WO2018013774A1 - Bicyclic heteroaryl substituted compounds - Google Patents

Bicyclic heteroaryl substituted compounds Download PDF

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Publication number
WO2018013774A1
WO2018013774A1 PCT/US2017/041878 US2017041878W WO2018013774A1 WO 2018013774 A1 WO2018013774 A1 WO 2018013774A1 US 2017041878 W US2017041878 W US 2017041878W WO 2018013774 A1 WO2018013774 A1 WO 2018013774A1
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och
methylquinoxalin
methoxy
thiazol
oxy
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English (en)
French (fr)
Inventor
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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Priority to ES17742925T priority Critical patent/ES2823180T3/es
Priority to JP2019501619A priority patent/JP7058256B2/ja
Priority to KR1020197004315A priority patent/KR102460385B1/ko
Priority to US16/317,248 priority patent/US20190292176A1/en
Priority to EP17742925.5A priority patent/EP3484878B1/en
Priority to CN201780056202.XA priority patent/CN109689647B/zh
Publication of WO2018013774A1 publication Critical patent/WO2018013774A1/en
Anticipated expiration legal-status Critical
Priority to US17/123,265 priority patent/US12060347B2/en
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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 PARI and PAR4. Inhibitors of PARI 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(l):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-(l-benzyl-lH-indazol-3-yl)benzoate (YD-3) derivatives", Bioorg. Med. Chem. , 16: 1262-1278 (2008).
  • EP 1166785 Al 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
  • R 1 is F, CI, -OH, C 1-4 alkyl, C 1-4 fiuoroalkyl, 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 -3O(phenyl), -(CH 2 ) 1 -3NRaRa, -C(O)O(C 1-6 al
  • R2 at each occurrence, is independently H, F, CI, Br, -OH, -CN, C 1-4 alkyl, C 1-4 fiuoroalkyl, 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 ,
  • R3 is a bicyclic group selected from indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazol[l,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl,
  • R.3a at each occurrence, is independently:
  • Rh and Ri are independently H, F, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, 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 Rj is H, C 1-6 alkyl, C1-5 fluoroalkyl, (C 1-3 alkoxy )-(C 1-3 alkylene), C 3 -8 cycloalkyl, C 3 -8 heterocyclyl, aryl, or heteroaryl;
  • R w is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, CI, cyano, C 1-3 alkyl, C 1-3 alkoxy, -OCF3, -OCHF 2 , and C 1-3 fluoroalkyl; or
  • R x is selected from H, CM alkyl, C 1-4 fluoroalkyl, aryl, heteroaryl, and -CH 2 (heteroaryl), each aryl and heteroaryl substituted with zero to 2 substituents independently selected from F, CI, Br, -CN, -OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-6 hydroxy-deuteroalkyl, C 1-6 hydroxyalkoxy, C 1-6 hydroxy-fluoroalkoxy, C 1-3 alkoxy, -C(O)OH, -(CH 2 ) 0-3 C(O)O(C 1-3 alkyl),
  • R 4 is H, F, CI, or -CH 3 ;
  • Ra at each occurrence, is independently H, C 1-4 alkyl, or C 1-4 fluoroalkyl
  • Rc 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;
  • Rd at each occurrence, is independently C 1-6 alkyl, C 1-4 fiuoroalkyl, C 1-6 hydroxyalkyl, (C 1-4 alkoxy)-(C 1-3 alkylene), (C1-2 fluoroalkoxy)-(C 1- 2 alkylene), (C 3-6 cycloalkyl)-(Co-2 alkylene), aryl(C 1- 2 alkylene), heteroaryl(C 1- 2 alkylene), aryloxy-(C 1- 2 alkylene), aryl-CH20-(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:
  • R2 at each occurrence, is independently H, F, CI, -CN, -CH3, -CH2F, -CHF2, -CF 3 , -OCH3, -OCF3, -CH2OH, -CH2CH2OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH,
  • R3a at each occurrence, is independently:
  • -OCH 2 (imidazolyl substituted with phenyl), -OCH2CH2OH, -OCH 2 CH(CH 3 )OH, -OCH 2 CH 2 OCH 3 , -OCH(CH 3 )CH 2 OH, -OCH 2 CH(OH)CH 3 , -OCH(CH 3 )CH(OH)CH 3 , -OCH 2 C(CH 3 ) 2 OH, -OCH 2 CH 2 O(phenyl), -OCH 2 CH 2 OCH2(phenyl),
  • R z is H, -CH 2 CF3, phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
  • pyrrolo[2,3-b]pyridinyl benzo[d]oxazolonyl, -CH 2 (pyrazolyl), -CH 2 (imidazolyl), or -CH 2 (pyridinyl), each substituted with zero to 2 substituents independently selected from F, CI, Br, -CN, -OH, -CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -CH 2 OH, -CD 2 OH,
  • R.4 is H, F, or -CH 3 ;
  • 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 R 1 , R 2 , R 3 , R4, and n are defined in the first aspect.
  • R 3 is:
  • ⁇ is zero, 1 , 2, or 3; and R 3a is defined in the first aspect. Also included in this embodiment are compounds in which R4 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 , 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 R 1 , R 2 , R 3 , R4, 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 , 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 R 1 , 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 R 1 , 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 R 1 , 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 R 1 , 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 R 1 , 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 R 1 , 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 R 1 , 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 R 1 , R2, R3, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
  • 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 R 1 , R2, R3, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
  • 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:
  • Rm is H or CI
  • Rk is H or F
  • R 1 , 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
  • R 1 , 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),
  • R 1 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
  • R 1 , R 3 , R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R2 is F, CI, -CN, -CH 3 , or -CH2OH. Also included in this embodiment are compounds in which R2 is -CH 3 .
  • One embodiment provides at least one compound of Formula (I), (II), (V), and (VII) or a salt thereof, wherein R4 is H, F, or -CH 3 ; and R 1 , R2, R 3 , 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.
  • R 3a at each occurrence, is independently, (i) F, CI, -CN, -OH, -CH 3 , -CF 3 , -CHFC(CH 3 ) 3 , cyclopropyl, -CH2OH, -CD2OH, -CH2CH2OH, -CH(OH)CH 3 , -C(CH 3 ) 2 OH, -CH(OH)C(CH 3 ) 3 ,
  • R w is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, CI, and -CH 3 ; or (vii)
  • R z is H, -CH 2 CF 3 , phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
  • pyrrolo[2,3-b]pyridinyl benzo[d]oxazolonyl, -CH 2 (pyrazolyl), -CH 2 (imidazolyl), or -CH 2 (pyridinyl), each substituted with zero to 2 substituents independently selected from F, CI, Br, -CN, -OH, -CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -CH 2 OH, -CD 2 OH, -CH(CH 3 )OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 C(O)OCH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 CH 2 OP(O)(OH) 2 , -CH 2 (morpholinyl), -OCH
  • R 3 is substituted with one R 3a selected from (i) F, CI, -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)(trifluoromethyl
  • -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, -OCH 2 CH(OH)CH 3 , -OCH(CH 3 )CH(OH)CH 3 , -OCH 2 C(CH 3 ) 2 OH, -OCH 2 CH 2 O(phenyl), -OCH 2 CH 2 OCH 2 (phenyl), -OCH 2 CH 2 NH(CH 3 ), -OCH 2 CH(CH 3 )NH(methoxy pyrimidinyl), -OCH 2 C(O)OH, -OCH 2 C(O)OCH 3 , -OCH 2 C(O)OCH 2 CH 3 , -OCH
  • R w is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, CI, and -CH 3 ; or (vii)
  • R z is H, -CH 2 CF 3 , phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
  • pyrrolo[2,3-b]pyridinyl benzo[d]oxazolonyl, -CH 2 (pyrazolyl), -CH 2 (imidazolyl), or -CH 2 (pyridinyl), each substituted with zero to 2 substituents independently selected from F, CI, Br, -CN, -OH, -CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -CH 2 OH, -CD 2 OH, -CH(CH 3 )OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 C(O)OCH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 CH 2 OP(O)(OH) 2 , -CH 2 (morpholinyl), -OCH
  • 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 , R4, Ra, Rb, Rd, and n are defined in the first aspect with the proviso that at least one R 3a is F, CI, -CN, -OH, C 1-3 alkyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-6 hydroxy-deuteroalkyl, C 1-6
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV),
  • R 3a is -CH(OH)CRhRiRj wherein Rh and Ri 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 Rj is H, C 1-6 alkyl, C1-5 fluoroalkyl, (C 1-3 alkoxy )-(C 1-3 alkylene), C 3 -8 cycloalkyl, C 3 -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 Ri, R 2 , R 3 , R 3a , R4, Ra, Rb, Rd, and n are defined in the first aspect with the proviso that at least one R 3a is
  • R w is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, CI, 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), (III), or (IV).
  • One embodiment provides at least one compound of Formulas (I), (II), (III), (IV),
  • R x is selected from H, CM alkyl, C 1-4 fluoroalkyl, aryl, heteroaryl, and -CH 2 (heteroaryl), each aryl and heteroaryl substituted with zero to 2 substituents independently selected from F, CI, Br, -CN, -OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-6 hydroxy-deuteroalkyl, C 1-6 hydroxy alkoxy, C 1-6 hydroxy-fluoroalkoxy, C 1-3 alkoxy, -C(O)OH, -(CH 2 ) 0-3 C(O)O(C 1-3 alkyl),
  • 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 , R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is F, CI, -CN, -OH, -CH3, -CF3, -CHFC(CH 3 )3, cyclopropyl, -CH 2 OH, -CD 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 ,
  • 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 , R3a, R4, and n are defined in the first aspect with the proviso that at least one R3a is -OCH3, -OCH 2 CH3, -OCH(CH 3 ) 2 , -OCF3, -OCHF2, -OCH 2 (phenyl), -OCH 2 (thiazolyl),
  • 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 , R4, 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 , R4, and n are defined in the first aspect with the proviso that at least one R 3a is -NHC(O)OCH 3 ,
  • 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 , R2, R 3 , R 3a , R4, and n are defined in the first aspect with the proviso that at least one R 3a is -OCH2CH2NHC(O)OCH 3 , -OCH2CH 2 NHC(O)O(tetrahydropyranyl), -OCH 2 CH 2 NHC(O)OCH2(phenyl),
  • 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 , R4, 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 Rw wherein R w is phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, CI, 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 , R4, 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)NHRz, -OCH 2 CH(CH 3 )OC(O)NHRz,
  • R z is H, -CH 2 CF 3 , phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,
  • pyrrolo[2,3-b]pyridinyl benzo[d]oxazolonyl, -CH 2 (pyrazolyl), -CH 2 (imidazolyl), or -CH 2 (pyridinyl), each substituted with zero to 2 substituents independently selected from F, CI, Br, -CN, -OH, -CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -CH 2 OH, -CD 2 OH, -CH(CH 3 )OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 C(O)OCH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 CH 2 OP(O)(OH) 2 , -CH 2 (morpholinyl), -OCH
  • 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, CI, -CN, -CH 3 , -OCH 3 , or -CH 2 OH; and
  • R 3 is: and R4, 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, CI, -CN, -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , or
  • R 3a at each occurrence, is independently F, CI, -CH 3 , -OCH 3 , -CH(OH)(trifluoromethylcyclobutyl),
  • 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-(lH-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:
  • 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
  • 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:
  • 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:
  • 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:
  • One embodiment provides compounds of Formulas (I), (II), (III), or (IV) or a salt thereof, wherein R3 is imidazol[l,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 R3 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 R3 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 R3 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 R3 is 4,5,6,7-tetrahydrobenzofuranyl. Included in this embodiment is a compound of Formula (I) selected from: tert-butyl
  • 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
  • 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:
  • 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:
  • 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.

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