Classifications

• • 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
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—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
  • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, 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 three hetero rings
  • C07D515/14—Ortho-condensed systems

Definitions

• the present invention generally relates to tricyclic heteroaryl substituted compounds useful as inhibitors of platelet aggregation.
• tricyclic heteroaryl substituted compounds Provided herein are tricyclic 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.
• 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.
• WO2013/163241 disclose various PAR4 antagonists which are useful as inhibitors of platelet aggregation.
• tricyclic 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 tricyclic heteroaryl substituted compounds which 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 Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII):
• Ri is F, CI, -OH, Ci-4 alkyl, Ci-4 fluoroalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, Ci-4 alkoxy, Ci-4 fluoroalkoxy, C2-4 hydroxyalkoxy, C3-6 cycloalkoxy, (C1-3 alkoxy )-(Ci-3 alkylene), (C1-3 alkoxy )-(Ci-3 fluoroalkylene), (C1-3 deuteroalkoxy)-(Ci-3 deuteroalkylene), (C1-3 fluoroalkoxy)-(Ci-3 alkylene), (C1-3 fluoroalkoxy )-(C 1-3 fluoroalkylene), -(CH 2 )i-30(phenyl), -(CH 2 )i-3NRaRa, -C(0)0(Ci-e alkyl), -C(0)NR a Ra, -C(0)NRbR
• R2 at each occurrence, is independently H, F, CI, Br, -OH, -CN, Ci-4 alkyl, Ci-4 fluoroalkyl, Ci-4 hydroxyalkyl, C1-3 aminoalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, Ci-6 alkoxy, C1-3 fluoroalkoxy, C1-3 alkylthio, C1-3 fluoroalkylthio, (Ci-3 alkoxy)-(Ci-3 alkylene), (C1-3 fluoroalkoxy )-(C 1-3 alkylene), -C(0)NH 2 ,
• R 3 is:
• Xi is N and X 2 is S, O, or NH;
• Xi is O and X 2 is CH or N;
• Xi is NH and X 2 is CH;
• Xi is CH and X2 is S or NH;
• each R3 is substituted with R.3a and zero to 3 R3t>;
• R.3a is:
• Rh and Ri are independently H, F, Ci-4 alkyl, Ci-4 fluoroalkyl, C1-3 alkoxy, or C 1-3 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, Ci-6 alkyl, C1-5 fluoroalkyl, (C1-3 alkoxy )-(C 1-3 alkyl), C3-8 cycloalkyl, C3-8 heterocyclyl, aryl, or heteroaryl;
• Rx is C3-6 cycloalkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
• benzo[d]oxazolyl benzo[d]thiazolyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, mo holinyl, imidazopyridinyl, or
• oxo-dihydrobenzo[d]oxazolyl each substituted with zero to two substituents independently selected from F, CI, Br, -CN, -OH, -CH3, -CF3, C1-3 alkoxy,
• Ci-3fluoroalkyl Ci-6 hydroxyalkyl, Ci-6 hydroxy alkoxy, Ci-6 hydroxy-fluoroalkoxy, phenoxy, -NR a Ra, -C(0)NRaR a , -C(0)NH(Ci-e alkyl), -C(0)N(Ci-e alkyl) 2 ,
• R3b at each occurrence, is independently H, F, CI, Br, -CN, C1-3 alkyl, C1-3 fluoroalkyl, Ci-3 hydroxyalkyl, -OCHF 2 , C3-6 cycloalkyl, C3-6 fluorocycloalkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, C1-3 alkoxy, C1-3 alkylthio, or C1-3 fluoroalkoxy;
• R 4 is H, F, CI, or -CH 3 ;
• Ra at each occurrence, is independently H, Ci-4alkyl, or Ci-4fluoroalkyl;
• One embodiment provides a compound of Formula (I) to (VIII) or a salt thereof, wherein Xi is N and X 2 is S, O, or NH; R3 is substituted with R3a and zero to 3 R3b; and Ri, R 2 , R3, R3a, R3b, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
• One embodiment provides a compound of Formula (I) to (VIII) or a salt thereof, wherein Xi is O and X2 is CH or N; R3 is substituted with R3a and zero to 3 R3t>; and Ri, R2, R3, R3a, R3b, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
• One embodiment provides a compound of Formula (I) to (VIII) or a salt thereof, wherein Xi is NH and X2 is CH; R3 is substituted with R3a and zero to 3 R3b; and Ri, R2, R3, R3a, R3b, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
• One embodiment provides a compound of Formula (I) to (VIII) or a salt thereof, wherein Xi is CH and X2 is S; and R3 is substituted with R3a and zero to 3 R3b; and Ri, R2, R.3, R.3a, R3b, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
• One embodiment provides a compound of Formula (I) to (VIII) or a salt thereof, wherein Xi is N and X2 is S; or Xi is O and X2 is CH; and R3 is substituted with R3a and zero to 3 R3b; and Ri, R2, R3, R3a, R3b, R4, and n are defined in the first aspect. Included in this embodiment are compounds in which R3 is:
• One embodiment provides a compound of Formula (I):
• Xi is N and X2 is S or O; or (ii) Xi is O and X2 is CH; and the dashed lines represent the variable position of a double bond to maintain aromaticity; each R3 is substituted with R3a and zero to 3 R3b; and Ri, R2, R3a, R3b, R4, and n are defined in the first aspect.
• One embodiment provides a compound having the structure of Formula (la):
• Ri is -CH 3 , -OCH3, or -OCHF2
• R2 is CI, -CN, -CH 3 , -CH2OH
• R 3 CH 2 ;
• each R3 is substituted with R 3a and zero to 3 R3t>;
• R3a is H, -CH2OH, -CH(CH 3 )OH, -CH 2 CH(CH 3 )OH, -CH(OH)C(CH 3 ) 3 ,
• R* is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, benzo[d]oxazolyl, benzo[d]thiazolyl, oxoisoindolinyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazopyridinyl, or oxo-dihydrobenzo[d]oxazolyl, each substituted with zero to two substituents independently selected from F, CI, Br, -CN, -OH, -CH 3 , -CF 3 , -CH2CH2OH, Ci-2 alkoxy, phenoxy, -NR a R a , -C(0)NRaRa, -C(0)OC
• One embodiment provides a compound having the structure of Formula (la) or a salt thereof, wherein said compound is selected from:
• R3b are defined in the first aspect.
• One embodiment provides a compound having the structure of Formula (la) or a salt thereof, wherein: Ri is C1-3 alkyl or C1-3 alkoxy; R2 is C1-2 alkyl or C1-2 hydroxyalkyl; R3 is:
• R3 is substituted with R3a and zero to 3 R3t>;
• R3a is C1-3 hydroxyalkyl, or -CH20C(0)NHR X ;
• R x is phenyl, pyridinyl, or pyrimidinyl, each substituted with zero to 2 substituents independently selected from F, CI, -CN, C1-2 alkyl, or Ci-2 alkoxy; and each R3b is independently CI, -CN, -CH3, -OCH3, or -OCHF2.
• Ri is -OCH3; R2 is -CH3; R3a is
• R x is pyridinyl substituted with zero to 1 substituent selected from -CH3 or -OCH3; and R3b is CI or -CH3.
• One embodiment provides a compound having the structure of Formula (la) or a salt thereof, wherein: Ri is C1-3 alkyl or C1-3 alkoxy; R2 is C1-2 alkyl or C1-2 hydroxyalkyl;
• R 3 is: , wherein R3 is substituted with R.3a and zero to 2 R3t>; Ri is C1-3 alkyl, C1-2 fluoroalkyl, or C1-3 alkoxy; R2 is H, F, CI, -CN, C1-3 alkyl, Ci-4 hydroxyalkyl, or
• R 3a is H, Ci-e hydroxyalkyl, -CH(OH)CHRi(C 3 -6 cycloalkyl),
• Ri is -CH 3 or -CF3;
• Ri is -CH3, -OCH3, or -OCHF 2
• R 3a is H, -CH 2 OH, -CH(OH)C(CH 3 )3,
• R x is benzo[d]oxazolyl, imidazopyridinyl, oxodihydrobenzo[d]oxazolyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolopyridinyl, or tetrahydroisoquinolinyl, each substituted with zero to 2 substituents independently selected from F, CI, Br, -CN, -OH, -CH3, -CF3,
• Ri is C1-3 alkyl or C1-3 alkoxy
• R 2 is CI, -CN, Ci -2 alkyl or Ci -2 hydroxyalkyl
• R3 is: , wherein R3 is substituted with R.3a and zero to 3 R3t>;
• R3a is H, C1-3
• R x is C3-6 cycloalkyl, morpholinyl, oxoisoindolinyl, phenyl, pyrdinyl, pyrimidinyl, pyridazinyl, tetrahydrofuranyl, tetrahydropyranyl, each substituted with zero to 2 substituents independently selected from F, CI, -CN, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, -OCH 2 CH 2 OH,
• each R 3 b is
• Ri is -OCH3 or -OCFhCFb
• R 2 is CI, -CN, -CH3, or -CH 2 OH
• R 3a is H, -CH 2 OH, -CH(CH 3 )OH, -CH 2 CH(CH 3 )OH, -C(0)OCH 3 ,
• R x is oxoisoindolinyl, phenyl, pyrdinyl, pyrimidinyl, pyridazinyl, tetrahydrofuranyl, tetrahydropyranyl, each substituted with zero to 2 substituents independently selected from F, CI, -CN, -CH3, -CH 2 CH 2 OH, -OCH3, -OCH 2 CH 2 OH, -OCH 2 CF 2 OH, -C(0)NRaRa, -C(0)(morpholinyl), or isoxazolyl; each R3b is independently F or -CH3; and each Ra is independently H or
• One embodiment provides a compound having the structure of Formula (Ila):
• Ri is -CH 3 , -OCH3, -OCH 2 CH 3 , or -OCHF 2 ;
• R 2 is F, CI, -CH 3 , -CH 2 F, or -CHF 2 ;
• R 3 is:
• R 3 b is F, -CH 3 , or - CH(OH)C(CH 3 ) 3 ; and R a , at each occurrence, is independently H or -CH 3 .
• R2, R3a, and R3b are defined in the first aspect.
• Ri is C1-3 alkoxy or C1-3 fiuoroalkoxy
• R2 is F, CI, -CN, C1-3 alkyl, or C i-3 fluoroalkyl
• R3 is:
• each R3 is substituted with R3a and zero to 2 R3t>;
• R3a is Ci-6 hydroxyalkyl or
• R x is phenyl, pyridinyl, or pyrimidinyl, each substituted with zero or 1 substituent selected from C1-3 alkyl, -C(0)NRaRa, and C i-4 alkoxy; each R3b is independently H, F, CI, -CH3, or -CF3; and each R a is independently H or -CH3.
• Ri is -OCH3, OCH2CH3, or -OCHF2
• R2 is F, CI, -CH3, -CH2F, or -CHF2
• each R3 is substituted with R3a and zero to 2 R3b
• R3a is -CH2OH, -CH(OH)C(CH 3 )3, or -CH 2 OC(0)NHR x
• R x is phenyl, pyridinyl, or
• pyrimidinyl each substituted with zero or 1 substituent selected from -CH3, -C(0)NH2, -OCH2CH2OH, and -OCH 2 CH(CH 3 )OH; and each R 3 b is independently F or -CH 3 .
• each R3 is substituted with R.3a and zero to 2 R3t>;
• R3a is H, Ci-6 hydroxyalkyl, -C(0)0(Ci-6 alkyl), -CRaRaNHC(0)(Ci-6 alkyl), -CRaRaNHC(0)(Ci-6 fluoroalkyl),
• R x is C3-6 cycloalkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzo[d]oxazolyl, benzo[d]thiazolyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, imidazopyridinyl, or
• Ci-3fluoroalkyl, Ci-6 hydroxyalkyl, Ci-6 hydroxy alkoxy, Ci-6 hydroxy-fluoroalkoxy, phenoxy, -NRaR a , -C(0)NR a R a , -C(0)NH(Ci-e alkyl), -C(0)N(Ci-e alkyl) 2 , -C(0)NRbRb, -C(0)NR a (Ci- 6 hydroxyalkyl), -C(0)0(Ci-e alkyl), -C(0)OCi- 4 alkyl, -C(0)(morpholinyl), -CH(OH)CH 2 OH, -CH CH 2 , -NHC(0)CH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 CH 2 OH, -OCH 2 CH(Me)OH, isoxazolyl, phenoxy, phenyl, pyrrolidinyl, thiophenyl, and
• R3 a is -CR a R£iOC(0)NHR x and R x is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, benzo[d]oxazolyl, benzo[d]thiazolyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, imidazopyridinyl, or oxo-dihydrobenzo[d]oxazolyl, each substituted with zero to two substituents independently selected from F, CI, Br, -CN, -OH, -CH3, -CF3, Ci -2 alkoxy, phenoxy, -NRaR a , -C(0)NH 2 , -C(0)NH(Ci-e alkyl), -C(0)N(Ci-e alkyl) 2 , -C(0)NRbRb, -C(0)OC
• R x is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, benzo[d]oxazolyl, benzo[d]thiazolyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, imidazopyridinyl, or oxo-dihydrobenzo[d]oxazolyl, each substituted with zero to two substituents
• Rx is: (i) pyridazinyl, benzo[d]oxazolyl, benzo[d]thiazolyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, methyl imidazopyridinyl, or oxo-dihydrobenzo[d]oxazolyl; (ii) phenyl substituted with zero to 1 substituent selected from -CN and -C(0)(morpholinyl); (iii) pyridinyl substituted with zero to two substituents independently selected from F, CI, Br, -CN, -OH, -CH 3 , -CF 3 , C1-2 alkoxy, phenoxy, -NH 2 , -N(CH 3 ) 2 , -C(0)NH 2 ,
• One embodiment provides a compound of Formula (I) to (VIII) or a salt thereof, wherein Ri is -OCHF 2 or -OCH 3 ; and R 2 , R 3 , R 3a , R3 ⁇ 4, R4, and n are defined in the first aspect. Included in this embodiment are compounds of which Ri is -OCH 3 . Also included are compounds in which Ri is -OCH 3 and R 2 is -CH 3 .
• Ri is -OCHF 2 or -OCH 3 ; and R 2 , R 3 , R 3a , and R3 ⁇ 4 are defined in the first aspect. Included in this embodiment are compounds of which Ri is -OCH 3 . Also included are compounds in which Ri is -OCH 3 and R 2 is -CH 3 .
• One embodiment provides a compound having the structure of Formula (la), wherein: Ri is -C -OCH 3 , or -OCHF 2 ; R 2 is CI, -CN, -CH 3 , -CH 2 OH, -CH(CH 3 )OH,
• R 3 is: ; each R 3 is substituted with R 3a and zero to 2 R3 ⁇ 4; R 3 a is H, -CH 2 OH, -CH 2 NHC(0)OC(CH 3 ) 3 , -CH 2 OC(0)(dimethylaminopyridinyl), or
• One embodiment provides a compound having the structure of Formula (la), wherein said compound is selected from:
• Ri is -CH 3 , -OCH 3 , or -OCHF 2
• R 3a is H, -CH 2 OH, -CH 2 NHC(0)OC(CH 3 ) 3 , -CH 2 OC(0)(dimethylaminopyridinyl), or
• R x is: (i) pyridazinyl, benzo[d]oxazolyl, benzo[d]thiazolyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, methyl imidazopyridinyl, or
• phenyl substituted with zero to 1 substituent selected from -CN and -C(0)(morpholinyl); (iii) pyridinyl substituted with zero to two substituents independently selected from F, CI, Br, -CN, -OH, -CH 3 , -CF 3 , Ci -2 alkoxy, phenoxy, -NH 2 , -N(CH 3 ) 2 , -C(0)NH 2 , -C(0)OC(CH 3 ) 3 , -C(0)OCH 3 , -CH(OH)CH 2 OH, -CH CH 2 , -NHC(0)CH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , phenyl, pyrrolidinyl, thiophenyl, and methyl triazolyl; or (iv) pyrimidinyl substituted with CI or -CH 3 ;
• One embodiment provides a compound or a salt thereof, selected from (4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydrobenzofuro[5,4-d]thiazol-7- yl)methyl (6-methoxypyridin-3-yl)carbamate (17);
• One embodiment provides a compound or a salt thereof, 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.
• cyano refers to the group -CN.
• amino refers to the group -NH2.
• 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 i-butyl), and pentyl (e.g.
• fluoroalkyl as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms.
• Ci-4 fluoroalkyl is intended to include Ci, C 2 , 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.
• 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.
• Ci-6 alkylene denotes straight and branched chain alkylene groups with one to six carbon atoms.
• C0-4 alkylene denotes a bond and straight and branched chain alkylene groups with one to four carbon atoms.
• C2-6 alkenyl denotes straight and branched chain alkenyl groups with two to six carbon atoms.
• Exemplary such groups include ethynyl.
• C2-6 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 poly cyclic 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.
• C3-6 cycloalkyl denotes cycloalkyl groups with three to six carbon atoms.
• cycloalkylalkylene refers to a cycloalkyl group attached through an alkylene group to the patent molecular moiety.
• (C3-6 cycloalkyl)-(Co-2 alkylene) denotes a C3-6 cycloalkyl group attached through a bond or a C1-2 alkylene to the parent molecular moiety.
• alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (-OCH3).
• C1-3 alkoxy denotes alkoxy groups with one to three carbon atoms.
• fluoroalkoxy and fluoroalkyl) represent a fluoroalkyl group as defined above attached through an oxygen linkage (-0-).
• Ci-4 fluoroalkoxy is intended to include Ci, C 2 , C3, and C4 fluoroalkoxy groups.
• hydroxy alkoxy represent a hydroxyalkyl group as defined above attached through an oxygen linkage (-0-).
• C1-4 hydroxy alkoxy is intended to include Ci, C2, C3, and C4 hydroxyalkoxy groups.
• cycloalkoxy refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom, for example, cyclopropoxy group (-O(cyclopropyl)).
• alkoxy alkoxy refers to an alkoxy group attached through an alkoxy group to the patent molecular moiety.
• (C1-3 alkoxy )-(C 1-6 alkoxy) denotes a C1-3 alkoxy group attached through a Ci-6 alkoxy group to the parent molecular moiety.
• alkoxyalkylene refers to an alkoxy group attached through an alkylene group to the patent molecular moiety.
• (C1-3 alkoxy )-(C 1-3 alkylene) denotes a C1-3 alkoxy group attached through a C1-3 alkylene to the parent molecular moiety.
• 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.
• 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 (O, S or N), said heteroatom containing ring preferably having 1 to 3 heteroatoms independently selected from O, 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.
• 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-l,l-dioxothienyl.
• Exemplary bicyclic heterocyclo groups include quinuclidin
• 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, pyrrolopyridinyl, furopyridinyl, 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(Ci-2 alkylene) refers to an aryl group attached through a Ci -2 alkylene to the parent molecular moiety.
• heteroarylalkylene refers to a heteroaryl group attached through an alkylene group to the patent molecular moiety.
• heteroaryl(Ci-2 alkylene) refers to a heteroaryl group attached through a C1-2 alkylene to the parent molecular moiety.
• aryloxyalkylene refers to an aryloxy group attached through an alkylene group to the patent molecular moiety.
• aryloxy-(Ci-2 alkylene) refers to an aryloxy group attached through a C1-2 alkylene to the parent molecular moiety.
• heteroaryloxyalkylene refers to a heteroaryloxy group attached through an alkylene group to the patent molecular moiety.
• heteroaryloxy-(Ci-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.
• 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.
• Solid 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 1 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 (-CH3) also includes deuterated methyl groups such as -CD3.
• 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 GPIIbllla 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 PARI and PAR4.
• compounds of the invention have IC50 values in the PAR4 FLIPR
• Assay (described hereinafter) of about 10 ⁇ , preferably 1 ⁇ 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 Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), preferably, a compound selected from one of the examples, more preferably, Examples 1 to 292, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, alone or in combination with another therapeutic agent.
• a pharmaceutical composition which includes a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), preferably, a compound selected from one of the examples, more preferably, Examples 1 to 292, 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 PARI 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 (pi. 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 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 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:
• 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, atrial 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.
• 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
• VTE venous thromboembolism
• 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.
• stage of the cancer i. e. , presence of metastases
• central vein catheters i. e. , central vein catheters
• surgery and anticancer therapies including chemotherapy iv
• hormones and antiangiogenic drugs i. heparin preparations have been approved by the FDA for these indications.
• 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.
• 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
• 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 FLIPR assay is an exemplary in vitro assay for measuring the activity of the PAR4 antagonists of the present invention.
• 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-NH 2 was validated as a PAR4 agonist in the FLIPR assay.
• a side-by-side comparison of the ICso values of -180 compounds were performed using AYPGKF versus
• 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 value that is 10 fold lower than the EC50 value 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 PARI antagonist activity in a cell line that expresses both PARI and PAR4.
• the PARI antagonist activity can be tested by the ability of the compound to inhibit calcium mobilization induced by the PARI agonist peptide SFLLRN or other PARI 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 PARI, selectively cleaves and activates PAR4 (Soslau, G. et al, "Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein lb", 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, PARI 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 PARI 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 PRP is initiated by the addition of tissue factor and CaCh.
• 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, FeCh-induced carotid artery thrombosis and
• SFFLRR is a known high affinity PARI selective agonist peptide.
• 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 (EC50 value of 8 ⁇ for
• 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 PARI and can elicit calcium signal upon stimulation with PARI agonist peptide. Therefore, the same cells were also used to determine selectivity against PARI 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)
• PRP Platelet Rich Plasma
• 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, NJ), a recombinant hirudin, at a final concentration of 1 unit/mL was added to the sample to selectively prevent PARI 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
• FLIPR-based calcium mobilization assay in HEK293 Cells FLIPR-based calcium mobilization assay in HEK293 cells was used to measure PAR4 antagonism, agonism, and selectivity against PARI .
• 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 PARI antagonist activity were also performed. Briefly, PARl/PAR4-expressing HEK293 cells were grown in DMEM (Life Technology, Grand Island, NY) containing 10% heat-inactivated FBS, 1%
• Cells were plated overnight prior to the experiment in a black 384- well Purecoat Amine clear bottom plate (Becton Dickinson Biosciences, San Jose, CA) at 10,000 cells /well in 30 growth medium and incubated in a humidified chamber at 37 °C with 5% CCh overnight. Prior to compound addition, the cell medium was replaced with 40 of IX 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).
• HBSS Hank's Balanced Saline Solution
• test compound diluted in IX HBSS buffer
• DMSO dimethyl sulfoxide
• the PAR4 agonist peptide H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2
• the PARI agonist peptide SFFLRR
• Compound potency was derived from 11 -point concentration-response curves.
• IP A platelet aggregation
• the aggregation assays were also employed to test the selectivity of the compound against other platelet receptors by using SFFLRR for PARI, collagen (Chrono-Log,
• 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 ⁇ 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 PARI 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 CaCh 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, CT) 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 reactions 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 lb with halides R3-X shown in Scheme 2.
• difluoroalkoxy may be displaced with a nucleophile containing an Ri group to compound la.
• Compound Ila can be condensed with dicarbonyl lib to give compound lie.
• Acid catalyzed cyclization provides the key bromide lid.
• 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 Vila, palladium catalyzed cross coupling of various boronic acids or stannanes yields substituted anilines of structure Vllb. Nitration of compound Vllb and reduction of compound VIIc allows access to compounds of Formula Vlld. Base mediated condensation of dianiline Vlld with substituted bromo-ketones provides heterocycles of Formula Vile. A final palladium-catalyzed cross coupling with aryl boronic acids or stannanes then furnishes the compounds of Formula VII. e 10
• 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 1 1.
• Compound Villa can be condensed with ami dines to give compound VHIb.
• Phosphorous oxychloride conversion of compound VHIb to aryl chloride VIIIc followed by palladium-catalyzed cross coupling with aryl boronic acids or stannanes furnishes the compound of Formula VIII.
• R -X in which R3 is a 7,8-dihydro-[l,4]dioxino[2',3':3,4]benzo[l,2-d]thiazole, can be prepared using the synthetic route described in Scheme 12.
• Phenol aldehyde of Formula IX is alkylated with an epoxide of Formula X to give epoxy aldehyde of
• R3-X in which R3 is a 2,3-dihydro-[l,4]dioxino[2,3-e]benzofuran, can be prepared using the synthetic route in Scheme 13.
• Alkylation of compound XVII with epoxide of Formula X gives rise to epoxy aldehyde of Formula XVIII.
• R3-X in which R3 is a 7,8-dihydrobenzofuro[5,4-d]thiazole, can be prepared using the synthetic route in Scheme 14.
• Compound XX can be alkylated with allyl bromide in the presence of a base such as K2CO3 to give compound XXI.
• Claisen rearrangement of XXI in a solvent such as NN-diethylaniline at heating yields ortho-allyl phenol XXII.
• Method A PHENOMENEX® Luna C18 column (4.6 x 50 mm or 4.6 x 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 CI 8 column (4.6 x 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 CI 8 column (4.6 x 50 mm or 4.6 x 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 P0 4 ; B: 10% water, 89.9% methanol, 0.1% H 3 P0 4 , UV 220 nm).
• Method D PHENOMENEX® Luna C18 column (4.6 x 50 mm or 4.6 x 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 OAc; B: 10% water, 89.9% methanol, 0.1% NH OAc, UV 220 nm).
• Method E BEH CI 8 2.1x50mm; 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 CI 8 2.1x50mm; 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 CI 8 2.1x50mm; 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
• Method A PHENOMENEX® Axia Luna 5 ⁇ CI 8 30 x 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 ⁇ C18 30 x l00 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 x 200 mm column, 5- ⁇ 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 x 100 mm column, 5- ⁇ 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 ⁇ C18 30 x 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 ⁇ C18 30 x 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 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
• Method C A linear gradient using solvent A (10% methanol, 90% water, 0.1% of
• Method D A linear gradient using solvent A (10% methanol, 90% water, 0.1% of
• Method F 10-95% methanol in water, 0.1% TFA in a 10 min run,
• Method G 5-95% acetonitrile in water, lOmM of modifier in 6 min run, Waters Xbridge 2.1x50mm 5 um CI 8, 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 CI 8 2.1x50mm; 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 CI 8 2.1x50mm; 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 CI 8 2.1x50mm; 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 x 50 mm, 1.7- ⁇ 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 x 50 mm, 1.7- ⁇ particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifiuoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifiuoroacetic 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. Injectionl 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 CI 8, 2.1 x 50 mm, 1.7- ⁇ 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;
• 2-chloro-2,2-difiuoroacetate (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 EtO Ac and water, extracted with EtO Ac (3 X). 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).
• Trifluoroacetic acid (0.471 mL, 6.1 1 mmol) in dichloromethane (6 mL) was added dropwise. The mixture was stirred at room temperature for 2.0 h. TLC indicated a completion of reaction. The reaction was quenched by addition of saturated sodium bicarbonate, followed by 10% sodium thiosulfite (20.0 mL), extracted with

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