USRE49594E1 - Apelin receptor (APJ) agonists and uses thereof - Google Patents

Apelin receptor (APJ) agonists and uses thereof Download PDF

Info

Publication number
USRE49594E1
USRE49594E1 US16/974,363 US202016974363A USRE49594E US RE49594 E1 USRE49594 E1 US RE49594E1 US 202016974363 A US202016974363 A US 202016974363A US RE49594 E USRE49594 E US RE49594E
Authority
US
United States
Prior art keywords
alkyl
mmol
cycloalkyl
aryl
pyrazole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US16/974,363
Inventor
Scott P. Runyon
Rangan Maitra
Sanju Narayanan
James Barnwell Thomas
Kenneth S. Rehder
Srinivas Olepu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Research Triangle Institute
Original Assignee
Research Triangle Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Research Triangle Institute filed Critical Research Triangle Institute
Priority to US16/974,363 priority Critical patent/USRE49594E1/en
Assigned to RESEARCH TRIANGLE INSTITUTE reassignment RESEARCH TRIANGLE INSTITUTE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MAITRA, Rangan, NARAYANAN, SANJU, OLEPU, SRINIVAS, REHDER, KENNETH S., RUNYON, SCOTT P., THOMAS, JAMES BARNWELL
Application granted granted Critical
Publication of USRE49594E1 publication Critical patent/USRE49594E1/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/08—Bridged 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
    • C07D487/08—Bridged systems

Definitions

  • This disclosure relates generally to the discovery of agonists of the apelin receptor (APJ) and uses of such agonists.
  • APJ apelin receptor
  • the apelin receptor was cloned in 1993 as an orphan G-protein coupled receptor (GPCR).
  • GPCR G-protein coupled receptor
  • the human APJ gene is located on the long arm of chromosome 11 and encodes a 377 amino acid G protein-coupled receptor.
  • the gene for APJ was designated angiotensin-receptor like 1 (AGTRL1) due to sequence similarities between the two receptors.
  • AGTRL1 angiotensin-receptor like 1
  • APJ remained an orphan GPCR until 1998 when the peptide apelin was identified as its endogenous ligand.
  • apelin and APJ have emerged as an important regulator of various physiological processes. Both apelin and APJ are expressed in the central nervous system (CNS) and peripherally in a number of tissues. Expression of APJ has been noted within the vasculature of some organs and is a potent regulator of related processes including angiogenesis and vasoconstriction. Cobellis et al. report increased of expression levels of both apelin and APJ receptor in preeclampsia-complicated pregnancies. Cobellis et al., Histol Histopathol. 2007; 22(1):1-8. APJ is also expressed in nonvascular cell types in heart, liver, and CNS where its primary role is currently under investigation. Medhurst et al., J Neurochem.
  • Apelin and APJ are often co-localized within the same organ suggesting an autocrine regulation of the receptor by its ligand.
  • apelin has since been detected in blood suggesting that concomitant paracrine regulation of the receptor is also possible.
  • the apelin-APJ system has been implicated as a regulator of various physiological functions and is believed to play an important role in thermoregulation, immunity, glucose metabolism, angiogenesis, fluid homeostasis, cardiac function, hepatic function and renal function. Ladeiras-Lopes et al., Arq Bras Cardiol. 2008; 90(5):343-349.
  • APJ also acts as a co-receptor during HIV infection. O′Donnell et al., J Neurochem. 2007; 102(6):1905-1917; Zou et al., FEBS Lett. 2000; 473(1):15-18.
  • apelin and APJ are either up- or down-regulated in various pathophysiological conditions.
  • the APJ appears to be an emerging target for the treatment of cardiovascular failure, liver fibrosis, cancer, angiopathies, pancreatitis, and as a prophylactic against HIV infection.
  • apelin and APJ reviewed apelin and APJ as an opportunity for therapeutic uses for pulmonary hypertension and pulmonary arterial hypertension (PAH). Andersen et al. Pulm. Circ. 2011; 1(3) 334-346.
  • R 1 is represented by the formula:
  • each A is independently C 1-8 alkyl, C 1-8 alkyl(aryl), C 1-8 alkoxy, C 1-8 alkoxy aryl, C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, —CF 3 , —(CH 2 ) x NR 7 R 8 , —CN, —CONR 7 R 8 , —COR 7 , —CO 2 (CH 2 ) x NR 7 R 8 , —CO 2 R 7 , halogen, hydroxyl, —N 3 , —NHCOR 7 , —NHSO 2 C 1-8 alkyl, —NHCO 2 C 1-8 alkyl, —NO 2 , —NR 7 R 8 , —O(CH 2 ) x NR 7 R 8 , —O(CH 2 ) x CO 2 R 7 , —OCOC 1-8 alkyl, —OCO
  • R 1 is represented by the formula:
  • each A is independently C 1-8 alkyl, C 1-8 alkyl(aryl), C 1-8 alkoxy, C 1-8 alkoxy aryl, C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, —CF 3 , —(CH 2 ) x NR 7 R 8 , —CN, —CONR 7 R 8 , —COR 7 , —CO 2 (CH 2 ) x NR 7 R 8 , —CO 2 R 7 , halogen, hydroxyl, —N 3 , —NHCOR 7 , —NHSO 2 C 1-8 alkyl, —NHCO 2 C 1-8 alkyl, —NO 2 , —NR 7 R 8 , —O(CH 2 ) x NR 7 R 8 , —O(CH 2 ) x CO 2 R 7 , —OCOC 1-8 alkyl, —OCO(CH 2 )
  • each A is independently C 1 -C 3 alkoxy, C 1 -C 3 alkyl, chloro, or fluoro.
  • each A is independently fluoro substituted C 1 -C 3 alkoxy or fluoro substituted C 1 -C 3 alkyl.
  • the disclosure provides the compound of any of par. [0008]-[0011], wherein R 2 is —C 4 H 9 , —C 5 H 11 , -cC 4 H 8 or -cC 5 H 10 .
  • the disclosure provides the compound of any of par. [0008]-[0012], wherein the R 4 group contains a nitrogen and two or more fluorine atoms.
  • R 4 is C 1-8 alkyl(aryl), C 1-4 alkyl cycloalkyl, C 1-8 alkyl heteroaryl, C 1-4 alkyl heterocycloalkyl, C 2-8 alkenyl(aryl), or C 2-8 alkenyl(heteroaryl).
  • the cycloalkyl group in the C 1-4 alkyl cycloalkyl may be a bicycloalkyl or a spiroalkyl group or the heterocycloalkyl group in the C 1-4 alkyl cycloalkyl may be a heterobicycloalkyl or a heterospiroalkyl group.
  • R 4 may be C 1-8 alkyl(difluoroaryl), C 1-4 alkyl difluorocycloalkyl, C 1-8 alkyl difluoro heteroaryl, C 1-4 alkyl difluoroheterocycloalkyl, C 2-8 alkenyl(difluoro aryl), or C 2-8 alkenyl(difluoro heteroaryl).
  • R 8 is heteroaryl.
  • R 8 may be oxadiazole, oxazole, n-methyl thiazole, tetrazole, thiazole, or triazole.
  • compositions comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of any of par. [0008]-[0014].
  • the therapeutically effective amount may be an amount effective for lowering blood pressure.
  • the therapeutically effective amount is an amount effective for the treatment of asthma, cardiomyopathy, diabetes, dyslipidemia, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, preeclampsia, or renal dysfunction.
  • the disclosure provides the use in a treatment of an apelin receptor (APJ) related disorder of a compound Formula I:
  • R 1 is represented by the formula:
  • each A is independently C 1-8 alkyl, C 1-8 alkyl(aryl), C 1-8 alkoxy, C 1-8 alkoxy aryl, C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, —CF 3 , —(CH 2 ) x NR 7 R 8 , —CN, —CONR 7 R 8 , —COR 7 , —CO 2 (CH 2 ) x NR 7 R 8 , —CO 2 R 7 , halogen, hydroxyl, —N 3 , —NHCOR 7 , —NHSO 2 C 1-8 alkyl, —NHCO 2 C 1-8 alkyl, —NO 2 , —NR 7 R 8 , —O(CH 2 ) x NR 7 R 8 , —O(CH 2 ) x CO 2 R 7 , —OCOC 1-8 alkyl, —OCO
  • the disclosure provides the use in a treatment of an apelin receptor (APJ) related disorder of a compound represented by the Formula II:
  • R 1 is represented by the formula:
  • each A is independently C 1-8 alkyl, C 1-8 alkyl(aryl), C 1-8 alkoxy, C 1-8 alkoxy aryl, C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, —CF 3 , —(CH 2 ) x NR 7 R 8 , —CN, —CONR 7 R 8 , —COR 7 , —CO 2 (CH 2 ) x NR 7 R 8 , —CO 2 R 7 , halogen, hydroxyl, —N 3 , —NHCOR 7 , —NHSO 2 C 1-8 alkyl, —NHCO 2 C 1-8 alkyl, —NO 2 , —NR 7 R 8 , —O(CH 2 ) x NR 7 R 8 , —O(CH 2 ) x CO 2 R 7 , —OCOC 1-8 alkyl, —OCO(CH 2 )
  • the disclosure provides the use of any of par. [0017]-[0019], wherein the apelin receptor (APJ) related disorder is asthma, cardiomyopathy, diabetes, dyslipidemia, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, preeclampsia, or renal dysfunction.
  • the apelin receptor (APJ) related disorder is asthma, cardiomyopathy, diabetes, dyslipidemia, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, preeclampsia, or renal dysfunction.
  • the disclosure provides the use of par. [0020], further comprising an ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a ⁇ -blocker, a calcium channel blocker, or a diuretic for the treatment of the apelin receptor (APJ) related disorder.
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • API apelin receptor
  • the disclosure provides a compound represented by the Formula IV:
  • R 1 is represented by the formula:
  • each A is independently C 1-8 alkyl, C 1-8 alkyl(aryl), C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, —CF 3 , —(CH 2 ) x NR 7 R 8 , —CN, —CONR 7 R 8 , —COR 7 , —CO 2 (CH 2 ) x NR 7 R 8 , —CO 2 R 7 , halogen, hydroxyl, —N 3 , —NHCOR 7 , —NHSO 2 C 1-8 alkyl, —NHCO 2 C 1-8 alkyl, —NO 2 , —NR 7 R 8 , —O(CH 2 ) x NR 7 R 8 , —O(CH 2 ) x CO 2 R 7 , —OCOC 1-8 alkyl, —OCO(CH 2 ) x NR 7 R 8 , —SF5, —SO
  • Formula IV may incorporate the modifications as described in par. [0011]-[0015] for Formulas I-III.
  • compounds of Formula IV may be prepared in pharmaceutical compositions as described in par. [0016].
  • disclosure provides the use in a treatment of apelin receptor (APJ) related disorders, as disclosed herein, of a compound represented by the Formula IV.
  • AJ apelin receptor
  • n is 1, group A is in the ortho position and is —CF 3 , —CF 2 CH 3 , —CH 2 CH 3 , Cl, -cC 3 H 5 , —OCF 2 H or —OCF 3 .
  • n is 2 and A 1 is —OCH 3 and A 2 is —OCH 3 or F. More specifically,
  • R 2 is —CH 2 cC 3 H 5 , —C(CH 3 ) 2 cC 3 H 5 , -cC 4 H 7 , -cC 4 H 6 (CH 3 ) 2 , —CH 2 cC 4 H 7 , -cC 5 H 9 , -cC 5 H 8 F, -cC 5 H 8 (CH 3 ), -cC 5 H 7 (CH 3 ) 2 , —CH 2 cC 5 H 9 , —CH 2 cC 5 H 9 , -cC 6 H 11 , —CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , or —C(CH 3 )CH(CH 3 ) 2 .
  • R 2 may be
  • R 4 may be
  • R 4 may be
  • the backbones of the R 4 groups in par. [0026]-[0027] may be modified to contain one or more fluorine atoms by the replacement of one or more hydrogens. Alternatively, if the R 4 groups in par. [0026]-[0027] contain fluorines, the backbone may be modified to incorporate additional fluorine substituents by replacement of aliphatic or aromatic hydrogens.
  • R 5 or R 10 may be
  • two groups in the set of R 1 , R 2 , R 4 , R 5 and R 10 are selected from the groups shown in par. [0024]-[0029]. In other preferred embodiments, three groups in the set of R 1 , R 2 , R 4 , R 5 and R 10 are selected from the groups in par. [0024]-[0029]. In yet another embodiment, four groups in the set of R 1 , R 2 , R 4 , R 5 and R 10 are selected from the groups in par. [0024]-[0029].
  • the disclosure also includes bioisosteres such as tetrazolones and pentafluorosulfanyl.
  • bioisosteres such as tetrazolones and pentafluorosulfanyl.
  • —CF 3 , —CH 3 , —O—CH 3 , or —O—CF 3 or an aryl —CF 3 , —CH 3 , —O—CH 3 , or —O—CF 3 may be replaced with —SF 5 or aryl-SF 5 , respectively.
  • a —CO 2 H may be replaced with a tetrazolone. See Duncton et al. 2016 Org Biomol Chem 14 9338-9342.
  • Alkenyl refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the Z- and E-forms (or cis or trans conformation) about the double bond(s).
  • alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and the like.
  • the alkenyl group may be substituted or unsubstituted.
  • an alkenyl group may be
  • Alkoxy refers to a radical —OR where R represents an alkyl, cycloalkyl, aryl, or heteroaryl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like. The alkoxy group may be substituted or unsubstituted.
  • Alkyl refers to a saturated, branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl, propan-2-yl, and cyclopropan-1-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, tert-butyl, and the like.
  • the alkyl group may be substituted or unsubstituted; for example with methyl or a halogen(s) such as difluoro or trifluoro.
  • an alkyl group comprises from 1 to 20 carbon atoms.
  • an alkyl group may comprise from 1 to 8 carbon atoms.
  • Alkyl(aryl) refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group.
  • Typical alkyl(aryl) groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • an alkyl(aryl) group can be (C 6-20 ) alkyl(aryl) e.g., the alkyl group may be (C 1-10 ) and the aryl moiety may be (C 5-10 ).
  • the alkyl(aryl) group may be substituted or unsubstituted.
  • Alkynyl refers to an unsaturated branched or straight-chain having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butenyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • an alkynyl group has from 3 to 20 carbon atoms and in other embodiments from 3 to 8 carbon atoms.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Aryl encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene or cyclopentadiene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane; or two aromatic ring systems, for example benzyl phenyl, biphenyl, diphenylethane, diphenylmethane.
  • the aryl group may be substituted or unsubstituted, for example with a halogen, such as fluorine.
  • Cycloalkyl refers to a saturated or unsaturated cyclic alkyl group. Where a specific level of saturation is intended, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. The cycloalkyl group may be substituted or unsubstituted. In certain embodiments, the cycloalkyl group can be C 3-10 cycloalkyl, such as, for example, C 6 cycloalkyl or cC 6 H 12 .
  • the cycloalkyl group may also be a bridged bicyclic cycloalkyl group, a fused cycloalkyl group or a spiro cycloalkyl group.
  • bridged bicyclic cycloalkyl groups are bicyclo[2.2.1]heptane, bicyclo[2.2.1]hexane, bicycle[2.2.2]octane.
  • An example of a fused cycloalkyl group is bicyclo[4.4.0]decane or decalin.
  • Non-limiting examples of spiro cycloalkyl groups are spiro [3.3] heptane, spiro [4.3] octane, or spiro [5.4] decane.
  • Disease refers to any disease, disorder, condition, symptom, or indication.
  • Halogen refers to a fluoro, chloro, bromo, or iodo group.
  • Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl encompasses: 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon; and polycyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • the heteroaryl group may be substituted or unsubstituted.
  • heteroaryl includes a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkyl ring and a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered heterocycloalkyl ring.
  • bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the cycloalkyl ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
  • the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 10 membered heteroaryl.
  • heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine.
  • Heterocycloalkyl refers to a non-aromatic monocyclic ring or fused non-aromatic polycyclic rings with one or more heteroatom(s) independently selected from N, S and O, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in each non-aromatic ring.
  • the heterocycle group may be a three-member ring, a four member ring, a five member ring, a six member ring or a seven member ring.
  • the heterocycloalkyl group is 1,4-dioxane, 1,3-dioxolane, 1,4-dithiane, imidazolidine, morpholine, piperidine, piperidone, piperazine, pyrolidone, pyrrolidine, or 1,3,5-trithiane. It may contain an imide.
  • the heterocycloalkyl group may be bicyclic such as an heterospiro group, e.g., heterospiro [3.3] heptanyl, heterospiro [3.4] octanyl, or heterospiro [5.5] undecanyls.
  • the heterocycloalkyl group may be substituted or unsubstituted.
  • heterocycloalkyl group encompasses heterocycloalkyl groups substituted with one or more halogens, such as 3,3-difluoropiperidine, or 4,4-difluoropiperidine.
  • the heterocycloalkyl group may be substituted with a C 1 -C 4 alkyl or C 1 -C 4 halo alkyl group such as a —CF 3 group.
  • “Pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkal
  • “Pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” or “pharmaceutically acceptable adjuvant” refer, respectively, to an excipient, carrier or adjuvant with which at least one compound of the present disclosure is administered.
  • “Pharmaceutically acceptable vehicle” refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered.
  • Prodrug refers to a precursor or derivative form of a pharmaceutically active substance that is less bioactive compared to the parent drug and is capable of being enzymatically activated or converted into the more active parent form.
  • Prodrug forms of the compounds described herein may designed to improve bioavailability or stability or reduce toxicity.
  • compounds of the invention having free amino, amido, carboxylic, hydroxyl, or thiol groups can be converted into prodrugs. See Rautio et al., 2008 Nat Rev Drug Dis 7 255-270.
  • free carboxyl groups can be derivatized as amides, carbamates, esters, or N-Mannich bases.
  • Free hydroxy groups may be derivatized using groups including but not limited to carbonates, dimethylaminoacetates, ethers, hemisuccinates, phosphate esters, and phosphoryloxymethyloxycarbonyls, as outlined in Fleisher et al., 1996 Advanced Drug Delivery Reviews 19, 115-130.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyloxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in Robinson et al., 1996 J Med Chem 39 10-18. Free amines can also be derivatized as amides, carbamates, imines, N-Mannich bases, oximes, phosphonamides, or sulfonamides. Carbonyls may be derivatized to imine or oxime prodrugs.
  • Thiols may be derivatized as esters or ethers.
  • Prodrugs may also include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
  • amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes beta-alanine, citrulline, demosine, gamma-aminobutyric acid, homocysteine, homoserine, 4-hydroxyproline, hydroxylysine, isodemosine, 3-methylhistidine, norvalin, methionine sulfone, and ornithine.
  • Stepoisomer refers to an isomer that differs in the arrangement of the constituent atoms in space. Stereoisomers that are mirror images of each other and optically active are termed “enantiomers,” and stereoisomers that are not mirror images of one another and are optically active are termed “diastereoisomers.”
  • Subject includes mammals and humans.
  • the terms “human” and “subject” are used interchangeably herein.
  • “Substituted” refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, CO 2 H, cyano, difluoro, difluoromethyl, halogen, hydroxyl, keto, methyl, —N 3 , —NH 2 , —SO( 1-3 )H, —SH, or trifluoromethyl.
  • “Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom.
  • the “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.
  • Treating” or “treatment” of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder.
  • Treating” or “treatment” also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further, “treating” or “treatment” refers to delaying the onset of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease or disorder.
  • Pairs of the functional groups defined herein may be combined in a chemically rational way.
  • C 1 -C 8 alkyl amino means the functional group C 1 -C 8 alkyl, e.g., -nC 5 H 11 , is combined with the functional group, amino, e.g., —NH 2 to form in this example -nC 5 H 10 NH 2 .
  • C 1 -C 8 alkyl alcohol would mean a group, e.g., nC 3 H 6 OH.
  • C 1 -C 8 alkoxy aryl means the functional group C 1 -C 8 alkoxy, e.g., —CH 2 CH 2 OCH 2 CH 3 or —OCH 2 CH 3 combined with an aryl group, e.g., —C 6 H 5 F to form —CH 2 CH 2 OCH 2 CH 2 —C 6 H 5 F or —OCH 2 CH 3 —C 6 H 5 F, respectively.
  • substituents R 4 , R 5 , R 6 , R 7 , or R 8 may independently may be single ⁇ , ⁇ , ⁇ , ⁇ amino acids, or their corresponding side chains, such as the twenty naturally occurring amino acids, e.g., alanine (Ala/A); arginine (Arg/R); asparagine (Asn/N); aspartic acid (Asp/D); cysteine (Cys/C); glutamic acid (Glu/E); glutamine (Gln/Q); glycine (Gly/G); histidine (His/H); isoleucine (Ile/I); leucine (Leu/L); lysine (Lys/K); methionine (Met/M); phenylalanine (Phe/F); proline (Pro/P); Serine (Ser/S); threonine (Thr/T); tryptophan (Trp/W); tyrosine (Tyr/Y
  • the individual amino acids may of either the R or the S chirality.
  • R 4 , R 5 , R 6 , R 7 , or R 8 independently may be two or three amino acids linked by a peptide bond.
  • R 4 , R 5 , R 6 , R 7 , or R 8 independently may be dipeptides or tripeptides (Hobbs et al., Proc Nat Acad Sci USA. 1993, 90, 6909-6913); U.S. Pat. No. 6,075,121 (Bartlett et al.) peptoids; or vinylogous polypeptides (Hagihara et al., J Amer Chem Soc.
  • R 4 , R 5 , R 6 , R 7 , or R 8 independently may be part of the extended unnatural amino acids, e.g., Xie and Schultz, Nat Rev Mol Cell Biol. 2006, 7(10):775-82 or Wang et al., Chem Biol. 2009, 16(3):323-36, the contents of which are hereby incorporated by reference in their entireties.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I, respectively.
  • Certain isotopic variations of a compound of the invention for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies.
  • PET Positron Emission Topography
  • isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • the isotope-labeled compounds contain deuterium ( 2 H), tritium ( 3 H) or 14 C isotopes.
  • Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art.
  • Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent.
  • compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D 2 SO 4 /D 2 O.
  • deuterium may be also incorporated into a compound using methods such as through reduction such as using LiAlD 4 or NaBD 3 , catalytic hydrogenation or acidic or basic isotopic exchange using appropriate deuterated reagents such as deuterides, D 2 and D 2 O.
  • methods such as through reduction such as using LiAlD 4 or NaBD 3 , catalytic hydrogenation or acidic or basic isotopic exchange using appropriate deuterated reagents such as deuterides, D 2 and D 2 O.
  • deuterated reagents such as deuterides, D 2 and D 2 O.
  • compositions comprising an effective amount of a compound Formula I (e.g., any of the formulae and/or structures disclosed herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • a compound Formula I e.g., any of the formulae and/or structures disclosed herein
  • a pharmaceutically acceptable carrier e.g., any of the formulae and/or structures disclosed herein
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphat
  • solubility and bioavailability of the compounds of the present disclosure in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples,” Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this disclosure optionally formulated with a poloxamer, such as LUTROLTM and PLURONICTM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide.
  • a poloxamer such as LUTROLTM and PLURONICTM (BASF Corporation)
  • block copolymers of ethylene oxide and propylene oxide such as LUTROLTM and PLURONICTM (BASF Corporation
  • compositions of the disclosure include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), pulmonary, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (17th ed. 1985).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the compound is administered orally.
  • compositions of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions of this disclosure may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this disclosure with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this disclosure may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g., U.S. Pat. No. 6,803,031 (Rabinowitz & Zaffaroni).
  • Topical administration of the pharmaceutical compositions of this disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene or polyoxypropylene compounds, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of this disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this disclosure.
  • compositions at the site of interest may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • implantable medical device such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Pat. No. 6,099,562 (Ding & Helmus); U.S. Pat. No.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • the disclosure provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
  • the disclosure provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this disclosure.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the disclosure provides an implantable medical device coated with a compound or a composition comprising a compound of this disclosure, such that said compound is therapeutically active.
  • the disclosure provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this disclosure, such that said compound is released from said device and is therapeutically active.
  • an organ or tissue is accessible because of removal from the subject, such organ or tissue may be bathed in a medium containing a composition of this disclosure, a composition of this disclosure may be painted onto the organ, or a composition of this disclosure may be applied in any other convenient way.
  • this disclosure provides a composition comprising a compound of Formula I, or more specific compounds disclosed herein, to treat or prevent asthma, atherosclerosis, cancer, cardiomyopathy, diabetes, dyslipidemia, HIV neurodegeneration, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, or preeclampsia.
  • the disclosure provides a composition comprising a compound of Formula I, or more specific compounds disclosed herein, to treat or prevent cancer, cell proliferation, diabetes, fluid homeostasis, heart diseases (e.g., hypertension and heart failure, such as congestive heart failure), HIV infection, immune function, obesity, stem cell trafficking, metastatic cancer or a vein-related disorder such as an angioma, a venous insufficiency, a stasis, or a thrombosis.
  • heart diseases e.g., hypertension and heart failure, such as congestive heart failure
  • HIV infection immune function
  • obesity stem cell trafficking
  • metastatic cancer or a vein-related disorder such as an angioma, a venous insufficiency, a stasis, or a thrombosis.
  • a composition of this disclosure further comprises a second therapeutic agent.
  • the second therapeutic agent is one or more additional compounds of the disclosure.
  • the second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as the APJ receptor compound of Formula I.
  • the second therapeutic is an agent useful in the treatment or prevention of a disease or condition selected from acute decompensated heart failure (ADHF), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atherosclerosis, atrial fibrillation, Brugada syndrome, burn injuries (including sunburn), cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accidents, chronic heart failure, diabetes (including gestational diabetes), dyslipidemia, HIV neurodegeneration, hypertension, inflammation, ischemic cardiovascular diseases, liver disease, metabolic disorder, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, pulmonary hypertension, restenosis, transient ischemic attacks, traumatic brain injuries, ventricular tachycardia, or water retention.
  • ADHF acute decompensated heart failure
  • amyotrophic lateral sclerosis arrhythmia
  • asthma atherosclerosis
  • atherosclerosis atherosclerosis
  • atrial fibrillation Brugada syndrome
  • burn injuries including sunburn
  • cancer cardiac
  • the second therapeutic is an agent useful in the treatment or prevention of a disease or condition selected from cancer, cell proliferation, diabetes, fluid homeostasis, heart diseases (e.g., hypertension and heart failure, such as congestive heart failure), HIV infection, immune function, obesity, stem cell trafficking, or metastatic cancer.
  • a disease or condition selected from cancer, cell proliferation, diabetes, fluid homeostasis, heart diseases (e.g., hypertension and heart failure, such as congestive heart failure), HIV infection, immune function, obesity, stem cell trafficking, or metastatic cancer.
  • the second therapeutic agent can be selected from: ACE inhibitors, beta blockers, vasodilators, calcium channel blockers, loop diuretics, aldosterone antagonists, and angiotensin receptor blockers.
  • the second therapeutic agent can be selected from: ⁇ -blockers, ⁇ -blockers, calcium channel blockers, diuretics, natriuretics, saluretics, centrally acting antihypertensives, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARB s), aldosterone synthase inhibitors, aldosterone-receptor antagonists, or endothelin receptor antagonists.
  • ACE angiotensin converting enzyme
  • NEP dual ACE and neutral endopeptidase
  • ARB s angiotensin-receptor blockers
  • aldosterone synthase inhibitors aldosterone-receptor antagonists
  • endothelin receptor antagonists or endothelin receptor antagonists.
  • Non-limiting examples of ⁇ -Blockers include doxazosin, prazosin, tamsulosin, and terazosin.
  • Non-limiting examples of ⁇ -Blockers for combination therapy are selected from acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propanolol, taliprolol, and their pharmaceutically acceptable salts.
  • Non-limiting examples of calcium channel blockers include dihydropyridines (DHPs) and non-DHPs.
  • the preferred DHPs are selected from the group consisting of amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine, and their pharmaceutically acceptable salts.
  • Non-DHPs are selected from anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamine, tiapamil, and verampimil and their pharmaceutically acceptable salts.
  • Non-limiting examples of thiazide derivative include amiloride, chlorothalidon, chlorothiazide, hydrochlorothiazide, and methylchlorothiazide.
  • Non-limiting examples of centrally acting antiphypertensives include clonidine, guanabenz, guanfacine and methyldopa.
  • Non-limiting examples of ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril.
  • Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril.
  • Non-limiting examples of dual ACE/NEP inhibitors are, for example, omapatrilat, fasidotril, and fasidotrilat.
  • Non-limiting examples of preferred ARBs include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan.
  • Non-limiting examples of preferred aldosterone synthase inhibitors are anastrozole, fadrozole, and exemestane.
  • Non-limiting examples of preferred aldosterone-receptor antagonists are spironolactone and eplerenone.
  • Non-limiting examples of preferred endothelin antagonist include, for example, bosentan, enrasentan, atrasentan, darusentan, sitaxentan, and tezosentan and their pharmaceutically acceptable salts.
  • the disclosure provides separate dosage forms of a compound of this disclosure and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another.
  • association with one another means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • the compound of the present disclosure is present in an effective amount.
  • the term “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder.
  • effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • the compound is present in the composition in an amount of from 0.1 to 50 wt. %, more preferably from 1 to 30 wt. %, most preferably from 5 to 20 wt. %.
  • Body surface area may be approximately determined from height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.
  • an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70% and 100% of the normal monotherapeutic dose.
  • the normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.
  • the compounds for use in the method of the disclosure can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily treatment dose or one of multiple daily treatment doses (e.g., about 1 to 4 or more times per day). When multiple daily treatment doses are used, the unit dosage form can be the same or different for each dose.
  • the disclosure also includes methods of treating diseases, disorders or pathological conditions which benefit from modulation of the APJ receptor comprising administering an effective amount of an APJ receptor compound of the disclosure to a subject in need thereof.
  • Diseases and conditions which can benefit from modulation (inhibition or activation) of the APJ receptor include, but are not limited to, acute decompensated heart failure (ADHF), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atherosclerosis, atrial fibrillation, Brugada syndrome, burn injuries (including sunburn), cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accidents, chronic heart failure, diabetes (including gestational diabetes), dyslipidemia, HIV neurodegeneration, hypertension, inflammation, ischemic cardiovascular diseases, liver disease, metabolic disorder, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, pulmonary hypertension, restenosis, transient ischemic attacks, traumatic brain injuries, ventricular tachycardia, or water retention.
  • ADHF acute decom
  • the hypertension may be pulmonary arterial hypertension.
  • the liver disease may be alcoholic liver disease, toxicant-induced liver disease or viral-induced liver disease and the renal dysfunction may be polycystic kidney disease.
  • the apelin receptor system is involved in vein-related disorders. See, e.g., Lathen et al., “ERG-APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease” 2014 Circulation 130: 1179-1191. Apelin receptor system has also been implicated in heart failure.
  • the disclosure provides a method of treating an apelin receptor (APJ) related disorder in a subject which comprises administering to the subject the compound of embodiment 1.
  • the apelin receptor (APJ) related disorder may be asthma, atherosclerosis, cancer, cardiomyopathy, diabetes, dyslipidemia, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, or preeclampsia.
  • the disclosure provides methods further comprising treating the subject with an ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a ⁇ -blocker, a calcium channel blocker, or a diuretic.
  • the disclosure provides a method to treat or prevent a vein-related disorder such as an angioma, a venous insufficiency, a stasis or a thrombosis.
  • the disclosure provides a method of preventing HIV neurodegeneration in a subject which comprises administering to the subject the compound of embodiment 1.
  • an effective amount of a compound of this disclosure can range from about 0.005 mg to about 5000 mg per treatment. In more specific embodiments, the range is from about 0.05 mg to about 1000 mg, or from about 0.5 mg to about 500 mg, or from about 5 mg to about 50 mg.
  • Treatment can be administered one or more times per day (for example, once per day, twice per day, three times per day, four times per day, five times per day, etc.). When multiple treatments are used, the amount can be the same or different. It is understood that a treatment can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days, etc.
  • a treatment dose can be initiated on Monday with a first subsequent treatment administered on Wednesday, a second subsequent treatment administered on Friday, etc.
  • Treatment is typically administered from one to two times daily.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
  • the effective amount of a compound of the disclosure is from about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 50 mg/kg/day, or from about 1 mg/kg/day to 10 mg/kg/day.
  • any of the above methods of treatment comprises the further step of co-administering to said subject one or more second therapeutic agents.
  • the choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with a compound that modulates the APJ receptor.
  • the choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this disclosure are those set forth above for use in combination compositions comprising a compound of this disclosure and a second therapeutic agent.
  • co-administered means that the second therapeutic agent may be administered together with a compound of this disclosure as part of a single dosage form (such as a composition of this disclosure comprising a compound of the disclosure and a second therapeutic agent as described above) or as separate, multiple dosage forms.
  • the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this disclosure.
  • both the compounds of this disclosure and the second therapeutic agent(s) are administered by conventional methods.
  • composition of this disclosure comprising both a compound of the disclosure and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this disclosure to said subject at another time during a course of treatment.
  • the effective amount of the compound of this disclosure is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this disclosure is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
  • kits for use to treat the target disease, disorder or condition comprise (a) a pharmaceutical composition comprising a compound of Formula I, or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat the target disease, disorder or condition.
  • the container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition.
  • Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In one embodiment, the container is a blister pack.
  • kits of this disclosure may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition.
  • a device may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.
  • kits of this disclosure may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this disclosure.
  • Ethyl 5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylate To a solution of cyclopentyl hydrazine ditrifluoroacetic acid salt (85 g, 251 mmol) in 500 mL EtOH was added AcOH (14.4 mL, 251 mmol). Sodium diethyl oxaloacetate (48 g, 228 mmol) was added portionwise under stirring and the resulting mixture was heated to reflux for 24 h. The reaction mixture was cooled to rt and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (500 mL) and 0.5 N HCl (750 mL) and the organic phase was separated.
  • EtOAc 500 mL
  • 0.5 N HCl 750 mL
  • Ethyl 5-bromo-1-cylopentyl-1H-pyrazole-3-carboxylate To a suspension of ethyl 5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylate (32.6 g, 145 mmol) in CH 3 CN (360 mL) was added POBr 3 (209 g, 725 mmol) in portions and the mixture was heated to reflux for 18 h. Reaction mixture was cooled to 0° C. and added slowly to sat. Na 2 CO 3 (1000 mL) at 0° C.
  • Ethyl 1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (200 mg, 0.70 mmol) and 2-trifluoromethoxyphenyl boronic acid (172.2 mg, 0.84 mmol) in the presence of Pd(PPh 3 ) 4 (16 mg, 0.014 mmol) and 2 M Na 2 CO 3 (1.04 mL, 2.1 mmol) in THF (5 mL) for 18 h provided 204 mg (80%) of ethyl 1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate as a colorless oil.
  • Ethyl 1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (200 mg, 0.7 mmol) and 2-ethylphenyl boronic acid (125.4 mg, 0.84 mmol) in the presence of Pd(PPh 3 ) 4 (16 mg, 0.014 mmol) and 2 M Na 2 CO 3 (1.04 mL, 2.1 mmol) in THF (5 mL) for 18 h provided 180 mg (83%) of ethyl 1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate as a colorless oil.
  • Ethyl 1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylate Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (150 mg, 0.52 mmol) and 2-methoxy, 6-fluorophenyl boronic acid (178 mg, 1.04 mmol) in the presence of Pd(PPh 3 ) 4 (21 mg, 0.026 mmol) and 2 M Na 2 CO 3 (0.78 mL, 1.56 mmol) in THF (5 mL) for 18 h provided 80 mg (46%) of ethyl 1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylate as a colorless oil.
  • Ethyl 1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylate Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (150 mg, 0.52 mmol) and thiazol-4-yl boronic acid (135 mg, 1.04 mmol) in the presence of Pd(PPh 3 ) 4 (21 mg, 0.026 mmol) and 2 M Na 2 CO 3 (0.78 mL, 1.56 mmol) in THF (5 mL) for 24 h provided 15 mg (10%) of ethyl 1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylate as a colorless oil.
  • reaction mixture was stirred at rt for 3 h.
  • Silica gel (4 g) was added and the solvent was removed under reduced pressure.
  • Reaction mixture was purified using Combiflash® R f (0-40% of EtOAc in hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford 1.38 g (93%) of o-nitrophenylselenide derivative as a reddish brown solid.
  • TLC R f 0.40 (hexanes/EtOAc, 2:1);
  • reaction mixture was stirred at rt for 18 h.
  • Reaction mixture was diluted with EtOAc (3 mL), and washed with sat. NaHCO 3 (2 mL).
  • Organic phase was extracted, added silica gel (100 mg) and purified using Combiflash® R f (0-60% of EtOAc in hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford 35 mg (86%) of (R,E)-N-(5-(cyclobutylamino)-1-(4-fluorophenyl)-5-oxopent-1-en-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide as a white sticky solid.
  • reaction mixture was stirred at rt for 18 h.
  • Reaction mixture was diluted with EtOAc (3 mL), and washed with sat. NaHCO 3 (2 mL).
  • Organic phase was extracted, added silica gel (100 mg) and purified using Combiflash® R f (0-60% of EtOAc in hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford 30 mg (54%) of (S)—N-(1-(cyclobutylamino)-5-(4-fluorophenyl)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide as a white sticky solid.
  • the solid was triturated with DCM and filtered through a short pad of Celite®.
  • the filtrate was concentrated and treated with ethyl 2-bromo acetate (90 ⁇ L, 0.60 mmol) in acetic acid (2 ml) at 60° C. for 1 h, 70° C. for 1 h and 80° C. for 1 h.
  • Step 1 To a solution of difluoropiperidine.HCl (1 eq) in water (1 mL/mmol of piperidine) was added Na 2 CO 3 (1 eq), and stirred at rt for 10 min. THF (2 mL/mmol of piperidine) was added, and the mixture was cooled to ⁇ 15° C. DBU (1%) was added, followed by acrolein (90%, 1 eq). After addition, the mixture was stirred at ⁇ 15° C. for 30 min, and the compound 3-(difluoropiperidin-1-yl)propanal in THF and water was used as is for the next step.
  • Step 2 To a solution of t-butyl diethylphosphonoacetate (1.2 eq to difluoropiperidine) in THF (1 mL/mmol of phosphonoacetate) at rt was added KOtBu (1.2 eq to 1 eq of difluoropiperidine). The mixture was stirred at rt for 10 min and then cooled to 5° C. Then, the solution 3-(difluoropiperidin-1-yl)propanal was added, and the resulting mixture was slowly warmed to rt. Stirring was continued at rt for 2 h before the mixture was quenched with water extracted with hexanes/EtOAc.
  • Step 3 To a solution of (S)-(N)-benzyl-1-phenylethylamine (1.5 eq) in THF (2 mL/mmol of amine) at ⁇ 75° C. was added slowly n-BuLi (1.5 eq). Stirring was continued at ⁇ 75° C. for 30 min before dropwise addition of a solution of (E)-tert-butyl 5-(difluoropiperidin-1-yl)pent-2-enoate (1 eq) in THF (1 ml/mmol of amine). After addition, the mixture was continued to stir at ⁇ 75° C. for 3 h, quenched with citric acid, and extracted with hexanes.
  • Step 4 A mixture of (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(difluoropiperidin-1-yl)pentanoate (1 eq), Pd/C (10% on carbon, 0.3 eq by mass) and MeOH (50 ml/g of amine) was hydrogenated under H 2 (50 Psi) using a Parr-Shaker at rt for 3 days until the completion of reaction monitored by LC-MS analysis.
  • N-methylmorpholine (4.46 mL, 40.6 mmol, 1.00 equiv.) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutanoic acid in DME (81 mL) at ⁇ 15° C.
  • Isobutylchloroformate (5.27 mL, 40.6 mmol, 1.00 equiv.) was then added dropwise. The reaction mixture was stirred at the same temperature for 1 h. The solution was filtered on a frit and the filtrate cooled back to ⁇ 15° C.
  • Eluent A pH 3.8 10 mM Ammonium Formate in Water
  • Eluent A pH 3.8 10 mM Ammonium Formate in Water
  • HATU (16 mg, 0.041 mmol, 1.1 equiv.) was added to a solution of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (12 mg, 0.037 mmol), HOAt (5.0 mg, 0.037 mmol, 1.0 equiv.) and diisopropylethylamine (19 ⁇ L, 0.11 mmol, 3.0 equiv.) in DMF (0.2 mL).
  • HATU (1 mg, 0.046 mmol, 1.1 equiv.) was added to a solution of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (14 mg, 0.042 mmol), HOAt (5.7 mg, 0.042 mmol, 1.0 equiv.) and diisopropylethylamine (22 ⁇ L, 0.13 mmol, 3.0 equiv.) in DMF (0.22 mL).
  • (R)-Benzyl3-amino-4-(4-fluorophenoxy)butanoate hydrochloride (R)-benzyl-3-((tert-butoxycarbonyl)amino)-4-(4-fluorophenoxy)butanoate (60 mg, 0.15 mmol, 1.00 equiv.) was dissolved in 3 mL of HCl 4N/Dioxane solution. Sol. was stirred at RT 2 hrs; nitrogen was bubbled in the sol. for 1 hr to remove as much HCl as possible. Solvent was evaporated; to the oily residue was added 1 mL diethylether. Product was soluble; hexane (c.a.
  • HATU 121 mg, 0.31 mmol
  • 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid 94 mg, 0.19 mmol
  • HOAt 39 mg, 0.29 mmol
  • diisopropylethylamine 150 ⁇ L, 0.87 mmol
  • DMF 1 mL
  • the reaction mixture was stirred for 10 min and a solution of (R)-benzyl 3-amino-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate hydrochloride (99 mg, 0.29 mmol) in DMF (0.85 mL) was added.
  • ADDP (41 mg, 0.16 mmol, 1.3 equiv.) in THF (0.6 mL) was added to a solution of (S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-hydroxypentanoate (40 mg, 0.12 mmol, 1.0 equiv.), glutarimide (14 mg, 0.12 mmol, 1.0 equiv.), diisopropylethylamine (24 ⁇ L, 0.14 mmol, 1.1 equiv.) and tributylphosphine (40 ⁇ L, 0.16 mmol, 1.3 equiv.) in THF (0.64 mL).
  • HATU 7.1 mg, 0.019 mmol, 1.1 equiv.
  • 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid 5.5 mg, 0.017 mmol, 1.0 equiv.
  • HOAt 2.3 mg, 0.017 mmol, 1.0 equiv.
  • diisopropylethylamine 8.9 ⁇ L, 0.051 mmol, 3.0 equiv.
  • (S)-tert-butyl 3-amino-5-(2,6-dioxopiperidin-1-yl)pentanoate 7.5 mg, 0.017 mmol, 1.0 equiv.
  • (3S)-tert-butyl-3-amino-5-hydroxy-2-methylpentanoate In a Parr shaker reactor (3S)-tert-butyl-3-(benzyl((S)-1-phenylethyl)amino)-5-(benzyloxy)-2-methylpentanoate (950 mg, 1.95 mmol, 1.00 equiv.) was dissolved in 20% AcOH/Ethanol (50 ml). Vessel was purged with nitrogen then Pd/C 10% (600 mg) was added. System was evacuated (house vacuum), filled with hydrogen (45 psi), shaken 5 min.
  • System was purged a second time then put under hydrogen pressure (50 psi) and shaken for 30 hrs.
  • System was purged 2 ⁇ nitrogen, mixture was filtered through a Celite® cake, washed 4 ⁇ 10 ml ethanol, filterate and washings were pooled and evaporated (rotavapor, high vacuum) to give the title compound, 403 mg, which was used as such for the next transformation.
  • (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-2-methyl-5-oxopentanoate To a stirred, ice cold DCM (2 mL) sol. of (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxy-2-methylpentanoate (80 mg, 0.157 mmol) under nitrogen was added Dess-Martin periodinane (100 mg, 0.236 mmol, 1.5 equiv.). The white suspension was stirred 15 min.
  • Solvent was removed in vacuo and diluted with CHCl 3 . Solvent was removed to provide 90% (3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (Acid 1) as a white solid.
  • Solvent was removed in vacuo and diluted with CH 2 Cl 2 . Solvent was removed to provide 90% of (3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (Acid 2) as a white solid.
  • Caco-2 cells (clone C2BBe1) were obtained from American Type Culture Collection (Manassas, Va.). Cell monolayers were grown to confluence on collagen-coated, microporous, polycarbonate membranes in 12-well Costar Transwell plates. Details of the plates and their certification are shown below.
  • the permeability assay buffer was Hanks' balanced salt solution (HBSS) containing 10 mM HEPES and 15 mM glucose at a pH of 7.4.
  • the buffer in the receiver chamber also contained 1% bovine serum albumin.
  • the dosing solution concentration was 5 M for each test article in the assay buffer.
  • Cell monolayers were dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37° C. with 5% CO 2 in a humidified incubator. Samples were taken from the donor and receiver chambers at 120 minutes. Each determination was performed in duplicate. After the experiment, all assay buffers were removed from the inserts. Cell monolayers were dosed with blank 500 ⁇ M lucifer yellow on the A-to-B side and blank HBSS on the B-to-A side and incubated at 37° C. Samples were taken from the B-to-A side at 60 minutes. The flux of lucifer yellow was measured for each monolayer to ensure no damage was inflicted to the cell monolayers during the flux period.
  • dC r /dt is the slope of the cumulative concentration in the receiver compartment versus time in ⁇ M s ⁇ 1 ;
  • V r is the volume of the receiver compartment in cm 3 ;
  • V d is the volume of the donor compartment in cm 3 ;
  • A is the area of the insert (1.13 cm 2 for 12-well Transwell);
  • C A is the average of the nominal dosing concentration and the measured 120-minute donor concentration in ⁇ M;
  • C N is the nominal concentration of the dosing solution in ⁇ M
  • C r final is the cumulative receiver concentration in ⁇ M at the end of the incubation period
  • C d final is the concentration of the donor in ⁇ M at the end of the incubation period.
  • Efflux ratio is defined as P app (B-to-A)/P app (A-to-B).
  • Apelin peptides are known to lower blood pressure, e.g., Tatemoto, K., et. al. Regul. Pept. 2001, 99, 87-92.
  • Animals were approximately 7-9 weeks of age and weighed between 247 g to 263 g just prior to surgery. Dose levels administered were 7.5, 15 or 30 mg/kg, dose volumes were 10 mL/kg, and dose route of administration was oral gavage. Animals were assigned to a crossover experimental treatment schedule as shown below.
  • Collected data included systolic, diastolic, and mean arterial blood pressure (MAP).
  • Data collection time points were for pre-dose baseline approximately 48 h (prior to treatment 1) or approximately 24 h (prior to treatment 2-4) for 10 sec every 2 min.
  • Data collection post-dose was collected through approximately 24 h (data collected for 10 sec every 2 min) per treatment. Resulting data is presented below as the 2-5 h mean change from baseline in mmHg.
  • Compound 423 treatment via oral gavage to male Sprague-Dawley rats resulted in a mild sustained decrease in blood pressure
  • compound 551 treatment resulted in a dose-dependent, mild sustained decrease in blood pressure

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Pulmonology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)

Abstract

This disclosure is directed to agonists of the apelin receptor (APJ) and uses of such agonists.

Description

CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Prov. Appn. 62/265,168 filed Dec. 9, 2015, Runyon et al., entitled “Improved Apelin Receptor (APJ) Agonists and Uses Thereof” and U.S. Prov. Appn. 62/265,177 filed Dec. 9, 2015, Runyon et al., entitled “Difluoro Apelin Receptor (APJ) Agonists and Uses Thereof” which are hereby incorporated by reference in their entireties.
1. FIELD
This disclosure relates generally to the discovery of agonists of the apelin receptor (APJ) and uses of such agonists.
2. BACKGROUND
2.1. Introduction: Apelin and the Apelin Receptor (APJ)
The apelin receptor (APJ) was cloned in 1993 as an orphan G-protein coupled receptor (GPCR). The human APJ gene is located on the long arm of chromosome 11 and encodes a 377 amino acid G protein-coupled receptor. The gene for APJ was designated angiotensin-receptor like 1 (AGTRL1) due to sequence similarities between the two receptors. Carpene et al., J Physiol Biochem. 2007; 63(4):359-373. However, none of the known peptidergic ligands for the angiotensin receptors, including angiotensin, activate APJ. APJ remained an orphan GPCR until 1998 when the peptide apelin was identified as its endogenous ligand. Lee et al., J Neurochem. 2000; 74(1):34-41; Habata et al., Biochim Biophys Acta. 1999; 1452(1):25-35.
Over the years, apelin and APJ have emerged as an important regulator of various physiological processes. Both apelin and APJ are expressed in the central nervous system (CNS) and peripherally in a number of tissues. Expression of APJ has been noted within the vasculature of some organs and is a potent regulator of related processes including angiogenesis and vasoconstriction. Cobellis et al. report increased of expression levels of both apelin and APJ receptor in preeclampsia-complicated pregnancies. Cobellis et al., Histol Histopathol. 2007; 22(1):1-8. APJ is also expressed in nonvascular cell types in heart, liver, and CNS where its primary role is currently under investigation. Medhurst et al., J Neurochem. 2003; 84(5):1162-1172. Apelin and APJ are often co-localized within the same organ suggesting an autocrine regulation of the receptor by its ligand. However, apelin has since been detected in blood suggesting that concomitant paracrine regulation of the receptor is also possible. The apelin-APJ system has been implicated as a regulator of various physiological functions and is believed to play an important role in thermoregulation, immunity, glucose metabolism, angiogenesis, fluid homeostasis, cardiac function, hepatic function and renal function. Ladeiras-Lopes et al., Arq Bras Cardiol. 2008; 90(5):343-349. APJ also acts as a co-receptor during HIV infection. O′Donnell et al., J Neurochem. 2007; 102(6):1905-1917; Zou et al., FEBS Lett. 2000; 473(1):15-18.
Expression of apelin and APJ are either up- or down-regulated in various pathophysiological conditions. In particular, the APJ appears to be an emerging target for the treatment of cardiovascular failure, liver fibrosis, cancer, angiopathies, pancreatitis, and as a prophylactic against HIV infection. In 2011 Andersen et al. reviewed apelin and APJ as an opportunity for therapeutic uses for pulmonary hypertension and pulmonary arterial hypertension (PAH). Andersen et al. Pulm. Circ. 2011; 1(3) 334-346.
Unfortunately, small molecule ligands of the APJ having suitable pharmacological properties are lacking. Few non-peptide ligand systems has been reported to date. Iturrioz et al. report compounds that contain polycyclic fluorophores, such as lissamine, which make them ill-suited for pharmaceutical uses. Iturrioz et al., FASEB J. 2010; 24:1506-1517; EP 1903052 (Llorens-Cortes et al.). US Publ. Pat. Appn. 2014/0094450 (Hachtel et al.) discloses benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators.
Accordingly, there is a need for small molecule agonists of APJ.
3. SUMMARY OF THE DISCLOSURE
This disclosure provides a compound represented by the Formula I:
Figure USRE049594-20230801-C00001
or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug,
wherein R1 is represented by the formula:
Figure USRE049594-20230801-C00002
wherein
Figure USRE049594-20230801-C00003
is a monocyclic aryl or heteroaryl group; each A is independently C1-8 alkyl, C1-8 alkyl(aryl), C1-8 alkoxy, C1-8 alkoxy aryl, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —CF3, —(CH2)xNR7R8, —CN, —CONR7R8, —COR7, —CO2(CH2)xNR7R8, —CO2R7, halogen, hydroxyl, —N3, —NHCOR7, —NHSO2C1-8 alkyl, —NHCO2C1-8 alkyl, —NO2, —NR7R8, —O(CH2)xNR7R8, —O(CH2)xCO2R7, —OCOC1-8 alkyl, —OCO(CH2)xNR7R8, —SF5, —SO2NR7R8, —SO(1-3)R7, —SR7, or tetrazolone; R7 and R8 are independently C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl tetrazol-5-one, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —(CH2)xCONHR9, —(CH2)xCOR9, —(CH2)xCO2R9, H, or heteroaryl; or R7 and R8 together make a 3-9 member ring which may contain one or more heteroatoms; or R7 and R8 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; n is 1, 2, 3, 4 or 5; R2 is C3-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl, heteroaryl, or substituted aryl; R4, R5 and R6 are independently adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)-CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4 alkyl heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-CO2R7, —(CH2)xNR7R8, —(CH2)xOR7, —(CH2)xNR9COR7, —(CH2)xNR9SO2R7, —(CH2)xN R9CO2R7, —(CH2)xNHCOR7, —(CH2)xNHSO2R7, —(CH2)xNHCO2R7, —(CH2)xCONR7R8, —(CH2)xCONR7(CH2)yCO2R9, —(CH2)xCONR7(CH2)yCONR7R8, —(CH2)xCONR7(CH2)yR9, —(CH2)xCOR7, —(CH2)xCO2R7, —(CH2)xSO2NR7(CH2)yR9, —CHR7COR9, —CHR7CONHCHR8COR9—CONR7R8, —CONR7(CH2)xCO2R8, —CONR7CHR8CO2R9, —CO2R9, H, or —NHCO2R7, —(CH2)x SO2NR7R8; —SF5; or R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms; or R4 and R5 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; wherein the group R4 is substituted with one or more fluorine atoms; R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl; each x is independently 0-8; and each y is independently 1-8.
The disclosure also provides a compound represented by the Formula II:
Figure USRE049594-20230801-C00004
or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug,
wherein R1 is represented by the formula:
Figure USRE049594-20230801-C00005
wherein
Figure USRE049594-20230801-C00006
is a monocyclic heteroaryl group; each A is independently C1-8 alkyl, C1-8 alkyl(aryl), C1-8 alkoxy, C1-8 alkoxy aryl, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —CF3, —(CH2)xNR7R8, —CN, —CONR7R8, —COR7, —CO2(CH2)xNR7R8, —CO2R7, halogen, hydroxyl, —N3, —NHCOR7, —NHSO2C1-8 alkyl, —NHCO2C1-8 alkyl, —NO2, —NR7R8, —O(CH2)xNR7R8, —O(CH2)xCO2R7, —OCOC1-8 alkyl, —OCO(CH2)xNR7R8, —SF5, —SO2NR7R8, —SO(1-3)R7, or —SR7; each R7 and R8 are independently C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —(CH2)xCONHR9, —(CH2)xCOR9, —(CH2)xCO2R9, H, or heteroaryl; or R7 and R8 together make a 3-9 member cycloalkyl or heterocycloalkyl group; n is 1, 2, 3, 4 or 5; each x is independently 0-8;
  • R2 is present or absent, and if present, is C3-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl, heteroaryl, or substituted aryl;
  • R3 is present or absent, is absent if R2 is present, and if present is C1-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl or substituted aryl;
  • R4, R5, and R6 are independently adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)-CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4 alkyl C6 heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-9 cycloalkyl, C3-8 cycloalkyl-CO2R7, —(CH2)xNR7R8, —(CH2)xOR7, —(CH2)xNHCOR7, —(CH2)xNHSO2R7, —(CH2)xNHCO2R7, —(CH2)xCONR7R8, —(CH2)xCONR7(CH2)yCO2R9, —(CH2)xCONR7(CH2)yCONR8R9, —(CH2)xCONR7(CH2)yR9, —(CH2)xCONR7(CH2)ySO2R9, —(CH2)xCOR7, —(CH2)xCO2R7, —(CH2)xSO2NR7(CH2)yR9, —CHR7COR9, —CHR7CONHCHR8COR9, —CONR7R8, —CONR7(CH2)xCO2R8, —CONR7CHR8CO2R9, —CO2R9, H, —NHCO2R7, —SF5, —SO2NR7R8, or R4 and R5 together make a 4-9 member cycloalkyl or heterocycloalkyl group; wherein the group R4 is substituted with one or more fluorine atoms; R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl; and each y is independently 1-8.
Furthermore, the disclosure provides a compound of par. [0008], represented by Formula III
Figure USRE049594-20230801-C00007
wherein n is 1, 2 or 3; each A is independently C1-C5 alkoxy, C1-C5 alkyl, C3-8 cycloalkyl, halogen, or —SF5; R2 is C3-C6 alkyl, C1-3 alkyl (C3-6 cycloalkyl) or C3-C7 cycloalkyl;
  • R4 is aryl, C1-4 alkyl, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl heteroaryl, C2-4 alkyl C6 heterocycloalkyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), or heteroaryl; wherein the group R4 is substituted with one or more fluorine atoms; and
  • R10 is aryl, C1-8 alkyl, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C3-8 cycloalkyl, or heteroaryl.
The disclosure provides the compound of any of par. [0008]-[0010], wherein each A is independently C1-C3 alkoxy, C1-C3 alkyl, chloro, or fluoro. In one embodiment, each A is independently fluoro substituted C1-C3 alkoxy or fluoro substituted C1-C3 alkyl.
The disclosure provides the compound of any of par. [0008]-[0011], wherein R2 is —C4H9, —C5H11, -cC4H8 or -cC5H10.
The disclosure provides the compound of any of par. [0008]-[0012], wherein the R4 group contains a nitrogen and two or more fluorine atoms.
The disclosure provides the compound of any of par. [0008]-[0013], wherein R4 is C1-8 alkyl(aryl), C1-4 alkyl cycloalkyl, C1-8 alkyl heteroaryl, C1-4 alkyl heterocycloalkyl, C2-8 alkenyl(aryl), or C2-8 alkenyl(heteroaryl). The cycloalkyl group in the C1-4 alkyl cycloalkyl may be a bicycloalkyl or a spiroalkyl group or the heterocycloalkyl group in the C1-4 alkyl cycloalkyl may be a heterobicycloalkyl or a heterospiroalkyl group. More specifically, R4 may be C1-8 alkyl(difluoroaryl), C1-4 alkyl difluorocycloalkyl, C1-8 alkyl difluoro heteroaryl, C1-4 alkyl difluoroheterocycloalkyl, C2-8 alkenyl(difluoro aryl), or C2-8 alkenyl(difluoro heteroaryl).
The disclosure also provides the compound of any of par. [0008]-[0014], wherein R8 is heteroaryl. In particular, R8 may be oxadiazole, oxazole, n-methyl thiazole, tetrazole, thiazole, or triazole.
Pharmaceutical compositions are also provided comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of any of par. [0008]-[0014]. The therapeutically effective amount may be an amount effective for lowering blood pressure. Alternatively, the therapeutically effective amount is an amount effective for the treatment of asthma, cardiomyopathy, diabetes, dyslipidemia, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, preeclampsia, or renal dysfunction.
In another embodiment, the disclosure provides the use in a treatment of an apelin receptor (APJ) related disorder of a compound Formula I:
Figure USRE049594-20230801-C00008
or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug, wherein R1 is represented by the formula:
Figure USRE049594-20230801-C00009
wherein
Figure USRE049594-20230801-C00010
is a monocyclic aryl or heteroaryl group; each A is independently C1-8 alkyl, C1-8 alkyl(aryl), C1-8 alkoxy, C1-8 alkoxy aryl, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —CF3, —(CH2)xNR7R8, —CN, —CONR7R8, —COR7, —CO2(CH2)xNR7R8, —CO2R7, halogen, hydroxyl, —N3, —NHCOR7, —NHSO2C1-8 alkyl, —NHCO2C1-8 alkyl, —NO2, —NR7R8, —O(CH2)xNR7R8, —O(CH2)xCO2R7, —OCOC1-8 alkyl, —OCO(CH2)xNR7R8, —SF5, —SO2NR7R8, —SO(1-3)R7, —SR7, or tetrazolone; R7 and R8 are independently C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl tetrazol-5-one, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —(CH2)xCONHR9, —(CH2)xCOR9, —(CH2)xCO2R9, H, or heteroaryl; or R7 and R8 together make a 3-9 member ring which may contain one or more heteroatoms; or R7 and R8 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; n is 1, 2, 3, 4 or 5;
  • R2 is C3-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl, heteroaryl, or substituted aryl;
  • R4, R5 and R6 are independently adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)-CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4 alkyl heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-CO2R7, —(CH2)xNR7R8, —(CH2)xOR7, —(CH2)xNR9COR7, —(CH2)xNR9SO2R7, —(CH2)xN R9CO2R7, —(CH2)xNHCOR7, —(CH2)xNHSO2R7, —(CH2)xNHCO2R7, —(CH2)xCONR7R8, —(CH2)xCONR7(CH2)yCO2R9, —(CH2)xCONR7(CH2)yCONR7R8, —(CH2)xCONR7(CH2)yR9, —(CH2)xCOR7, —(CH2)xCO2R7, —(CH2)xSO2NR7(CH2)yR9, —CHR7COR9, —CHR7CONHCHR8COR9—CONR7R8, —CONR7(CH2)xCO2R8, —CONR7CHR8CO2R9, —CO2R9, H, or —NHCO2R7, —(CH2)x SO2NR7R8; —SF5; or R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms; or R4 and R5 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups;
    wherein the group R4 is substituted with one or more fluorine atoms;
  • R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl; each x is independently 0-8; and each y is independently 1-8.
In yet another embodiment, the disclosure provides the use in a treatment of an apelin receptor (APJ) related disorder of a compound represented by the Formula II:
Figure USRE049594-20230801-C00011
or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug,
wherein R1 is represented by the formula:
Figure USRE049594-20230801-C00012
wherein
Figure USRE049594-20230801-C00013
is a monocyclic heteroaryl group;
each A is independently C1-8 alkyl, C1-8 alkyl(aryl), C1-8 alkoxy, C1-8 alkoxy aryl, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —CF3, —(CH2)xNR7R8, —CN, —CONR7R8, —COR7, —CO2(CH2)xNR7R8, —CO2R7, halogen, hydroxyl, —N3, —NHCOR7, —NHSO2C1-8 alkyl, —NHCO2C1-8 alkyl, —NO2, —NR7R8, —O(CH2)xNR7R8, —O(CH2)xCO2R7, —OCOC1-8 alkyl, —OCO(CH2)xNR7R8, —SF5, —SO2NR7R8, —SO(1-3)R7, or —SR7; each R7 and R8 are independently C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —(CH2)xCONHR9, —(CH2)xCOR9, —(CH2)xCO2R9, H, or heteroaryl; or R7 and R8 together make a 3-9 member cycloalkyl or heterocycloalkyl group; n is 1, 2, 3, 4 or 5; each x is independently 0-8;
  • R2 is present or absent, and if present, is C3-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl, heteroaryl, or substituted aryl;
  • R3 is present or absent, is absent if R2 is present, and if present is C1-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl or substituted aryl;
  • R4, R5, and R6 are independently adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)-CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4 alkyl C6 heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-9 cycloalkyl, C3-8 cycloalkyl-CO2R7, —(CH2)xNR7R8, —(CH2)xOR7, —(CH2)xNHCOR7, —(CH2)xNHSO2R7, —(CH2)xNHCO2R7, —(CH2)xCONR7R8, —(CH2)xCONR7(CH2)yCO2R9, —(CH2)xCONR7(CH2)yCONR8R9, —(CH2)xCONR7(CH2)yR9, —(CH2)xCONR7(CH2)ySO2R9, —(CH2)xCOR7, —(CH2)xCO2R7, —(CH2)xSO2NR7(CH2)yR9, —CHR7COR9, —CHR7CONHCHR8COR9, —CONR7R8, —CONR7(CH2)xCO2R8, —CONR7CHR8CO2R9, —CO2R9, H, —NHCO2R7, —SF5, —SO2NR7R8, or R4 and R5 together make a 4-9 member cycloalkyl or heterocycloalkyl group;
    wherein the group R4 is substituted with one or more fluorine atoms;
  • R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl; and each y is independently 1-8.
The use in a treatment of an apelin receptor (APJ) related disorder of a compound represented by the represented by Formula III
Figure USRE049594-20230801-C00014
wherein n is 1, 2 or 3; each A is independently C1-C5 alkoxy, C1-C5 alkyl, C3-8 cycloalkyl, halogen, or —SF5;
  • R2 is C3-C6 alkyl, C1-3 alkyl (C3-6 cycloalkyl) or C3-C7 cycloalkyl;
  • R4 is aryl, C1-4 alkyl, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl heteroaryl, C2-4 alkyl C6 heterocycloalkyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), or heteroaryl;
    wherein the group R4 is substituted with one or more fluorine atoms; and
  • R10 is aryl, C1-8 alkyl, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C3-8 cycloalkyl, or heteroaryl.
In another embodiment, the disclosure provides the use of any of par. [0017]-[0019], wherein the apelin receptor (APJ) related disorder is asthma, cardiomyopathy, diabetes, dyslipidemia, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, preeclampsia, or renal dysfunction.
In one embodiment, the disclosure provides the use of par. [0020], further comprising an α-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a β-blocker, a calcium channel blocker, or a diuretic for the treatment of the apelin receptor (APJ) related disorder.
In another embodiment, the disclosure provides a compound represented by the Formula IV:
Figure USRE049594-20230801-C00015
or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug, wherein R1 is represented by the formula:
Figure USRE049594-20230801-C00016
wherein
Figure USRE049594-20230801-C00017
is a monocyclic heteroaryl group; each A is independently C1-8 alkyl, C1-8 alkyl(aryl), C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —CF3, —(CH2)xNR7R8, —CN, —CONR7R8, —COR7, —CO2(CH2)xNR7R8, —CO2R7, halogen, hydroxyl, —N3, —NHCOR7, —NHSO2C1-8 alkyl, —NHCO2C1-8 alkyl, —NO2, —NR7R8, —O(CH2)xNR7R8, —O(CH2)xCO2R7, —OCOC1-8 alkyl, —OCO(CH2)xNR7R8, —SF5, —SO2NR7R8, —SO(1-3)R7, —SR7, or tetrazalone; R7 and R8 are independently alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl imidazolyl, C1-8 alkyl indolyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, —(CH2)xCONHR9, —(CH2)xCOR9, —(CH2)xCO2R9, H, or heteroaryl;
or R7 and R8 together make a 3-8 member ring which may be substituted with one or more heteroatoms;
n is 1, 2, 3, 4 or 5;
each x is independently 0-8;
  • R2 is present or absent, and if present, is C3-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C2-8 alkyl(aryl), C3-8 cycloalkyl, heteroaryl, or substituted aryl;
  • R3 is present or absent, is absent if R2 is present, and if present is C1-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C2-8 alkyl(aryl), C3-8 cycloalkyl or substituted aryl; provided that if n is two, both A's are not chlorine;
  • R4, R5, and R6 are independently adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)-CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl imidazolyl, C1-8 alkyl indolyl, C1-8 alkyl tetrazol-5-one, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-CO2R7, —(CH2)xNR7R8, —(CH2)xOR7, —(CH2)xNHCOR7, —(CH2)xNHSO2R7, —(CH2)xNHCO2R7, —(CH2)xCONR7R8, —(CH2)xCONR7(CH2)yCO2R9, —(CH2)xCONR7(CH2)yCONR7R8, —(CH2)xCONR7(CH2)yR9, —(CH2)xCOR7, —(CH2)xCO2R7, —(CH2)xSO2NR7(CH2)yR9, —CHR7COR9, —CHR7CONHCHR8COR9, —CONR7R8, —CONR7(CH2)xCO2R8, —CONR7CHR8CO2R9, —CO2R9, H, or —NHCO2R7, —SF5, —SO2NR7R8; or R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms; R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl;
    each y is independently 1-8;
    and Z is H2 or ═O.
The composition of par. [0022] Formula IV may incorporate the modifications as described in par. [0011]-[0015] for Formulas I-III. In addition, compounds of Formula IV may be prepared in pharmaceutical compositions as described in par. [0016]. Moreover, disclosure provides the use in a treatment of apelin receptor (APJ) related disorders, as disclosed herein, of a compound represented by the Formula IV.
In a preferred embodiment of the compositions or uses of any of par. [0008]-[0023],
Figure USRE049594-20230801-C00018
is phenyl or 2- or 3-pyridyl, n is 1, group A is in the ortho position and is —CF3, —CF2CH3, —CH2CH3, Cl, -cC3H5, —OCF2H or —OCF3. Alternatively, n is 2 and A1 is —OCH3 and A2 is —OCH3 or F. More specifically,
Figure USRE049594-20230801-C00019
is
Figure USRE049594-20230801-C00020
In another preferred embodiment of the compositions or uses of any of par. [0008]-[0023], R2 is —CH2cC3H5, —C(CH3)2cC3H5, -cC4H7, -cC4H6(CH3)2, —CH2cC4H7, -cC5H9, -cC5H8F, -cC5H8(CH3), -cC5H7(CH3)2, —CH2cC5H9, —CH2cC5H9, -cC6H11, —CH2CH2CH3, —CH2CH(CH3)2, or —C(CH3)CH(CH3)2. In particular, R2 may be
Figure USRE049594-20230801-C00021
In another preferred embodiment of the compositions or uses of any of par. [0008]-[0024], R4 may be
Figure USRE049594-20230801-C00022
In an additional preferred embodiment, R4 may be
Figure USRE049594-20230801-C00023
Figure USRE049594-20230801-C00024
If there are no fluorines in the group, the backbones of the R4 groups in par. [0026]-[0027] may be modified to contain one or more fluorine atoms by the replacement of one or more hydrogens. Alternatively, if the R4 groups in par. [0026]-[0027] contain fluorines, the backbone may be modified to incorporate additional fluorine substituents by replacement of aliphatic or aromatic hydrogens.
In yet another preferred embodiment, R5 or R10 may be
Figure USRE049594-20230801-C00025
In preferred embodiments, two groups in the set of R1, R2, R4, R5 and R10 are selected from the groups shown in par. [0024]-[0029]. In other preferred embodiments, three groups in the set of R1, R2, R4, R5 and R10 are selected from the groups in par. [0024]-[0029]. In yet another embodiment, four groups in the set of R1, R2, R4, R5 and R10 are selected from the groups in par. [0024]-[0029].
For the compounds and uses above, the disclosure also includes bioisosteres such as tetrazolones and pentafluorosulfanyl. In particular, —CF3, —CH3, —O—CH3, or —O—CF3 or an aryl —CF3, —CH3, —O—CH3, or —O—CF3 may be replaced with —SF5 or aryl-SF5, respectively. See Alvarez et al. 2015 ACS Med Chem Let 6 1225-1230. Alternatively, a —CO2H may be replaced with a tetrazolone. See Duncton et al. 2016 Org Biomol Chem 14 9338-9342.
4. DETAILED DESCRIPTION OF THE DISCLOSURE
4.1. Definitions
“Alkenyl” refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z- and E-forms (or cis or trans conformation) about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and the like. The alkenyl group may be substituted or unsubstituted. In certain embodiments, an alkenyl group has from 2 to 20 carbon atoms and in other embodiments from 2 to 8 carbon atoms.
“Alkoxy” refers to a radical —OR where R represents an alkyl, cycloalkyl, aryl, or heteroaryl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like. The alkoxy group may be substituted or unsubstituted.
“Alkyl” refers to a saturated, branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl, propan-2-yl, and cyclopropan-1-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, tert-butyl, and the like. The alkyl group may be substituted or unsubstituted; for example with methyl or a halogen(s) such as difluoro or trifluoro. In certain embodiments, an alkyl group comprises from 1 to 20 carbon atoms. Alternatively, an alkyl group may comprise from 1 to 8 carbon atoms.
“Alkyl(aryl)” refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl group. Typical alkyl(aryl) groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. In certain embodiments, an alkyl(aryl) group can be (C6-20) alkyl(aryl) e.g., the alkyl group may be (C1-10) and the aryl moiety may be (C5-10). The alkyl(aryl) group may be substituted or unsubstituted.
“Alkynyl” refers to an unsaturated branched or straight-chain having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butenyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. The alkynyl group may be substituted or unsubstituted. In certain embodiments, an alkynyl group has from 3 to 20 carbon atoms and in other embodiments from 3 to 8 carbon atoms.
“Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene or cyclopentadiene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane; or two aromatic ring systems, for example benzyl phenyl, biphenyl, diphenylethane, diphenylmethane. The aryl group may be substituted or unsubstituted, for example with a halogen, such as fluorine.
“Cycloalkyl” refers to a saturated or unsaturated cyclic alkyl group. Where a specific level of saturation is intended, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. The cycloalkyl group may be substituted or unsubstituted. In certain embodiments, the cycloalkyl group can be C3-10 cycloalkyl, such as, for example, C6 cycloalkyl or cC6H12. The cycloalkyl group may also be a bridged bicyclic cycloalkyl group, a fused cycloalkyl group or a spiro cycloalkyl group. Non-limiting examples of bridged bicyclic cycloalkyl groups are bicyclo[2.2.1]heptane, bicyclo[2.2.1]hexane, bicycle[2.2.2]octane. An example of a fused cycloalkyl group is bicyclo[4.4.0]decane or decalin. Non-limiting examples of spiro cycloalkyl groups are spiro [3.3] heptane, spiro [4.3] octane, or spiro [5.4] decane.
“Disease” refers to any disease, disorder, condition, symptom, or indication.
“Halogen” refers to a fluoro, chloro, bromo, or iodo group.
“Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl encompasses: 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon; and polycyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring. The heteroaryl group may be substituted or unsubstituted.
For example, heteroaryl includes a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkyl ring and a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered heterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine.
“Heterocycloalkyl” refers to a non-aromatic monocyclic ring or fused non-aromatic polycyclic rings with one or more heteroatom(s) independently selected from N, S and O, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in each non-aromatic ring. The heterocycle group may be a three-member ring, a four member ring, a five member ring, a six member ring or a seven member ring. In certain embodiments, the heterocycloalkyl group is 1,4-dioxane, 1,3-dioxolane, 1,4-dithiane, imidazolidine, morpholine, piperidine, piperidone, piperazine, pyrolidone, pyrrolidine, or 1,3,5-trithiane. It may contain an imide. The heterocycloalkyl group may be bicyclic such as an heterospiro group, e.g., heterospiro [3.3] heptanyl, heterospiro [3.4] octanyl, or heterospiro [5.5] undecanyls. The heterocycloalkyl group may be substituted or unsubstituted. Thus, heterocycloalkyl group encompasses heterocycloalkyl groups substituted with one or more halogens, such as 3,3-difluoropiperidine, or 4,4-difluoropiperidine. In addition, the heterocycloalkyl group may be substituted with a C1-C4 alkyl or C1-C4 halo alkyl group such as a —CF3 group.
“Pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.
“Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.
“Pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” or “pharmaceutically acceptable adjuvant” refer, respectively, to an excipient, carrier or adjuvant with which at least one compound of the present disclosure is administered. “Pharmaceutically acceptable vehicle” refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered.
“Prodrug” refers to a precursor or derivative form of a pharmaceutically active substance that is less bioactive compared to the parent drug and is capable of being enzymatically activated or converted into the more active parent form. Prodrug forms of the compounds described herein may designed to improve bioavailability or stability or reduce toxicity. For example, compounds of the invention having free amino, amido, carboxylic, hydroxyl, or thiol groups can be converted into prodrugs. See Rautio et al., 2008 Nat Rev Drug Dis 7 255-270. For instance, free carboxyl groups can be derivatized as amides, carbamates, esters, or N-Mannich bases. Free hydroxy groups may be derivatized using groups including but not limited to carbonates, dimethylaminoacetates, ethers, hemisuccinates, phosphate esters, and phosphoryloxymethyloxycarbonyls, as outlined in Fleisher et al., 1996 Advanced Drug Delivery Reviews 19, 115-130. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in Robinson et al., 1996 J Med Chem 39 10-18. Free amines can also be derivatized as amides, carbamates, imines, N-Mannich bases, oximes, phosphonamides, or sulfonamides. Carbonyls may be derivatized to imine or oxime prodrugs. Thiols may be derivatized as esters or ethers. Prodrugs may also include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes beta-alanine, citrulline, demosine, gamma-aminobutyric acid, homocysteine, homoserine, 4-hydroxyproline, hydroxylysine, isodemosine, 3-methylhistidine, norvalin, methionine sulfone, and ornithine.
“Stereoisomer” refers to an isomer that differs in the arrangement of the constituent atoms in space. Stereoisomers that are mirror images of each other and optically active are termed “enantiomers,” and stereoisomers that are not mirror images of one another and are optically active are termed “diastereoisomers.”
“Subject” includes mammals and humans. The terms “human” and “subject” are used interchangeably herein.
“Substituted” refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, CO2H, cyano, difluoro, difluoromethyl, halogen, hydroxyl, keto, methyl, —N3, —NH2, —SO(1-3)H, —SH, or trifluoromethyl.
“Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.
“Treating” or “treatment” of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder. “Treating” or “treatment” also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further, “treating” or “treatment” refers to delaying the onset of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease or disorder.
Pairs of the functional groups defined herein may be combined in a chemically rational way. For example, C1-C8 alkyl amino means the functional group C1-C8 alkyl, e.g., -nC5H11, is combined with the functional group, amino, e.g., —NH2 to form in this example -nC5H10NH2. Likewise, C1-C8 alkyl alcohol would mean a group, e.g., nC3H6OH. Similarly, C1-C8 alkoxy aryl means the functional group C1-C8 alkoxy, e.g., —CH2CH2OCH2CH3 or —OCH2CH3 combined with an aryl group, e.g., —C6H5F to form —CH2CH2OCH2CH2—C6H5F or —OCH2CH3—C6H5F, respectively.
As used herein the substituents R4, R5, R6, R7, or R8 may independently may be single α, β, γ, δ amino acids, or their corresponding side chains, such as the twenty naturally occurring amino acids, e.g., alanine (Ala/A); arginine (Arg/R); asparagine (Asn/N); aspartic acid (Asp/D); cysteine (Cys/C); glutamic acid (Glu/E); glutamine (Gln/Q); glycine (Gly/G); histidine (His/H); isoleucine (Ile/I); leucine (Leu/L); lysine (Lys/K); methionine (Met/M); phenylalanine (Phe/F); proline (Pro/P); Serine (Ser/S); threonine (Thr/T); tryptophan (Trp/W); tyrosine (Tyr/Y); and valine (Val/V). The individual amino acids may of either the R or the S chirality. Alternatively, R4, R5, R6, R7, or R8 independently may be two or three amino acids linked by a peptide bond. R4, R5, R6, R7, or R8 independently may be dipeptides or tripeptides (Hobbs et al., Proc Nat Acad Sci USA. 1993, 90, 6909-6913); U.S. Pat. No. 6,075,121 (Bartlett et al.) peptoids; or vinylogous polypeptides (Hagihara et al., J Amer Chem Soc. 1992, 114, 6568), the contents of which are hereby incorporated by reference in their entireties. R4, R5, R6, R7, or R8 independently may be part of the extended unnatural amino acids, e.g., Xie and Schultz, Nat Rev Mol Cell Biol. 2006, 7(10):775-82 or Wang et al., Chem Biol. 2009, 16(3):323-36, the contents of which are hereby incorporated by reference in their entireties.
4.2. Deuterated and Other Isotopic Variants
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I and 131I, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies.
Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents. In another embodiment, the isotope-labeled compounds contain deuterium (2H), tritium (3H) or 14C isotopes. Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art.
Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent. In some instances, compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D2SO4/D2O. Alternatively, deuterium may be also incorporated into a compound using methods such as through reduction such as using LiAlD4 or NaBD3, catalytic hydrogenation or acidic or basic isotopic exchange using appropriate deuterated reagents such as deuterides, D2 and D2O. In addition to the above, PCT publications, WO2014/169280; WO2015/058067; U.S. Pat. Nos. 8,354,557; 8,704,001 and US Patent Application Publication Nos.; 2010/0331540; 2014/0081019; 2014/0341994; 2015/0299166, the methods are hereby incorporated by reference.
4.3. Pharmaceutical Compositions
The disclosure also provides pharmaceutical compositions comprising an effective amount of a compound Formula I (e.g., any of the formulae and/or structures disclosed herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. If required, the solubility and bioavailability of the compounds of the present disclosure in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples,” Kishor M. Wasan, ed. Wiley-Interscience, 2006.
Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this disclosure optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See U.S. Pat. No. 7,014,866 (Infeld et al.); and US Pat. Pubs. 20060094744 (Maryanoff et al.) and 20060079502 (Lang).
The pharmaceutical compositions of the disclosure include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), pulmonary, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (17th ed. 1985).
Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product. In certain embodiments, the compound is administered orally. Compositions of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
The pharmaceutical compositions of this disclosure may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this disclosure with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g., U.S. Pat. No. 6,803,031 (Rabinowitz & Zaffaroni).
Topical administration of the pharmaceutical compositions of this disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene or polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this disclosure.
Application of the therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gels, stents, sustained drug release polymers or other devices which provide for internal access. Thus, according to yet another embodiment, the compounds of this disclosure may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Pat. No. 6,099,562 (Ding & Helmus); U.S. Pat. No. 5,886,026 (Hunter et al.); and U.S. Pat. No. 5,304,121 (Sahatjian). The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
According to another embodiment, the disclosure provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
According to another embodiment, the disclosure provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this disclosure. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
According to another embodiment, the disclosure provides an implantable medical device coated with a compound or a composition comprising a compound of this disclosure, such that said compound is therapeutically active.
According to another embodiment, the disclosure provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this disclosure, such that said compound is released from said device and is therapeutically active. Where an organ or tissue is accessible because of removal from the subject, such organ or tissue may be bathed in a medium containing a composition of this disclosure, a composition of this disclosure may be painted onto the organ, or a composition of this disclosure may be applied in any other convenient way.
In one embodiment, this disclosure provides a composition comprising a compound of Formula I, or more specific compounds disclosed herein, to treat or prevent asthma, atherosclerosis, cancer, cardiomyopathy, diabetes, dyslipidemia, HIV neurodegeneration, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, or preeclampsia. In another embodiment, the disclosure provides a composition comprising a compound of Formula I, or more specific compounds disclosed herein, to treat or prevent cancer, cell proliferation, diabetes, fluid homeostasis, heart diseases (e.g., hypertension and heart failure, such as congestive heart failure), HIV infection, immune function, obesity, stem cell trafficking, metastatic cancer or a vein-related disorder such as an angioma, a venous insufficiency, a stasis, or a thrombosis.
In another embodiment, a composition of this disclosure further comprises a second therapeutic agent. In one embodiment, the second therapeutic agent is one or more additional compounds of the disclosure. In another embodiment, the second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as the APJ receptor compound of Formula I.
In a particular embodiment, the second therapeutic is an agent useful in the treatment or prevention of a disease or condition selected from acute decompensated heart failure (ADHF), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atherosclerosis, atrial fibrillation, Brugada syndrome, burn injuries (including sunburn), cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accidents, chronic heart failure, diabetes (including gestational diabetes), dyslipidemia, HIV neurodegeneration, hypertension, inflammation, ischemic cardiovascular diseases, liver disease, metabolic disorder, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, pulmonary hypertension, restenosis, transient ischemic attacks, traumatic brain injuries, ventricular tachycardia, or water retention. In another embodiment, the second therapeutic is an agent useful in the treatment or prevention of a disease or condition selected from cancer, cell proliferation, diabetes, fluid homeostasis, heart diseases (e.g., hypertension and heart failure, such as congestive heart failure), HIV infection, immune function, obesity, stem cell trafficking, or metastatic cancer.
For example, when the disease or condition is congestive heart failure, the second therapeutic agent can be selected from: ACE inhibitors, beta blockers, vasodilators, calcium channel blockers, loop diuretics, aldosterone antagonists, and angiotensin receptor blockers.
When the disease or condition being treated is hypertension, the second therapeutic agent can be selected from: α-blockers, β-blockers, calcium channel blockers, diuretics, natriuretics, saluretics, centrally acting antihypertensives, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARB s), aldosterone synthase inhibitors, aldosterone-receptor antagonists, or endothelin receptor antagonists.
Non-limiting examples of α-Blockers include doxazosin, prazosin, tamsulosin, and terazosin.
Non-limiting examples of β-Blockers for combination therapy are selected from acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propanolol, taliprolol, and their pharmaceutically acceptable salts.
Non-limiting examples of calcium channel blockers include dihydropyridines (DHPs) and non-DHPs. The preferred DHPs are selected from the group consisting of amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine, and their pharmaceutically acceptable salts. Non-DHPs are selected from anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamine, tiapamil, and verampimil and their pharmaceutically acceptable salts.
Non-limiting examples of thiazide derivative include amiloride, chlorothalidon, chlorothiazide, hydrochlorothiazide, and methylchlorothiazide.
Non-limiting examples of centrally acting antiphypertensives include clonidine, guanabenz, guanfacine and methyldopa.
Non-limiting examples of ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril. Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril.
Non-limiting examples of dual ACE/NEP inhibitors are, for example, omapatrilat, fasidotril, and fasidotrilat.
Non-limiting examples of preferred ARBs include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan.
Non-limiting examples of preferred aldosterone synthase inhibitors are anastrozole, fadrozole, and exemestane.
Non-limiting examples of preferred aldosterone-receptor antagonists are spironolactone and eplerenone.
Non-limiting examples of preferred endothelin antagonist include, for example, bosentan, enrasentan, atrasentan, darusentan, sitaxentan, and tezosentan and their pharmaceutically acceptable salts.
In one embodiment, the disclosure provides separate dosage forms of a compound of this disclosure and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another. The term “associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
In the pharmaceutical compositions of the disclosure, the compound of the present disclosure is present in an effective amount. As used herein, the term “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. Preferably, the compound is present in the composition in an amount of from 0.1 to 50 wt. %, more preferably from 1 to 30 wt. %, most preferably from 5 to 20 wt. %.
The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.
For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.
The compounds for use in the method of the disclosure can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily treatment dose or one of multiple daily treatment doses (e.g., about 1 to 4 or more times per day). When multiple daily treatment doses are used, the unit dosage form can be the same or different for each dose.
4.4. Methods of Treatment
The disclosure also includes methods of treating diseases, disorders or pathological conditions which benefit from modulation of the APJ receptor comprising administering an effective amount of an APJ receptor compound of the disclosure to a subject in need thereof. Diseases and conditions which can benefit from modulation (inhibition or activation) of the APJ receptor include, but are not limited to, acute decompensated heart failure (ADHF), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atherosclerosis, atrial fibrillation, Brugada syndrome, burn injuries (including sunburn), cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accidents, chronic heart failure, diabetes (including gestational diabetes), dyslipidemia, HIV neurodegeneration, hypertension, inflammation, ischemic cardiovascular diseases, liver disease, metabolic disorder, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, pulmonary hypertension, restenosis, transient ischemic attacks, traumatic brain injuries, ventricular tachycardia, or water retention. More specifically, the hypertension may be pulmonary arterial hypertension. The liver disease may be alcoholic liver disease, toxicant-induced liver disease or viral-induced liver disease and the renal dysfunction may be polycystic kidney disease. The apelin receptor system is involved in vein-related disorders. See, e.g., Lathen et al., “ERG-APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease” 2014 Circulation 130: 1179-1191. Apelin receptor system has also been implicated in heart failure. See, e.g., Sheikh et al., “In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure” 2007 Am J Physiol Heart Circ Physiol 294:H88-H98. The contents of both Lathen et al. and Sheikh et al. are hereby incorporated by reference in their entireties into the present disclosure.
In one non-limiting embodiment, the disclosure provides a method of treating an apelin receptor (APJ) related disorder in a subject which comprises administering to the subject the compound of embodiment 1. The apelin receptor (APJ) related disorder may be asthma, atherosclerosis, cancer, cardiomyopathy, diabetes, dyslipidemia, hypertension, inflammation, liver disease, metabolic disorder, neurodegenerative disease, obesity, or preeclampsia. The disclosure provides methods further comprising treating the subject with an α-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a β-blocker, a calcium channel blocker, or a diuretic. Alternatively, the disclosure provides a method to treat or prevent a vein-related disorder such as an angioma, a venous insufficiency, a stasis or a thrombosis.
In addition, the disclosure provides a method of preventing HIV neurodegeneration in a subject which comprises administering to the subject the compound of embodiment 1.
In one embodiment, an effective amount of a compound of this disclosure can range from about 0.005 mg to about 5000 mg per treatment. In more specific embodiments, the range is from about 0.05 mg to about 1000 mg, or from about 0.5 mg to about 500 mg, or from about 5 mg to about 50 mg. Treatment can be administered one or more times per day (for example, once per day, twice per day, three times per day, four times per day, five times per day, etc.). When multiple treatments are used, the amount can be the same or different. It is understood that a treatment can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days, etc. For example, with every other day administration, a treatment dose can be initiated on Monday with a first subsequent treatment administered on Wednesday, a second subsequent treatment administered on Friday, etc. Treatment is typically administered from one to two times daily. Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
Alternatively, the effective amount of a compound of the disclosure is from about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 50 mg/kg/day, or from about 1 mg/kg/day to 10 mg/kg/day.
In another embodiment, any of the above methods of treatment comprises the further step of co-administering to said subject one or more second therapeutic agents. The choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with a compound that modulates the APJ receptor. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this disclosure are those set forth above for use in combination compositions comprising a compound of this disclosure and a second therapeutic agent.
The term “co-administered” as used herein means that the second therapeutic agent may be administered together with a compound of this disclosure as part of a single dosage form (such as a composition of this disclosure comprising a compound of the disclosure and a second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this disclosure. In such combination therapy treatment, both the compounds of this disclosure and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this disclosure, comprising both a compound of the disclosure and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this disclosure to said subject at another time during a course of treatment.
In one embodiment of the disclosure, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this disclosure is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this disclosure is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
4.5. Kits
The present disclosure also provides kits for use to treat the target disease, disorder or condition. These kits comprise (a) a pharmaceutical composition comprising a compound of Formula I, or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat the target disease, disorder or condition.
The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In one embodiment, the container is a blister pack.
The kits of this disclosure may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. Such a device may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.
In certain embodiments, the kits of this disclosure may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this disclosure.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The article “a” and “an” are used herein to refer to one or more than one (i.e., to at least one) of the grammatical object(s) of the article. By way of example, “an element” means one or more elements.
Throughout the specification the word “comprising,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The present disclosure may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and/or reagents described in the claims.
It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
The following Examples further illustrate the disclosure and are not intended to limit the scope of the disclosure. In particular, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
5. Examples
5.1. Representative Compounds
TABLE 1
ID [M + H]+/
# STRUCTURE [M − H]−
253
Figure USRE049594-20230801-C00026
 		587.3
296
Figure USRE049594-20230801-C00027
 		533.7
297
Figure USRE049594-20230801-C00028
 		464.8
298
Figure USRE049594-20230801-C00029
 		522.7
299
Figure USRE049594-20230801-C00030
 		516.8
300
Figure USRE049594-20230801-C00031
 		450.8
301
Figure USRE049594-20230801-C00032
 		498.9
302
Figure USRE049594-20230801-C00033
 		505.7
303
Figure USRE049594-20230801-C00034
 		557.9
304
Figure USRE049594-20230801-C00035
 		570.9
305
Figure USRE049594-20230801-C00036
 		543.9
306
Figure USRE049594-20230801-C00037
 		578.4
307
Figure USRE049594-20230801-C00038
 		499.7
308
Figure USRE049594-20230801-C00039
 		512.3
309
Figure USRE049594-20230801-C00040
 		485.4
310
Figure USRE049594-20230801-C00041
 		522.6
311
Figure USRE049594-20230801-C00042
 		464.8
312
Figure USRE049594-20230801-C00043
 		555.0
313
Figure USRE049594-20230801-C00044
 		567.5
314
Figure USRE049594-20230801-C00045
 		540.3
315
Figure USRE049594-20230801-C00046
 		504.7
316
Figure USRE049594-20230801-C00047
 		541.7
317
Figure USRE049594-20230801-C00048
 		485.1
318
Figure USRE049594-20230801-C00049
 		538.6
319
Figure USRE049594-20230801-C00050
 		569.8
320
Figure USRE049594-20230801-C00051
 		567.6
321
Figure USRE049594-20230801-C00052
 		519.8
322
Figure USRE049594-20230801-C00053
 		513.7
323
Figure USRE049594-20230801-C00054
 		511.5
324
Figure USRE049594-20230801-C00055
 		566.5
325
Figure USRE049594-20230801-C00056
 		564.6
326
Figure USRE049594-20230801-C00057
 		565.8
327
Figure USRE049594-20230801-C00058
 		568.7
328
Figure USRE049594-20230801-C00059
 		552.9
329
Figure USRE049594-20230801-C00060
 		580.8
330
Figure USRE049594-20230801-C00061
 		527.7
331
Figure USRE049594-20230801-C00062
 		566.4
332
Figure USRE049594-20230801-C00063
 		583.1
333
Figure USRE049594-20230801-C00064
 		555.0
334
Figure USRE049594-20230801-C00065
 		570.9
335
Figure USRE049594-20230801-C00066
 		588.5
336
Figure USRE049594-20230801-C00067
 		557.1
337
Figure USRE049594-20230801-C00068
 		580.7
338
Figure USRE049594-20230801-C00069
 		582.0
339
Figure USRE049594-20230801-C00070
 		565.4
340
Figure USRE049594-20230801-C00071
 		579.9
341
Figure USRE049594-20230801-C00072
 		553.8
342
Figure USRE049594-20230801-C00073
 		716.4
343
Figure USRE049594-20230801-C00074
 		537.6
344
Figure USRE049594-20230801-C00075
 		604.4
345
Figure USRE049594-20230801-C00076
 		568.4
346
Figure USRE049594-20230801-C00077
 		582.5
347
Figure USRE049594-20230801-C00078
 		526.4
348
Figure USRE049594-20230801-C00079
 		588.6
349
Figure USRE049594-20230801-C00080
 		564.6
350
Figure USRE049594-20230801-C00081
 		566.5
351
Figure USRE049594-20230801-C00082
 		595.6
352
Figure USRE049594-20230801-C00083
 		497.6
353
Figure USRE049594-20230801-C00084
 		688.5
354
Figure USRE049594-20230801-C00085
 		546.4
355
Figure USRE049594-20230801-C00086
 		572.4
356
Figure USRE049594-20230801-C00087
 		580.5
357
Figure USRE049594-20230801-C00088
 		554.5
358
Figure USRE049594-20230801-C00089
 		484.6
359
Figure USRE049594-20230801-C00090
 		576.4
360
Figure USRE049594-20230801-C00091
 		538.4
361
Figure USRE049594-20230801-C00092
 		522.5
362
Figure USRE049594-20230801-C00093
 		498.4
363
Figure USRE049594-20230801-C00094
 		520.5
364
Figure USRE049594-20230801-C00095
 		523.6
365
Figure USRE049594-20230801-C00096
 		492.5
366
Figure USRE049594-20230801-C00097
 		608.4
367
Figure USRE049594-20230801-C00098
 		570.4
368
Figure USRE049594-20230801-C00099
 		494.5
369
Figure USRE049594-20230801-C00100
 		511.5
370
Figure USRE049594-20230801-C00101
 		556.5
371
Figure USRE049594-20230801-C00102
 		520.5
372
Figure USRE049594-20230801-C00103
 		540.5
373
Figure USRE049594-20230801-C00104
 		594.5
374
Figure USRE049594-20230801-C00105
 		509.4
375
Figure USRE049594-20230801-C00106
 		493.5
376
Figure USRE049594-20230801-C00107
 		481.2
377
Figure USRE049594-20230801-C00108
 		495.2
378
Figure USRE049594-20230801-C00109
 		499.4
379
Figure USRE049594-20230801-C00110
 		580.7
380
Figure USRE049594-20230801-C00111
 		574.7
381
Figure USRE049594-20230801-C00112
 		557.9
382
Figure USRE049594-20230801-C00113
 		588.5
383
Figure USRE049594-20230801-C00114
 		573.6
384
Figure USRE049594-20230801-C00115
 		617.4
385
Figure USRE049594-20230801-C00116
 		428.3
386
Figure USRE049594-20230801-C00117
 		442.2
387
Figure USRE049594-20230801-C00118
 		559.2
388
Figure USRE049594-20230801-C00119
 		574.2
389
Figure USRE049594-20230801-C00120
 		478.3
390
Figure USRE049594-20230801-C00121
 		517.0
391
Figure USRE049594-20230801-C00122
 		473.6
392
Figure USRE049594-20230801-C00123
 		491.4
393
Figure USRE049594-20230801-C00124
 		456.4
394
Figure USRE049594-20230801-C00125
 		509.3
395
Figure USRE049594-20230801-C00126
 		545.2
396
Figure USRE049594-20230801-C00127
 		560.1
397
Figure USRE049594-20230801-C00128
 		534.5
398
Figure USRE049594-20230801-C00129
 		538.4
399
Figure USRE049594-20230801-C00130
 		538.5
400
Figure USRE049594-20230801-C00131
 		556.5
401
Figure USRE049594-20230801-C00132
 		476.8
402
Figure USRE049594-20230801-C00133
 		560.6
403
Figure USRE049594-20230801-C00134
 		502.0
404
Figure USRE049594-20230801-C00135
 		539.1
405
Figure USRE049594-20230801-C00136
 		539.1
406
Figure USRE049594-20230801-C00137
 		549.7
407
Figure USRE049594-20230801-C00138
 		526.5
408
Figure USRE049594-20230801-C00139
 		560.5
409
Figure USRE049594-20230801-C00140
 		585.7
410
Figure USRE049594-20230801-C00141
 		585.6
411
Figure USRE049594-20230801-C00142
 		556.9
412
Figure USRE049594-20230801-C00143
 		557.0
413
Figure USRE049594-20230801-C00144
 		532.4
414
Figure USRE049594-20230801-C00145
 		522.4
415
Figure USRE049594-20230801-C00146
 		561.2
416
Figure USRE049594-20230801-C00147
 		563.1
417
Figure USRE049594-20230801-C00148
 		592.3
418
Figure USRE049594-20230801-C00149
 		544.1
419
Figure USRE049594-20230801-C00150
 		543.9
420
Figure USRE049594-20230801-C00151
 		545.8
421
Figure USRE049594-20230801-C00152
 		566.1
422
Figure USRE049594-20230801-C00153
 		523.1
423
Figure USRE049594-20230801-C00154
 		543.2
424
Figure USRE049594-20230801-C00155
 		543.9
425
Figure USRE049594-20230801-C00156
 		596.9
426
Figure USRE049594-20230801-C00157
 		625.7
427
Figure USRE049594-20230801-C00158
 		609.0
428
Figure USRE049594-20230801-C00159
 		621.0
429
Figure USRE049594-20230801-C00160
 		591.0
430
Figure USRE049594-20230801-C00161
 		625.9
431
Figure USRE049594-20230801-C00162
 		639.0
432
Figure USRE049594-20230801-C00163
 		539.4
433
Figure USRE049594-20230801-C00164
 		509.0
434
Figure USRE049594-20230801-C00165
 		566.4
435
Figure USRE049594-20230801-C00166
 		544.1
436
Figure USRE049594-20230801-C00167
 		639.7
437
Figure USRE049594-20230801-C00168
 		566.4
438
Figure USRE049594-20230801-C00169
 		516.9
439
Figure USRE049594-20230801-C00170
 		632.7
440
Figure USRE049594-20230801-C00171
 		638.9
441
Figure USRE049594-20230801-C00172
 		541.5
442
Figure USRE049594-20230801-C00173
 		485.4
443
Figure USRE049594-20230801-C00174
 		588.4
445
Figure USRE049594-20230801-C00175
 		536.9
447
Figure USRE049594-20230801-C00176
 		605.8
448
Figure USRE049594-20230801-C00177
 		539.9
449
Figure USRE049594-20230801-C00178
 		478.3
450
Figure USRE049594-20230801-C00179
 		532.6
451
Figure USRE049594-20230801-C00180
 		623.4
452
Figure USRE049594-20230801-C00181
 		588.9
457
Figure USRE049594-20230801-C00182
 		563.5
458
Figure USRE049594-20230801-C00183
 		545.7
459
Figure USRE049594-20230801-C00184
 		599.9
460
Figure USRE049594-20230801-C00185
 		597.9
463
Figure USRE049594-20230801-C00186
 		518.0
464
Figure USRE049594-20230801-C00187
 		532.0
465
Figure USRE049594-20230801-C00188
 		522.7
466
Figure USRE049594-20230801-C00189
 		563.5
467
Figure USRE049594-20230801-C00190
 		508.5
468
Figure USRE049594-20230801-C00191
 		508.5
469
Figure USRE049594-20230801-C00192
 		563.4
470
Figure USRE049594-20230801-C00193
 		541.5
471
Figure USRE049594-20230801-C00194
 		556.1
475
Figure USRE049594-20230801-C00195
 		610.0
479
Figure USRE049594-20230801-C00196
 		598.2
480
Figure USRE049594-20230801-C00197
 		582.9
481
Figure USRE049594-20230801-C00198
 		571.9
482
Figure USRE049594-20230801-C00199
 		585.8
483
Figure USRE049594-20230801-C00200
 		588.4
484
Figure USRE049594-20230801-C00201
 		506.5
485
Figure USRE049594-20230801-C00202
 		527.8
486
Figure USRE049594-20230801-C00203
 		508.5
487
Figure USRE049594-20230801-C00204
 		573.7
488
Figure USRE049594-20230801-C00205
 		573.7
489
Figure USRE049594-20230801-C00206
 		671.7
490
Figure USRE049594-20230801-C00207
 		573.9
491
Figure USRE049594-20230801-C00208
 		561.9
492
Figure USRE049594-20230801-C00209
 		575.8
493
Figure USRE049594-20230801-C00210
 		561.9
494
Figure USRE049594-20230801-C00211
 		595.8
495
Figure USRE049594-20230801-C00212
 		605.8
496
Figure USRE049594-20230801-C00213
 		628.6
497
Figure USRE049594-20230801-C00214
 		570.7
498
Figure USRE049594-20230801-C00215
 		585.8
499
Figure USRE049594-20230801-C00216
 		491.7
500
Figure USRE049594-20230801-C00217
 		600.5
501
Figure USRE049594-20230801-C00218
 		557.6
502
Figure USRE049594-20230801-C00219
 		614.6
503
Figure USRE049594-20230801-C00220
 		571.7
504
Figure USRE049594-20230801-C00221
 		546.7
505
Figure USRE049594-20230801-C00222
 		573.7
506
Figure USRE049594-20230801-C00223
 		559.6
507
Figure USRE049594-20230801-C00224
 		573.4
508
Figure USRE049594-20230801-C00225
 		521.3
509
Figure USRE049594-20230801-C00226
 		557.2
510
Figure USRE049594-20230801-C00227
 		585.9
511
Figure USRE049594-20230801-C00228
 		588.0
514
Figure USRE049594-20230801-C00229
 		574.3
515
Figure USRE049594-20230801-C00230
 		610.4
516
Figure USRE049594-20230801-C00231
 		519.2
517
Figure USRE049594-20230801-C00232
 		588.3
518
Figure USRE049594-20230801-C00233
 		513.6
519
Figure USRE049594-20230801-C00234
 		528.0
520
Figure USRE049594-20230801-C00235
 		595.8
521
Figure USRE049594-20230801-C00236
 		586.2
522
Figure USRE049594-20230801-C00237
 		603.1
523
Figure USRE049594-20230801-C00238
 		568.6
524
Figure USRE049594-20230801-C00239
 		582.9
526
Figure USRE049594-20230801-C00240
 		464.2
527
Figure USRE049594-20230801-C00241
 		438.1
528
Figure USRE049594-20230801-C00242
 		424.1
529
Figure USRE049594-20230801-C00243
 		672.5
533
Figure USRE049594-20230801-C00244
 		519.8
534
Figure USRE049594-20230801-C00245
 		515.2
535
Figure USRE049594-20230801-C00246
 		568.2
536
Figure USRE049594-20230801-C00247
 		588.2
537
Figure USRE049594-20230801-C00248
 		525.2
538
Figure USRE049594-20230801-C00249
 		535.2
539
Figure USRE049594-20230801-C00250
 		576.2
540
Figure USRE049594-20230801-C00251
 		592.3
541
Figure USRE049594-20230801-C00252
 		646.3
542
Figure USRE049594-20230801-C00253
 		557.3
544
Figure USRE049594-20230801-C00254
 		521.1
545
Figure USRE049594-20230801-C00255
 		520.3
546
Figure USRE049594-20230801-C00256
 		573.4
547
Figure USRE049594-20230801-C00257
 		574.9
548
Figure USRE049594-20230801-C00258
 		529.2
549
Figure USRE049594-20230801-C00259
 		574.3
550
Figure USRE049594-20230801-C00260
 		590.6
551
Figure USRE049594-20230801-C00261
 		567.3
552
Figure USRE049594-20230801-C00262
 		529.2
553
Figure USRE049594-20230801-C00263
 		559.2
554
Figure USRE049594-20230801-C00264
 		559.8
555
Figure USRE049594-20230801-C00265
 		575.8
556
Figure USRE049594-20230801-C00266
 		577.6
557
Figure USRE049594-20230801-C00267
 		529.2
558
Figure USRE049594-20230801-C00268
 		535.2
559
Figure USRE049594-20230801-C00269
 		523.2
560
Figure USRE049594-20230801-C00270
 		533.1
561
Figure USRE049594-20230801-C00271
 		588.4
562
Figure USRE049594-20230801-C00272
 		576.3
563
Figure USRE049594-20230801-C00273
 		515.2
565
Figure USRE049594-20230801-C00274
 		531.2
566
Figure USRE049594-20230801-C00275
 		613.7
567
Figure USRE049594-20230801-C00276
 		541.7
568
Figure USRE049594-20230801-C00277
 		545.3
570
Figure USRE049594-20230801-C00278
 		559.3
571
Figure USRE049594-20230801-C00279
 		543.2
572
Figure USRE049594-20230801-C00280
 		641.8
573
Figure USRE049594-20230801-C00281
 		596.8
574
Figure USRE049594-20230801-C00282
 		565.5
575
Figure USRE049594-20230801-C00283
 		556.0
576
Figure USRE049594-20230801-C00284
 		556.1
577
Figure USRE049594-20230801-C00285
 		478.3
578
Figure USRE049594-20230801-C00286
 		561.4
579
Figure USRE049594-20230801-C00287
 		543.2
580
Figure USRE049594-20230801-C00288
 		517.2
581
Figure USRE049594-20230801-C00289
 		530.1
582
Figure USRE049594-20230801-C00290
 		527.8
583
Figure USRE049594-20230801-C00291
 		525.7
584
Figure USRE049594-20230801-C00292
 		523.7
585
Figure USRE049594-20230801-C00293
 		509.7
587
Figure USRE049594-20230801-C00294
 		521.3
588
Figure USRE049594-20230801-C00295
 		507.4
589
Figure USRE049594-20230801-C00296
 		511.3
590
Figure USRE049594-20230801-C00297
 		509.7
591
Figure USRE049594-20230801-C00298
 		553.7
592
Figure USRE049594-20230801-C00299
 		539.3
593
Figure USRE049594-20230801-C00300
 		519.8
594
Figure USRE049594-20230801-C00301
 		525.7
595
Figure USRE049594-20230801-C00302
 		537.6
596
Figure USRE049594-20230801-C00303
 		557.3
597
Figure USRE049594-20230801-C00304
 		557.2
598
Figure USRE049594-20230801-C00305
 		525.5
599
Figure USRE049594-20230801-C00306
 		537.4
600
Figure USRE049594-20230801-C00307
 		537.5
601
Figure USRE049594-20230801-C00308
 		537.4
602
Figure USRE049594-20230801-C00309
 		567.7
603
Figure USRE049594-20230801-C00310
 		539.5
604
Figure USRE049594-20230801-C00311
 		535.3
605
Figure USRE049594-20230801-C00312
 		539.3
606
Figure USRE049594-20230801-C00313
 		569.8
607
Figure USRE049594-20230801-C00314
 		553.3
608
Figure USRE049594-20230801-C00315
 		535.3
609
Figure USRE049594-20230801-C00316
 		523.7
610
Figure USRE049594-20230801-C00317
 		541.3
611
Figure USRE049594-20230801-C00318
 		545.4
612
Figure USRE049594-20230801-C00319
 		557.3
613
Figure USRE049594-20230801-C00320
 		537.3
614
Figure USRE049594-20230801-C00321
 		537.5
615
Figure USRE049594-20230801-C00322
 		573.7
618
Figure USRE049594-20230801-C00323
 		577.5
621
Figure USRE049594-20230801-C00324
 		496.7
622
Figure USRE049594-20230801-C00325
 		510.6
623
Figure USRE049594-20230801-C00326
 		470.6
624
Figure USRE049594-20230801-C00327
 		551.6
625
Figure USRE049594-20230801-C00328
 		565.7
626
Figure USRE049594-20230801-C00329
 		526.0
627
Figure USRE049594-20230801-C00330
 		571.7
628
Figure USRE049594-20230801-C00331
 		565.4
629
Figure USRE049594-20230801-C00332
 		527.8
630
Figure USRE049594-20230801-C00333
 		553.7
631
Figure USRE049594-20230801-C00334
 		528.0
634
Figure USRE049594-20230801-C00335
 		555.9
635
Figure USRE049594-20230801-C00336
 		555.9
636
Figure USRE049594-20230801-C00337
 		608.9
637
Figure USRE049594-20230801-C00338
 		579.8
638
Figure USRE049594-20230801-C00339
 		579.8
639
Figure USRE049594-20230801-C00340
 		541.5
640
Figure USRE049594-20230801-C00341
 		542.7
641
Figure USRE049594-20230801-C00342
 		568.5
643
Figure USRE049594-20230801-C00343
 		519.6
646
Figure USRE049594-20230801-C00344
 		442.6
647
Figure USRE049594-20230801-C00345
 		538.7
648
Figure USRE049594-20230801-C00346
 		524.8
649
Figure USRE049594-20230801-C00347
 		498.9
655
Figure USRE049594-20230801-C00348
 		559.3
5.2. Method and Preparation of Representative Compounds
Figure USRE049594-20230801-C00349
Intermediates 1-cyclopentyl-5-phenyl-1H-pyrazole-3-carboxylic acids were synthesized as described in Scheme 2. Ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-3-carboxylate was obtained by reacting cyclopentylhydrazine-TFA salt and sodium diethyl oxaloacetate in the presence of acetic acid. Treatment of ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-3-carboxylate with phosphorus oxybromide provided ethyl 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylatein 51% yield. Suzuki coupling of ethyl 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate with appropriate aryl boronic acids provided intermediates with diverse 5-substituted pyrazole ester that were then subjected to basic hydrolysis to afford carboxylic acid intermediates.
Figure USRE049594-20230801-C00350
Ethyl 5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylate: To a solution of cyclopentyl hydrazine ditrifluoroacetic acid salt (85 g, 251 mmol) in 500 mL EtOH was added AcOH (14.4 mL, 251 mmol). Sodium diethyl oxaloacetate (48 g, 228 mmol) was added portionwise under stirring and the resulting mixture was heated to reflux for 24 h. The reaction mixture was cooled to rt and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (500 mL) and 0.5 N HCl (750 mL) and the organic phase was separated. The aqueous phase was extracted with EtOAc (200 mL×2) and the organic phases were combined, washed with brine (300 mL), dried using Na2SO4 and concentrated to afford crude oil. Crude oil was diluted with 30 mL EtOAc and then MTBE (200 mL) was added to afford a white crystalline precipitate which was filtered and dried to give 32.6 g of ethyl 5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylate as white solid. TLC Rf=0.50 (hexane/EtOAc, 3:1); 1H NMR (200 MHz, CDCl3): δ=1.22-1.30 (t, 3H, CH3), 1.58-1.68 (m, 2H, CH2), 1.82-2.10 (m, 6H, CH2×3), 4.22-4.32 (q, 2H, CH2), 4.80-4.90 (m, 1H, CH), 6.90 (s, 1H, Ar). LCMS (ESI): m/z calculated for C11H16N2O3 [M+H+]: 225, Found: 225.2.
Figure USRE049594-20230801-C00351
Ethyl 5-bromo-1-cylopentyl-1H-pyrazole-3-carboxylate: To a suspension of ethyl 5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylate (32.6 g, 145 mmol) in CH3CN (360 mL) was added POBr3 (209 g, 725 mmol) in portions and the mixture was heated to reflux for 18 h. Reaction mixture was cooled to 0° C. and added slowly to sat. Na2CO3 (1000 mL) at 0° C. The product was extracted using EtOAc (500 mL×3) and the organic phase was dried using Na2SO4, silica gel (60 g) was added, and the solvent were evaporated in vacuo to afford a silica plug. Purification was performed by flash chromatography using Combiflash® Rf (0-10% EtOAc in Hexanes) and the fractions containing the product (TLC) were pooled and evaporated to provide 21 g of ethyl 5-bromo-1-cylopentyl-1H-pyrazole-3-carboxylate as a brown oil. TLC Rf=0.80 (hexane/EtOAc, 3:1); 1H NMR (200 MHz, CDCl3): δ=1.22-1.30 (t, 3H, CH3), 1.58-1.68 (m, 2H, CH2), 1.82-2.10 (m, 6H, CH2×3), 4.22-4.32 (q, 2H, CH2), 4.80-4.90 (m, 1H, CH), 6.90 (s, 1H, Ar). LCMS (ESI): m/z calculated for C11H15BrN2O2 [M+, Br79]: 287, Found: 287.3; m/z calculated for C11H15BrN2O2 [M+, Br81]: 289, Found: 289.2.
General Procedure for the Synthesis of ethyl 1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylates: To a solution of ethyl 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (1 equiv.) in THF under nitrogen atmosphere was added Pd(PPh3)4 (2 or 5 mol %) and appropriate aryl boronic acid (1.2 or 2.0 equiv.) followed by 2 M Na2CO3 (3 equiv.). The mixture was heated to reflux until TLC/LCMS showed no further utilization of reactant 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate. Reaction mixture was cooled to rt and then quenched with water (2 mL) and extracted with EtOAc (2 mL×2). Organic phases were combined, dried using Na2SO4, silica gel (200 mg) was added, and the solvent were evaporated in vacuo to afford a silica plug. Purification was performed by flash chromatography using Combiflash® Rf (0-10% EtOAc in Hexanes) and the fractions containing the product (TLC) were pooled and evaporated to provide ethyl 1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylates.
Examples
Figure USRE049594-20230801-C00352
Ethyl 1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate: Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (200 mg, 0.70 mmol) and 2-trifluoromethoxyphenyl boronic acid (172.2 mg, 0.84 mmol) in the presence of Pd(PPh3)4 (16 mg, 0.014 mmol) and 2 M Na2CO3 (1.04 mL, 2.1 mmol) in THF (5 mL) for 18 h provided 204 mg (80%) of ethyl 1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate as a colorless oil. TLC Rf=0.85 (hexane/EtOAc, 3:1); 1H NMR (200 MHz, CDCl3): δ=1.30-1.40 (t, 3H, CH3), 1.42-1.60 (m, 2H, CH2), 1.80-2.25 (m, 6H, CH2×3), 4.20-4.45 (m, 3H, CH and CH2), 6.85 (s, 1H, Ar), 7.20-7.50 (m, 4H, Ar). LCMS (ESI): m/z calculated for C18H19F3N2O3+H [M+H+]: 369, Found: 369.1.
Figure USRE049594-20230801-C00353
Ethyl 1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate: Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (200 mg, 0.7 mmol) and 2-ethylphenyl boronic acid (125.4 mg, 0.84 mmol) in the presence of Pd(PPh3)4 (16 mg, 0.014 mmol) and 2 M Na2CO3 (1.04 mL, 2.1 mmol) in THF (5 mL) for 18 h provided 180 mg (83%) of ethyl 1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate as a colorless oil. TLC Rf=0.76 (hexane/EtOAc, 3:1); 1H NMR (200 MHz, CDCl3): δ=1.00-1.15 (t, 3H, CH3), 1.25-1.40 (t, 3H, CH3), 1.40-1.60 (m, 2H, CH2), 1.80-2.30 (m, 6H, CH2×3), 2.40-2.55 (q, 2H, CH2), 4.15-4.25 (m, 1H, CH), 4.25-4.35 (q, 2H, CH2), 6.60 (s, 1H, Ar), 7.05-7.40 (m, 4H, Ar). LCMS (ESI): m/z calculated for C19H24N2O2 [M+H+]: 313, Found: 313.2.
Figure USRE049594-20230801-C00354
Ethyl 1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylate: Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (150 mg, 0.52 mmol) and 2-methoxy, 6-fluorophenyl boronic acid (178 mg, 1.04 mmol) in the presence of Pd(PPh3)4 (21 mg, 0.026 mmol) and 2 M Na2CO3 (0.78 mL, 1.56 mmol) in THF (5 mL) for 18 h provided 80 mg (46%) of ethyl 1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylate as a colorless oil. TLC Rf=0.75 (hexane/EtOAc, 3:1); 1H NMR (200 MHz, CDCl3): δ=1.30-1.40 (t, 3H, CH3), 1.40-1.60 (m, 2H, CH2), 1.80-2.25 (m, 6H, CH2×3), 3.80 (s, 3H, CH3), 4.20-4.40 (m, 3H, CH and CH2), 6.70-6.85 (m, 3H, Ar), 7.30-7.40 (m, 1H, Ar). LCMS (ESI): m/z calculated for C18H21FN2O3[M+H+]: 333, Found: 333.4.
Figure USRE049594-20230801-C00355
Ethyl 1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylate: Using the general procedure described above, reaction between 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (150 mg, 0.52 mmol) and thiazol-4-yl boronic acid (135 mg, 1.04 mmol) in the presence of Pd(PPh3)4 (21 mg, 0.026 mmol) and 2 M Na2CO3 (0.78 mL, 1.56 mmol) in THF (5 mL) for 24 h provided 15 mg (10%) of ethyl 1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylate as a colorless oil. TLC Rf=0.72 (hexane/EtOAc, 3:1); 1H NMR (200 MHz, CDCl3): δ=1.20-1.30 (t, 3H, CH3), 1.80-2.25 (m, 8H, CH2×4), 4.65-4.80 (m, 2H, CH2), 5.20-5.40 (m, 1H, CH), 6.75 (s, 1H, Ar), 7.40 (s, 1H, Ar), 8.90 (s, 1H, Ar). 1H NMR purity: 85-90%. LCMS (ESI): m/z calculated for C14H17N3O2S [M+H+]: 292, Found: 292.2.
General Procedure for the Synthesis of 1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylic acids:
To a solution of appropriate ester ethyl 1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylate (1 equiv.) in THF (1 mL), MeOH (2 mL) and H2O (1 mL) was added LiOH.H2O (5 equiv.) and stirred at rt for 18 h. Solvent was evaporated in vacuo and the reaction mixture was acidified to pH=4.0 using 1 N HCl and extracted with EtOAc (3 mL×2). Organic phases were combined, washed with brine (3 mL), dried using Na2SO4, and the solvent were evaporated in vacuo to provide intermediates 1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylic acids.
Figure USRE049594-20230801-C00356
1-Cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylic acid: Using the general procedure described above, reaction between ethyl 1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate (120 mg, 0.33 mmol) and LiOH.H2O (68.4 mg, 1.65 mmol) provided 103 mg (93%) of 1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylic acid as a white solid. TLC Rf=0.45 (CHCl3/MeOH, 10:1); 1H NMR (200 MHz, DMSO-d6): δ=1.40-1.60 (m, 2H, CH2), 1.70-2.00 (m, 6H, CH2×3), 4.25-4.40 (m, 1H, CH), 6.70 (s, 1H, Ar), 7.50-7.70 (m, 4H, Ar). LCMS (ESI): m/z calculated for C16H15F3N2O3[M+H+]: 341, Found: 341.1.
Figure USRE049594-20230801-C00357
1-Cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylic acid: Using the general procedure described above, reaction between ethyl 1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate (120 mg, 0.38 mmol) and LiOH.H2O (80.7 mg, 1.90 mmol) provided 109 mg (99%) of 1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylic acid as a white solid. TLC Rf=0.50 (CHCl3/MeOH, 10:1); 1H NMR (200 MHz, DMSO-d6): δ=0.95-1.05 (t, 3H, CH3), 1.40-1.60 (m, 2H, CH2), 1.65-1.95 (m, 6H, CH2×3), 2.30-2.40 (q, 2H, CH2), 4.15-4.30 (m, 1H, CH), 6.60 (s, 1H, Ar), 7.15-7.45 (m, 4H, Ar). LCMS (ESI): m/z calculated for C17H20N2O2 [M+H+]: 285, Found: 285.2.
Figure USRE049594-20230801-C00358
1-Cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylic acid: Using the general procedure described above, reaction between ethyl 1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylate (80 mg, 0.24 mmol) and LiOH.H2O (50.5 mg, 1.20 mmol) provided 80 mg (93% pure, 99%) of 1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylic acid as a white solid. TLC Rf=0.35 (CHCl3/MeOH, 10:1); 1H NMR (200 MHz, CDCl3): δ=1.40-1.60 (m, 2H, CH2), 1.80-2.25 (m, 6H, CH2×3), 3.80 (s, 3H, CH3), 4.25-4.40 (m, 1H, CH), 6.70-6.85 (m, 3H, Ar), 7.30-7.50 (m, 1H, Ar). LCMS (ESI): m/z calculated for C16H17FN2O3[M+H+]: 305, Found: 305.2.
Figure USRE049594-20230801-C00359
1-Cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylic acid: Using the general procedure described above, reaction between ethyl 1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylate (15 mg, 0.05 mmol) and LiOH.H2O (10.8 mg, 0.25 mmol) provided 13 mg (96%) of 1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylic acid as a white solid. TLC Rf=0.35 (CHCl3/MeOH, 10:1); NMR, LCMS (ESI): m/z calculated for C12H13N3O2S [M+H+]: 264, Found: 264.0.
Figure USRE049594-20230801-C00360
Figure USRE049594-20230801-C00361
Figure USRE049594-20230801-C00362
(R)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pent-4-enoate: To a stirred solution of (S)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-hydroxypentanoate (1.07 g, 22 mmol) and o-nitrophenylselenocyanate (1 g, 44 mmol) in THF (30 mL) at 0° C. was added tributylphosphine (1.1 mL, 44 mmol) under nitrogen atmosphere. The reaction mixture was stirred at rt for 3 h. Silica gel (4 g) was added and the solvent was removed under reduced pressure. Reaction mixture was purified using Combiflash® Rf (0-40% of EtOAc in hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford 1.38 g (93%) of o-nitrophenylselenide derivative as a reddish brown solid. TLC Rf=0.40 (hexanes/EtOAc, 2:1); LCMS (ESI): m/z calculated for C32H40N4O7Se+H+ [M+H+]: 673; Found: 673.2.
To a stirred solution of o-nitrophenylselenide derivative (1.38 g, 20 mmol) in THF (6 mL) and MeOH (40 mL) was added 0.8 M aq. NaIO4 solution (8 mL, 60 mmol) dropwise at 0° C. Reaction mixture was brought to rt and stirred for 4 h. Ether was added and the mixture was washed with saturated NaHCO3 solution, brine and dried over Na2SO4. Silica gel (3 g) was added and the solvent was removed under reduced pressure to afford a silica gel plug which was purified using Combiflash® Rf (0-5% of EtOAc in hexanes). Fractions containing the product (TLC) were pooled and evaporated to provide 940 mg (97%) of (R)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pent-4-enoate as red semisolid. TLC Rf=0.50 (hexanes/EtOAc, 2:1); 1H NMR (200 MHz, CDCl3): δ=1.45 (s, 9H, CH3×3), 1.50-1.60 (m, 2H, CH2), 1.80-2.10 (m, 6H, CH2×3), 2.60-2.70 (d, 2H, CH2), 3.70 (s, 6H, CH3×2), 4.20-4.35 (m, 1H, CH), 4.95-5.10 (m, 1H, CH), 5.15-5.20 (m, 1H, CH), 5.25-5.35 (m, 1H, CH), 5.85-6.05 (m, 1H, CH), 6.55-6.70 (m, 3H, Ar), 7.30-7.40 (t, 1H, Ar), 7.45-7.55 (d, 1H, NH). LCMS (ESI): m/z calculated for C26H37N3O5 [M+H+]: 470; Found: 470.2.
Figure USRE049594-20230801-C00363
(R,E)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoate: To a solution of (R)-tert-butyl 3-(1-cyclopentyl-5-(2.6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pent-4-enoate (185 mg, 0.40 mmol) in anhydrous DMF (4 mL) was added 4-fluorophenyl bromide (0.08 mL, 0.80 mmol) and degassed for 5 min. Under argon atmosphere, Pd(OAc)2 (8.5 mg, 0.04 mmol), P(o-tolyl)3 (23.5 mg, 0.08 mmol) and K2CO3 (204 mg, 1.60 mmol) were added and the reaction mixture was stirred at 110° C. for 20 h. Reaction mixture was cooled to rt, diluted with H2O (10 mL) and extracted with EtOAc (10 mL×2). Combined organic phases were washed with brine and dried over Na2SO4. Silica gel (300 mg) was added and the solvent was removed in vacuo to afford a silica gel plug which was purified using Combiflash® Rf (0-30% of EtOAc in hexanes). Fractions containing the product (TLC) were pooled and evaporated to provide 160 mg (72%) of (R,E)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoate as red oil. TLC Rf=0.55 (hexanes/EtOAc, 2:1); 1H NMR (200 MHz, CDCl3): δ=1.40 (s, 9H, CH3×3), 1.50-1.60 (m, 2H, CH2), 1.75-2.10 (m, 6H, CH2×3), 2.70-2.80 (d, 2H, CH2), 2.80 (s, 1.2H, DMF “CH3”), 2.90 (s, 1.2H, DMF “CH3”), 3.70 (s, 6H, CH3×2), 4.20-4.35 (m, 1H, CH), 5.10-5.20 (m, 1H, CH), 6.20-6.30 (m, 1H, CH), 6.55-6.70 (m, 4H, Ar and CH), 6.90-7.05 (m, 2H, Ar), 7.30-7.40 (m, 3H, Ar), 7.45-7.55 (d, 1H, NH), 8.00 (s, 0.4H, DMF “CHO”). LCMS (ESI): m/z calculated for C32H38FN3O5+H+ [M+H+]: 564; Found: 564.0.
Figure USRE049594-20230801-C00364
(R,E)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoic acid: To a solution of (R,E)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoate (40 mg, 0.07 mmol) in DCM (1 mL) was added TFA (0.25 mL, 3.5 mmol) and stirred at rt for 2 h. Solvent was removed in vacuo and diluted with CHCl3. Solvent was removed to provide 45 mg (99%) of (R,E)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoic acid as colorless oil. TLC Rf=0.25 (CHCl3/MeOH, 10:1); LCMS (ESI): m/z calculated for C28H30FN3O5[M+H+]: 508, Found: 508.0.
Figure USRE049594-20230801-C00365
(R,E)-N-(5-(cyclobutylamino)-1-(4-fluorophenyl)-5-oxopent-1-en-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide: To a solution of (R,E)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoic acid (45 mg, 0.08 mmol) and cyclobutylamine (16 mg, 0.2 mmol) in ACN (1 mL) was added anhydrous NEt3 (0.12 mL, 0.8 mmol) followed by TBTU (64 mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. Reaction mixture was diluted with EtOAc (3 mL), and washed with sat. NaHCO3 (2 mL). Organic phase was extracted, added silica gel (100 mg) and purified using Combiflash® Rf (0-60% of EtOAc in hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford 35 mg (86%) of (R,E)-N-(5-(cyclobutylamino)-1-(4-fluorophenyl)-5-oxopent-1-en-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide as a white sticky solid. TLC Rf=0.45 (hexanes/EtOAc, 2:1); 1H NMR (200 MHz, CDCl3): δ=1.45-2.05 (m, 12H, CH2×6), 2.20-2.40 (m, 2H, CH2), 2.70-2.85 (m, 2H, CH2), 3.70 (s, 6H, CH3×2), 4.20-4.45 (m, 3H, CH×3), 5.00-5.10 (m, 1H, CH), 6.25-6.50 (m, 2H, CH and NH), 6.50-6.60 (m, 1H, Ar), 6.60-6.70 (m, 2H, Ar), 6.90-7.00 (m, 2H, Ar), 7.25-7.40 (m, 3H, Ar), 7.45-7.60 (d, 1H, NH). LCMS (ESI): m/z calculated for C32H37FN4O4 [M+H+]: 561; Found: 561.2.
Figure USRE049594-20230801-C00366
Figure USRE049594-20230801-C00367
Figure USRE049594-20230801-C00368
(S)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoate: To a solution of (R,E)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoate (120 mg, 0.2 mmol) in EtOAc (5 mL) was added 10% Pd/C (23 mg, 0.02 mmol) and stirred at rt under hydrogen atmosphere (balloon) for 18 h. Reaction mixture was filtered over Celite®, washed with EtOAc (15 mL), concentrated, and dried to obtain 120 mg (99%) of (S)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoate as colorless oil. TLC Rf=0.50 (hexanes/EtOAc, 2:1); LCMS (ESI): m/z calculated for C32H40FN3O5[M+H+]: 566, Found: 566.1.
Figure USRE049594-20230801-C00369
(S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoic acid: To a solution of (S)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoate (115 mg, 0.2 mmol) in DCM (3 mL) was added TFA (0.50 mL, 7 mmol) and stirred at rt for 2 h. Solvent was removed in vacuo and diluted with CHCl3. Solvent was removed to provide 98 mg (95%) of (S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoic acid as colorless oil. TLC Rf=0.25 (CHCl3/MeOH, 10:1); LCMS (ESI): m/z calculated for C28H32FN3O5[M+H+]: 510, Found: 510.2.
Figure USRE049594-20230801-C00370
(S)—N-(1-(cyclobutylamino)-5-(4-fluorophenyl)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide: To a solution of (S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoic acid (50 mg, 0.1 mmol) and cyclobutylamine (16 mg, 0.2 mmol) in ACN (1 mL) was added anhydrous Et3N (0.12 mL, 0.8 mmol) followed by TBTU (64 mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. Reaction mixture was diluted with EtOAc (3 mL), and washed with sat. NaHCO3 (2 mL). Organic phase was extracted, added silica gel (100 mg) and purified using Combiflash® Rf (0-60% of EtOAc in hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford 30 mg (54%) of (S)—N-(1-(cyclobutylamino)-5-(4-fluorophenyl)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide as a white sticky solid. TLC Rf=0.25 (hexanes/EtOAc, 2:1); 1H NMR (200 MHz, CDCl3): δ=1.45-2.10 (m, 14H, CH2×7), 2.10-2.25 (m, 2H, CH2), 2.45-2.60 (m, 2H, CH2), 2.60-2.80 (m, 2H, CH2), 3.70 (s, 6H, CH3×2), 4.20-4.45 (m, 3H, CH×3), 6.50-6.70 (m, 4H, Ar and NH), 6.85-7.00 (m, 2H, Ar), 7.05-7.40 (m, 4H, Ar and NH). LCMS (ESI): m/z calculated for C32H39FN4O4[M+H+]: 563; Found: 563.1.
Figure USRE049594-20230801-C00371
Figure USRE049594-20230801-C00372
(S)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate: To a solution of 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid (0.31 g, 0.98 mmol) in DCM (6 ml) were added DMF (1 drop) and oxalyl chloride (0.11 ml, 1.28 mmol). The solution was stirred at rt for 1 h, concentrated to dryness and dissolved in DCM (3 ml). The DCM solution was added dropwise to a solution of (S)-tert-butyl 3-amino-5-(piperidin-1-yl)pentanoate (0.23 g, 0.90 mmol) and Et3N (0.42 ml, 2.7 mmol) in DCM (5 ml) at rt, and the mixture was stirred at rt for 2 h. It was washed with NaHCO3 (sat., 10 mL), dried (Na2SO4), concentrated, and purified using 0-3% MeOH in DCM (with 1% NH3) to give the title product (S)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate (0.30 g) as a white foam. TLC Rf=0.35 (DCM: MeOH 10:1); 1H NMR (200 MHz, CDCl3): δ=1.45 (s, 3H), 1.50-1.70 (m, 6H), 1.70-2.20 (m, 10H), 2.30-2.80 (m, 8H), 3.71 and 3.73 (s and s, total 6H), 4.15-4.40 (m, 1H), 4.30-4.60 (m, 1H), 6.62 (d, 2H, J=8.4 Hz); 6.66 (s, 1H), 7.36 (t, 1H J=8.5 Hz), 7.66 (d, 1H, J=8.4 Hz); LC-MS (ESI): m/z calculated for C31H47N4O5 [M+H+]: 555, Found: 555.3.
Figure USRE049594-20230801-C00373
(S)-methyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate: To a solution of (S)-tert-butyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate (1.73 g, 5.5 mmol) in DCM (10 mL) was added TFA (2 mL, 28 mmol) and stirred at rt for 2 h. Solvent was removed to provide crude (S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoic acid as yellow solid (2.1 g), which was used as is for the next reaction without further purification; LC-MS (ESI): m/z calculated for C27H39N4O5 [M+H+]: 499, Found: 499.5. To a solution of acid (120 mg, 0.24 mmol) in MeOH (2 ml) was added sulfuric acid (conc., 0.20 mL), and stirred at rt for 15 h. The solution was quenched with NaHCO3 (sat., 20 mL), extracted with EtOAc (10 mL), dried (Na2SO4) and concentrated to give crude (S)-methyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate (0.11 g) as a colorless oil, which was used as is for the next without further purification; LC-MS (ESI): m/z calculated for C27H41N6O4 [M+H+]: 513, Found: 513.1.
Figure USRE049594-20230801-C00374
(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(1-hydrazinyl-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1H-pyrazole-3-carboxamide: A mixture of (S)-methyl 3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate (0.11 g), NH2NH2.H2O (1.0 ml) and EtOH (3.0 ml) was heated at 80° C. for 3 h. The solution was cooled to rt, concentrated and purified using 0-15% MeOH in DCM (with 1% NH3) to give (S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(1-hydrazinyl-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1H-pyrazole-3-carboxamide (50 mg) as a colorless material; 1H NMR (200 MHz, CDCl3): δ=1.40-2.20 (m, 18H), 2.20-2.80 (m, 6H), 3.73 (s, 6 H), 3.89 (br s, 2 H), 4.15-4.30 (m, 1H), 4.30-4.50 (m, 1H), 6.62 (d, 2H, J=8.4 Hz), 6.66 (s, 1H), 7.37 (t, 1H J=8.4 Hz), 8.06 (d, 1H, J=7.4 Hz), 8.37 (br s, 1H); LC-MS (ESI): m/z calculated for C28H41N4O5 [M+H+]: 513, Found: 513.1.
Figure USRE049594-20230801-C00375
(S)—N-(1-(1,3,4-oxadiazol-2-yl)-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide: To a solution of (S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(1-hydrazinyl-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1H-pyrazole-3-carboxamide (50 mg, 0.10 mmol) in CH(OMe)3 was added PTSA.H2O (25 mg, 0.13 mmol). The mixture was heated at 85° C. for 2 h, cooled to rt, diluted with EtOAc (10 mL) and washed with NaHCO3 (sat., 10 mL). The EtOAc solution was dried (Na2SO4), concentrated, and purified using 0-15% MeOH in DCM (with 1% NH3) to give the title product (S)—N-(1-(1,3,4-oxadiazol-2-yl)-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide (30 mg) as a white foam; 1H NMR (200 MHz, CDCl3): δ=1.40-2.20 (m, 18H), 2.20-2.80 (m, 4H), 3.15-3.50 (m, 2H), 3.73 (s, 6 H), 4.15-4.30 (m, 1H), 4.30-4.50 (m, 1H), 6.62 (d, 2H, J=8.0 Hz), 6.65 (s, 1H), 7.37 (t, 1H J=8.4 Hz), 7.90 (d, 1H, J=8.4 Hz), 8.36 (s, 1H); LC-MS (ESI): m/z calculated for C28H40N7O3 [M+H+]: 523, Found: 523.2.
Figure USRE049594-20230801-C00376
Figure USRE049594-20230801-C00377
(S)—N-(1-amino-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide: To a solution of (S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoic acid (1.0 g, 1.8 mmol) in pyridine (20 ml) and dioxane (20 ml) were added ammonium carbonate (0.21 g, 2.7 mmol), followed by Boc2O (0.47 g, 2.16 mmol). The progress of the reaction was monitored by LC-MS. Additional ammonium carbonate and Boc2O (2 eq each) were added after 1 h. Stirring was continued for 12 h, and additional ammonium carbonate and Boc2O (2 eq each) were added. After further stirring for 1 h, LC-MS indicated the completion of the reaction. The mixture was concentrated to dryness, quenched with NaHCO3 (sat., 20 ml) and extracted with EtOAc (20 ml). The EtOAc solution was dried (Na2SO4), concentrated, and purified using 0-15% MeOH in DCM (with 1% NH3) to give the title product (S)—N-(1-amino-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide (0.64 g) as a white solid; 1H NMR (200 MHz, CDCl3): δ=1.50-2.20 (m, 16H), 2.20-2.80 (m, 8H), 3.15-3.50 (m, 2H), 3.72 (s, 6 H), 4.15-4.30 (m, 1H), 4.30-4.50 (m, 1H), 5.37 (br s, 1 H), 6.62 (d, 2H, J=8.4 Hz), 6.65 (s, 1H), 7.18 (br s, 1 H), 7.20-7.40 (m, 2H), 7.64 (t, 1H, J=7.0 Hz), 8.13 (d, 1H, J=8.4 Hz), 8.61 (d, 1H, J=4.0 Hz); LC-MS (ESI): m/z calculated for C27H40N5O4 [M+H+]: 498, Found: 498.3.
Figure USRE049594-20230801-C00378
(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperididin-1-yl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide: A solution of (S)—N-(1-amino-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide (40 mg, 0.80 mmol) in DMF-DMA (1 ml) was heated at 120° C. for 2 h. The solution was concentrated to dryness and the residue was dissolved in HOAc (1.0 ml), followed by addition of NH2NH2.H2O (0.10 ml). The resulting solution was heated at 90° C. for 2 h, cooled to rt, quenched with NaHCO3 (sat., 20 ml), and extracted with EtOAc (10 ml). The EtOAc solution was dried (Na2SO4), concentrated, and purified using 0-15% MeOH in DCM (with 1% NH3) to give the title product (S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide (24 mg) as a white solid; 1H NMR (200 MHz, CDCl3): δ1.40-2.20 (m, 16H), 2.30-2.80 (m, 6H), 3.20-3.40 (m, 2H), 3.72 (s, 6 H), 4.15-4.30 (m, 1H), 4.50-4.70 (m, 1H), 6.62 (d, 2H, J=8.6 Hz), 6.68 (s, 1H), 7.35 (t, 1H, J=7.5 Hz), 7.91 (s, 1H), 8.20 (d, 1H, J=8.6 Hz); LC-MS (ESI): m/z calculated for C28H39N7O3 [M+H+]: 522, Found: 522.3.
Figure USRE049594-20230801-C00379
Figure USRE049594-20230801-C00380
(S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide: To a solution of (S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide (50 mg, 0.10 mmol) in DCM (1 ml) at rt were added Et3N (56 μL, 0.40 mmol) and trifluoroacetic anhydride (56 μL, 0.40 mmol). The solution was stirred at rt for 15 h. LC-MS analysis showed the completion of the reaction. The mixture was quenched with NaHCO3 (sat., 10 ml) and extracted with DCM (10 ml). The extract was dried (Na2SO4), concentrated, and purified using 0-10% MeOH in DCM to give the title product (S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide (13 mg) as a yellow solid; 1H NMR (200 MHz, CDCl3): δ=1.40-2.20 (m, 24H), 2.79 (d, 2H, J=6.1 Hz) 3.74 and 3.75 (s and s, total 6 H), 4.20-4.30 (m, 1H), 4.30-4.50 (m, 1H), 6.63 (d, 2H, J=8.2 Hz); 6.67 (s, 1H), 7.38 (t, 1 H, J=8.4 Hz), 7.98 (br s, 1H); LC-MS (ESI): m/z calculated for C27H38N5O3 [M+H+]: 480, Found: 479.9.
Figure USRE049594-20230801-C00381
(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(1H-tetrazol-5-yl)butan-2-yl)-1H-pyrazole-3-carboxamide: A mixture of (S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide (50 mg) and Me3SnN3 (71 mg) in toluene (1 ml) was heated at 100° C. for 20 h. The mixture was concentrated and purified using 0-15% MeOH in DCM (with 1% NH3) to give the title product (S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(1H-tetrazol-5-yl)butan-2-yl)-1H-pyrazole-3-carboxamide (42 mg) as an orange foam; 1H NMR (200 MHz, CDCl3): δ=1.40-2.20 (m, 24H), 3.29 (d, 2H, J=4.6 Hz) 3.73 and 3.74 (s and s, total 6 H), 4.20-4.40 (m, 1H), 4.50-4.70 (m, 1H), 6.62 (d, 2H, J=8.4 Hz); 6.67 (s, 1H), 7.37 (t, 2H, J=8.4 Hz), 9.68 (s, 1 H); LC-MS (ESI): m/z calculated for C27H39N8O3 [M+H+]: 523, Found: 522.9.
Figure USRE049594-20230801-C00382
(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(thiazol-2-yl)butan-2-yl)-1H-pyrazole-3-carboxamide: A mixture of (S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide (96 mg, 0.20 mmol), P2S5 (90 mg, 0.40 mmol) and EtOH (2 ml) was heated at 80° C. for 17 h. The mixture was concentrated to dryness to give a yellow solid. The solid was triturated with DCM and filtered through a short pad of Celite®. The filtrate was concentrated and treated with ethyl 2-bromo acetate (90 μL, 0.60 mmol) in acetic acid (2 ml) at 60° C. for 1 h, 70° C. for 1 h and 80° C. for 1 h. The mixture was cooled to rt, and diluted with EtOAc (20 ml), washed with NaHCO3 (20 ml×2), dried (Na2SO4), concentrated, and purified using 0-15% MeOH in DCM (with 1% NH3) to give (S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(thiazol-2-yl)butan-2-yl)-1H-pyrazole-3-carboxamide (20 mg) as a yellow oil; 1H NMR (200 MHz, CDCl3): δ1.40-2.00 (m, 14H), 2.30-2.60 (m, 6H), 3.30-3.50 (m, 2H), 3.40-3.70 (m, 2 H), 3.73 (s, 6 H), 4.20-4.35 (m, 1H), 4.50-4.70 (m, 1H), 6.62 (d, 2H, J=8.4 Hz); 6.67 (s, 1H), 7.22 (d, 1 H, J=3.2 Hz), 7.36 (t, 1H, J=8.4 Hz), 7.70 (d, 1 H, J=3.4 Hz), 7.99 (d, 1 H, J=5.8 Hz); LC-MS (ESI): m/z calculated for C29H40N5O3S [M+H+]: 538, Found: 537.8.
Figure USRE049594-20230801-C00383
Figure USRE049594-20230801-C00384
(S)-methyl 3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate: To a solution of (S)-3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid hydrochloride (0.50 g) in MeOH (10 ml) was added sulfuric acid (con., 0.30 mL). The solution was heated at 50° C. for 1 h and 75° C. for 18 h. The mixture was diluted with EtOAc and washed with NaHCO3. The EtOAc layer was dried (Na2SO4), and concentrated to give crude (S)-methyl 3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate (0.41 g) as a white foam; 1H NMR (200 MHz, CDCl3): δ1.40-2.20 (m, 14H), 2.30-2.80 (m, 8H), 3.67 (s, 3 H), 4.20-4.40 (m, 1H), 4.40-4.60 (m, 1H), 6.68 (s, 1H), 7.20-7.60 (m, 5H); LC-MS (ESI): m/z calculated for C26H34F2ClN4O3 [M+H+]: 523 and 525, Found: 523.1 and 525.2.
Figure USRE049594-20230801-C00385
(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(5-(3,3-difluoropiperidin-1-yl)-1-hydrazinyl-1-oxopentan-3-yl)-1H-pyrazole-3-carboxamide: A mixture of (S)-methyl 3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate (0.40 g), hydrazine monohydrate (1.0 ml) and EtOH (5 ml) was refluxed at 85° C. for 4 h. Additional hydrazine monohydrate (2.0 ml) was added, and refluxed at 90° C. for 4 h. LC-MS indicated the completion of the reaction. The mixture was concentrated to dryness, and purified using 0-15% MeOH in DCM (with 1% NH3) to give (S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(5-(3,3-difluoropiperidin-1-yl)-1-hydrazinyl-1-oxopentan-3-yl)-1H-pyrazole-3-carboxamide (0.35 g) as a white foam; 1H NMR (200 MHz, CDCl3): δ1.40-2.20 (m, 14 H), 2.30-2.80 (m, 8H), 4.20-4.50 (m, 2H), 6.72 (s, 1H), 7.20-7.60 (m, 4H), 7.65 (s, 1H), 7.72 (d, 1H, J=8.4 Hz); LC-MS (ESI): m/z calculated for C25H34ClN6O2[M+H+]: 523 and 525, Found: 522.7 and 524.9.
Figure USRE049594-20230801-C00386
(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-methyl-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide: To a suspension of (S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(5-(3,3-difluoropiperidin-1-yl)-1-hydrazinyl-1-oxopentan-3-yl)-1H-pyrazole-3-carboxamide (104 mg, 0.20 mmol), amidine.HCl (58 mg, 0.60 mmol) in BuOH (20 ml) was added KOtBu (0.60 ml, 1.0M in THF, 0.60 mmol). The mixture was heated at 120° C. for 4 h, cooled to rt, diluted with water (10 ml) and extracted with EA (10 ml). The extract was dried (Na2SO4), concentrated, and purified using 0-10% MeOH in DCM (with 1% NH3) to give (S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-methyl-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide (90 mg) as a white foam; 1H NMR (200 MHz, CDCl3): δ1.40-2.20 (m, 14H), 2.41 (s, 3 H), 2.42-2.80 (m, 6H), 3.05-3.20 (m, 2H), 4.20-4.40 (m, 1H), 4.50-4.70 (m, 1H), 6.73 (s, 1H), 7.26-7.60 (m, 4H), 7.80-7.95 (m, 1H); LC-MS (ESI): m/z calculated for C27H35ClF2N7O [M+H+]: 546 and 548, Found: 545.7 and 547.9.
Figure USRE049594-20230801-C00387
(S)—N-(1-amino-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide: To a solution of (S)-3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid hydrochloride (1.6 g, 2.76 mmol) in pyridine (40 ml) and dioxane (40 ml) was added Boc2O (0.60 g, 2.76 mmol), followed by ammonium carbonate (0.22 g, 2.76 mmol). The progress of the reaction was monitored by LC-MS. Additional ammonium carbonate and Boc2O (2 eq each) were added after 1 h. Stirring was continued for 12 h, and additional ammonium carbonate and Boc2O (2 eq each) were added. After further stirring for 1 h, LC-MS indicated the completion of the reaction. The mixture was concentrated to dryness, quenched with NaHCO3 (sat., 40 ml) and extracted with EtOAc (40 mL). The EtOAc solution was dried (Na2SO4), concentrated, and purified using 0-15% MeOH in DCM (with 1% NH3) to give the title product (S)—N-(1-amino-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide (1.30 g) as a white foam; 1H NMR (200 MHz, CDCl3): δ1.40-2.20 (m, 14H), 2.30-2.80 (m, 8H), 4.20-4.60 (m, 2H), 5.33 (br s, 1H), 6.50 (br s, 1H), 6.72 (s, 1H), 7.20-7.60 (m, 4H), 7.71 (d, 1H, J=9.0 Hz); LC-MS (ESI): m/z calculated for C25H33ClN5O2[M+H+]: 508 and 510, Found: 508.0 and 510.1.
Figure USRE049594-20230801-C00388
(S)-5-(2-chlorophenyl)-N-(1-cyano-4-(3,3-difluoropiperidin-1-yl)butan-2-yl)-1-cyclopentyl-1H-pyrazole-3-carboxamide: To a mixture of (S)—N-(1-amino-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide (0.80 g, 1.6 mmol) and imidazole (109 mg, 1.6 mmol) in pyridine (15 ml) at 5° C. was added dropwise of POCl3 (0.30 ml, 3.2 mmol). After addition, the mixture was continued to stir at 5° C. for 1 h before it was quenched with NaHCO3, and extracted with EtOAc. The EtOAc solution was dried (Na2SO4), concentrated, and purified using 0-10% MeOH in DCM (with 1% NH3) to give the title product (S)-5-(2-chlorophenyl)-N-(1-cyano-4-(3,3-difluoropiperidin-1-yl)butan-2-yl)-1-cyclopentyl-1H-pyrazole-3-carboxamide (0.80 g) as a brown oil (contaminated with pyridine); 1H NMR (200 MHz, CDCl3): δ1.70-2.20 (m, 14H), 2.40-2.80 (m, 6H), 2.86 (d, 2H, J=5.0 Hz), 4.20-4.50 (m, 2H), 6.74 (s, 1H), 7.20-7.60 (m, 5H); LC-MS (ESI): m/z calculated for C25H31ClF2N5O [M+H+]: 490 and 492, Found: 489.9 and 492.2.
Figure USRE049594-20230801-C00389
(S)-methyl 3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanimidothioate: A mixture of (S)-5-(2-chlorophenyl)-N-(1-cyano-4-(3,3-difluoropiperidin-1-yl)butan-2-yl)-1-cyclopentyl-1H-pyrazole-3-carboxamide (0.80 g, 1.5 mmol), P2S5 (1.0 g, 4.5 mmol) and EtOH (15 ml) was heated at 85° C. for 17 h. It was cooled to rt, diluted with EtOAc and washed with NaHCO3. The EtOAc layer was dried (Na2SO4) and concentrated to give a yellow foam.
To a mixture of the above yellow foam (0.53 g, about 1.0 mmol), K2CO3 (0.55 g, 4.0 mmol) and acetone (10 ml) was added MeI (0.25 ml, 4.0 mmol). The mixture was stirred at rt for 1.5 h before quenched with water and EA. The EtOAc layer was separated, dried (Na2SO4) and concentrated to give crude (S)-methyl 3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanimidothioate (0.53 g) as a brown oil.
Figure USRE049594-20230801-C00390
(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide: A mixture of (S)-methyl 3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanimidothioate (0.12 g, 0.24 mmol), trifluoroacetyl hydrazide (30 mg, 0.24 mmol) and toluene (3 ml) was heated at 110° C. for 4 h. LC-MS showed little progress. Then 1,2-dichloro benzene was added, and the mixture was heated at 160° C. for 17 h. It was cooled to rt, concentrated to dryness and purified to give (S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide (20 mg) as an off-white foam; 1H NMR (200 MHz, CDCl3): δ1.40-2.20 (m, 14H), 2.30-2.80 (m, 6H), 3.10-3.40 (m, 2H), 4.20-4.40 (m, 2H), 4.60-4.80 (m, 1H), 6.75 (s, 1H), 7.20-7.60 (m, 4H), 7.72 (d, 1H, J=8.4 Hz); LC-MS (ESI): nm/z calculated for C27H32ClF5N7O [M+H+]: 600 and 602, Found: 599.9 and 602.0.
Figure USRE049594-20230801-C00391
General Procedure for the Synthesis of (S)-tert-butyl 3-amino-5-(difluoropiperidin-1-yl)pentanoates
Step 1: To a solution of difluoropiperidine.HCl (1 eq) in water (1 mL/mmol of piperidine) was added Na2CO3 (1 eq), and stirred at rt for 10 min. THF (2 mL/mmol of piperidine) was added, and the mixture was cooled to −15° C. DBU (1%) was added, followed by acrolein (90%, 1 eq). After addition, the mixture was stirred at −15° C. for 30 min, and the compound 3-(difluoropiperidin-1-yl)propanal in THF and water was used as is for the next step.
Step 2: To a solution of t-butyl diethylphosphonoacetate (1.2 eq to difluoropiperidine) in THF (1 mL/mmol of phosphonoacetate) at rt was added KOtBu (1.2 eq to 1 eq of difluoropiperidine). The mixture was stirred at rt for 10 min and then cooled to 5° C. Then, the solution 3-(difluoropiperidin-1-yl)propanal was added, and the resulting mixture was slowly warmed to rt. Stirring was continued at rt for 2 h before the mixture was quenched with water extracted with hexanes/EtOAc. The extract was dried (Na2SO4), concentrated and purified using 0-10% EtOAc in Hexanes to give compound (E)-tert-butyl 5-(difluoropiperidin-1-yl)pent-2-enoate.
Step 3: To a solution of (S)-(N)-benzyl-1-phenylethylamine (1.5 eq) in THF (2 mL/mmol of amine) at −75° C. was added slowly n-BuLi (1.5 eq). Stirring was continued at −75° C. for 30 min before dropwise addition of a solution of (E)-tert-butyl 5-(difluoropiperidin-1-yl)pent-2-enoate (1 eq) in THF (1 ml/mmol of amine). After addition, the mixture was continued to stir at −75° C. for 3 h, quenched with citric acid, and extracted with hexanes. The extract was dried (Na2SO4), concentrated and purified using 0-10% EtOAc in Hexanes to give (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(difluoropiperidin-1-yl)pentanoate.
Step 4: A mixture of (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(difluoropiperidin-1-yl)pentanoate (1 eq), Pd/C (10% on carbon, 0.3 eq by mass) and MeOH (50 ml/g of amine) was hydrogenated under H2 (50 Psi) using a Parr-Shaker at rt for 3 days until the completion of reaction monitored by LC-MS analysis. The mixture was then quenched with celited, and filtered through a short-pad of Celite®, concentrated to give crude (S)-tert-butyl 3-amino-5-(difluoropiperidin-1-yl)pentanoate.
Figure USRE049594-20230801-C00392
(E)-tert-butyl 5-(3,3-difluoropiperidin-1-yl)pent-2-enoate: Using the general procedure (Step 1 and 2) described above, 3,3-difluoropipiridine.HCl (4.36 g, 27.7 mmol) was used to give (E)-tert-butyl 5-(3,3-difluoropiperidin-1-yl)pent-2-enoate (1.96 g) as a colorless oil after column purification using 0-10% EtOAc in Hexanes; 1H NMR (200 MHz, CDCl3): δ1.57 (s, 9H), 1.60-2.00 (m, 4H), 2.30-2.80 (m, 8H), 5.78 (m, 1H), 6.82 (m, 1H); LC-MS (ESI): m/z calculated for C14H26NO2 [M+H+]: 240, Found: 240.1.
Figure USRE049594-20230801-C00393
(E)-tert-butyl 5-(4,4-difluoropiperidin-1-yl)pent-2-enoate: Using the general procedure (Step 1 and 2) described above, 4,4-difluoropipiridine.HCl (5.0 g, 31.7 mmol) was used to give (E)-tert-butyl 5-(4,4-difluoropiperidin-1-yl)pent-2-enoate (3.59 g) as white solid after column purification using 0-10% EtOAc in Hexanes; 1H NMR (200 MHz, CDCl3): δ1.50 (s, 9H), 1.80-2.20 (m, 4H), 2.30-2.60 (m, 8H), 5.78 (m, 1H), 6.82 (m, 1H); LC-MS (ESI): m/z calculated for C14H24F2NO2 [M+H+]: 276, Found: 275.8.
Figure USRE049594-20230801-C00394
(S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(3,3-difluoropiperidin-1-yl)pentanoate: Using the general procedure (Step 3) described above, (E)-tert-butyl 5-(3,3-difluoropiperidin-1-yl)pent-2-enoate (1.96 g, 7.1 mmol) was used to give (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(3,3-difluoropiperidin-1-yl)pentanoate (1.87 g) as a white solid after column purification using 0-10% EtOAc in Hexanes. 1H NMR (200 MHz, CDCl3): δ1.35 (d, 3H, J=7.4 Hz), 1.45 (s, 9H), 1.50-2.00 (m, 8H), 2.30-2.80 (m, 6H), 3.30-3.40 (m, 1H), 3.48 (d, 1H, J=15.0 Hz), 3.70-3.90 (m, 2H), 7.15-7.45 (m, 10H); LC-MS (ESI): m/z calculated for C29H41F2N2O2[M+H+]: 487, Found: 486.7.
Figure USRE049594-20230801-C00395
(S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(4,4-difluoropiperidin-1-yl)pentanoate: Using the general procedure (Step 3) described above, (E)-tert-butyl 5-(4,4-difluoropiperidin-1-yl)pent-2-enoate (4.0 g, 19.1 mmol) was used to give (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(4,4-difluoropiperidin-1-yl)pentanoate (3.78 g) as a colorless oil after column purification using 0-10% EtOAc in Hexanes. 1H NMR (200 MHz, CDCl3): δ1.34 (d, 3H, J=7.0 Hz), 1.42 (s, 9H), 1.40-1.60 (m, 2H), 1.80-2.10 (m, 6H), 2.30-2.70 (m, 6H), 3.30-3.40 (m, 1H), 3.48 (d, 1H, J=15.0 Hz), 3.70-3.90 (m, 2H), 7.15-7.45 (m, 10H); LC-MS (ESI): m/z calculated for C29H41F2N2O2 [M+H+]: 487, Found: 486.6.
Figure USRE049594-20230801-C00396
(S)-tert-butyl 3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate: Using the general procedure (Step 4) described above, (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(3,3-difluoropiperidin-1-yl)pentanoate (1.9 g, 3.9 mmol) was used to give crude (S)-tert-butyl 3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate (1.29 g) as a white foam, 1H NMR (200 MHz, CDCl3): δ1.43 (s, 9H), 1.70-2.40 (m, 8H), 2.60-3.20 (m, 7H), 3.60-3.80 (m, 1H); LC-MS (ESI): m/z calculated for C14H28F2N2O2[M+H+]: 293, Found: 292.8.
Figure USRE049594-20230801-C00397
(S)-tert-butyl 3-amino-5-(4,4-difluoropiperidin-1-yl)pentanoate: Using the general procedure (Step 4) described above, (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(4,4-difluoropiperidin-1-yl)pentanoate (9.3 g, 19.1 mmol) was used to give crude (S)-tert-butyl 3-amino-5-(4,4-difluoropiperidin-1-yl)pentanoate (5.5 g) as a white solid; 81.45 (s, 9H), 1.70-2.40 (m, 8H), 2.50-3.20 (m, 7H), 3.60-3.80 (m, 1H); LC-MS (ESI): m/z calculated for C14H28F2N2O2[M+H+]: 293, Found: 292.8.
Figure USRE049594-20230801-C00398
(S)-tert-butyl 3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate: A mixture of 1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxylic acid (70 mg, 0.24 mmol), (S)-tert-butyl 3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate (58 mg, 0.20 mmol), Et3N (81 μl, 0.80 mmol) and TBTU (96 mg, 0.30 mmol) in MeCN (4 ml) was stirred at rt for 15 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic layer was dried (Na2SO4), concentrated, and purified using EtOAc/Hex to give (S)-tert-butyl 3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate (50 mg) as a colorless oil; 1H NMR (200 MHz, CDCl3): δ1.44 (s, 9H), 1.60-2.20 (m, 15H), 2.10-2.80 (m, 10H), 4.00-4.20 (m, 1H), 4.30-4.50 (m, 1H), 6.67 (s, 1H), 7.19 (d, 1H, J=6.2 Hz), 7.30-7.60 (m, 3H), 7.60-7.80 (m, 1H); LC-MS (ESI): m/z calculated for C31H43F4N4O3[M+H+]: 595, Found: 594.9.
(S)-3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid: To a solution of(S)-tert-butyl 3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate (50 mg, 0.096 mmol) in DCM (2 mL) was added TFA (0.5 mL) and stirred at rt for 2 h. Solvent was removed in vacuo and diluted with CHCl3. Solvent was removed to provide (S)-3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid (38 mg) as a white solid; 1H NMR (200 MHz, CDCl3): δ1.40-2.20 (m, 18H), 2.40-2.80 (m, 7H), 4.00-4.20 (m, 1H), 4.30-4.50 (m, 1H), 6.67 (s, 1H), 7.19 (d, 1H, J=7.6 Hz), 7.40-7.80 (m, 3H); LC-MS (ESI): m/z calculated for C27H35F4N4O3[M+H+]: 539, Found: 538.7.
(S)-1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-N-(5-(3,3-difluoropiperidin-1-yl)-1-oxo-1-(thiazol-2-ylamino)pentan-3-yl)-1H-pyrazole-3-carboxamide: A mixture of (S)-3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid (35 mg, 0.065 mmol), 2-aminothiazole (13 mg, 0.13 mmol), Et3N (36 μL, 0.26 mmol) and TBTU (42 mg, 0.13 mmol) in DMF (1 ml) was stirred at rt for 15 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4), concentrated, and purified using 0-100% EtOAc in hexanes to give the desired product (S)-1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-N-(5-(3,3-difluoropiperidin-1-yl)-1-oxo-1-(thiazol-2-ylamino)pentan-3-yl)-1H-pyrazole-3-carboxamide (18 mg) as a white solid; 1H NMR (200 MHz, CDCl3): δ 1.40-2.20 (m, 18H), 2.40-2.80 (m, 7H), 4.00-4.20 (m, 1H), 4.40-4.60 (m, 1H), 6.70 (s, 1H), 6.97 (d, 1H, J=3.8 Hz), 7.19 (d, 1H, J=6.6 Hz), 7.40-7.60 (m, 3H), 7.67 (d, 1H, J=6.6 Hz), 7.81 (d, 1H, J=8.0 Hz), 11.5 (br s, 1H); LC-MS (ESI): m/z calculated for C30H37F4N6O2S [M+H+]: 621, Found: 620.9.
Figure USRE049594-20230801-C00399
Figure USRE049594-20230801-C00400
(S)-N-(1-(cyclobutylamino)-5-hydroxy-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: A mixture of (S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxypentanoate (0.15 g), cyclobutylamine (0.50 ml) and EtOH (1 mL) was heated in a sealed tube at 90° C. for 24 h. The mixture was concentrated and purified using EtOAc in hexanes (0-25%) to give (S)-N-(1-(cyclobutylamino)-5-hydroxy-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (97 mg) as a white solid; 1H NMR (200 MHz, CDCl3): δ 0.80-0.95 (m, 2H), 1.40-2.70 (m, 16H), 3.60-3.80 (m, 2H), 4.04-4.20 (m, 1H), 4.20-4.45 (m, 1H), 4.50-4.70 (m, 1H), 6.18 (br s, 1H), 6.73 (s, 1H), 7.25-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1H), 7.98 (br s, 1H); LC-MS (ESI): m/z calculated for C25H32F3N4O3[M+H+]: 493, Found: 493.1.
Figure USRE049594-20230801-C00401
(S)-N-(1-(cyclobutylamino)-1,5-dioxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: To a solution of (S)-N-(1-(cyclobutylamino)-5-hydroxy-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (90 mg, 0.18 mmol) in DCM (2 mL) was added Dess-Martin Reagent (153 mg, 0.36 mmol). The mixture was stirred at rt for 0.5 h before it was quenched with sodium thiosulfate (10%) and NaHCO3. The mixture was extracted with DCM, and the extract was dried (Na2SO4), concentrated and purified using EtOAc in hexanes (0-20%) to give (S)-N-(1-(cyclobutylamino)-1,5-dioxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (32 mg) as a white solid; 1H NMR (200 MHz, CDCl3): δ 1.29 (t, 2H, J=7.0 Hz), 1.40-2.70 (m, 15H), 2.90-3.10(m, 1H), 4.04-4.20 (m, 1H), 4.50-4.6 (m, 1H), 4.65-4.90 (m, 1H), 5.28 (br s, 1H), 6.73 (s, 1H), 6.84 (d, 1H, J=7.8 Hz), 7.25-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.85 (m, 1 H), 9.81 (s, 1H); LC-MS (ESI): m/z calculated for C25H30F3N4O3[M+H+]: 491, Found: 490.6.
Figure USRE049594-20230801-C00402
(S)-N-(1-(cyclobutylamino)-5-(cyclopentyl(methyl)amino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide
To a mixture of crude aldehyde, (S)-N-(1-(cyclobutylamino)-1,5-dioxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (74 mg, 0.150 mmol) and N-methylcyclopentanamine (30 mg, 0.300 mmol) in MeOH (4 mL) was added sodium cyanoborohydride (19 mg, 0.300 mmol). The resulting mixture was stirred at rt for 1-3 h until the completion of the reaction by LC-MS analysis. Then mixture was concentrated and purified using MeOH in DCM (with 1% NH3) to give (S)-N-(1-(cyclobutylamino)-5-(cyclopentyl(methyl)amino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (23 mg) as a colorless oil; 1H NMR (200 MHz, CDCl3): δ 1.40-2.90 (m, 31H), 4.04-4.20 (m, 1H), 4.20-4.50 (m, 2H), 6.74 (s, 1H), 7.03 (br s, 1H), 7.14 (br s, 1 H), 7.25-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1 H), 8.56 (br s, 1H); LC-MS (ESI): m/z calculated for C31H43F3N5O2[M+H+]: 574, Found: 573.9.
Figure USRE049594-20230801-C00403
Preparation of Zn(N3)2.Py2: To a solution of Zn(NO3)2 (3.57 g, 12 mmol) in water (6mL) was added a solution of sodium azide (0.78 g, 12.0 mmol) in water (6 mL). The mixture was stirred at rt for 5 min and heated to 50° C., followed by dropwise addition of pyridine (2.0 mL, 24.7 mmol). After addition, the oil bath was removed, and stirring was continued for 1 h to give a cloudy mixture. The suspension was filtered, washed with cold water (5mL) and air dried to give the title compound (1.3 g) as a white solid.
Figure USRE049594-20230801-C00404
(S)-tert-butyl 5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoate: To a mixture of (S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxypentanoate (2.5 g, 5.0 mmol), Zn(N3)2.Py2 (1.15 g, 3.75 mmol), PPh3 (2.62 g, 10.0 mmol) and toluene (50 mL) was added dropwise of DIAD (2.0 mL, 10 mmol) and stirred at rt for 20 h. The mixture was filtered, rinsed with EtOAc, and the filtrate was concentrated and purified using EtOAc in hexanes (0-40%) to give (S)-tert-butyl 5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoate (2.04 g) as a white semi-solid; 1H NMR (200 MHz, CDCl3): δ 1.46 (s, 9H), 1.50-1.60 (m, 2H), 1.80-2.10 (m, 8H), 2.55-2.65 (m, 2H), 3.45 (t, 2H, J=7.1 Hz), 4.40-4.60 (m, 1H), 4.85-5.05 (m, 1H), 6.31 (br s, 1H), 6.76 (s, 1H), 7.28-7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1 H); LC-MS (ESI): m/z calculated for C25H32F3N6O3[M+H+]: 521, Found: 520.9.
Figure USRE049594-20230801-C00405
(S)-N-(5-azido-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: To a solution of (S)-tert-butyl 5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoate (99 mg, 0.190 mmol) in DCM (2 mL) was added TFA (0.15 mL, 1.90 mmol) and stirred at rt for 2 h. Solvent was removed to provide crude (S)-5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoic acid (100 mg) as yellow oil which was used as is for the next reaction without further purification.
To a solution of (S)-5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoic acid (100 mg, 0.215 mmol) and cyclobutylamine (30 mg, 0.430 mmol) in ACN (1 mL) was added anhydrous NEt3 (0.090 mL, 0.645 mmol) followed by TBTU (138 mg, 0.430 mmol). The reaction mixture was stirred at rt for 18 h. Reaction mixture was diluted with EtOAc (10 mL) and washed with sat. NaHCO3 (5 mL). Organic phase was extracted, added silica gel (100 mg) and purified using Combiflash® Rf (EtOAc/hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford 35 mg of (S)-N-(5-azido-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide as a white foam; 1H NMR (200 MHz, CDCl3): δ 1.40-2.40 (m, 16H), 2.55-2.65 (m, 2H), 3.44 (t, 2H, J=7.6 Hz), 4.10-4.50 (m, 3H), 6.64 (br s, 1H), 6.75 (s, 1H), 7.28-7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1 H); LC-MS (ESI): m/z calculated for C25H30F3N7O2[M+H+]: 518, Found: 518.2.
Figure USRE049594-20230801-C00406
(S)-N-(5-amino-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: A mixture of (S)-N-(5-azido-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (35 mg) Pd/C (10%, 7 mg) and EtOH (3 mL) was stirred under a balloon of hydrogen for 17 h. LC-MS showed the completion of the reduction. Then the mixture was filtered through a short pad of Celite®, and the filtrate was concentrated to give crude (S)-N-(5-amino-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide as a colorless oil (30 mg); LC-MS (ESI): m/z calculated for C25H33F3N5O2[M+H+]: 492, Found: 492.2.
Figure USRE049594-20230801-C00407
(S)-N-(1-(cyclobutylamino)-5-(oxetane-3-carboxamido)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: To a solution of (S)-N-(5-amino-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (30 mg, 0.061 mmol) and 3-oxetanecarboxylic acid (13 mg, 0.122 mmol) in ACN (2 mL) was added anhydrous NEt3 (0.018 mL, 0.183 mmol) followed by TBTU (39 mg, 0.122 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with sat. NaHCO3 (5 mL). The organic phase was extracted, added silica gel (100 mg) and purified using Combiflash® Rf (EtOAc/hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford(S)-N-(1-(cyclobutylamino)-5-(oxetane-3-carboxamido)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (6 mg) as a white solid; 1H NMR (200 MHz, CDCl3): δ 1.40-2.80 (m, 19H), 3.60-3.90 (m, 2H), 4.10-4.50 (m, 3H), 4.70-5.00 (m, 4H). 6.32 (br s, 1H), 6.71 (s, 1H), 7.18 (br s, 1H), 7.28-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1H), 8.15 (d, 1H, J=8.8 Hz); LC-MS (ESI): m/z calculated for C29H37F3N5O4 [M+H+]: 576, Found: 576.2.
Figure USRE049594-20230801-C00408
Figure USRE049594-20230801-C00409
Figure USRE049594-20230801-C00410
(S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-hydroxybutanoate:
N-methylmorpholine (4.46 mL, 40.6 mmol, 1.00 equiv.) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutanoic acid in DME (81 mL) at −15° C. Isobutylchloroformate (5.27 mL, 40.6 mmol, 1.00 equiv.) was then added dropwise. The reaction mixture was stirred at the same temperature for 1 h. The solution was filtered on a frit and the filtrate cooled back to −15° C. A solution of sodium borohydride (2.30 g, 60.9 mmol, 1.50 equiv.) in water (20 mL) was added. Right after this addition, 800 mL of water was added (a white precipitate formed). The solution was filtered, the solid was ground to a fine powder and dried under reduced pressure to provide 9.13 g (63%) of the title compound as a white solid mixed with some of the corresponding lactonized product. m/z (M+H)+=356.1; RT=1.51 min; purity=65%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
Figure USRE049594-20230801-C00411
(S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-iodobutanoate: Iodine (5.46 g, 21.5 mmol, 1.00 equiv.) was added to a solution of triphenylphosphine (5.65 g, 21.5 mmol, 1.00 equiv.) and imidazole (1.76 g, 25.8 mmol, 1.20 equiv.) in DCM (86 mL) at 0° C. The reaction mixture was stirred for 20 min at the same temperature and the alcohol was added. The reaction mixture was stirred at rt for 18 h. An aqueous saturated solution of Na2S2O3 was added and the mixture was stirred for 10 min and extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dry packing) using a solution of ethyl acetate in hexane (5 to 30%) to provide 1.27 g (13%) of the title compound as a white solid and 4.0 g of a mixture of the title compound and an impurity (LCMS ratio=58:42). Pure compound: m/z (M+H)+=466.0; RT=1.86 min; purity=94%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile, 1H NMR (500 MHz, DMSO) δ 2.57-2.53 (m, 1H), 2.64 (dd, J=15.8, 5.3 Hz, 1H), 3.27 (dd, J=10.0, 6.9 Hz, 1H), 3.37 (dd, J=10.1, 5.2 Hz, 1H), 3.58 (s, 3H), 3.90-3.81 (m, 1H), 4.23 (t, J=6.9 Hz, 1H), 4.37-4.27 (m, 2H), 7.33 (td, J=7.5, 1.1 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.5 Hz, 2H), 7.89 (d, J=7.5 Hz, 2H).
Figure USRE049594-20230801-C00412
(S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(acetylthio)butanoate: Potassium thioacetate (393 mg, 3.44 mmol, 2.00 equiv.) was added to a solution of (S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-iodobutanoate in DMF (6.9 mL). The reaction mixture was stirred for 15 h. An aqueous saturated solution of sodium bicarbonate was added, followed by ethyl acetate. The phases were separated and the organic layer was washed 2× with sat'd aq. NaHCO3, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexane (5 to 40%) to provide 555 mg (78%) of the title compound as a white solid. m/z (M+H)+==414.1; RT=1.76 min; purity=99.3%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile, 1H NMR (500 MHz, DMSO) δ 2.32 (s, 3H), 2.54-2.52 (m, 2H), 2.90 (dd, J=13.5, 7.7 Hz, 1H), 3.10 (dd, J=13.5, 5.5 Hz, 1H), 3.57 (s, 3H), 3.96-3.89 (m, 1H), 4.21 (t, J=7.0 Hz, 1H), 4.32-4.27 (m, 2H), 7.33 (td, J=7.4, 1.1 Hz, 2H), 7.45-7.39 (m, 3H), 7.67 (d, J=7.4 Hz, 2H), 7.89 (d, J=7.5 Hz, 2H).
Figure USRE049594-20230801-C00413
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutane-1-sulfonic acid:
A 30% w/w solution of hydrogen peroxide in water (1.3 mL) was added to formic acid (5.0 mL) at 0° C. The reaction mixture was stirred at that temperature for 1 h. A suspension of (S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(acetylthio)butanoate in formic acid (4.0 mL) was added. The reaction mixture was stirred at rt 18. The solvent was evaporated and then the crude product was co-evaporated with toluene and a mixture of DCM/toluene to provide 554 mg (98%) of the title compound as a pale orange solid. m/z (M+H)+=420.1; RT=1.31 min; purity=87.7%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile, 1H NMR (500 MHz, DMSO) δ 2.54-2.51 (m, 1H), 2.65-2.59 (m, 1H), 2.71-2.65 (m, 1H), 3.06 (dd, J=15.8, 5.0 Hz, 1H), 3.55 (s, 3H), 4.13-4.08 (m, 1H), 4.28-4.18 (m, 3H), 7.19-7.12 (m, 1H), 7.27-7.22 (m, 1H), 7.32 (t, J=7.4 Hz, 2H), 7.41 (dd, J=7.4, 6.5 Hz, 2H), 7.66 (d, J=7.5 Hz, 2H), 7.88 (d, J=7.5 Hz, 2H).
Figure USRE049594-20230801-C00414
(S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(chlorosulfonyl)butanoate:
Thionyl chloride (1.4 mL, 20 mmol, 15 equiv.), containing three drops of DMF, was added to (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutane-1-sulfonic acid (554 mg, 1.32 mmol, 1.00 equiv.). The reaction mixture was stirred at rt for 3 days and was heated at 40° C. for 1.5 h. Volatiles were evaporated and the mixture was co-evaporated 2× with DCM to provide 550 mg (95%) of the title compound as a dark orange solid. m/z (M+H)+=438.1; RT=1.77 min; purity=94.8%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 2.68 (dd, J=13.4, 4.5 Hz, 1H), 2.54-2.48 (m, J=7.7 Hz, 1H), 2.62 (dd, J=13.8, 7.8 Hz, 1H), 3.06 (dd, J=15.7, 5.0 Hz, 1H), 3.55 (s, 3H), 4.15-4.07 (m, 1H), 4.27-4.18 (m, 3H), 7.26 (d, J=7.9 Hz, 1H), 7.32 (t, J=7.5 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.66 (d, J=7.0 Hz, 2H), 7.88 (d, J=7.5 Hz, 2H).
Figure USRE049594-20230801-C00415
(S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoate: A concentrated aqueous solution of ammonium hydroxyde (0.22 mL, 3.1 mmol, 5.0 equiv.) was added to a solution of (S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(chlorosulfonyl)butanoate (275 mg, 0.628 mmol, 1.00 equiv.) in THF (3.1 mL). The reaction mixture was stirred for 2 min and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (5 to 60%) to provide 140 mg (53%) of the title compound as a pale orange solid. m/z (M+H)+=419.1; RT=1.52 min; purity=>95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 2.64-2.58 (m, 1H), 2.80 (dd, J=15.8, 4.7 Hz, 1H), 3.18 (dd, J=14.0, 6.9 Hz, 1H), 3.25 (dd, J=14.0, 6.0 Hz, 1H), 3.58 (s, 3H), 4.31-4.19 (m, 4H), 6.92 (s, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.42 (t, J=7.3 Hz, 2H), 7.49 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.4 Hz, 2H), 7.89 (d, J=7.5 Hz, 2H).
Figure USRE049594-20230801-C00416
(S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoic acid: HCl (conc., 1.1 mL) was added to a solution of (I)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoate (140 mg, 0.335 mmol, 1.00 equiv.) in AcOH (11 mL). The reaction mixture was heated at 100° C. for 15 h. The reaction mixture was poured in 70 mL of water and ethyl acetate was added. The phases were separated and the organic layer was dried with sodium sulfate, filtered and evaporated. The crude mixture was co-evaporated with dioxane and DCM to provide 122 mg (90%) of the title compound as a pale yellow solid. m/z (M+H)+=405.2; RT=1.45 min; purity=96.6%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
Figure USRE049594-20230801-C00417
(S)-(9H-fluoren-9-yl)methyl (4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2-yl)carbamate: HATU (126 mg, 0.332 mmol, 1.10 equiv.) was added to a solution of (I)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoic acid (122 mg, 0.302 mmol, 1.00 equiv.), HOAt (41 mg, 0.30 mmol, 1.0 equiv.), 3,3-difluoropiperidine hydrochloride (95 mg, 0.60 mmol, 2.0 equiv.) and diisopropylethylamine (0.16 mL, 0.91 mmol, 3.0 equiv.) in DMF (1.2 mL) at 0° C. The reaction was stirred at rt for 3 days. Water was added, followed by ethyl acetate. The phases were separated and the organic layer was washed with satd. aq. NaHCO3 (3×), dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of MeOH in DCM (0 to 5%) to provide 136 mg (89%) of the title compound as a pale orange solid. m/z (M+H)+=508.2; RT=1.65 min; purity=97.2%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.62-1.53 (m, 1H), 1.70-1.63 (m, 1H), 2.09-1.98 (m, 3H), 2.09-1.98 (m, 3H), 2.77-2.70 (m, 1H), 3.30-3.18 (m, J=7.1 Hz, 3H), 3.46-3.42 (m, 1H), 3.82-3.71 (m, 2H), 4.24-4.18 (m, 1H), 4.32-4.26 (m, 3H), 6.88 (d, J=5.5 Hz, 2H), 7.35-7.30 (m, 3H), 7.41 (t, J=7.2 Hz, 2H), 7.68 (d, J=7.5 Hz, 2H), 7.89 (d, J=7.5 Hz, 2H).
Figure USRE049594-20230801-C00418
(S)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: Diethylamine (0.28 mL, 2.7 mmol, 10 equiv.) was added to a solution of (S)-(9H-fluoren-9-yl)methyl (4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2-yl)carbamate (135 mg, 0.266 mmol, 1.00 equiv.) in acetonitrile (2.7 mL). The reaction was stirred for 1.5 h. The solvent was evaporated and the crude mixture was co-evaporated 2× with DCM to provide 118 mg of the crude amine (64% w/w considering an hypothetic quantitative yield) which was used as is. HATU (16 mg, 0.041 mmol, 1.1 equiv.) was added to a solution of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (12 mg, 0.037 mmol), HOAt (5.0 mg, 0.037 mmol, 1.0 equiv.) and diisopropylethylamine (19 μL, 0.11 mmol, 3.0 equiv.) in DMF (0.2 mL). A suspension of the crude amine (16 mg, 0.037 mmol, 1.0 equiv., 64% w/w) in DMF (0.17 mL) was added. The reaction mixture was stirred for 2 h. The reaction was put on top of a C-18 column and was purified by reverse phase chromatography using a solution of MeCN in water (containing 10 mM of ammonium formate, pH=3.8) (5 to 65%). Fractions were combined and lyophilized to give 10 mg of the title compound which was further purified by semi-prep HPLC-MS (column X-Bridge 30×50) using a solution of MeCN in water (containing 10 mM of ammonium formate, pH=3.8) (45 to 65%). Fractions were combined and lyophilized to provide 2.2 mg (10%) of the title compound. m/z (M+H)+=592.3; RT=1.76 min; purity=>99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 8.10 and 8.05 (d, J=8.6 Hz, 1H, NH, rotamers), 1.64-1.45 (m, 4H), 1.73-1.65 (m, 1H), 2.10-1.76 (m, 10H), 2.22-2.12 (m, 2H), 2.84-2.73 (m, 1H), 3.02-2.88 (m, 1H), 3.28-3.23 (m, 4H), 3.60-3.37 (m, 3H), 3.91-3.68 (m, 3H), 4.20 (quint, J=7.4 Hz, 1H), 4.70-4.65 (m, 1H), 6.63 (s, 1H), 7.57-7.51 (m, 2H), 7.76 (t, J=7.6 Hz, 1H), 7.82 (t, J=7.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H).
Figure USRE049594-20230801-C00419
Figure USRE049594-20230801-C00420
(S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoate: Cyclobutylamine (0.13 mL, 1.6 mmol, 2.5 equiv.) was added to a solution of (S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(chlorosulfonyl)butanoate (275 mg, 0.628 mmol) in THF (3.1 mL). The reaction mixture was stirred for 10 min and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (5 to 60%) to provide 159 mg (54%) of the title compound as an orange viscous oil. m/z (M+H)+=473.1; RT=1.72 min; purity=>95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.59-1.48 (m, 2H), 1.95-1.84 (m, 2H), 2.20-2.11 (m, 2H), 2.58 (dd, J=15.7, 8.7 Hz, 1H), 2.76 (dd, J=15.7, 4.9 Hz, 1H), 3.10 (dd, J=14.2, 6.5 Hz, 1H), 3.16 (dd, J=14.1, 6.3 Hz, 1H), 3.58 (s, 3H), 3.70 (six, J=8.4 Hz, 1H), 4.25-4.18 (m, 2H), 4.34-4.26 (m, 2H), 7.34-7.30 (m, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.68 (d, J=7.5 Hz, 2H), 7.89 (d, J=7.5 Hz, 2H).
Figure USRE049594-20230801-C00421
(S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoic acid
HCl (conc., 0.84 mL) was added to a solution of (S)-methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoate (140 mg, 0.335 mmol, 1.00 equiv.) in AcOH (8.4 mL). The reaction mixture was heated at 100° C. for 15 h. The reaction mixture was poured in 70 mL of water and ethyl acetate was added. The phases were separated and the organic layer was dried with sodium sulfate, filtered and evaporated. The crude mixture was co-evaporated with dioxane and DCM to provide 81 mg (70%) of the title compound as a pale brown solid. m/z (M+H)+=459.2; RT=1.64 min; purity=98.1%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
Figure USRE049594-20230801-C00422
(S)-(9H-fluoren-9-yl)methyl (1-(N-cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl)carbamate: HATU (74 mg, 0.19 mmol, 1.10 equiv.) was added to a solution of (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoic acid (81 mg, 0.18 mmol, 1.0 equiv.), HOAt (24 mg, 0.18 mmol, 1.0 equiv.), 3,3-difluoropiperidine hydrochloride (56 mg, 0.35 mmol, 2.0 equiv.) and diisopropylethylamine (92 μL, 0.53 mmol, 3.0 equiv.) in DMF (0.7 mL) at 0° C. The reaction was stirred at rt for 3 days. Water was added, followed by ethyl acetate. The phases were separated and the organic layer was washed with aq. satd. NaHCO3 (3×), dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of MeOH in DCM (1 to 2%) to provide 73 mg (74%) of the title compound as a pale orange solid. m/z (M+H)+=562.3; RT=1.84 min; purity=99.2%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.59-1.48 (m, 3H), 1.70-1.63 (m, 2H), 1.94-1.85 (m, 2H), 2.10-1.99 (m, 3H), 2.19-2.10 (m, 2H), 2.74-2.66 (m, 1H), 3.18-3.12 (m, 1H), 3.47-3.41 (m, 1H), 3.83-3.65 (m, 4H), 4.25-4.19 (m, 2H), 4.31-4.27 (m, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.41 (t, J=7.1 Hz, 2H), 7.51-7.47 (m, 1H), 7.68 (d, J=6.9 Hz, 2H), 7.89 (d, J=7.6 Hz, 2H).
Figure USRE049594-20230801-C00423
(S)-N-(1-(N-cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: Diethylamine (0.13 mL, 1.3 mmol, 10 equiv.) was added to a solution of (S)-(9H-fluoren-9-yl)methyl (1-(N-cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl)carbamate (73 mg, 0.13 mmol, 1.0 equiv.) in acetonitrile (1.3 mL). The reaction was stirred for 1.5 h. The solvent was evaporated and the crude mixture was co-evaporated 2× with DCM to provide 68 mg of the crude amine (65% w/w considering an hypothetic quantitative yield) which was used as is. HATU (17 mg, 0.046 mmol, 1.1 equiv.) was added to a solution of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (14 mg, 0.042 mmol), HOAt (5.7 mg, 0.042 mmol, 1.0 equiv.) and diisopropylethylamine (22 μL, 0.13 mmol, 3.0 equiv.) in DMF (0.22 mL). A suspension of the crude amine (22 mg, 0.042 mmol, 1.0 equiv., 65% w/w) in DMF (0.20 mL) was added. The reaction mixture was stirred for 2 h. Water was added, followed by ethyl acetate. The phases were separated and the organic layer was washed 2× with an aqueous saturated solution of sodium bicarbonate, dried with sodium sulfate, filtered and evaporated. The crude product was purified by semi-prep HPLC-MS (column X-Bridge 30×50) using a solution of MeCN in water (containing 10 mM of ammonium formate, pH=3.8) (55 to 75%). Pure fractions were combined and lyophilized to provide 6.7 mg (25%) of the title compound. m/z (M+H)+=646.3; RT=1.93 min; purity=>99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 8.15 and 8.11 (d, J=8.4 Hz, 1H, NH, rotamers), 1.64-1.47 (m, 2H), 1.73-1.65 (m, 1H), 1.98-1.75 (m, 4H), 2.11-1.99 (m, 2H), 2.89-2.77 (m, 1H), 3.04-2.92 (m, 1H), 3.40-3.34 (m, 4H), 3.61-3.42 (m, 3H), 3.91-3.70 (m, 2H), 4.20 (quint, J=7.2 Hz, 1H), 4.77-4.68 (m, 1H), 6.62 (s, 1H), 6.99-6.94 (m, 2H), 7.54 (d, J=7.8 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H).
Figure USRE049594-20230801-C00424
Figure USRE049594-20230801-C00425
(R)-Benzyl-3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate: To a stirred and cooled (−20° C., CryoCool) THF (150 mL) sol. of Boc-D-Asp(βOBn)-OH (10.00 g, 30.93 mmol, 1.00 equiv.) under nitrogen was added N-methylmorpholine (3.40 mL, 30.93 mmol, 1.00 equiv.). Isobutyl chloroformate (4.01 mL, 30.93 mmol, 1.00 equiv.) was next added over 45 min. (syringe pump). The resulting white suspension was stirred 1 hr. Sodium borohydride (3.51 g, 92.79 mmol, 3.00 equiv.) was added in one portion, mixture stirred in the cold 1 hr. Methanol (50 mL) was added drop-wise over c.a. 30 min. Mixture was stirred 30 min. then 40 mL of aq. 1 M KHSO4 was slowly added (over 30 min.), stirring continued 15 min. then organic solvent was evaporated. Residue was treated with 30 ml of aq. IM HCl and product was extracted 2×100 mL EtOAc. Organic extracts were pooled, washed with 25 mL aq. IM HCl, 25 ml sat. aq. NaHCO3, 25 mL water, 25 ml sat. aq. NaCl. Sol. was dried (MgSO4), filtered, filtrate evaporated. Residue was purified CombiFlash®, 100 g column, DCM isocratic 5 min. then to 10% MeOH/DCM in 15 min. Purest fractions were pooled, solvent evaporated, residue dried under high vacuum overnight to yield the title compound, 3.0 g (31%) clear thick oil. m/z (M+H)+-Boc=210.1; RT=1.48 min; purity=80%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 2.37 (dd, J=15.3, 8.6 Hz, 1H), 2.60 (dd, J=15.2, 5.2 Hz, 1H), 3.25-3.18 (m, 1H), 3.39-3.34 (m, 1H), 3.87-3.77 (m, 1H), 4.77 (t, J=5.7 Hz, 1H), 5.06 (s, 2H), 6.67 (d, J=8.6 Hz, 1H), 7.38-7.30 (m, 5H).
Figure USRE049594-20230801-C00426
(R)-Benzyl-3-((tert-butoxycarbonyl)amino)-4-(4-fluorophenoxy)butanoate: To a stirred, ice cold toluene (3 mL) solution of (R)-benzyl-3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (100 mg, 0.320 mmol, 1.00 equiv.) under nitrogen was added p-fluorophenol (47 mg, 0.420 mmol, 1.30 equiv.), triphenylphosphine (110 mg, 0.420 mmol, 1.30 equiv.) and finally diamide (72 mg, 0.420 mmol, 1.30 equiv.). Suspension was stirred 1 hr in the cold, allowed to warm to RT, stirred overnight. Solvent was evaporated, residue purified CombiFlash®, 4 g column, dry-pack, 10% ethyl acetate/hexane isocratic 3 min. then to 50:50 EtOAc:Hex in 15 min. Fractions containing product were pooled and solvent was evaporated. Residue was still impure. It was re-purified, CombiFlash®, 12 g column, hexane, isocratic 4 min. then to 5% iPrOH/Hex. in 10 min. Purest fractions were pooled, solvent evaporated, residue dried under high vacuum to give the title compound, 62 mg (48%) as a clear oil. 1H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 2.58 (dd, J=14.6, 8.0 Hz, 1H), 2.67 (dd, J=15.6, 5.9 Hz, 1H), 3.83 (dd, J=9.6, 6.2 Hz, 1H), 3.92 (dd, J=9.6, 5.9 Hz, 1H), 5.09 (s, 2H), 4.23-4.12 (m, 1H), 6.95-6.87 (m, 2H), 7.12-7.06 (m, 2H), 7.45-7.30 (m, 6H).
Figure USRE049594-20230801-C00427
(R)-Benzyl3-amino-4-(4-fluorophenoxy)butanoate hydrochloride: (R)-benzyl-3-((tert-butoxycarbonyl)amino)-4-(4-fluorophenoxy)butanoate (60 mg, 0.15 mmol, 1.00 equiv.) was dissolved in 3 mL of HCl 4N/Dioxane solution. Sol. was stirred at RT 2 hrs; nitrogen was bubbled in the sol. for 1 hr to remove as much HCl as possible. Solvent was evaporated; to the oily residue was added 1 mL diethylether. Product was soluble; hexane (c.a. 0.5 mL) was slowly added to obtain a white precipitate. Suspension was sonicated 5 min. then centrifuged 10 min. at 3000 rpm, supernatant was decanted. Residual solid was re-suspended in 1.5 mL diethylether, sonicated 10 min., centrifuged 10 min at 3000 rpm, supernatant was decanted, solid was dried under high vacuum to give the title compound, 36 mg (71%) as a white solid. m/z (M+H)+=304.0; RT=1.32 min; purity=91.3%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 2.89 (d, J=6.7 Hz, 2H), 3.90-3.82 (m, 1H), 4.09 (dd, J=10.4, 6.2 Hz, 1H), 4.18 (dd, J=10.4, 3.8 Hz, 1H), 5.16 (s, 2H), 7.01-6.95 (m, 2H), 7.18-7.12 (m, 2H), 7.41-7.32 (m, 5H), 8.36 (s, broad, 3H).
Figure USRE049594-20230801-C00428
(R)-Benzyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoate: To a stirred DMF (1 mL) sol. of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (42 mg, 0.130 mmol, 1.25 equiv.) under nitrogen was added HATU (49 mg, 0.130 mmol, 1.25 equiv.), HOAt (18 mg, 0.130 mmol, 1.25 equiv.) and DIPEA (72 μL, 0.412 mmol, 4.00 equiv.). Yellow sol. was stirred 10 min. then (R)-benzyl 3-amino-4-(4-fluorophenoxy)butanoate hydrochloride (32 mg, 0.103 mmol, 1.00 equiv.) was added. Sol. was stirred 2 hrs at RT, diluted with EtOAc (20 ml), washed 2×10 ml aq. 0.5N citric acid, 3×10 ml sat. aq. NaHCO3, 10 ml sat. aq. NaCl, dried (MgSO4), filtered, filtrate evaporated. Residue was purified CombiFlash®, 12 g column, 10% EtOAc/Hex isocratic 3 min. then to 50% EtOAc/Hex in 10 min. Purest fractions were pooled, solvent evaporated, residue dried under high vacuum to give the title compound, 34 mg (61%) as a clear amorphous solid. m/z (M+H)+=610.4; RT=2.17 min; purity=87.0%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.58-1.45 (m, 2H), 2.05-1.72 (m, 6H), 2.91-2.83 (m, 2H), 4.03-3.97 (m, 1H), 4.25-4.07 (m, 2H), 4.78-4.68 (m, 1H), 5.11 (s, 2H), 6.66 (s, 1H), 7.00-6.93 (m, 2H), 7.14-7.07 (m, 2H), 7.35-7.25 (m, 5H), 7.54 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.83 (t, J=7.4 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H).
Figure USRE049594-20230801-C00429
(R)-3-(1-Cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoic acid: To a stirred EtOAc (5 mL) sol. of (R)-benzyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoate (30 mg, 0.050 mmol, 1.00 equiv.) under nitrogen was added Pd/C 10% (25 mg). System was purged 3×H2 then hydrogenated (H2 balloon) overnight. Mixture was filtered through Celite®, cake washed 3×10 mL EtOAc, filtrates pooled, solvent evaporated. Residue purified CombiFlash®, 12 g C18 column, 1 min. isocratic aq. 10 mM ammonium bicarbonate then to 50% acetonitrile/aq. 10 mM ammonium bicarbonate in 12 min. Purest fractions were pooled, acetonitrile evaporated, remaining aq. sol. was frozen and lyophilized to give the title compound, 15 mg (58%) as a solid. m/z (M+H)+=520.3; RT=1.85 min; purity=92.2%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, CDCl3) δ 1.60-1.46 (m, 2H), 2.15-1.80 (m, 6H), 2.98-2.88 (m, 2H), 4.21-4.11 (m, 2H), 4.24 (dd, J=9.5, 4.0 Hz, 1H), 4.88-4.78 (m, 1H), 6.77 (s, 1H), 6.94-6.86 (m, 2H), 6.98-6.95 (m, 2H), 7.30 (d, J=7.1 Hz, 1H), 7.65-7.57 (m, 3H), 7.67 (d, J=7.9 Hz, 1H), 7.80 (dd, J=7.4, 1.5 Hz, 1H).
Figure USRE049594-20230801-C00430
(R)-N-(4-(Cyclobutylamino)-1-(4-fluorophenoxy)-4-oxobutan-2-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: To a stirred DMF (500 μL) sol. of (R)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoic acid (12 mg, 0.023 mmol, 1.00 equiv.) under nitrogen was added HATU (13 mg, 0.035 mmol, 1.50 equiv.), HOAt (4.8 mg, 0.035 mmol, 1.50 equiv.) and DIPEA (16 μL, 0.092 mmol, 4.00 equiv.). Yellow sol. was stirred 10 min. then cyclobutylamine (3.3 mg, 0.046 mmol, 2.00 equiv.) was added. Sol. was stirred 4 hrs at RT, diluted with EtOAc (20 ml), washed 2×10 ml aq. 0.5N citric acid, 3×10 ml sat. aq. NaHCO3, 10 ml sat. aq. NaCl, dried (MgSO4), filtered, filtrate evaporated. Residue was purified CombiFlash®, 12 g column, DCM isocratic 2 min. to 2% MeOH/DCM in 6 min. Purest fractions were pooled, solvent evaporated, residue dried under high vacuum to give the title compound, 5.2 mg (40%) as a clear amorphous solid. m/z (M+H)+=573.4; RT=1.95 min; purity=98.5%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.64-1.47 (m, 4H), 2.02-1.75 (m, 8H), 2.17-2.05 (m, 2H), 2.52-2.45 (m, 1H), 2.55 (dd, J=14.6, 7.0 Hz, 1H), 3.98 (dd, J=9.9, 6.2 Hz, 1H), 4.24-4.07 (m, 3H), 4.62-4.53 (m, 1H), 6.63 (s, 1H), 7.03-6.97 (m, 2H), 7.14-7.08 (m, 2H), 7.53 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.93 (d, J=7.3 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.7 Hz, 1H).
Figure USRE049594-20230801-C00431
Figure USRE049594-20230801-C00432
(R)-benzyl 3-((tert-butoxycarbonyl)amino)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate:
HOBt (240 mg, 1.78 mmol, 1.15 equiv.) was added to a solution of (R)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (500 mg, 1.55 mmol) and tetrahydro-2H-pyran-4-amine (240 mg, 1.55 mmol) in DMF (10 mL). EDC.HCl (296 mg, 1.55 mmol) and N-methylmorpholine (202 mg, 2.00 mmol) were added at 0° C. and the reaction mixture was stirred at rt for 15 h. Ethyl acetate was added and the mixture was washed with an aqueous saturated solution of sodium bicarbonate, with brine (2×), dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (10 to 20%) to provide 488 mg (78%) of the title compound as a white solid. m/z (M+H)+=407.2; RT=1.51 min; purity=>95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
Figure USRE049594-20230801-C00433
(R)-benzyl 3-amino-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate hydrochloride:
4M HCl in dioxane (3.0 mL, 12 mmol) was added to (R)-benzyl 3-((tert-butoxycarbonyl)amino)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate (488 mg, 1.20 mmol). The reaction was stirred at rt for 18 h. A saturated aqueous solution of NaHCO3 (25 mL) was added, followed by 6N NaOH until pH=10. The mixture was extracted 4× with a solution of THF in DCM (1:3), the combined organic layers were dried with sodium sulfate, filtered and evaporated to provide 415 mg (quantitative yield) of the title compound as a white foam. m/z (M+H)+=307.2; RT=1.00 min; purity=>95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
Figure USRE049594-20230801-C00434
(R)-benzyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate:
HATU (121 mg, 0.31 mmol) was added to a solution of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (94 mg, 0.19 mmol), HOAt (39 mg, 0.29 mmol) and diisopropylethylamine (150 μL, 0.87 mmol) in DMF (1 mL). The reaction mixture was stirred for 10 min and a solution of (R)-benzyl 3-amino-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate hydrochloride (99 mg, 0.29 mmol) in DMF (0.85 mL) was added. The reaction mixture was stirred at rt for 2 h. Water was added, followed by ethyl acetate. The phases were separated and the organic layer was washed 2× with an aqueous saturated solution of sodium bicarbonate, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (20 to 40%) to provide 85 mg of the title compound as a colorless viscous oil. m/z (M+H)+=613.4; RT=1.87 min; purity=99.5%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
Figure USRE049594-20230801-C00435
(R)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoic acid:
10% Pd/C (10 mg) was added to a nitrogen purged flask containing a solution of (R)-benzyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate (85 mg (0.14 mmol) in EtOH (0.5 mL). The flask was put under vacuum for 30 sec and put back under nitrogen. This procedure was done another time. The flask was put back again under vacuum and a balloon of hydrogen was inserted through the septum. The reaction was vigorously stirred for 15 h. The flask was put under vacuum for 30 sec and put back under nitrogen. This procedure was done two other times. The solution was filtered on Celite®, the solid cake was washed with EtOH and the filtrate was evaporated to provide 61 mg (85%) of the title compound as a white solid. Half the compound was dissolved in a mixture of acetonitrile and water and was lyophilized to give 23 mg of a white solid. m/z (M+H)+=523.2; RT=1.51 min; purity=99.1%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.48-1.36 (m, 2H), 1.58-1.48 (m, 2H), 1.71-1.63 (m, 2H), 1.90-1.77 (m, 3H), 2.01-1.90 (m, 3H), 2.78-2.66 (m, 2H), 3.38-3.33 (m, 2H), 3.85-3.70 (m, 3H), 4.21 (quint, J=7.4 Hz, 1H), 4.76-4.69 (m, 1H), 6.66 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 8.14-8.00 (m, 2H), 12.43-12.22 (m, 1H).
Figure USRE049594-20230801-C00436
Figure USRE049594-20230801-C00437
Figure USRE049594-20230801-C00438
(S)-5-((3-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentyl)amino)pentanoic acid: To a stirred methanol (2 mL) sol. of 5-aminovaleric acid (38 mg, 0.372 mmol, 1.20 equiv.) under nitrogen was added (S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-oxopentanoate (100 mg, 0.310 mmol) in 1 mL methanol. Sol. was stirred at RT 1 hr then sodium triacetoxyborohydride (79 mg, 0.372 mmol, 1.2 equiv.) was added. Sol. was stirred a further hour, solvent evaporated, residue purified CombiFlash®, 30 g column (C18), 10 mM aq. ammonium formate isocratic 5 min. then to 50% aq. AF-acetonitrile in 10 min., isocratic 8 min. then to 100% acetonitrile in 10 min. Purest fractions were pooled, solvents evaporated (rotavapor, 45° C., high vacuum), residue re-dissolved in ethanol (30 mL), solvent re-evaporated, residue dried under high vacuum to give the title compound, 59 mg (45%) amorphous solid. m/z (M+H)+=423.4; RT=1.28 min; purity=92.7%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 1.70-1.42 (m, 6H), 2.16 (t, J=6.7 Hz, 2H), 2.40-2.30 (m, 2H), 2.65-2.54 (m, 3H), 4.40-3.20 (m, 4H), 5.05-4.97 (m, 2H), 7.38-7.25 (m, 5H), 8.37 (s, boad, 1H).
Figure USRE049594-20230801-C00439
(S)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-5-(2-oxopiperidin-1-yl)pentanoate: To a stirred DMF (500 μL) sol. of (S)-5-((3-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentyl)amino)pentanoic acid (55 mg, 0.130 mmol, 1.00 equiv.) under nitrogen was added DIPEA (90 μL, 0.520 mmol, 4.00 equiv.) followed by HOAt (28 mg, 0.208 mmol, 1.60 equiv.) and HATU (74 mg, 0.195 mmol, 1.50 equiv.). Yellow sol. was stirred at RT 1 hr, diluted with EtOAc (20 mL), washed 4×10 mL sat. aq. NaHCO3, 2×10 mL sat. aq. NaCl, dried (MgSO4), filtered, filtrate evaporated. Crude material was used as such for next transformation. m/z (M+H)+=405.2; RT=1.57 min; purity: 69%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 1.73-1.50 (m, 6H), 2.20-2.12 (m, 2H), 2.38-2.27 (m, 2H), 3.31-3.12 (m, 4H), 3.82-3.74 (m, 1H), 5.07-4.95 (m, 2H), 7.24 (d, J=8.8 Hz, 1H), 7.38-7.28 (m, 5H).
Figure USRE049594-20230801-C00440
(S)-tert-butyl-3-amino-5-(2-oxopiperidin-1-yl)pentanoate: To a stirred EtOAc (5 mL) sol. of (S)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-5-(2-oxopiperidin-1-yl)pentanoate (25 mg, 0.062 mmol, 1.00 equiv.) under nitrogen was added Pd/C 10% (50 mg). System was purged 3× with H2 then hydrogenated (balloon) 4 hrs. Mixture was filtered over Celite® (under a nitrogen stream), cake washed 4×10 mL EtOAc, all filtrates pooled, solvent evaporated. Residue dried under high vacuum overnight to give the title compound, 6.8 mg (41%) as a glassy solid. Crude material was used as such for next transformation.
Figure USRE049594-20230801-C00441
(S)-tert-butyl-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2-oxopiperidin-1-yl)pentanoate: To a stirred DMF (1 mL) sol. of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-H-pyrazole-3-carboxylic acid (9.4 mg, 0.029 mmol, 1.20 equiv.) under nitrogen was added HATU (11 mg, 0.030 mmol, 1.25 equiv.), HOAt (4 mg, 0.030 mmol, 1.25 equiv.) and DIPEA (17 μL, 0.096 mmol, 4.00 equiv.). Yellow sol. was stirred 5 min. then (S)-tert-butyl 3-amino-5-(2-oxopiperidin-1-yl)pentanoate (6.8 mg, 0.024 mmol, 1.00 equiv.) was added. Sol. was stirred 3 hrs at RT, diluted with EtOAc (20 ml), washed 4×10 ml sat. aq. NaHCO3, 10 ml sat. aq. NaCl, dried (MgSO4), filtered, filtrate evaporated. Residue was purified CombiFlash®, 4 g column, isocratic DCM 1 min. then to 5% MeOH/DCM in 12 min. Purest fractions were pooled, solvent evaporated, residue dried overnight under high vacuum to give the title compound, 9.4 mg (68%) amorphous solid. m/z (M+H)+=577.4; RT=1.90 min; purity: 98%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 9H), 2.20-1.65 (m, 12H), 2.40-2.28 (m, 2H), 2.70-2.58 (m, 2H), 3.46-3.17 (m, 3H), 3.77-3.47 (m, 1H), 1.60-1.48 (m, 2H), 4.22-4.10 (m, 1H), 4.43-4.34 (m, 1H), 6.74 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.66-7.56 (m, 2H), 7.80 (dd, J=7.9, 1.0 Hz, 1H).
Figure USRE049594-20230801-C00442
(S)-tert-butyl-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,5-dimethyl-1H-pyrazol-1-yl)pentanoate: (S)-tert-butyl-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2-oxopiperidin-1-yl)pentanoate (9.0 mg, 0.016 mmol, 1.00 equiv.) was dissolved in 4N HCl/dioxane (2 mL) solution and stirred at RT 3 hrs. Solvent was evaporated, residue dried under high vacuum. Residue was purified CombiFlash®, 12 g C18 column, 1 min. isocratic aq. 10 mM ammonium bicarbonate then to 50% acetonitrile/aq. 10 mM ammonium bicarbonate in 12 min. Purest fractions were pooled, acetonitrile evaporated, remaining aq. sol. was frozen and lyophilized to give the title compound, 8.0 mg (96%). m/z (M+H)+=521.3; RT=1.55 min; purity: 96%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.53-1.46 (m, 2H), 2.03-1.60 (m, 10H), 2.19-2.13 (m, 2H), 2.63-2.46 (m, 4H), 3.75-3.15 (m, 4H), 4.30-4.15 (m, 2H), 6.62 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.4 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.98-7.90 (m, broad, 1H), 12.40-12.00 (s, broad, 1H).
Figure USRE049594-20230801-C00443
(S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(2,6-dioxopiperidin-1-yl)pentanoate
Figure USRE049594-20230801-C00444
A solution of ADDP (41 mg, 0.16 mmol, 1.3 equiv.) in THF (0.6 mL) was added to a solution of (S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-hydroxypentanoate (40 mg, 0.12 mmol, 1.0 equiv.), glutarimide (14 mg, 0.12 mmol, 1.0 equiv.), diisopropylethylamine (24 μL, 0.14 mmol, 1.1 equiv.) and tributylphosphine (40 μL, 0.16 mmol, 1.3 equiv.) in THF (0.64 mL). The reaction mixture was stirred at rt for 16 h and was filtered in a pipette with a cotton wool. Water was added to the filtrate and the mixture was extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (30 to 60%) to provide 34 mg (66%) of the title compound as a pale yellow oil. m/z (M+H)+=419.3; RT=1.62 min; purity=>90%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.35 (d, J=8.5 Hz, 1H), 5.15-5.03 (m, 2H), 3.95-3.79 (m, 3H), 2.66-2.57 (m, 4H), 2.51-2.44 (m, 2H), 1.96-1.87 (m, 2H), 1.83-1.71 (m, 2H), 1.43 (s, 9H).
(S)-tert-butyl 3-amino-5-(2,6-dioxopiperidin-1-yl)pentanoate
Figure USRE049594-20230801-C00445
10% Pd/C (10 mg) was added to a nitrogen purged flask containing a solution of (S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(2,6-dioxopiperidin-1-yl)pentanoate (34 mg, 0.081 mmol, 1.00 equiv.) in EtOH (0.27 mL). The flask was put under vacuum for 30 sec and put back under nitrogen. This procedure was done another time. The flask was put back again under vacuum and a balloon of hydrogen was inserted through the septum. The reaction was vigorously stirred for 18 h. The flask was put under vacuum for 30 sec and put back under nitrogen. This procedure was done two other times. The solution was filtered on Celite®, the solid cake was washed with EtOH and the filtrate was evaporated. The obtained product (23 mg) was resubmitted to the above reaction, using ethyl acetate as the solvent this time, to provide 7.5 mg (32%) of the title compound as a colorless oil. m/z (M+H)+=285.3; RT=1.08 min; purity=77.8%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
(S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2,6-dioxopiperidin-1-yl)pentanoate
Figure USRE049594-20230801-C00446
HATU (7.1 mg, 0.019 mmol, 1.1 equiv.) was added to a solution of 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (5.5 mg, 0.017 mmol, 1.0 equiv.), HOAt (2.3 mg, 0.017 mmol, 1.0 equiv.) and diisopropylethylamine (8.9 μL, 0.051 mmol, 3.0 equiv.) and (S)-tert-butyl 3-amino-5-(2,6-dioxopiperidin-1-yl)pentanoate (7.5 mg, 0.017 mmol, 1.0 equiv.) in DMF (0.17 mL) at 0° C. The reaction mixture was stirred at rt for 18 h. The mixture was dissolved in ethyl acetate and was washed with a saturated aqueous solution of sodium bicarbonate, dried with sodium sulfate, filtered and evaporated to provide 6.5 mg (65%, crude) of the title compound which was used as is. m/z (M+H)+=591.3; RT=1.93 min; purity=hard to say. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.
(S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2,6-dioxopiperidin-1-yl)pentanoic acid
Figure USRE049594-20230801-C00447
A 4M solution of HCl in dioxane (0.28 mL, 1.1 mmol, 100 equiv.) was added to crude (S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2,6-dioxopiperidin-1-yl)pentanoate (6.5 mg, 0.011 mmol, 1.00 equiv.). The reaction mixture was stirred at rt for 18 h and the solvent was evaporated. The crude product was purified by semi-prep HPLC-MS (column X-Bridge 30×50) using a solution of MeCN in water (containing 10 mM of ammonium formate, pH=3.8) (40 to 60%). Pure fractions were lyophilized to provide 0.65 mg (11%) of the title compound as a white solid. m/z (M+H)+=535.3; RT=1.60 min; purity=>99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, CD3CN) δ 7.88 (d, J=7.3 Hz, 1H), 7.74 (t, J=7.1 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 6.64 (s, 1H), 4.32-4.22 (m, 2H), 3.80-3.71 (m, 2H), 2.68-2.61 (m, 1H), 2.61-2.51 (m, 1H), 2.54 (t, J=6.7 Hz, 4H), 2.10-2.05 (m, 2H), 1.96-1.92 (m, 2H), 1.88-1.77 (m, 6H), 1.59-1.51 (m, 2H).
Figure USRE049594-20230801-C00448
Figure USRE049594-20230801-C00449
Figure USRE049594-20230801-C00450
(3S)-tert-butyl-3-(benzyl((S)-1-phenylethyl)amino)-5-(benzyloxy)-2-methylpentanoate: To a stirred THF (10 mL) sol. of freshly distilled (over CaH2) diisopropylamine (651 μL, 4.64 mmol, 2.20 equiv.) at −78° C. under nitrogen was added drop-wise n-BuLi 2.46 M/Hexane (1.80 mL, 4.43 mmol, 2.10 equiv.). Resulting sol. was stirred 1 hr at −78° C., (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-(benzyloxy)pentanoate (1.00 g, 2.11 mmol, 1.00 equiv.) dissolved in THF (2 mL) was added drop-wise, sol. was stirred 2 hrs at −78° C. Iodomethane (525 μL, 8.44 mmol, 4.00 equiv.) was added drop-wise, sol. stirred 4 hrs at −78° C., stirring was continued overnight, temperature rose to c.a. −10° C. during this period. Reaction was quenched by the addition of 1 ml sat. aq. NH4Cl, stirred 15 min, THF was evaporated, residue parted between sat. aq. NaHCO3 (50 ml) and EtOAc (50 ml). Organic layer was washed 50 ml sat. aq. NaHCO3, 50 mL sat. aq. NaCl, dried (MgSO4), filtered, filtrate evaporated, residue dried under high vacuum to give the title compound, 953 mg (92%) thick amber oil. m/z (M+H)+=488.3; RT=2.44 min; purity: 93%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO, mixture of conformers/rotamers) δ 7.40-7.15 (m, 15H), 4.47-4.36 (m, 2H), 3.95-3.63 (m, 3H), 3.55-3.35 (m, 2H), 3.27-3.22 (m, 0.5H), 2.88-2.83 (m, 0.5H), 2.36-2.25 (m, 1H), 1.88-1.75 (m, 1H), 1.70-1.60 (m, 1H), 1.31; 1.32 (2s, 9H), 1.25-1.20 (m, 3H), 0.82-0.76 (m, 3H).
Figure USRE049594-20230801-C00451
(3S)-tert-butyl-3-amino-5-hydroxy-2-methylpentanoate: In a Parr shaker reactor (3S)-tert-butyl-3-(benzyl((S)-1-phenylethyl)amino)-5-(benzyloxy)-2-methylpentanoate (950 mg, 1.95 mmol, 1.00 equiv.) was dissolved in 20% AcOH/Ethanol (50 ml). Vessel was purged with nitrogen then Pd/C 10% (600 mg) was added. System was evacuated (house vacuum), filled with hydrogen (45 psi), shaken 5 min. System was purged a second time then put under hydrogen pressure (50 psi) and shaken for 30 hrs. System was purged 2×nitrogen, mixture was filtered through a Celite® cake, washed 4×10 ml ethanol, filterate and washings were pooled and evaporated (rotavapor, high vacuum) to give the title compound, 403 mg, which was used as such for the next transformation.
Figure USRE049594-20230801-C00452
(3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxy-2-methylpentanoate: 1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid (159 mg, 0.49 mmol) was gently refluxed in thionyl chloride (4 mL) under nitrogen for 4 hrs. Volatiles were evaporated, residue re-dissolved in 4 mL dioxane, solvent evaporated, solid dried under high vacuum 1 hr. This solid was dissolved in THF, DIPEA (257 μL, 1.48 mmol, 3.00 equiv.) was added drop-wise followed by (3S)-tert-butyl 3-amino-5-hydroxy-2-methylpentanoate (100 mg, 0.49 mmol) dissolved-suspended in THF (1 mL). Resulting sol. turned to white suspension shortly after addition. Stirred under nitrogen 2 hrs, diluted with EtOAc (40 ml), washed 3×20 ml sat. aq. NaHCO3, 20 ml sat. aq. NaCl, dried (MgSO4), filtered, filtrate evaporated. Product purified CombiFlash®, dry-pack, 10 g column, 20% EtOAc isocratic 2 min. then to 50% EtOAc/Hex. in 6 min, isocratic 2 min. Purest fractions were pooled, solvent evaporated, residue dried under high vacuum to give the title compound, 83 mg (33%) as an amorphous solid. m/z (M+H)+=510.4; RT=1.96 min; purity: 99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. 1H NMR (500 MHz, DMSO) δ 1.09-1.02 (m, 3H), 1.38 (s, 1H), broad (9H), 1.42 (s, 1H), 1.58-1.46 (m, 2H), 1.73-1.63 (m, 2H), 2.05-1.75 (m, 6H), 2.73-2.60 (m, 1H), 3.48-3.36 (m, 2H), 4.25-4.10 (m, 2H), 4.50-4.44 (m, 2H), 6.63 (d, J=6.2 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.3 Hz, 1H), 7.82 (t, J=7.3 Hz, 1H), 7.82 (t, J=7.3 Hz, 1H).
Figure USRE049594-20230801-C00453
(3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-2-methyl-5-oxopentanoate: To a stirred, ice cold DCM (2 mL) sol. of (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxy-2-methylpentanoate (80 mg, 0.157 mmol) under nitrogen was added Dess-Martin periodinane (100 mg, 0.236 mmol, 1.5 equiv.). The white suspension was stirred 15 min. in the cold, allowed to warm to RT and stirred overnight. Mixture was diluted with EtOAc (40 mL) washed 4×25 ml sat. aq. NaHCO3, 25 ml sat. aq. NaCl, dried (MgSO4), filtered, filtrate was evaporated, residue dried under high vacuum 1 hr. Crude material was used as such for next transformation.
Figure USRE049594-20230801-C00454
(3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoate (A and B)
To a stirred methanol (2 mL) sol. of 3,3-difluoropyrollidine hydrochloride (42 mg, 0.268 mmol, 1.00 equiv.) under nitrogen was added triethylamine (50 μL, 0.358 mmol, 3.00 equiv.). Sol. was stirred 15 min. then (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-2-methyl-5-oxopentanoate (60 mg, 0.118 mmol, 1.00 equiv.) in 1 mL methanol was added. Sol. was stirred at RT 1 h then sodium triacetoxyborohydride (45 mg, 0.215 mmol, 1.80 equiv.) was added. Solution was stirred a further 3 hrs, solvent was evaporated, residue taken in ethyl acetate (30 mL), washed 3×20 mL sat. aq. NaHCO3, 20 mL sat. aq. NaCl, dried (MgSO4), filtered, filtrate evaporated. Residue purified CombiFlash®, 12 g column, DCM isocratic 3 min. then to 1% MeOH/DCM in 6 min. isocratic 5 min. Two products were separated;
(3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoate A (less polar diastereomer), 17.6 mg (24%) amorphous solid [49% based on a 1:1 mixture of diastereoisomers].
m/z (M+H)+=614.5; RT=2.12 min; purity: 95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: CH3CN. 1H NMR (500 MHz, CDCl3) δ 1.21 (d, J=7.1 Hz, 3H), 1.48 (s, 9H), 1.58-1.49 (m, 2H), 2.20-1.61 (m, 12H), 2.79-2.37 (m, 7H), 4.16 (p, J=7.6 Hz, 1H), 4.35-4.26 (m, 1H), 6.75 (s, 1H), 7.28 (d, broad, J=9.8 Hz, 1H), 7.32 (d, broad, J=7.1 Hz, 1H), 7.65-7.56 (m, 2H), 7.80 (dd, J=7.8, 1.0 Hz, 1H).
(3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoate B (more polar diastereomer), 23.5 mg (33%) amorphous solid [65% based on a 1:1 mixture of diastereoisomers].
m/z (M+H)+=614.5; RT=2.12 min; purity: 93%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: CH3CN. 1H NMR (500 MHz, CDCl3) δ 1.22 (d, J=6.1 Hz, 3H), 1.48 (s, 9H), 1.55-1.50 (m, 2H), 2.17-1.70 (m, 12H), 2.74-2.37 (m, 7H), 4.21-4.12 (m, 1H), 4.32-4.23 (m, 1H), 6.74 (s, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.56-7.45 (m, 1H), 7.65-7.57 (m, 2H), 7.80 (d, J=7.2 Hz, 1H).
Figure USRE049594-20230801-C00455
(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoic acid (Acid 1): (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoate A (16 mg, 0.026 mmol, 1.00 equiv.) was dissolved in 4NHCl/dioxane solution (4 mL). Stirred at RT 4 hrs, volatiles were evaporated, residue purified CombiFlash®, 12 g Biotage KP-C18-HS column, aq. 10 mM ammonium bicarbonate isocratic 1 min., to 50% acetonitrile in 5 min., isocratic 3 min. Purest fractions were pooled, most acetonitrile was evaporated, remaining solution was frozen and lyophilized to give the title compound, 7.5 mg (52%) white solid. m/z (M+H)+=557.3; RT=1.54 min; purity: 98%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: CH3CN. 1H NMR (500 MHz, DMSO) δ 1.06 (d, J=7.0 Hz, 3H), 1.56-1.45 (m, 2H), 1.73-1.57 (m, 4H), 2.05-1.75 (m, 8H), 2.44-2.30 (m, 4H), 2.65-2.55 (m, 3H), 4.23-4.09 (m, 2H), 6.63 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.4 Hz, 1H), 7.88-7.79 (s, broad, 1H), 7.93 (d, J=7.4 Hz, 1H), 11.70 (s, broad, 1H).
Figure USRE049594-20230801-C00456
(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoic acid (Acid 2): (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoate B (22 mg, 0.036 mmol, 1.00 equiv.) was dissolved in 4N HCl/dioxane solution (4 mL). Stirred at RT 4 hrs, volatiles were evaporated, residue purified CombiFlash®, 12 g Biotage KP-C18-HS column, aq. 10 mM ammonium bicarbonate isocratic 1 min., to 40% acetonitrile in 5 min., isocratic 4 min. Purest fractions were pooled, most acetonitrile was evaporated, remaining solution was frozen and lyophilized to give the title compound, 14.6 mg (73%) white solid. m/z (M+H)+=557.2; RT=1.56 min; purity: >99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: CH3CN. 1H NMR (500 MHz, DMSO) δ 13.20-11.80 (s, broad, 1H), 1.09 (d, J=7.1 Hz, 3H), 1.56-1.45 (m, 2H), 1.75-1.58 (m, 4H), 2.00-1.75 (m, 8H), 2.45-2.32 (m, 4H), 2.73-2.55 (m, 3H), 4.15-4.05 (m, 1H), 4.20 (p, J=7.2 Hz, 1H), 6.62 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.4 Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 8.13-7.92 (s, broad, 1H)
Figure USRE049594-20230801-C00457
Figure USRE049594-20230801-C00458
Figure USRE049594-20230801-C00459
(3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxyhexanoate: To a solution of (S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxopentanoate (230 mg, 0.466 mmol) in THF (10 mL) at −78° C. was slowly added a solution of CH3MgBr (0.31 mL, 0.93 mmol, 3.0 M in Et2O). The mixture was allowed to stir at −78° C. for 30 min. Then the solution was warmed to rt and stirring for 4 h. The reaction was quenched with water (2 mL). Then the solution was extracted with Et2O (3×15 mL), the combined organic layers were dried over MgSO4, concentrated in vacuo and purified by chromatography over silica gel, eluting with 0-40% EtOAc/Hexanes to give known (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxyhexanoate, yield 85% colorless oil. 1H NMR (300 MHz, CDCl3) δ1.23-1.29 (m, 3H), 1.39-1.61 (m, 11H), 1.80-2.16 (m, 8H), 2.58-2.74 (m, 2H), 3.91-4.05 (m, 1H), 4.08-4.25 (m, 1H), 4.43-4.68 (m, 1H), 6.73-6.79 (m, 1H), 7.29-7.37 (m, 1H), 7.49-7.70 (m, 3H), 7.76-7.87 (m, 1H). LC-MS (ESI): m/z [M+H+] 510.5.
Figure USRE049594-20230801-C00460
(S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxohexanoate: To a solution of crude (3S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxyhexanoate (100 mg 0.196 mmol) in DCM (6 mL) was added sodium bicarbonate (33 mg, 0.39 mmol) followed by Dess Martins reagent (166 mg, 0.39 mmol). The mixture was allowed to stir for overnight before the reaction was quenched with 10% aqueous sodium bicarbonate (2 mL). Then the solution was extracted with Et2O (3×15 mL), the combined organic layers were dried over MgSO4, concentrated in vacuo and purified by chromatography over silica gel, eluting with 0-40% EtOAc/Hexanes to give known ketone (S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxohexanoate, yield 85% colorless oil. 1H NMR (300 MHz, CDCl3) δ1.45 (s, 9H), 1.78-2.04 (m, 8H), 1.50-1.61 (m, 2H), 2.20 (s, 3H), 2.66-2.76 (m, 2H), 2.90-3.10 (m, 2H), 4.08-4.23 (m, 1H), 4.65-4.82 (m, 1H), 6.74 (s, 1H), 7.28-7.36 (m, 1H), 7.51-7.67 (m, 3H), 7.76-7.84 (m, 1H). LC-MS (ESI): m/z [M+H+] 508.5.
Figure USRE049594-20230801-C00461
(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (A and B): A solution of the ketone (S)-tert-butyl 3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxohexanoate (75 mg, 0.147 mmol), 3,3 difluoro piperidine hydrochloride (28 mg, 0.177 mmol), crushed 4 A molecular sieves in dichloroethane (10 mL) was treated with sodium triacetoxyborohydride (63 mg 0.294 mmol) and the resulting mixture was stirred at ambient temperature overnight. The sieves were filtered off through a plug of Celite®, the filtrate was washed with a saturated solution of sodium bicarbonate, water and brine. The combined aqueous solutions were back extracted with dichloromethane, the combined organic extracts were dried with anhydrous sodium sulfate, and the solvent was evaporated in vacuo and purified by chromatography over silica gel, eluting with 0-35% EtOAc/Hexanes to give the two diastereoisomers (A and B).
(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (A, less polar diastereomer), yield 20 mg (30%) colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.02 (d, J=6.59 Hz, 3H), 1.47 (s., 9H), 1.50-1.61 (m, 2H), 1.69-2.05 (m, 12H), 2.31-2.46 (m, 1H), 2.55-2.71 (m, 4H), 2.72-2.92 (m, 2H), 4.10-4.23 (m, 1H), 4.45-4.60 (m, 1H), 6.75 (s, 1H), 7.30-7.43 (m, 1H), 7.56-7.67 (m, 3H), 7.77-7.83 (m, 1H). LC-MS (ESI): m/z [M+H+] 613.7.
(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (B, more polar diastereomer), yield 6.5 mg (10%) colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=6.59 Hz, 3H), 1.45 (s, 9H), 1.50-1.61 (m, 2H), 1.67-2.18 (m, 12H), 2.31-2.46 (m, 1H), 2.61-2.95 (m, 6H), 4.04-4.22 (m, 1H), 4.44-4.58 (m, 1H), 6.75 (s, 1H), 7.28-7.35 (m, 1H), 7.51-7.68 (m, 3H), 7.77-7.84 (m, 1H). LC-MS (ESI): m/z [M+H+] 613.8.
Figure USRE049594-20230801-C00462
(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (Acid 1): To a solution of (3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (A)(20 mg) in DCM:TFA (1:1, 1 mL) and stirred at rt for 2 h. Solvent was removed in vacuo and diluted with CHCl3. Solvent was removed to provide 90% (3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (Acid 1) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.40-1.56 (m, 6H), 1.77-2.21 (m, 12H), 2.43-2.63 (m, 1H), 2.70-2.81 (m, 2H), 3.2-3.93 (m, 4H), 4.07-4.24 (m, 1H), 4.45-4.65 (m, 1H), 6.74 (s, 1H), 7.37-7.28 (m, 1H), 7.62 (t, J=6.40 Hz, 2H), 7.81 (d, J=8.48 Hz, 1H), 7.85-7.98 (m, 1H). LC-MS (ESI): m/z[M+H+] 557.9, [M−H+] 556.0.
Figure USRE049594-20230801-C00463
(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (Acid 2): To a solution of (3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (B)(6 mg) in DCM:TFA (1:1, 1 mL) and stirred at rt for 2 h. Solvent was removed in vacuo and diluted with CH2Cl2. Solvent was removed to provide 90% of (3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid (Acid 2) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.32-1.58 (m, 6H), 1.78-2.43 (m, 12H), 2.80-2.95 (m, 2H), 3.04-3.61 (m, 4H), 4.16 (d, J=6.97 Hz, 1H), 4.25-4.44 (m, 1H), 6.74 (br. s., 1H), 7.28-7.37 (m, 1H), 7.63 (t, J=6.12 Hz, 2H), 7.81 (d, J=7.91 Hz, 1H), 8.02-8.23 (m, 1H). LC-MS (ESI): m/z [M+H+] 557.9, [M−H+] 556.1.
Figure USRE049594-20230801-C00464
Figure USRE049594-20230801-C00465
Ethyl 1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate: To a solution of 85 (0.90 g, 4.0 mmol) in Et2O (40 ml) at −78° C. was added dropwise of nBuLi (1.9 ml, 2.5 M in hexanes, 4.8 mmol). After addition the mixture was stirred at −78° C. for 1 h, followed by dropwise addition of Bu3SnCl (1.20 ml, 4.4 mmol). Stirring was continued at this temperature for 1 h and then slowly warmed to rt. The solution was quenched with ammonium chloride (sat., 20 ml) and extracted with hexanes (20 ml). The extract was dried (Na2SO4) and concentrated. The concentrate was triturated with hexanes, filtered and concentrated to give a brown oil (1.51 g).
To a mixture of the above oil (0.79 g), bromopyrazole (0.43 g, 1.5 mmol) and toluene (15 ml) in a sealed tube was added Pd(PPh3)2Cl2 (53 mg, 0.075 mmol) under N2. The mixture was heated at 120° C. for 40 h. Then it was concentrated and purified using EA in hexanes to give the desired product 86 (50 mg) as a yellow oil; 1H NMR (200 MHz, CDCl3): δ=1.39 (t, 3H, J=7.4 Hz), 1.40-1.70 (m, 2H), 1.80-2.30 (m, 6H), 4.30-4.50 (m, 3H), 6.91 (s, 1H), 7.40-7.60 (m, 1H), 8.17 (d, 1H, J=8.0 Hz), 8.93 (d, 1H, J=4.6 Hz); LC-MS (ESI): m/z calculated for C17H20F3N3O2[M+H+]: 354, Found: 354.0.
1-Cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid: To a solution of ethyl 1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate (50 mg, 0.141 mmol) in THF (5 ml) and H2O (1 ml) was added LiOH (10 mg). The mixture was stirred at rt for 20 h, acidified to PH 4, and extracted with EtOAc. The EtOAc extract was dried (Na2SO4), concentrated and purified (if necessary) to give title compound (45 mg) as a brown solid; 1H NMR (200 MHz, CDCl3): δ=1.40-1.70 (m, 2H), 1.80-2.30 (m, 6H), 4.40-4.60 (m, 1H), 6.99 (s, 1H), 7.50-7.60 (m, 1H), 8.17 (d, 1H, J=8.0 Hz), 8.93 (d, 1H, J=4.4 Hz); LC-MS (ESI): m/z calculated for C15H16F3N3O2[M+H+]: 326, Found: 325.9.
(S)-Tert-butyl 3-(1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate: A mixture of 1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (42 mg, 0.15 mmol), (S)-tert-butyl 3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate (67 mg, 0.23 mmol), Et3N (0.060 ml, 0.60 mmol) and TBTU (72 mg, 0.22) in MeCN (5 ml) was stirred at rt for 15 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic layer was dried (Na2SO4), concentrated, and purified using 0-10% MeOH in DCM (with 1% NH3) to give the title compound (58 mg) as a colorless oil; 1H NMR (200 MHz, CDCl3): δ=1.40 (s, 9H), 1.50-2.20 (m, 14H), 2.30-2.80 (m, 8H), 4.30-4.60 (m, 2H), 6.61 (d, 1H, J=9.8 Hz), 6.89 (s, 1H), 7.40-7.60 (m, 1H), 8.13 (d, 1H, J=8.0 Hz), 8.91 (d, 1H, J=4.0 Hz); LC-MS (ESI): m/z calculated for C29H39F5N5O3 [M+H+]: 600, Found: 599.8.
(S)-3-(1-Cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid: To a solution of (S)-tert-butyl 3-(1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate (50 mg) in DCM (2 ml) was added HCl (4 M in dioxane, 0.1 ml). The mixture was stirred at rt for 15 h and concentrated to dryness to give the acid as the HCl salt. (40 mg). LC-MS (ESI): m/z calculated for C25H31F5N5O3[M+H+]: 544, Found: 543.7.
(S)-N-(1-(Cyclobutylamino)-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamide: A mixture of (S)-3-(1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid hydrochloride (40 mg, 0.073 mmol), cyclobutylamine (10 mg, 0.10 mmol), Et3N (0.030 ml, 0.29 mmol) and TBTU (24 mg, 0.10) in MeCN (5 ml) was stirred at rt for 15 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic layer was dried (Na2SO4), concentrated, and purified using 0-10% MeOH in DCM (with 1% NH3) to give the title product (34 mg) as a white solid; 1H NMR (200 MHz, CDCl3): δ=1.40-2.80 (m, 28H), 4.30-4.50 (m, 3H), 6.42 (d, 1H, J=8.4 Hz), 6.90 (s, 1H), 7.50-7.70 (m, 1H), 8.14 (d, 1H, J=8.2 Hz), 8.91 (d, 1H, J=4.0 Hz); LC-MS (ESI): m/z calculated for C29H38F5N6O2[M+H+]: 597, Found: 596.8; LC purity: 96.4%.
Figure USRE049594-20230801-C00466
Figure USRE049594-20230801-C00467
3-Cyclohexylpropanal To a solution of commercially available 3-cyclohexylpropanol (45.5 g, 0.32 mol) in CH2Cl2 (1000 mL) was added PCC (103.5 g, 0.48 mol), Celite® 545 (50 g) and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl ether (1000 mL), stirred at rt for 1 h, before it was filtered through Celite® and silica gel (1:1) pad. The filtrate was concentrated to give crude residue. Crude product was purified by silica gel flash chromatography (0-30% EtOAc/hexanes) to give the title compound as oil (50.7 g), which contained residual hexanes as judged by NMR analysis. 1H NMR (300 MHz, CDCl3) δ 0.83-0.98 (m, 3 H), 1.15-1.31 (m, 4 H), 1.49-1.56 (m, 2 H), 1.61-1.73 (m, 4 H), 2.41-2.46 (m, 2 H), 9.77 (s, 1 H).
Figure USRE049594-20230801-C00468
(E)-Tert-butyl 5-cyclohexylpent-2-enoate To a stirred solution of tert-butyl diethylphosphonoacetate (82.67 mL, 0.352 mol) in THF (500 mL) was slowly added n-BuLi (2.5 M in hexanes) (141 mL, 0.352 mol) dropwise with cooling at −78° C. After stirring for 30 minutes at −78° C., a solution of 3-cyclohexylpropanal (50.7 g, 0.32 mol) in 250 mL of THF also cooled at −78° C. was transferred via cannula. The resulting solution was stirred at −78° C. for 40 minutes before being allowed to warm at rt and then stirred at 40 minutes. The solution was subsequently cooled to −78° C. and quenched with sat. aqs. NH4Cl (250 mL). The layers were separated and the aqueous layer was extracted in DCM (3×200 mL) and the combined organics were dried over Na2SO4, filtered and the solvent was evaporated in vacuo to give the crude residue. Crude product was purified by silica gel flash chromatography (0-2% EtOAc/hexanes) to give the title compound as oil (59.8 g, 78%). 1H NMR (300 MHz, CDCl3) δ 0.82-0.94 (m, 3 H), 1.11-1.37 (m, 3 H), 1.48 (s, 9 H), 1.63-1.87 (m, 3 H), 2.14-2.21 (m, 2 H), 3.73-3.77 (m, 1 H), 4.12-4.22 (m, 2 H), 5.73 (dt, J=15.45, 1.51 Hz, 1H), 6.86 (m, 1 H).
Figure USRE049594-20230801-C00469
(S)-Tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-cyclohexylpentanoate: To a stirred solution of (S)-N-benzyl-N-α-methylbenzylamine (84.86 g, 0.402 mol) in THF (312 mL) was slowly added n-BuLi (2.5 M in hexanes) (161 mL, 0.402 mol) with cooling at −78° C. After 30 minutes, a solution of (E)-tert-butyl 5-cyclohexylpent-2-enoate (59.81 g, 0.251 mol) in 100 mL of THF also at −78° C. was transferred via cannula. The resulting solution was stirred at −78° C. for 3 h before quenching with sat. aqs. NH4Cl (200 mL). Upon warming to rt, THF was removed and the aqueous layer was extracted in DCM (3×200 mL). The combined organic layers were washed with 10% aqs. citric acid (3×50 mL) to remove the excess amine. The organic layer was then washed with aqs. NaHCO3 (50 mL), brine (50 mL), dried with Na2SO4 and the solvent was removed in vacuo to give the crude product. Crude product was purified by silica gel flash chromatography (0-2% EtOAc/hexanes) to give the title compound as oil (97.3 g, 86%). 1H NMR (300 MHz, CDCl3) δ 0.80-0.90 (m, 4 H), 1.04-1.33 (m, 9 H), 1.39 (m, 9 H), 1.60-1.74 (m, 4 H), 1.82-1.99 (m, 2 H), 3.21-3.29 (m, 1 H), 3.47 (d, J=14.69 Hz, 1H), 3.76-3.84 (m, 2 H), 7.20-7.43 (m, 10 H)
Figure USRE049594-20230801-C00470
(S)-Tert-butyl 3-amino-5-cyclohexylpentanoate
A mixture of (S)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-5-cyclohexylpentanoate (50 g, 0.111 mol) and 10% Pd/C (7.44 g) in 20% AcOH/EtOH (500 mL) was hydrogenated at 45 psi for 24 h. The mixture was filtered through Celite® pad and concentrated. The residue was dissolved in DCM (500 mL), basified with sat. sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM (3×200 mL). The combined DCM extracts were dried with Na2SO4, filtered and solvent was removed in vacuo to obtain crude product (28.3 g, 100%) as clear oil. 1H NMR (300 MHz, CDCl3) δ 0.85-0.95 (m, 3 H), 1.11-1.27 (m, 6 H), 1.46 (s, 9 H), 1.62-1.75 (m, 6 H), 2.128-2.22 (m, 1 H), 2.34-2.40 (m, 1 H), 3.05-3.14 (m, 1 H)
Figure USRE049594-20230801-C00471
Figure USRE049594-20230801-C00472
(S)-Tert-butyl 5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoate
1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid (100 mg, 0.316 mmol) was dissolved in THF (5 mL). To the solution was added benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (184 mg, 0.416 mmol) and triethylamine (0.130 mL, 0.948 mmol). The resulting mixture was stirred at room temperature for 15 minutes. tert-butyl (S)-3-amino-5-cyclohexylpentanoate (89 mg, 0.347 mmol) in 0.4 mL of THF was added dropwise, and stirred at room temperature for 3 h. THF was evaporated in vacuo, water was added to the residue and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with water, brine and then dried with Na2SO4, followed by filtration. The solvent was evaporated in vacuo. The residue was purified by silica gel flash chromatography (EtOAc:Hex) to give the title compound as oil (152 mg, 87%). 1H NMR (CDCl3, 300 MHz) δ 0.81-0.96 (m, 2 H), 1.10-1.38 (m, 8 H), 1.48 (s, 9 H), 1.59-1.77 (m, 8 H), 1.81-1.96 (m, 4 H), 2.00-2.16 (m, 2 H), 2.55 (d, J=5.46 Hz, 2 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.21-4.30 (m, 1 H), 4.30-4.43 (m, 1H), 6.62 (d, J=8.48 Hz, 2 H), 6.67 (s, 1 H), 7.25 (br. s., 1 H),7.37 (t, J=8.38 Hz, 1 H). MS m/z: Calcd. for C32H47N3O5 553.73 [M]+, found 555.0 [M+H]+.
Figure USRE049594-20230801-C00473
(S)-5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoic acid
To a solution of (S)-tert-butyl 5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoate (150 mg) in DCM (2 ml) was added HCl (4 M in dioxane, 0.7 ml). The mixture was stirred at rt for 15 h and concentrated to dryness to give the acid as the HCl salt (120 mg). 1H NMR (CDCl3, 300 MHz) δ ppm 0.78-1.00 (m, 3 H), 1.09-1.40 (m, 6 H), 1.49-1.77 (m, 4 H), 1.71 (t, J=7.44 Hz, 4 H), 1.82-1.98 (m, 4 H), 1.99-2.13 (m, 2 H), 2.65-2.80 (m, 2 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.21-4.33 (m, 2 H), 6.63 (d, J=8.48 Hz, 2 H), 6.68 (s, 1 H), 7.29 (s, 1 H), 7.38 (t, J=8.38 Hz, 1 H). MS (ESI) m/z: Calcd. for C28H39N3O5 497.63 [M]+, found 496.7[M−H]−.
Figure USRE049594-20230801-C00474
(S)-N-(1-(cyclobutylamino)-5-cyclohexyl-1-oxopentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide
(S)-5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoic acid (97 mg, 0.195 mmol) was dissolved in THF (5 mL). To the solution was added benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (95 mg, 0.214 mmol) and triethylamine (0.080 mL, 0.585 mmol). The resulting mixture was stirred at room temperature for 15 minutes. Cyclobutylamine (33 mg, 0.389 mmol) in 0.4 mL of THF was added dropwise, and stirred at room temperature for 3 h. THF was evaporated in vacuo, water was added to the residue and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with water, brine and then dried with Na2SO4, followed by filtration. The solvent was evaporated in vacuo. The residue was purified by silica gel flash chromatography (EtOAc:Hex) to give the title compound as white solid (80 mg, 75%). 1H NMR (CDCl3, 300 MHz) δ ppm 0.88 (d, J=11.30 Hz, 2 H), 1.12-1.39 (m, 6 H), 1.60-1.77 (m, 9 H), 1.80-1.97 (m, 6 H), 2.00-2.13 (m, 2 H), 2.18-2.32 (m, 2 H), 2.24 (d, J=7.16 Hz, 2 H), 2.53 (d, J=6.40 Hz, 2 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 4.15-4.46 (m, 3 H), 6.63 (d, J=8.29 Hz, 2 H), 6.67 (s, 1 H), 6.75 (d, J=8.29 Hz, 1 H), 7.06 (d, J=9.04 Hz, 1 H), 7.38 (t, J=8.38 Hz, 1 H). MS (ESI) m/z: Calcd. for C32H46N4O4 550.73 [M]+, found 551.6 [M+H].
Characterization of the Apelin Agonist Activity of the Compounds
The compounds above were studied for their in vitro activity as apelin agonists using the methods described by Giddings et al. Giddings et al., 2010 Int J High Thro Screen. 1:39-47, the contents of which are hereby incorporated by reference in its entirety. Using the methods described in Giddings et al. and Apelin-13 as a positive control.
TABLE 2
ID# IUPAC Name EC50 (nM) Ave
253 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 382 nM
yl]formamido}-5-(piperidin-1-yl)pentanamide
296 (3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol- 83
3-yl]formamido}-5-phenylpentanamide
297 (3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-3- >10000
yl]formamido}-4-phenylbutanoic acid
298 (3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3- 589
yl]formamido}pentanoic acid
299 (3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3- 2906
yl]formamido}-5-phenylpentanoic acid
300 (3R)-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-3- >10000
yl]formamido}-3-phenylpropanoic acid
301 (3S)-6-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol- 2593
3-yl]formamido}hexanoic acid
302 (2S)-N-cyclobutyl-2-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol- >10000
3-yl]formamido}-3-phenylpropanamide
303 tert-butyl (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-(morpholin-4-yl)pentanoate
304 tert-butyl (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-(4-methylpiperazin-1-yl)pentanoate
305 tert-butyl (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-(diethylamino)pentanoate
306 tert-butyl (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-[(pyridin-4-ylmethyl)amino]pentanoate
307 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 6010
(morpholin-4-yl)pentanoic acid
308 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000
(4-methylpiperazin-1-yl)pentanoic acid
309 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000
(diethylamino)pentanoic acid
310 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000
[(pyridin-4-ylmethyl)amino]pentanoic acid
311 (2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-3- >10000
yl]formamido}-4-phenylbutanoic acid
312 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 343
yl]formamido}-5-(morpholin-4-yl)pentanamide
313 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-(4-methylpiperazin-1-yl)pentanamide
314 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 1845
yl]formamido}-5-(diethylamino)pentanamide
315 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(4S)-2-oxo-1-(pyridin-4- >10000
ylmethyl)piperidin-4-yl]-1H-pyrazole-3-carboxamide
316 tert-butyl (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-(pyrrolidin-1-yl)pentanoate
317 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 9350
(pyrrolidin-1-yl)pentanoic acid hydrochloride
318 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 996
yl]formamido}-5-(pyrrolidin-1-yl)pentanamide
319 tert-butyl (3S)-5-(azepan-1-yl)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H- 3510
pyrazol-3-yl]formamido}pentanoate
320 tert-butyl (3S)-5-{7-azabicyclo[2.2.1]heptan-7-yl}-3-{[1-cyclopentyl-5-(2,6- >10000
dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanoate
321 (3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol- 114
3-yl]formamido}-4-phenylbutanamide
322 (3S)-5-(azepan-1-yl)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 1441
yl]formamido}pentanoic acid
323 (3S)-5-{7-azabicyclo[2.2.1]heptan-7-yl}-3-{[1-cyclopentyl-5-(2,6- >10000
dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanoic acid
324 (3S)-5-(azepan-1-yl)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)- 107
1H-pyrazol-3-yl]formamido}pentanamide
325 (3S)-5-{7-azabicyclo[2.2.1]heptan-7-yl}-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6- 3578
dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanamide
326 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 1041
(1-methylcyclobutyl)-5-(piperidin-1-yl)pentanamide
327 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 675
(3-methyloxetan-3-yl)-5-(piperidin-1-yl)pentanamide
328 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- ia
(1-methylcyclopropyl)-5-(piperidin-1-yl)pentanamide
329 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 170
yl]formamido}-5-(2,6-dimethylpiperidin-1-yl)pentanamide
330 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 5165
(2,6-dimethylpiperidin-1-yl)pentanoic acid
331 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 353
yl]formamido}-N-methyl-5-(piperidin-1-yl)pentanamide
332 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 391
(oxan-4-yl)-5-(piperidin-1-yl)pentanamide
333 (3S)-N-tert-butyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 2533
yl]formamido}-5-(piperidin-1-yl)pentanamide
334 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 6574
(2-methoxyethyl)-N-methyl-5-(piperidin-1-yl)pentanamide
335 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 63
yl]formamido}-5-(4,4-difluoropiperidin-1-yl)pentanamide
336 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 4738
(2-methoxyethyl)-5-(piperidin-1-yl)pentanamide
337 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(3S)-1-{2-oxa-6-azaspiro[3.3]heptan- >10000
6-yl}-1-oxo-5-(piperidin-1-yl)pentan-3-yl]-1H-pyrazole-3-carboxamide
338 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 12
(piperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
339 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 31
(1,3-oxazol-2-yl)-5-(piperidin-1-yl)pentanamide
340 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 543
(1,3-oxazol-2-ylmethyl)-5-(piperidin-1-yl)pentanamide
341 cyclobutyl (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 997
yl]formamido}-5-(piperidin-1-yl)pentanoate
342 (3S)-3-(1-{5-[2,6-bis(2,2,2-trifluoroethoxy)phenyl]-1-cyclopentyl-1H-pyrazol-3- >10000
yl}-N-ethylformamido)-N-cyclobutyl-5-(piperidin-1-yl)pentanamide
343 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-1-(5-methyl-1,3,4-oxadiazol-2- 1534
yl)-4-(piperidin-1-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
344 (3S)-N-cyclobutyl-3-(1-{1-cyclopentyl-5-[2-(trifluoromethoxy)phenyl]-1H- 2374
pyrazol-3-yl}-N-ethylformamido)-5-(piperidin-1-yl)pentanamide
345 (3S)-N-cyclobutyl-3-{1-[1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazol- >10000
3-yl]-N-ethylformamido}-5-(piperidin-1-yl)pentanamide
346 (3S)-N-cyclobutyl-3-{1-[5-(2,6-dimethoxyphenyl)-1-(pentan-3-yl)-1H-pyrazol-3- >10000
yl]-N-ethylformamido}-5-(piperidin-1-yl)pentanamide
347 (3S)-N-cyclobutyl-3-{1-[1-cyclopentyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl]-N- >10000
ethylformamido}-5-(piperidin-1-yl)pentanamide
348 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 15
yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanamide
349 (3S)-5-{2-azaspiro[3.3]heptan-2-yl}-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6- 197
dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanamide
350 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 720
(piperidin-1-yl)-N-(1H-1,2,3,4-tetrazol-5-yl)pentanamide
351 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 73
methyl-5-(piperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
352 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000
(piperidin-1-yl)pentanamide
353 (3S)-3-({5-[2,6-bis(2,2,2-trifluoroethoxy)phenyl]-1-cyclopentyl-1H-pyrazol-3- >10000
yl}formamido)-N-cyclobutyl-5-(piperidin-1-yl)pentanamide
354 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,4,6-trifluorophenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-(piperidin-1-yl)pentanamide
355 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(4-ethoxy-2,6-difluorophenyl)-1H-pyrazol- 5085
3-yl]formamido}-5-(piperidin-1-yl)pentanamide
356 (3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylcyclohexyl)-1H- >10000
pyrazol-3-yl]formamido}-5-(piperidin-1-yl)pentanamide
357 (3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(pentan-3-yl)-1H-pyrazol-3- >10000
yl]formamido}-5-(piperidin-1-yl)pentanamide
358 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(3S)-1-hydroxy-5-(piperidin-1- >10000
yl)pentan-3-yl]-1H-pyrazole-3-carboxamide
359 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethoxy)phenyl]-1H-pyrazol- 271
3-yl}formamido)-5-(piperidin-1-yl)pentanamide
360 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(methylsulfanyl)phenyl]-1H-pyrazol-3- 376
yl}formamido)-5-(piperidin-1-yl)pentanamide
361 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-methoxyphenyl)-1H-pyrazol-3- 234
yl]formamido}-5-(piperidin-1-yl)pentanamide
362 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(thiophen-2-yl)-1H-pyrazol-3- 5856
yl]formamido}-5-(piperidin-1-yl)pentanamide
363 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3- 44
yl]formamido}-5-(piperidin-1-yl)pentanamide
364 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-(piperidin-1-yl)-1-(1H-1,2,3,4- 235
tetrazol-5-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
365 (3S)-N-cyclobutyl-3-[(1-cyclopentyl-5-phenyl-1H-pyrazol-3-yl)formamido]-5- >10000
(piperidin-1-yl)pentanamide
366 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]- >10000
1H-pyrazol-3-yl}formamido)-5-(piperidin-1-yl)pentanamide
367 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-methanesulfonylphenyl)-1H-pyrazol-3- 2966
yl]formamido}-5-(piperidin-1-yl)pentanamide
368 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(pyrimidin-5-yl)-1H-pyrazol-3- >10000
yl]formamido}-5-(piperidin-1-yl)pentanamide
369 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(dimethyl-1,2-oxazol-4-yl)-1H-pyrazol-3- >10000
yl]formamido}-5-(piperidin-1-yl)pentanamide
370 (3S)-3-{[5-(2-chloro-6-methoxyphenyl)-1-cyclopentyl-1H-pyrazol-3- 1028
yl]formamido}-N-cyclobutyl-5-(piperidin-1-yl)pentanamide
371 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethylphenyl)-1H-pyrazol-3- 3841
yl]formamido}-5-(piperidin-1-yl)pentanamide
372 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazol-3- 90
yl]formamido}-5-(piperidin-1-yl)pentanamide
373 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000
(piperidin-1-yl)-N-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]pentanamide
374 2-(3-{[(2S)-1-(cyclobutylcarbamoyl)-4-(piperidin-1-yl)butan-2-yl]carbamoyl}-1- >10000
cyclopentyl-1H-pyrazol-5-yl)pyridin-1-ium-1-olate
375 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(pyridin-2-yl)-1H-pyrazol-3- >10000
yl]formamido}-5-(piperidin-1-yl)pentanamide
376 (2S)-N-cyclobutyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-3-cyclopropylpropanamide
377 (2S)-N,3-dicyclobutyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol- >10000
3-yl]formamido}propanamide
378 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(1,3-thiazol-4-yl)-1H-pyrazol-3- 9386
yl]formamido}-5-(piperidin-1-yl)pentanamide
379 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 1407
(piperidin-1-yl)-N-(1H-1,2,3,4-tetrazol-5-ylmethyl)pentanamide
380 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 94
phenyl-N-(1,3-thiazol-2-yl)pentanamide
381 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 647
phenyl-N-(1H-1,2,3,4-tetrazol-5-yl)pentanamide
382 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 3441
phenyl-N-(1,3-thiazol-2-ylmethyl)pentanamide
383 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 5177
phenyl-N-(1H-1,2,3,4-tetrazol-5-ylmethyl)pentanamide
384 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 15
(3,3-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
385 (2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-3- >10000
cyclopropylpropanoic acid
386 (2S)-3-cyclobutyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 6170
yl]formamido}propanoic acid
387 (2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- 8716
phenyl-N-(1H-1,2,3,4-tetrazol-5-ylmethyl)butanamide
388 (2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- 399
phenyl-N-(1,3-thiazol-2-ylmethyl)butanamide
389 (2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000
phenylbutanoic acid
390 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-phenyl-1-(1H-1,2,3,4-tetrazol- 429
5-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
391 N-[(2S)-1-cyano-4-phenylbutan-2-yl]-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H- 6344
pyrazole-3-carboxamide
392 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000
phenylpentanamide
393 (2S)-3-cyclopentyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 424
yl]formamido}propanoic acid
395 (2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000
phenyl-N-(1H-1,2,3,4-tetrazol-5-yl)butanamide
396 (2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000
phenyl-N-(1,3-thiazol-2-yl)butanamide
397 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(propan-2-yl)phenyl]-1H-pyrazol-3- 140
yl}formamido)-5-(piperidin-1-yl)pentanamide
398 N-[(3R)-1-(cyclobutylamino)-5-(piperidin-1-yl)pentan-3-yl]-1-cyclopentyl-5-(2,6- >10000
dimethoxyphenyl)-1H-pyrazole-3-carboxamide
399 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethyl-4-fluorophenyl)-1H-pyrazol-3- 264
yl]formamido}-5-(piperidin-1-yl)pentanamide
400 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol- 46
3-yl}formamido)-5-(piperidin-1-yl)pentanamide
401 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000
phenylbutanoic acid
402 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- 203
phenyl-N-(1,3-thiazol-2-yl)butanamide
403 (3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5- 42
(piperidin-1-yl)pentanoic acid hydrochloride
404 (3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(3,3- 65
difluoropiperidin-1-yl)pentanoic acid
405 (3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(4,4- 227
difluoropiperidin-1-yl)pentanoic acid
406 (3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5- 22
(piperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
407 (3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N- 162
cyclobutyl-5-(piperidin-1-yl)pentanamide
408 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 64
yl}formamido)-5-(piperidin-1-yl)pentanamide
409 (3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(4,4- 12.5
difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
410 (3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(3,3- 7
difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
411 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3- 14.5
yl]formamido}-5-(4,4-difluoropiperidin-1-yl)pentanamide
412 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3- 5
yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanamide
413 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-cyclopropylphenyl)-1H-pyrazol-3- 49
yl]formamido}-5-(piperidin-1-yl)pentanamide
414 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-(piperidin-1-yl)-1-(4H-1,2,4- 200
triazol-3-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
415 (3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 292
yl]formamido}-5-(4-fluorophenyl)pent-4-enamide
416 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 606
yl]formamido}-5-(4-fluorophenyl)pentanamide
417 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- 36
(4-fluorophenyl)-N-(1,3-thiazol-2-yl)pentanamide
418 (3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 664
yl]formamido}-5-(pyridin-3-yl)pent-4-enamide
419 (3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}-5-(pyridin-4-yl)pent-4-enamide
420 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 883
yl]formamido}-5-(pyridin-3-yl)pentanamide
421 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 3312
yl]formamido}-5-(1-methylpiperidin-4-yl)pentanamide
422 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-1-(1,3,4-oxadiazol-2-yl)-4- 1422
(piperidin-1-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
423 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 35
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
424 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 110
yl}formamido)-5-(4,4-difluoropiperidin-1-yl)pentanoic acid
425 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 10.9
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanamide
426 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 10.6
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
427 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 8.5
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-(1,3-oxazol-2-yl)pentanamide
428 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol- 7.5
3-yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
429 (3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3- 6.1
difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
430 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 17.5
yl}formamido)-5-(4,4-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide
431 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 22.5
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-methyl-N-(1,3-thiazol-2-
yl)pentanamide
432 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 16
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
433 (3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3- 151
difluoropiperidin-1-yl)pentanoic acid
434 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)thiophen-3-yl]-1H- 641
pyrazol-3-yl}formamido)-5-(piperidin-1-yl)pentanamide
435 (3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 9211
yl]formamido}-5-(pyridin-2-yl)pent-4-enamide
436 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 58
yl}formamido)-5-(4,4-difluoropiperidin-1-yl)-N-(5-methyl-1,3-thiazol-2-
yl)pentanamide
437 1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(4H-1,2,4-triazol-3- 21
yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
438 (3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethynylphenyl)-1H-pyrazol-3- 290
yl]formamido}-5-(piperidin-1-yl)pentanamide
439 (3S)-N-benzyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 920
yl}formamido)-5-(4,4-difluoropiperidin-1-yl)pentanamide
440 (3S)-N-(cyclohexylmethyl)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H- 301
pyrazol-3-yl}formamido)-5-(4,4-difluoropiperidin-1-yl)pentanamide
441 (3S)-N-benzyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000
yl}formamido)-5-methylhexanamide
442 N-benzyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000
yl}formamido)propanamide
443 (3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N- 73
(3,3-difluorocyclobutyl)-5-(piperidin-1-yl)pentanamide
445 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-1-(1-methyl-1H-1,2,3,4-tetrazol- 2835
5-yl)-4-(piperidin-1-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
447 (3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3- 84
difluoropiperidin-1-yl)-N-methyl-N-(1,3-thiazol-2-yl)pentanamide
448 1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-(piperidin-1-yl)-1-(1,3-thiazol- 1338
2-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
449 3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)-N- 12670
(1,3-thiazol-2-yl)propanamide
450 5-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(4H- 30
1,2,4-triazol-3-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
451 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 27
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-methyl-N-(1,3-oxazol-2-
yl)pentanamide
452 (3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3- 70
difluoropiperidin-1-yl)-N-methyl-N-(1,3-oxazol-2-yl)pentanamide
457 (3S)-3-{[5-(3-chloropyridin-4-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N- 1324
cyclobutyl-5-(3,3-difluoropiperidin-1-yl)pentanamide
458 5-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(5- 261
methyl-4H-1,2,4-triazol-3-yl)butan-2-yl]-1H-pyrazole-3-carboxamide
459 5-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-[5- 243
(trifluoromethyl)-4H-1,2,4-triazol-3-yl]butan-2-yl]-1H-pyrazole-3-carboxamide
460 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[4-(trifluoromethyl)pyridin-3-yl]-1H- 23
pyrazol-3-yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanamide
463 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1236
yl}formamido)-5-(4-fluorophenyl)pentanoic acid
464 1-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-(hydrazinecarbonyl)butan-2-yl]-5-[2- 1036
(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
465 5-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1- 191
(hydrazinecarbonyl)butan-2-yl]-1H-pyrazole-3-carboxamide
466 (3S)-3-{[5-(4-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N- 1217
cyclobutyl-5-(3,3-difluoropiperidin-1-yl)pentanamide
467 (3S)-3-{[5-(4-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5- >10,000
(3,3-difluoropiperidin-1-yl)pentanoic acid
468 (3S)-3-{[5-(2-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5- 1674
(3,3-difluoropiperidin-1-yl)pentanoic acid
469 (3S)-3-{[5-(2-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N- 133
cyclobutyl-5-(3,3-difluoropiperidin-1-yl)pentanamide
470 1-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl]-5- 435
[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
471 1-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-(5-methyl-4H-1,2,4-triazol-3- 1144
yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
475 1-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-[5-(trifluoromethyl)-1,3,4-oxadiazol- 146
2-yl]butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
479 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1H- 0.86
pyrazol-3-yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanamide
480 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 2.76
yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)pentanamide
481 (3S)-5-(3-cyanopyrrolidin-1-yl)-N-cyclobutyl-3-({1-cyclopentyl-5-[2- 1.96
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide
482 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 474
yl}formamido)-5-(4-fluorophenyl)-N-(1-methylazetidin-3-yl)pentanamide
483 (3S)-N-cyclobutyl-5-[cyclohexyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 14
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide
484 (3S)-5-cyclohexyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1518
yl}formamido)pentanoic acid
485 (3S)-3-({1-cyclopentyl-5-[2-(trifruoromethyl)phenyl]-1H-pyrazol-3- 110
yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)pentanoic acid
486 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 931
yl}formamido)-5-(morpholin-4-yl)pentanoic acid
487 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 211
yl}formamido)-5-[(2S)-2-(trifluoromethyl)piperidin-1-yl]pentanoic acid
488 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1342
yl}formamido)-5-[(2R)-2-(trifluoromethyl)piperidin-1-yl]pentanoic acid
489 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 161
yl}formamido)-N-methyl-N-(1,3-thiazol-2-yl)-5-[(2R)-2-
(trifluoromethyl)piperidin-1-yl]pentanamide
490 (3S)-N-cyclobutyl-5-[cyclopentyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 10.3
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide
491 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 68
yl}formamido)-5-(morpholin-4-yl)pentanamide
492 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 36
yl}formamido)-5-(dipropylamino)pentanamide
493 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 24
yl}formamido)-5-[methyl(2-methylpropyl)amino]pentanamide
494 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 215
yl}formamido)-5-(piperidin-1-yl)pentanoic acid
495 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 165
yl}formamido)-N-methyl-5-(morpholin-4-yl)-N-(1,3-thiazol-2-yl)pentanamide
496 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 30
yl}formamido)-5-[(2S)-2-(trifluoromethyl)piperidin-1-yl]pentanamide
497 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 103
yl}formamido)-5-(4-fluorophenyl)pentanamide
498 (3S)-5-{8-azabicyclo[3.2.1]octan-8-yl}-N-cyclobutyl-3-({1-cyclopentyl-5-[2- 105
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide
499 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 548
yl}formamido)-5-(pyrrolidin-1-yl)pentanoic acid
500 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 79
yl}formamido)-N-methyl-5-(4-methyl-1H-pyrazol-1-yl)-N-(1,3-thiazol-2-
yl)pentanamide
501 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 26
yl}formamido)-5-(4-methyl-1H-pyrazol-1-yl)pentanamide
502 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 77
yl}formamido)-5-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methyl-N-(1,3-thiazol-2-
yl)pentanamide
503 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 157
yl}formamido)-5-(3,5-dimethyl-1H-pyrazol-1-yl)pentanamide
504 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 59
yl}formamido)-5-(pyrrolidin-1-yl)pentanamide
505 (3S)-5-(azepan-1-yl)-N-cyclobutyl-3-({1-cyclopentyl-5-[2- 34
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide
506 (3S)-N-cyclobutyl-5-[cyclobutyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 32
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide
507 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 162
yl}formamido)-5-{2-oxa-6-azaspiro[3.3]heptan-6-yl}pentanamide
508 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 475
yl}formamido)-5-oxo-5-(piperidin-1-yl)pentanoic acid
509 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1065
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-5-oxopentanoic acid
510 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 2192
yl}formamido)-5-(4-fluorophenyl)-N-(pyrrolidin-1-yl)pentanamide
511 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 35
yl}formamido)-5-[methyl(1-methylcyclopentyl)amino]pentanamide
514 (3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 79
yl}formamido)-5-oxo-5-(piperidin-1-yl)pentanamide
515 (3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 47
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-5-oxopentanamide
516 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 834
yl}formamido)-5-(dimethylamino)pentanamide
517 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 261
yl}formamido)-5-(2,2-dimethylpiperidin-1-yl)pentanamide
518 (3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000
yl}formamido)-4-(3,3-difluoropyrrolidin-1-yl)butanoic acid
519 (3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000
yl}formamido)-4-(3,3-difluoropiperidin-1-yl)butanoic acid
520 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 45
yl}formamido)-N-(3,3-difluorocyclobutyl)-5-(piperidin-1-yl)pentanamide
521 (3S)-5-{2-azabicyclo[2.2.2]octan-2-yl}-N-cyclobutyl-3-({1-cyclopentyl-5-[2- 100
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide
522 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 64
yl}formamido)-5-{2-oxa-5-azaspiro[3.5]nonan-5-yl}pentanamide
523 (3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1207
yl}formamido)-4-(3,3-difluoropyrrolidin-1-yl)butanamide
524 (3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 910
yl}formamido)-4-(3,3-difluoropiperidin-1-yl)butanamide
525 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-1,2,4-triazol-3- >10,000
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
526 (2S)-3-cyclopentyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1717
yl}formamido)propanoic acid
527 (2S)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000
yl}formamido)-4-methylpentanoic acid
528 (2S)-2-({1-cyclopentyl-5-[2-(trifruoromethyl)phenyl]-1H-pyrazol-3- >10,000
yl}formamido)-3-methylbutanoic acid
529 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 134
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-
(trifluoromethane)sulfonylpentanamide
533 (3R)-4-[cyclohexyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 822
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)butanoic acid
534 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 388
yl}formamido)-5-(3,3-difluoroazetidin-1-yl)pentanoic acid
535 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 32
yl}formamido)-5-(3,3-difluoroazetidin-1-yl)pentanamide
536 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 39
yl}formamido)-5-(cyclopentylformamido)pentanamide
537 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 16
yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)pentanoic acid
538 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 544
yl}formamido)-5-(cyclopentylformamido)pentanoic acid
539 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 176
yl}formamido)-5-(oxetan-3-ylformamido)pentanamide
540 1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2- 1382
yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
541 N-[(2S)-1-(cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl]- 1058
1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
542 (2S)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 105
yl}formamido)-N-(2-methoxyethyl)-N-methyl-4-phenylbutanamide
544 (3R)-3-(cyclohexylcarbamoyl)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]- 205
1H-pyrazol-3-yl}formamido)propanoic acid
545 (3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1233
yl}formamido)-4-(4-fluorophenoxy)butanoic acid
546 (3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 114
yl}formamido)-4-(4-fluorophenoxy)butanamide
547 (3R)-N-cyclobutyl-4-[cyclohexyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 5125
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)butanamide
548 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 255
yl}formamido)-5-[(3,3-difluorocyclobutyl)amino]pentanoic acid
549 (2R)-N-cyclobutyl-N′-cyclohexyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]- 152
1H-pyrazol-3-yl}formamido)butanediamide
550 (3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 8679
yl}formamido)-N-(3-methyloxetan-3-yl)-5-oxo-5-(piperidin-1-yl)pentanamide
551 1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(1H-1,2,3,4-tetrazol-5- 25
yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
552 (3S)-3-({1-cyclobutyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)- 167
5-(3,3-difluoropiperidin-1-yl)pentanoic acid
553 (3S)-5-(3,3-difluoropiperidin-1-yl)-3-{[1-(oxan-4-yl)-5-[2- 1482
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]formamido}pentanoic acid
554 (3S)-3-({1-cyclopentyl-5-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 126
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
555 (3S)-3-({5-[4-chloro-2-(trifluoromethyl)phenyl]-1-cyclopentyl-1H-pyrazol-3- 1573
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
556 (3S)-3-({5-[2-chloro-6-(trifluoromethyl)phenyl]-1-cyclopentyl-1H-pyrazol-3- >10
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
557 (3S)-3-{[1-(cyclopropylmethyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 401
yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
558 (3R)-3-[cyclohexyl(methyl)carbamoyl]-3-({1-cyclopentyl-5-[2- 1172
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)propanoic acid
559 (3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 596
yl}formamido)-3-[(oxan-4-yl)carbamoyl]propanoic acid
560 (3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 738
yl}formamido)-3-[(4-fluorophenyl)carbamoyl]propanoic acid
561 (2R)-N-cyclobutyl-N′-cyclohexyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]- 879
1H-pyrazol-3-yl}formamido)-N′-methylbutanediamide
562 (2R)-N-cyclobutyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 169
yl}formamido)-N′-(oxan-4-yl)butanediamide
563 1-cyclopentyl-N-[(3R)-1-(4-fluorophenyl)-2,5-dioxopyrrolidin-3-yl]-5-[2- >10,000
(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
564 (2S)-2-({1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3- 982
yl}formamido)-N-(2-methoxyethyl)-N-methyl-4-phenylbutanamide
565 (3S)-5-(3,3-difluoropiperidin-1-yl)-3-{[1-(2-methylpropyl)-5-[2- 544
(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]formamido}pentanoic acid
566 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 3051
yl}formamido)-5-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)pentanoic acid
567 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 648
yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanoic acid
568 (3S)-5-(3,3-difluoropiperidin-1-yl)-3-{[1-(2,2-dimethylpropyl)-5- >10,000
[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]formamido}pentanoic acid
570 (2S)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 4250
yl}formamido)-N-(2-methoxyethyl)-N-methyl-3-phenoxypropanamide
571 (3S)-3-{[1-(cyclobutylmethyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 130
yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
572 (3S,5S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 124
yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanoic acid
573 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 299
yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanamide
574 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 981
yl}formamido)-5-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pentanoic acid
575 (3S,5R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 91
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid
576 (3S,5S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1374
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid
577 (2S)-3-cyclohexyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1026
yl}formamido)propanoic acid
578 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 78
yl}formamido)-5-[3-(trifluoromethyl)pyrrolidin-1-yl]pentanoic acid
579 (3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1874
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid
580 (3S)-5-(3,3-difluoropiperidin-1-yl)-3-({1-propyl-5-[2-(trifluoromethyl)phenyl]-1H- 718
pyrazol-3-yl}formamido)pentanoic acid
581 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 215
yl}formamido)-5-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]pentanoic acid
582 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 109
yl}formamido)-5-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pentanoic acid
583 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 302
yl}formamido)-5-[(3S)-3-fluoropiperidin-1-yl]pentanoic acid
584 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 184
yl}formamido)-5-[(3R)-3-fluoropiperidin-1-yl]pentanoic acid
585 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 654
yl}formamido)-5-[(3S)-3-fluoropyrrolidin-1-yl]pentanoic acid
587 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 355
yl}formamido)-5-(2-oxopiperidin-1-yl)pentanoic acid
588 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 502
yl}formamido)-5-(3,3-dimethylazetidin-1-yl)pentanoic acid
589 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 171
yl}formamido)-5-(3,3-difluoroazetidin-1-yl)pentanoic acid
590 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1159
yl}formamido)-5-[(3R)-3-fluoropyrrolidin-1-yl]pentanoic acid
591 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 528
yl}formamido)-5-{5,5-difluoro-2-azaspiro[3.3]heptan-2-yl}pentanoic acid
592 (2S)-3-(tert-butoxy)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol- 5549
3-yl}formamido)-N-(2-methoxyethyl)-N-methylpropanamide
593 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 79
yl}formamido)-5-[(3R)-3-fluoropiperidin-1-yl]pentanoic acid
594 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 44
yl}formamido)-5-[trans-3,4-difluoropyrrolidin-1-yl]pentanoic acid
595 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 140
yl}formamido)-5-[trans-3,4-dimethylpyrrolidin-1-yl]hexanoic acid
596 (2S,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 88
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoic acid
597 (2R,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 23
yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoic acid
598 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 103
yl}formamido)-5-[cis-3,4-difluoropyrrolidin-1-yl]pentanoic acid
599 (3S,5R)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 24
yl}formamido)-5-[trans-3,4-difluoropyrrolidin-1-yl]hexanoic acid
600 (3S,5S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 67
yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanoic acid
601 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 128
yl}formamido)-5-[3-(trifluoromethyl)azetidin-1-yl]pentanoic acid
602 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 346
yl}formamido)-5-{3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl}pentanoic acid
603 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 46
yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pentanoic acid
604 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 55
yl}formamido)-5-(2,6-dioxopiperidin-1-yl)pentanoic acid
605 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 11
yl}formamido)-5-[(2R)-4,4-difluoro-2-methylpyrrolidin-1-yl]pentanoic acid
606 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 310
yl}formamido)-5-{8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl}pentanoic acid
607 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 69
yl}formamido)-5-(5,5-difluoro-2-methylpiperidin-1-yl)pentanoic acid
608 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1074
yl}formamido)-5-(2,2-dimethyl-4-oxopyrrolidin-1-yl)pentanoic acid
609 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 98
yl}formamido)-5-(3-fluoro-3-methylpyrrolidin-1-yl)pentanoic acid
610 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 43
yl}formamido)-5-[(3S,4R)-3,4-difluoropiperidin-1-yl]pentanoic acid
611 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 509
yl}formamido)-5-(2,2-dimethyl-4-oxopiperidin-1-yl)pentanoic acid
612 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 231
yl}formamido)-5-(4,4-difluoro-2,2-dimethylpyrrolidin-1-yl)pentanoic acid
613 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 104
yl}formamido)-5-(3-fluoro-3-methylpiperidin-1-yl)pentanoic acid trifluoroacetate
614 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 41
yl}formamido)-5-[(3S)-3-fluoro-3-methylpiperidin-1-yl]pentanoic acid
615 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 353
yl}formamido)-5-{[1-(trifluoromethyl)cyclopentyl]amino}pentanoic acid
trifluoroacetate
618 (3S)-N-cyclobutyl-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)- 425
1H-pyrazol-3-yl]formamido}pentanamide
621 (3S)-5-cyclohexyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 424
yl]formamido}pentanoic acid
622 (3S)-5-cyclohexyl-3-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- 380
yl]formamido}pentanoic acid
623 (3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-propyl-1H-pyrazol-3- 416
yl]formamido}pentanoic acid
624 (3S)-N-cyclobutyl-5-cyclohexyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H- 70
pyrazol-3-yl]formamido}pentanamide
625 (3S)-N-cyclobutyl-5-cyclohexyl-3-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H- 101
pyrazol-3-yl]formamido}pentanamide
626 (3S)-N-cyclobutyl-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-propyl-1H- 49
pyrazol-3-yl]formamido}pentanamide
628 1-cyclopentyl-N-[(2S)-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-1-(1H- 61
1,2,3,4-tetrazol-5-yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-
carboxamide
629 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 77
yl}formamido)-5-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pentanoic acid
630 1-cyclopentyl-N-[(2S)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-1-(1H-1,2,3,4- 24
tetrazol-5-yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-
carboxamide
631 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 75
yl}formamido)-5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]pentanoic acid
634 (2S,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 87
yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpentanoic
acid
635 (2R,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 13
yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpentanoic
acid
636 (3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 158
yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
methylpentanamide
637 1-cyclopentyl-N-[(3S)-1-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-(1H- 21
1,2,3,4-tetrazol-5-yl)pentan-3-yl]-5-[2-(trifluoromethyl)phenyl]-1H-
pyrazole-3-carboxamide
638 1-cyclopentyl-N-[(3S,4R)-1-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-(1H- 14
1,2,3,4-tetrazol-5-yl)pentan-3-yl]-5-[2-(trifluoromethyl)phenyl]-1H-
pyrazole-3-carboxamide
639 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 40
yl}formamido)-5-(3,5-difluoropiperidin-1-yl)pentanoic acid
641 1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(1H-1,2,3,4-tetrazol-5- 27
yl)butan-2-yl]-5-[3-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-3-carboxamide
643 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 182
yl}formamido)-5-(2,5-dioxopyrrolidin-1-yl)pentanoic acid
646 (3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-methyl-1H-pyrazol-3- 1476
yl]formamido}pentanoic acid
647 (3S)-5-cyclohexyl-3-{[1-cyclooctyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000
yl]formamido}pentanoic acid
648 (3S)-5-cyclohexyl-3-{[1-(cyclohexylmethyl)-5-(2,6-dimethoxyphenyl)-1H- >10000
pyrazol-3-yl]formamido}pentanoic acid
649 (3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(pentan-3-yl)-1H-pyrazol-3- >10000
yl]formamido}pentanoic acid
655 1-cyclopentyl-N-[(2S)-4-(2,6-dioxopiperidin-1-yl)-1-(1H-1,2,3,4-tetrazol-5- 66
yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide
5.3. Cellular Uptake Assay
Caco-2 cells (clone C2BBe1) were obtained from American Type Culture Collection (Manassas, Va.). Cell monolayers were grown to confluence on collagen-coated, microporous, polycarbonate membranes in 12-well Costar Transwell plates. Details of the plates and their certification are shown below. The permeability assay buffer was Hanks' balanced salt solution (HBSS) containing 10 mM HEPES and 15 mM glucose at a pH of 7.4. The buffer in the receiver chamber also contained 1% bovine serum albumin. The dosing solution concentration was 5 M for each test article in the assay buffer. Cell monolayers were dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37° C. with 5% CO2 in a humidified incubator. Samples were taken from the donor and receiver chambers at 120 minutes. Each determination was performed in duplicate. After the experiment, all assay buffers were removed from the inserts. Cell monolayers were dosed with blank 500 μM lucifer yellow on the A-to-B side and blank HBSS on the B-to-A side and incubated at 37° C. Samples were taken from the B-to-A side at 60 minutes. The flux of lucifer yellow was measured for each monolayer to ensure no damage was inflicted to the cell monolayers during the flux period. All samples were analyzed by LC-MS/MS using electrospray ionization. The apparent permeability (Papp) and percent recovery were calculated as follows:
Papp=(dCr/dt)×Vr/(A×CA)  (1)
Percent Recovery=100×((Vr×Cr final)+(Vd×Cd final))/(Vd×CN)  (2)
Where, dCr/dt is the slope of the cumulative concentration in the receiver compartment versus time in μM s−1;
Vr is the volume of the receiver compartment in cm3;
Vd is the volume of the donor compartment in cm3;
A is the area of the insert (1.13 cm2 for 12-well Transwell);
CA is the average of the nominal dosing concentration and the measured 120-minute donor concentration in μM;
CN is the nominal concentration of the dosing solution in μM;
Cr final is the cumulative receiver concentration in μM at the end of the incubation period;
Cd final is the concentration of the donor in μM at the end of the incubation period.
Efflux ratio (ER) is defined as Papp (B-to-A)/Papp (A-to-B).
Absorption Potential Classification:
Papp (A-to-B)<1.0×10−6 cm/s: Low
Papp (A-to-B)≥1.0×10−6 cm/s: High
Significant Efflux is defined as: ER≥2.0 and Papp (B-to-A)≥1.0×10−6 cm/
TABLE 3
Cellular Uptake Results
ID # EC50 (nM) Efflux ratio
253 382 34
348 15 2.1
335 63 1
363 44 3.6
384 15 1.7
410 7 1

In Vivo Blood Pressure Lowering Activity of the Compounds
Select compounds were evaluated for their effects upon oral administration on hemodynamic changes, including blood pressure reduction, in conscious, telemetered male Sprague-Dawley rats. Apelin peptides are known to lower blood pressure, e.g., Tatemoto, K., et. al. Regul. Pept. 2001, 99, 87-92.
Animals were approximately 7-9 weeks of age and weighed between 247 g to 263 g just prior to surgery. Dose levels administered were 7.5, 15 or 30 mg/kg, dose volumes were 10 mL/kg, and dose route of administration was oral gavage. Animals were assigned to a crossover experimental treatment schedule as shown below.
Animal Treatment 1 Treatment 2 Treatment 3 Treatment 4
No. Compound (mg/kg)
1 30 15 7.5 0 (vehicle)
2 15 7.5 0 (vehicle) 30
3 7.5 0 (vehicle) 30 15
4 0 (vehicle) 30 15 7.5
5 30 15 7.5 0 (vehicle)
6 15 7.5 0 (vehicle) 30
7 7.5 0 (vehicle) 30 15
8 0 (vehicle) 30 15 7.5
Collected data included systolic, diastolic, and mean arterial blood pressure (MAP). Data collection time points were for pre-dose baseline approximately 48 h (prior to treatment 1) or approximately 24 h (prior to treatment 2-4) for 10 sec every 2 min. Data collection post-dose was collected through approximately 24 h (data collected for 10 sec every 2 min) per treatment. Resulting data is presented below as the 2-5 h mean change from baseline in mmHg.
Compound 423 Compound 551
Systolic Diastolic MAP Systolic Diastolic MAP
Vehicle −3.7 −3.2 −4.7 −2.6 −2.1 −2.4
(0 mg/kg)
7.5 mg/kg −13.0 −9.9 −10.0 −6.6 −4.3 −4.5
15 mg/kg −9.8 −7.3 −8.4 −9.6 −7.3 −8.5
30 mg/kg −10.7 −8.3 −9.3 −11.3 −8.4 −9.8
Compound 423 treatment via oral gavage to male Sprague-Dawley rats resulted in a mild sustained decrease in blood pressure, and compound 551 treatment resulted in a dose-dependent, mild sustained decrease in blood pressure.
It is to be understood that, while the disclosure has been described in conjunction with the detailed description, thereof, the foregoing description is intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages, and modifications of the disclosure are within the scope of the claims set forth below. All publications, patents, and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims (1)

What is claimed is:
1. A compound represented by the Formula I:
Figure USRE049594-20230801-C00475
or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a salt of a prodrug thereof,
wherein
R1 is represented by the formula:
Figure USRE049594-20230801-C00476
wherein
Figure USRE049594-20230801-C00477
 is a monocyclic aryl or heteroaryl group;
each A is independently fluoro substituted C1-C3 alkoxy or fluoro substituted C1-C3 alkyl;
n is 1, 2, 3, 4, or 5;
R2 is C3-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl, heteroaryl, or substituted aryl;
R4 is adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)—CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4 alkyl heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl—CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9 (CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)xSO2NR7R8;
R5 and R6 each are independently is adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)—CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4 alkyl heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9, (CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)x SO2NR7R8; or
R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms; or
R4 and R5 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups;
wherein the group R4 is substituted with one or more fluorine atoms;
R6 is H;
R7 and R8 each are independently H, C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl tetrazol-5-one, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, C1-8 alkyl thiol, C1-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, (CH2)xCONHR9, (CH2)xCOR9, (CH2)xCO2R9, or heteroaryl; or
R7 and R8 together make a 3-9 member ring which may contain one or more heteroatoms, wherein the ring is substituted with at least two fluorine atoms; or
R7 and R8 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups;
R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl;
each x is independently 0-8; and
each y is independently 1-8.
US16/974,363 2015-12-09 2020-05-04 Apelin receptor (APJ) agonists and uses thereof Active 2037-01-06 USRE49594E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/974,363 USRE49594E1 (en) 2015-12-09 2020-05-04 Apelin receptor (APJ) agonists and uses thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562265177P 2015-12-09 2015-12-09
US201562265168P 2015-12-09 2015-12-09
US15/374,386 US10100059B2 (en) 2015-12-09 2016-12-09 Apelin receptor (APJ) agonists and uses thereof
US16/974,363 USRE49594E1 (en) 2015-12-09 2020-05-04 Apelin receptor (APJ) agonists and uses thereof

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US15/374,386 Reissue US10100059B2 (en) 2015-12-09 2016-12-09 Apelin receptor (APJ) agonists and uses thereof

Publications (1)

Publication Number Publication Date
USRE49594E1 true USRE49594E1 (en) 2023-08-01

Family

ID=57796972

Family Applications (4)

Application Number Title Priority Date Filing Date
US15/374,386 Ceased US10100059B2 (en) 2015-12-09 2016-12-09 Apelin receptor (APJ) agonists and uses thereof
US15/983,519 Active US10954247B2 (en) 2015-12-09 2018-05-18 Apelin receptor (APJ) agonists and uses thereof
US16/974,363 Active 2037-01-06 USRE49594E1 (en) 2015-12-09 2020-05-04 Apelin receptor (APJ) agonists and uses thereof
US17/082,650 Active US11535630B2 (en) 2015-12-09 2020-10-28 Apelin receptor (APJ) agonists and uses thereof

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US15/374,386 Ceased US10100059B2 (en) 2015-12-09 2016-12-09 Apelin receptor (APJ) agonists and uses thereof
US15/983,519 Active US10954247B2 (en) 2015-12-09 2018-05-18 Apelin receptor (APJ) agonists and uses thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
US17/082,650 Active US11535630B2 (en) 2015-12-09 2020-10-28 Apelin receptor (APJ) agonists and uses thereof

Country Status (17)

Country Link
US (4) US10100059B2 (en)
EP (1) EP3386976A1 (en)
JP (2) JP2019501899A (en)
KR (1) KR20180090852A (en)
CN (1) CN108602806B (en)
AU (1) AU2016366310C1 (en)
BR (1) BR112018011784A2 (en)
CA (1) CA3006205A1 (en)
CO (1) CO2018005871A2 (en)
HK (1) HK1255452A1 (en)
IL (1) IL259634A (en)
MA (1) MA43417A (en)
MX (2) MX2018006979A (en)
PE (1) PE20190258A1 (en)
RU (2) RU2766148C1 (en)
WO (1) WO2017100558A1 (en)
ZA (1) ZA201803301B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024148104A1 (en) 2023-01-03 2024-07-11 BioAge Labs, Inc. Combination therapy of apelin receptor agonist and glp-1 receptor agonist for treating a disease or condition associated with weight gain

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10377718B2 (en) 2014-06-06 2019-08-13 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
EA034776B1 (en) 2015-05-20 2020-03-19 Эмджен Инк. Triazole agonists of the apj receptor
TN2017000503A1 (en) 2015-06-03 2019-04-12 Bristol Myers Squibb Co 4-hydroxy-3-(heteroaryl)pyridine-2-one apj agonists for use in the treatment of cardiovascular disorders
JP2019501899A (en) 2015-12-09 2019-01-24 リサーチ トライアングル インスティテュート Modified apelin receptor (APJ) agonists and uses thereof
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
BR112019003420A2 (en) 2016-10-12 2019-05-21 Research Triangle Institute heterocyclic apelin receptor (apj) agonist and its uses
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
EP3541805B1 (en) 2016-11-16 2020-10-14 Amgen Inc. Heteroaryl-substituted triazoles as apj receptor agonists
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
WO2018097944A1 (en) 2016-11-16 2018-05-31 Amgen Inc. Triazole furan compounds as agonists of the apj receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
WO2018093576A1 (en) 2016-11-16 2018-05-24 Amgen Inc. Alkyl substituted triazole compounds as agonists of the apj receptor
CA3072362A1 (en) 2017-10-06 2019-04-11 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor
CA3098628A1 (en) 2018-05-17 2019-11-21 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
PT3860989T (en) 2018-10-05 2023-06-30 Forma Therapeutics Inc Fused pyrrolines which act as ubiquitin-specific protease 30 (usp30) inhibitors
JP2022545698A (en) 2019-08-29 2022-10-28 リサーチ トライアングル インスティテュート Methods and uses for apelin receptor agonists
WO2022182547A1 (en) * 2021-02-25 2022-09-01 Research Triangle Institute Heteroaryl derivatives as apelin receptor agonists

Citations (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58194866A (en) 1982-05-07 1983-11-12 Kureha Chem Ind Co Ltd Triazole derivative and herbicide containing the same
JPS5998004A (en) 1982-11-25 1984-06-06 Kureha Chem Ind Co Ltd Herbicide containing 1,2,4-triazole derivative
US4795484A (en) 1982-05-07 1989-01-03 Kureha Kagaku Kogyo Kabushiki Kaisha Herbicidal composition containing a derivative of 1,2,4-triazole as an active ingredient
EP0477049A1 (en) 1990-08-20 1992-03-25 Sanofi Amido-3-pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them
EP0576357A1 (en) * 1992-06-23 1993-12-29 Sanofi Pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
CA2136893A1 (en) 1993-12-02 1995-06-21 Francis Barth Substituted n-piperidino-pyrazole-3-carboxamide
US5502059A (en) 1993-10-12 1996-03-26 Sanofi Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them
US5723483A (en) 1995-04-11 1998-03-03 Sanofi Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6028084A (en) 1995-11-23 2000-02-22 Sanofi-Synthelabo Pyrazole derivatives, method for preparing same, and pharmaceutical compositions containing said derivatives
US6075121A (en) 1990-05-15 2000-06-13 Chiron Corporation Modified peptide and peptide libraries with protease resistance, derivatives thereof and methods of producing and screening such
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
WO2003027076A2 (en) 2001-09-21 2003-04-03 Solvay Pharmaceuticals B.V. 1h-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1- antagonistic activity
WO2003040107A1 (en) 2001-09-24 2003-05-15 Bayer Pharmaceuticals Corporation Imidazole-4-carboxamide derivatives, preparation and use thereof for treatment of obesity
WO2004026301A1 (en) 2002-09-19 2004-04-01 Solvay Pharmaceuticals B.V. 1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands
US20040082496A1 (en) 1999-04-30 2004-04-29 Acton Susan L. ACE-2 modulating compounds and methods of use thereof
US6803031B2 (en) 2001-05-24 2004-10-12 Alexza Molecular Delivery Corporation Delivery of erectile dysfunction drugs through an inhalation route
US20050054679A1 (en) 2001-09-21 2005-03-10 Solvay Pharmaceuticals B.V. 1 H-imidazole derivatives having CB1 agonistic, CB1 partial agonistic or CB1-antagonistic activity
WO2005063737A1 (en) 2003-12-26 2005-07-14 Daiichi Pharmaceutical Co., Ltd. Amidopyrazole derivative
WO2005099705A2 (en) 2004-03-24 2005-10-27 Bayer Pharmaceuticals Corporation Preparation of imidazole derivatives and methods of use
US20060014813A1 (en) 2003-11-26 2006-01-19 Patrick Connelly Pharmaceutical compounds that regenerate in vivo
US7014866B2 (en) 2001-05-03 2006-03-21 Hoffmann-La Roche Inc. High dose solid unit oral pharmaceutical dosage form of amorphous nelfinavir mesylate and process for making same
US20060079502A1 (en) 1999-11-02 2006-04-13 Steffen Lang Pharmaceutical compositions
WO2006043594A1 (en) 2004-10-19 2006-04-27 Daiichi Pharmaceutical Co., Ltd. 1,5-diheterocycle-1h-triazole derivative
US20060094744A1 (en) 2004-09-29 2006-05-04 Maryanoff Cynthia A Pharmaceutical dosage forms of stable amorphous rapamycin like compounds
WO2006133926A1 (en) 2005-06-17 2006-12-21 Carex Sa Pyrazole derivates as cannabinoid receptor modulators
US7186741B2 (en) 2002-03-18 2007-03-06 Solvay Pharmaceuticals B.V. Neurotensin active 2,3,diaryl-pyrazolidine derivatives
US20070213302A1 (en) 2006-03-10 2007-09-13 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
WO2008017932A2 (en) 2006-08-09 2008-02-14 Pfizer Products Inc. Heterocycles useful as inhibitors of carbonic anhydrase
EP1903052A2 (en) 2006-07-28 2008-03-26 Faust Pharmaceuticals SA APJ receptor ligands and uses thereof
WO2008098104A1 (en) 2007-02-07 2008-08-14 Smithkline Beecham Corporation Inhibitors of akt activity
US7531592B2 (en) 1996-12-31 2009-05-12 Rhodia Chimie Use of mixtures based on Pt and on compounds based on transition metals other than Pt, for enhancing the arc-resistance properties of silicone elastomers
CN101519430A (en) 2009-03-20 2009-09-02 中国农业大学 Novel juvenile hormone synthesis inhibitor-phenylpropyl alcohol-glycerol-bright tripeptide amide analogue
WO2010053545A2 (en) 2008-11-04 2010-05-14 Anchor Therapeutics, Inc. Apj receptor compounds
US20100160323A1 (en) 2008-12-23 2010-06-24 Alexander Bischoff NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE
US20100331540A1 (en) 2008-02-01 2010-12-30 Haruki Shimodaira Method for producing compound having deuterated aromatic ring or heterocyclic ring
WO2011005052A2 (en) 2009-07-10 2011-01-13 Green Gross Corporation Novel arylpiperazine-containing imidazole 4-carboxamide derivatives and pharmaceutical composition comprising same
WO2011012630A1 (en) 2009-07-30 2011-02-03 Aicuris Gmbh & Co. Kg Substituted bis-aryl pyrazole amides having terminal primary amide functionalization for treating retroviral diseases
WO2011156557A2 (en) * 2010-06-11 2011-12-15 Thomas James B Compounds active at the neurotensin receptor
US8252790B2 (en) * 2008-11-21 2012-08-28 Raqualia Pharma Inc. Pyrazole-3-carboxamide derivative having 5-HT2B receptor antagonist activity
WO2012166387A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
US8354557B2 (en) 2008-06-17 2013-01-15 Concert Pharmaceuticals, Inc. Synthesis of deuterated morpholine derivatives
WO2013014204A2 (en) 2011-07-26 2013-01-31 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
WO2013079223A1 (en) 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases
JP2013231000A (en) 2012-04-27 2013-11-14 Dainippon Sumitomo Pharma Co Ltd 3-aminomethyl pyrazole derivative
WO2013178362A1 (en) 2012-05-31 2013-12-05 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma]
WO2014023367A1 (en) 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma
US20140081019A1 (en) 2011-05-23 2014-03-20 Sanofi Process for the preparation of deuterated compounds containing n-alkyl groups
WO2014044738A1 (en) 2012-09-21 2014-03-27 Sanofi Benzoimidazole-carboxylic acid amide derivatives as apj receptor modulators
WO2014053533A1 (en) 2012-10-05 2014-04-10 Sanofi Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation
US8704001B2 (en) 2008-09-16 2014-04-22 Concert Pharmaceuticals, Inc. Deuterated 2-amino-3-hydroxypropanoic acid derivatives
WO2014152588A1 (en) 2013-03-15 2014-09-25 Araxes Pharma Llc Covalent inhibitors of kras g12c
WO2014169280A2 (en) 2013-04-12 2014-10-16 Achillion Pharmaceuticals, Inc. Deuterated nucleoside prodrugs useful for treating hcv
US20140341994A1 (en) 2012-09-18 2014-11-20 Auspex Pharmaceuticals, Inc. Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
WO2015058067A1 (en) 2013-10-17 2015-04-23 Vertex Pharmaceuticals Incorporated Co-crystals of (s)-n-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and deuterated derivatives thereof as dna-pk inhibitors
US20150299166A1 (en) 2012-12-20 2015-10-22 Concert Pharmaceuticals, Inc. Deuterated alk inhibitors
WO2015184011A2 (en) 2014-05-28 2015-12-03 Sanford-Burnham Medical Research Institute Agonists of the apelin receptor and methods of use thereof
WO2015188073A1 (en) 2014-06-06 2015-12-10 Research Triangle Institute Apelin receptor (apj) agonists and uses thereof
US20170174633A1 (en) 2014-03-25 2017-06-22 Research Triangle Institute Pyrazole compounds selective for neurotensin 2 receptor
WO2018010398A1 (en) 2016-07-11 2018-01-18 Zhejiang Dahua Technology Co., Ltd. Methods and systems for sound source locating
WO2018071526A1 (en) 2016-10-12 2018-04-19 Research Triangle Institute Heterocyclic apelin receptor (apj) agonists and uses thereof
US10100059B2 (en) 2015-12-09 2018-10-16 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
WO2021041791A1 (en) 2019-08-29 2021-03-04 Rti International, Inc. Methods and uses for apelin receptor agonists

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4795484A (en) 1982-05-07 1989-01-03 Kureha Kagaku Kogyo Kabushiki Kaisha Herbicidal composition containing a derivative of 1,2,4-triazole as an active ingredient
JPS58194866A (en) 1982-05-07 1983-11-12 Kureha Chem Ind Co Ltd Triazole derivative and herbicide containing the same
JPS5998004A (en) 1982-11-25 1984-06-06 Kureha Chem Ind Co Ltd Herbicide containing 1,2,4-triazole derivative
US6075121A (en) 1990-05-15 2000-06-13 Chiron Corporation Modified peptide and peptide libraries with protease resistance, derivatives thereof and methods of producing and screening such
US5744493A (en) 1990-08-20 1998-04-28 Sanofi 3-amidopyrazole derivatives and pharmaceutical compositions containing them
JPH04244065A (en) 1990-08-20 1992-09-01 Sanofi Sa 3-amidopyrazole derivative, process for producing same and medicinal composition
US5420141A (en) 1990-08-20 1995-05-30 Sanofi 3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them
US5744491A (en) 1990-08-20 1998-04-28 Sanofi 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
US5616592A (en) 1990-08-20 1997-04-01 Sanofi 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
EP0477049A1 (en) 1990-08-20 1992-03-25 Sanofi Amido-3-pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them
US5635526A (en) 1990-08-20 1997-06-03 Sanofi 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
US5607958A (en) 1990-08-20 1997-03-04 Sanofi 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
EP0576357A1 (en) * 1992-06-23 1993-12-29 Sanofi Pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them
US5624941A (en) 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US5585497A (en) 1993-10-12 1996-12-17 Sanofi Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin
US5523455A (en) 1993-10-12 1996-06-04 Sanofi Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them
US5502059A (en) 1993-10-12 1996-03-26 Sanofi Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them
CA2136893A1 (en) 1993-12-02 1995-06-21 Francis Barth Substituted n-piperidino-pyrazole-3-carboxamide
US5965579A (en) 1995-04-11 1999-10-12 Sanofi Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US5939449A (en) 1995-04-11 1999-08-17 Sanofi Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US5925661A (en) 1995-04-11 1999-07-20 Sanofi Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US6172239B1 (en) 1995-04-11 2001-01-09 Sanofi Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharamaceutical compositions containing them
US5936123A (en) 1995-04-11 1999-08-10 Sanofi Hydrazine derivative compounds as intermediates for preparing substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors
US5723483A (en) 1995-04-11 1998-03-03 Sanofi Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US6028084A (en) 1995-11-23 2000-02-22 Sanofi-Synthelabo Pyrazole derivatives, method for preparing same, and pharmaceutical compositions containing said derivatives
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
US7531592B2 (en) 1996-12-31 2009-05-12 Rhodia Chimie Use of mixtures based on Pt and on compounds based on transition metals other than Pt, for enhancing the arc-resistance properties of silicone elastomers
US20040082496A1 (en) 1999-04-30 2004-04-29 Acton Susan L. ACE-2 modulating compounds and methods of use thereof
US20060079502A1 (en) 1999-11-02 2006-04-13 Steffen Lang Pharmaceutical compositions
US7014866B2 (en) 2001-05-03 2006-03-21 Hoffmann-La Roche Inc. High dose solid unit oral pharmaceutical dosage form of amorphous nelfinavir mesylate and process for making same
US6803031B2 (en) 2001-05-24 2004-10-12 Alexza Molecular Delivery Corporation Delivery of erectile dysfunction drugs through an inhalation route
WO2003027076A2 (en) 2001-09-21 2003-04-03 Solvay Pharmaceuticals B.V. 1h-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1- antagonistic activity
JP2005504805A (en) 2001-09-21 2005-02-17 ソルベイ・フアーマシユーチカルズ・ベー・ブイ 1H-imidazole derivative having CB1 agonist activity, CB1 partial agonist activity or CB1-antagonism activity
US20050054679A1 (en) 2001-09-21 2005-03-10 Solvay Pharmaceuticals B.V. 1 H-imidazole derivatives having CB1 agonistic, CB1 partial agonistic or CB1-antagonistic activity
US20040235854A1 (en) 2001-09-21 2004-11-25 Kruse Cornelis G. 1H-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1 antagonistic activity
US20040063691A1 (en) 2001-09-24 2004-04-01 Smith Roger A. Preparation and use of imidazole derivatives for treatment of obesity
JP2005508384A (en) 2001-09-24 2005-03-31 バイエル・フアーマシユーチカルズ・コーポレーシヨン Imidazole-4-carboxamide derivatives, their preparation and use for the treatment of obesity
WO2003040107A1 (en) 2001-09-24 2003-05-15 Bayer Pharmaceuticals Corporation Imidazole-4-carboxamide derivatives, preparation and use thereof for treatment of obesity
US7186741B2 (en) 2002-03-18 2007-03-06 Solvay Pharmaceuticals B.V. Neurotensin active 2,3,diaryl-pyrazolidine derivatives
WO2004026301A1 (en) 2002-09-19 2004-04-01 Solvay Pharmaceuticals B.V. 1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands
US20060014813A1 (en) 2003-11-26 2006-01-19 Patrick Connelly Pharmaceutical compounds that regenerate in vivo
WO2005063737A1 (en) 2003-12-26 2005-07-14 Daiichi Pharmaceutical Co., Ltd. Amidopyrazole derivative
US20070219210A1 (en) 2003-12-26 2007-09-20 Daiichi Pharmaceutical Co., Ltd. Amidopyrazole Derivative
WO2005099705A2 (en) 2004-03-24 2005-10-27 Bayer Pharmaceuticals Corporation Preparation of imidazole derivatives and methods of use
US20060094744A1 (en) 2004-09-29 2006-05-04 Maryanoff Cynthia A Pharmaceutical dosage forms of stable amorphous rapamycin like compounds
WO2006043594A1 (en) 2004-10-19 2006-04-27 Daiichi Pharmaceutical Co., Ltd. 1,5-diheterocycle-1h-triazole derivative
US20080125409A1 (en) 2004-10-19 2008-05-29 Daiichi Pharmaceutical Co., Ltd. 1,5-Diheterocycle-1H-Triazole Derivative
WO2006133926A1 (en) 2005-06-17 2006-12-21 Carex Sa Pyrazole derivates as cannabinoid receptor modulators
US20070213302A1 (en) 2006-03-10 2007-09-13 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
WO2007106721A2 (en) 2006-03-10 2007-09-20 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
EP1903052A2 (en) 2006-07-28 2008-03-26 Faust Pharmaceuticals SA APJ receptor ligands and uses thereof
WO2008017932A2 (en) 2006-08-09 2008-02-14 Pfizer Products Inc. Heterocycles useful as inhibitors of carbonic anhydrase
WO2008098104A1 (en) 2007-02-07 2008-08-14 Smithkline Beecham Corporation Inhibitors of akt activity
US20100331540A1 (en) 2008-02-01 2010-12-30 Haruki Shimodaira Method for producing compound having deuterated aromatic ring or heterocyclic ring
US8354557B2 (en) 2008-06-17 2013-01-15 Concert Pharmaceuticals, Inc. Synthesis of deuterated morpholine derivatives
US8704001B2 (en) 2008-09-16 2014-04-22 Concert Pharmaceuticals, Inc. Deuterated 2-amino-3-hydroxypropanoic acid derivatives
WO2010053545A2 (en) 2008-11-04 2010-05-14 Anchor Therapeutics, Inc. Apj receptor compounds
US8252790B2 (en) * 2008-11-21 2012-08-28 Raqualia Pharma Inc. Pyrazole-3-carboxamide derivative having 5-HT2B receptor antagonist activity
US20100160323A1 (en) 2008-12-23 2010-06-24 Alexander Bischoff NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE
CN101519430A (en) 2009-03-20 2009-09-02 中国农业大学 Novel juvenile hormone synthesis inhibitor-phenylpropyl alcohol-glycerol-bright tripeptide amide analogue
WO2011005052A2 (en) 2009-07-10 2011-01-13 Green Gross Corporation Novel arylpiperazine-containing imidazole 4-carboxamide derivatives and pharmaceutical composition comprising same
WO2011012630A1 (en) 2009-07-30 2011-02-03 Aicuris Gmbh & Co. Kg Substituted bis-aryl pyrazole amides having terminal primary amide functionalization for treating retroviral diseases
WO2011156557A2 (en) * 2010-06-11 2011-12-15 Thomas James B Compounds active at the neurotensin receptor
US20140081019A1 (en) 2011-05-23 2014-03-20 Sanofi Process for the preparation of deuterated compounds containing n-alkyl groups
WO2012166387A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
US8513244B2 (en) 2011-05-31 2013-08-20 Theravance, Inc. Neprilysin inhibitors
US9353068B2 (en) 2011-07-26 2016-05-31 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
US9751858B2 (en) 2011-07-26 2017-09-05 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
US20160237060A1 (en) 2011-07-26 2016-08-18 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
WO2013014204A2 (en) 2011-07-26 2013-01-31 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
US20130053416A1 (en) 2011-07-26 2013-02-28 Sanofi 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
JP2014525912A (en) 2011-07-26 2014-10-02 サノフイ 3-Heteroaroylamino-propionic acid derivatives and their use as medicaments
WO2013079223A1 (en) 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases
JP2013231000A (en) 2012-04-27 2013-11-14 Dainippon Sumitomo Pharma Co Ltd 3-aminomethyl pyrazole derivative
WO2013178362A1 (en) 2012-05-31 2013-12-05 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma]
WO2014023367A1 (en) 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma
US20140341994A1 (en) 2012-09-18 2014-11-20 Auspex Pharmaceuticals, Inc. Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
US9156796B2 (en) 2012-09-21 2015-10-13 Sanofi Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators
CN104640846A (en) 2012-09-21 2015-05-20 赛诺菲 Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators
WO2014044738A1 (en) 2012-09-21 2014-03-27 Sanofi Benzoimidazole-carboxylic acid amide derivatives as apj receptor modulators
US20140094450A1 (en) 2012-09-21 2014-04-03 Sanofi Benzoimidazole-carboxylic acid amide derivatives as apj receptor modulators
WO2014053533A1 (en) 2012-10-05 2014-04-10 Sanofi Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation
US20150299166A1 (en) 2012-12-20 2015-10-22 Concert Pharmaceuticals, Inc. Deuterated alk inhibitors
WO2014152588A1 (en) 2013-03-15 2014-09-25 Araxes Pharma Llc Covalent inhibitors of kras g12c
WO2014169280A2 (en) 2013-04-12 2014-10-16 Achillion Pharmaceuticals, Inc. Deuterated nucleoside prodrugs useful for treating hcv
WO2015058067A1 (en) 2013-10-17 2015-04-23 Vertex Pharmaceuticals Incorporated Co-crystals of (s)-n-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and deuterated derivatives thereof as dna-pk inhibitors
US20170174633A1 (en) 2014-03-25 2017-06-22 Research Triangle Institute Pyrazole compounds selective for neurotensin 2 receptor
WO2015184011A2 (en) 2014-05-28 2015-12-03 Sanford-Burnham Medical Research Institute Agonists of the apelin receptor and methods of use thereof
US20160207889A1 (en) 2014-06-06 2016-07-21 Scott P. Runyon Apelin receptor (apj) agonists and uses thereof
WO2015188073A1 (en) 2014-06-06 2015-12-10 Research Triangle Institute Apelin receptor (apj) agonists and uses thereof
US10377718B2 (en) 2014-06-06 2019-08-13 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
US11401244B2 (en) * 2014-06-06 2022-08-02 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
US10100059B2 (en) 2015-12-09 2018-10-16 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
US10954247B2 (en) * 2015-12-09 2021-03-23 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
WO2018010398A1 (en) 2016-07-11 2018-01-18 Zhejiang Dahua Technology Co., Ltd. Methods and systems for sound source locating
WO2018071526A1 (en) 2016-10-12 2018-04-19 Research Triangle Institute Heterocyclic apelin receptor (apj) agonists and uses thereof
WO2021041791A1 (en) 2019-08-29 2021-03-04 Rti International, Inc. Methods and uses for apelin receptor agonists

Non-Patent Citations (85)

* Cited by examiner, † Cited by third party
Title
Alvarez et al., "Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97", ACS. MED. CHEM. LET., 2015, pp. 1225-1230, vol. 6.
Anderson et al.; "Apelin and pulmonary hypertension", Pulm. Circ. Jul.-Sep. 2011, 1(3) pp. 334-346.
Baxendale et al., "The Synthesis of Neurotensin Antagonist SR 48692 for Prostate Cancer Research," Bioorg. Med. Chem., 2013, vol. 21, pp. 4378-4387.
Carpéné et al.; "Expanding role for the apelin/APJ system in physiopathology" J. Physiol. Biochem., 63 (4), 359-374, 2007.
CAS Nos. 1415511-07-7, 2022.
CAS Nos. 1415511-09-09, 2022.
CAS Registry No. 1185029-85-9 which entered STN Sep. 16, 2009.
CAS Registry No. 1185070-07-8 which entered STN Sep. 16, 2009.
CAS Registry No. 1185080-91-4 which entered STN Sep. 16, 2009.
CAS Registry No. 1185108-25-1 which entered STN on Sep. 16, 2009.
CAS Registry No. 1189436-73-4 which entered STN Oct. 22, 2009.
CAS Registry No. 1189470-51-6 which entered STN on Oct. 22, 2009.
CAS Registry No. 1189643-98-8 which entered STN Oct. 23, 2009.
CAS Registry No. 1189885-22-0 which entered STN Oct. 25, 2009.
CAS Registry No. 1423365-99-4, which entered STN on Mar. 14, 2013.
CAS Registry No. 1569560-23-1, which entered STN on Mar. 18, 2014.
CAS Registry No. 1569675-43-9, which entered STN on Mar. 18, 2014 (Year: 2014).
CAS Registry No. 1578083-00-7.
CAS Registry No. 1580321-28-3, which entered STN on Apr. 4, 2014 (Year: 2014).
CAS Registry No. 1584603-48-4.
CAS Registry No. 1606440-69-0.
CAS Registry No. 1830232-36-4 which entered STN on Jun. 24, 2016.
CAS Registry No. 1831835-31-4 which entered STN on Jun. 24, 2016.
CAS Registry No. 1833984-41-0.
CAS Registry No. 1938292-99-9 which entered STN on Jun. 24, 2016.
CAS Registry No. 1938533-13-1 which entered STN on Jun. 24, 2016.
CAS Registry No. 931620-33-6, which entered STN on Apr. 22, 2007.
Charo et al.; "Endogenous regulation of cardiovascular function by apelin-APJ" Am J Physiol Heart Circ Physiol 297: H1904-H1913, 2009.
Cho, K-I, et al., "Targeting the cyclophilin domain of ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, mnRNPA2B1 and M-Opsin", ACS Chemical Neuroscience (Aug. 2015), vol. 6, No. 8, pp. 1476-1485.
Cobellis et al.; "Modulation of apelin and APJ receptor in normal and preeclampsia-complicated placentas." Histol Histopathol. Jan. 2007, 22(1) pp. 1-8. (abstract only).
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 16 September 2009 (2009-09-16), XP002768455, retrieved from STN
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2 August 2009 (2009-08-02), XP002768458, retrieved from STN
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 22 October 2009 (2009-10-22), XP002768454, retrieved from STN
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 23 October 2009 (2009-10-23), XP002768456, retrieved from STN
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 October 2009 (2009-10-25), XP002768457, retrieved from STN
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002768459, retrieved from STN
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002768460, retrieved from STN
Duncton et al., "A one-pot synthesis of tetrazolones from acid chlorides: understanding functional group compatibility, and application to the late-stage functionalization of marketed drugs", ORG. BIOMOL. CHEM (2016) vol. 14, pp. 9338-9342.
Dyck, B, et al., "Potent imidazole and triazole CP1receptor antagonists related to SR141716", Bioorganic & Medicinal Chemistry Letters, (2004), vol. 14, No. 5, pp. 1151-1154.
Fleisher et al., "Improved Review oral drug delivery: solubility limitations of prodrugs", Advanced Drug Delivery Reviews, 1996, p. 115-130, vol. 19.
Freireich et al., "Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man," Cancer Chemother. Rep., 1966, 50(4) pp. 219-244.
Geigy Pharmaceuticals, "Scientific Tables Excerpts From the Seventh Edition—Documenta Geigy," Ardsley, New York, 1970, p. 537.
Giddings et al.; "Development of a functional HTS assay for the APJ receptor" International Journal of High Throughput Screening 2010:1 pp. 39-47.
Gross, TJ et al, "Idiopathic Pulmonary Fibrosis" NEngl J Med, 2001, pp. 517-525, vol. 345, No. 7.
Habata et al., "Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum," Biochim. Biophys. Acta., 1999,1452(1), pp. 25-35.
Hagihara, M. et al., "Reassignment of stereochemistry and total synthesis of the thrombin inhibitor cyclotheonamide B," J. Amer. Chem. Soc. 1992, 114(16) pp. 6570-6571.
Hershberger et al., "Imidazole-derived agonists for the neurotensin 1 receptor" Bioorg. Med. Chem. Lett. (2014), vol. 247, pp. 262-267.
Hobbs Dewitt et al., "‘Diversomers’: An approach to nonpeptide, nonoligomeric chemical diversity," Proc. Natl. Acad. Sci. USA, 1993, 90(15) pp. 6909-6913.
Huang, S. et al., "The apelin—APJ axis: A novel potential therapeutic target for organ fibrosis" Clinica Chimica Acta, 2016, p. 81-88, vol. 456.
International Search Report and Written Opinion dated Jan. 27, 2017 for International Application No. PCT/US2016/065808.
International Search Report and Written Opinion dated Sep. 25, 2015 for International Application No. PCT/US2015/034427.
Iturrioz et al.; "Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist" The FASEB Journal, May 2010, vol. 24, pp. 1506-1517.
Khan et al.; "Probe Report" Molecular Libraries, Jul. 2011, pp. 1-22.
Kourtis et al.; "Apelin levels in normal pregnancy" Clinical Endocrinology (2011) 75, pp. 367-371.
Laderias-Lopez et al., "The apelinergic system: the role played in human physiology and pathology and pootential therapeutic applications," Arq Bras Cardiol., 2008, 90(5) pp. 343-349.
Lathen et al.; "ERG-APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease" Circulation 2014;130: pp. 1179-1191.
Lee et al., "Characterization of Apelin, the Ligand for the APJ Receptor," Neurochem., 2000, 74(1), pp. 34-41.
Maloney et al.; "Discovery of 4-0xo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor" Bioorganic & Medicinal Chemistry Letters 22 (2012) pp. 6656-6660.
Maloney et al.; "Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor" Bioorganic & Medicinal Chemistry Letters 22 (2012) pp. 6656-6660.
Martinez, FJ et al. "The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis" Ann Intern Med, 2005, p. 963-967, vol. 142.
Medhurst et al., "Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin," J. Neurochem., 2003, 84(5) pp. 1162-1172.
Narayanan et al.; "141—Discovery of small molecule functional agonist leads of APJ receptor" MEDI: Division of Medical Chemistry.
O'Donnell et al., "Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury," J. Neurochem., 2007, 102(6) pp. 1905-1917.
Preissl, S. et al., "Development of an Assay for Complex I/Complex III of the Respiratory Chain Using Solid Supported Membranes and Its Application in Mitochondrial Toxicity Screening in Drug Discovery," Assay and Drug Development Technologies, 2011 vol. 9 pp. 147-156.
Rautio et al., "Prodrugs: design and clinical Applications", Nat Rev Drug Dis, 2008 p. 255-270, vol. 7.
Robinson et al., "Discovery of the Hemifumarate and (r-L-Alanyloxy)methyl Ether as Prodrugs of an Antirheumatic Oxindole: Prodrugs for the Enolic OH Group" J Med Chem, 1996, p. 10-18, vol. 39.
Selman M et al., "Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy", Ami Intern Med, 2001, p. 134-136, vo. 51.
Selman. M., et al., Role of Epithelial Cells in Idiopathic Pulmonary Fibrosis, Am Thorac Soc, 2006, p. 364-372, vol. 4.
Sheikh et al.: "In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-entered pathway activated in ischemic heart failure" Am J Physiol Heart Circ Physiol 294: H88-H98, 2008.
Tatemoto et al.; "Isolation and Characterization of a Novel Endogenous Peptide Ligand for the Human APJ Receptor" Biochemical and Biophysical Research Communications 251, pp. 471-476 (1998).
Tatemoto et al.; "The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism" Regulatory Peptides 99 {hacek over (Z)}2001. pp. 87-92.
Thomas et al., "Identification of 1-({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino) cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound," J. Med. Chem., 2014, vol. 57, pp. 5318-5332.
Tiemann et al., "Increasing myocardial contraction and blood pressure in C57BL/6 mice during early postnatal delevelopment" Am J Physiol Heart Circ Physiol 284:H464-H474, 2003.
Tiemann et al., "Increasing myocardial contraction and blood pressure in C57BU6 mice during early postnatal delevelopment" Am J Physiol Heart Circ Physiol 284:H464-H474, 2003.
Wang et al., "Expanding the genetic code for biological studies," Chem Biol., 2009, 16(3) pp. 323-336.
Xie, "A chemical toolkit for proteins—an expanded genetic code," Nat. Rev. Mol. Cell Biol., 2006, 7(10) pp. 775-782.
XP-002768454 Database Registry, Chemical Abstracts Service. Oct. 22, 2009.
XP-002768455 Database Registry, Chemical Abstracts Service. Sep. 16, 2009.
XP-002768456 Database Registry, Chemical Abstracts Service. Oct. 23, 2009.
XP-002768457 Database Registry, Chemical Abstracts Service. Oct. 25, 2009.
XP-002768458 Database Registry, Chemical Abstracts Service. Aug. 2, 2009.
XP-002768459 Database Registry, Chemical Abstracts Service. Nov. 20, 2009.
XP-002768460 Database Registry, Chemical Abstracts Service. Nov. 22, 2009.
Zhong et al. "Targeting the apelin pathway asa novel therapeutic approach for cardiovascular diseases," Biochimica et Biophysica Acta, 2017, 1863, 1942-50.
Zou, M.X. et al., "Apelin peptides block the entry of human immunodeficiency virus (HIV)," FEBS Lett., 2000, 473(1) pp. 15-18.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024148104A1 (en) 2023-01-03 2024-07-11 BioAge Labs, Inc. Combination therapy of apelin receptor agonist and glp-1 receptor agonist for treating a disease or condition associated with weight gain

Also Published As

Publication number Publication date
JP2019501899A (en) 2019-01-24
US20180265518A1 (en) 2018-09-20
US20210070767A1 (en) 2021-03-11
MA43417A (en) 2018-10-17
AU2016366310A8 (en) 2021-06-03
CA3006205A1 (en) 2017-06-15
US10954247B2 (en) 2021-03-23
CN108602806A (en) 2018-09-28
RU2766148C1 (en) 2022-02-08
MX2022002026A (en) 2022-03-11
IL259634A (en) 2018-07-31
AU2016366310B2 (en) 2021-05-20
US10100059B2 (en) 2018-10-16
ZA201803301B (en) 2019-07-31
EP3386976A1 (en) 2018-10-17
KR20180090852A (en) 2018-08-13
JP7195356B2 (en) 2022-12-23
US11535630B2 (en) 2022-12-27
PE20190258A1 (en) 2019-02-25
HK1255452A1 (en) 2019-08-16
MX2018006979A (en) 2019-05-16
AU2016366310B8 (en) 2021-06-03
CN108602806B (en) 2022-07-12
BR112018011784A2 (en) 2018-12-04
AU2016366310A1 (en) 2018-06-07
RU2021133849A (en) 2022-03-21
AU2016366310C1 (en) 2021-09-09
US20170166577A1 (en) 2017-06-15
JP2021100934A (en) 2021-07-08
CO2018005871A2 (en) 2018-07-10
WO2017100558A1 (en) 2017-06-15

Similar Documents

Publication Publication Date Title
USRE49594E1 (en) Apelin receptor (APJ) agonists and uses thereof
US11401244B2 (en) Apelin receptor (APJ) agonists and uses thereof
US11926612B2 (en) Heterocyclic apelin receptor (APJ) agonists and uses thereof
US20240174638A1 (en) Heteroaryl derivatives as apelin receptor agonists

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FEPP Fee payment procedure

Free format text: PETITION RELATED TO MAINTENANCE FEES GRANTED (ORIGINAL EVENT CODE: PTGR); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

AS Assignment

Owner name: RESEARCH TRIANGLE INSTITUTE, NORTH CAROLINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RUNYON, SCOTT P.;MAITRA, RANGAN;NARAYANAN, SANJU;AND OTHERS;REEL/FRAME:063611/0122

Effective date: 20161219

CC Certificate of correction