F, Cl, —CN, —CH3, —OCH3, or —CH2OH; and
R3 is:
Figure US20190292176A1-20190926-C01876
7. The compound according to claim 1 or a salt thereof, wherein said compound is selected from Examples 1-129, 131-133, 135-152, 154-176, 178-184, 186-189, 191-511, 516-624, 627-647, 658, 661-669, 671-702, 708-731, 733-738, 740-768, and 805-837.
8. The compound according to claim 1 having the structure of Formula (II):
Figure US20190292176A1-20190926-C01877
or a salt thereof.
9. The compound according to claim 8 or a salt thereof, wherein:
R1 is —OH, —OCH3, —OCH2CH3, —OCHF2, —OCH2CHF2, —CH2OCH3, or —NH(CH3);
R2, at each occurrence, is independently F, Cl, —CN, —CH3, —CH2OH, —CH2F, —CHF2, or —OCH3;
R3 is:
Figure US20190292176A1-20190926-C01878
and
R3a, at each occurrence, is independently F, Cl, —CH3, —OCH3, —CH(OH)(trifluoromethylcyclobutyl), —OCH2CH(CH3)OC(O)NHRz, or —OCH(CH3)CH(CH3)OC(O)NHRz, wherein Rz is pyridinyl, pyrimidinyl, or benzo[d]oxazolonyl, each substituted with zero to 2 substituents independently selected from F, —OH, —CN, —CH3, —CF3, —CH2OH, —CH2CH2OH, —OCH2CH2OH, —OCH3, —CH2CH(CH3)OH, and —OCH2CH2C(CH3)2OH.
10. The compound according to claim 1 or a salt thereof, wherein said compound is selected from Examples 177, 185, 190, 512-515, 625-626, 648-657, 659-660, and 769-804.
11. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound according to claim 1 or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent.
12. A method for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder, which comprises the steps of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.
13. The method according to claim 8 wherein the thromboembolic disorder is selected from the group consisting of unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, and procedures in which blood is exposed to an artificial surface that promotes thrombosis.
14. A method of inhibiting or preventing platelet aggregation, which comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a salt thereof.
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