Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • 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
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • 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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • 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
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • 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
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
  • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom

Definitions

• Hypoxia-inducible factor mediates gene expression in response to changes in cellular oxygen concentration.
• HIF is a heterodimer having an oxygen-regulated subunit (HIF- ⁇ ) and a constitutively expressed subunit (HIF- ⁇ ) .
• HIF prolyl hydroxylase which is also known as prolyl hydroxylase domain-containing protein (PHD) , exists as three isoforms in humans (PHD1 , PHD2, and PHD3) .
• PHDs act as oxygen sensors modulating the hypoxia-inducible factor ( “HIF” ) degradation pathway. Briefly, PHDs are responsible for hydroxylation of HIF ⁇ , a subunit of HIF, which initiates the pathway that eventually results in the degradation of HIF ⁇ by the proteasome.
• There are three subtypes of PHDs including PHD1, PHD2 and PHD3. Inhibition of PHDs has been indicated as a promising therapy for the HIF ⁇ related disease, such as anemia and inflammatory bowel disease (IBD) .
• X is N or CR 2 ;
• R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
• each R 7 and R 8 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl,
• p 0-4;
• n 0-4;
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• composition comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
• Also disclosed herein is a method of treating a disease or disorder in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, wherein the disease or disorder is cardiovascular disorders, metabolic disorders, hematological disorders, pulmonary disorders, kidney disorders, liver disorders, wound healing disorders, or cancer.
• the disease or disorder is Parkinson's disease (PD) . In some embodiments of a method disclosed herein, the disease or disorder is Alzheimer's disease (AD) . In some embodiments of a method disclosed herein, the disease or disorder is anemia, inflammatory bowel disease (IBD) , or chronic kidney disease (CKD) . In some embodiments of a method disclosed herein, the disease or disorder is anemia. In some embodiments of a method disclosed herein, the disease or disorder is inflammatory bowel disease (IBD) . In some embodiments of a method disclosed herein, the disease or disorder is ulcerative colitis ( “UC” ) or Crohn’s disease ( “CD” ) . In some embodiments of a method disclosed herein, the disease or disorder is chronic kidney disease (CKD) .
• UC ulcerative colitis
• CD Crohn’s disease
• Carboxyl refers to -COOH.
• Cyano refers to -CN.
• a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
• the alkyl is a C 1-10 alkyl.
• the alkyl is a C 1-6 alkyl.
• the alkyl is a C 1-5 alkyl.
• the alkyl is a C 1-4 alkyl.
• the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
• Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
• Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
• a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
• Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
• heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
• heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
• the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
• the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
• the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
• an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
• Y is -O-, -S-, or -NR 6 -;
• R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
• L is - (CR 7 R 8 ) p -;
• each R 7 and R 8 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
• R 7 and R 8 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 7a ;
• p 0-4;
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted;
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted; and
• W is absent or C 1 -C 6 alkylene
• X is N or CR 2 ;
• Y is -O-, -S-, or -NR 6 -;
• R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
• R 2 is hydrogen, fluoro, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen.
• Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is phenyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is 6-membered pyridyl.
• n is 0. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 3.
• R 1 is optionally substituted C 1 -C 6 haloalkyl. In some embodiments, R 1 is optionally substituted C 1 -C 6 hydroxyalkyl. In some embodiments, R 1 is optionally substituted C 1 -C 6 aminoalkyl. In some embodiments, R 1 is optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 1 is optionally substituted C 2 -C 6 alkenyl. In some embodiments, R 1 is optionally substituted C 2 -C 6 alkynyl. In some embodiments, R 1 is optionally substituted cycloalkyl. In some embodiments, R 1 is optionally substituted heterocycloalkyl.
• R 1 is heterocycloalkyl optionally and independently substituted with one or more R 1a .
• R 1 is a monocyclic heterocycloalkyl optionally and independently substituted with one or more R 1a .
• R 1 is a 4 membered, optionally substituted monocyclic heterocycloalkyl.
• R 1 is a 5 membered, optionally substituted monocyclic heterocycloalkyl.
• R 1 is which is optionally substituted with 1 or 2 R 1a . In some embodiments, R 1 is which is optionally substituted with 1 or 2 R 1a . In some embodiments, R 1 is which is optionally substituted with 1 or 2 R 1a . In some embodiments, R 1 is which is optionally substituted with 1 or 2 R 1a .
• R 1 is a bicyclic heterocycloalkyl optionally and independently substituted with one or more R 1a .
• R 1 is a spiro bicyclic heterocycloalkyl.
• R 1 is a fused bicyclic heterocycloalkyl.
• R 1 is a bridged bicyclic heterocycloalkyl.
• R 1 is a 8-10 membered, optionally substituted bicyclic heterocycloalkyl.
• R 1 is each of which is optionally substituted with one or more R 1a (e.g., 1, 2, or 3 R 1a ) .
• R 1 is which is unsubstituted or substituted with 1 or 2 R 1a .
• R 1 is which is unsubstituted or substituted with 1 or 2 R 1a .
• R 1 is which is unsubstituted or substituted with 1 or 2 R 1a .
• R 1 is which is unsubstituted or substituted with 1 or 2 R 1a .
• R 1 is which is unsubstituted or substituted with 1 or 2 R 1a .
• R 1 is which is unsubstituted or substituted with 1 or 2 R 1a . In some embodiments, R 1 is which is unsubstituted or substituted with 1 or 2 R 1a . In some embodiments, R 1 is which is unsubstituted or substituted with 1 or 2 R 1a . In some embodiments, R 1 is which is unsubstituted or substituted with 1 or 2 R 1a . In some embodiments, R 1 is which is unsubstituted or substituted with 1 or 2 R 1a .
• R 1 is piperidinyl optionally substituted with one or more R 1a .
• R 1 is 2-oxa-5-azabicyclo [2.2.1] heptane optionally substituted with one or more R 1a .
• R 1 is heterocycloalkyl optionally and independently substituted with one or more R 1a (e.g., 1 or 2 R 1a ) .
• R 1 is monocyclic heterocycloalkyl optionally and independently substituted with 1 or 2 R 1a .
• R 1 is unsubstituted.
• R 1 is -W-OR a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is -OR a . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is -O-C 1 -C 6 alkylene (cycloalkyl) or -O-C 1 -C 6 alkylene (heterocycloalkyl) , each optionally and independently substituted with one or more R 1a .
• R 1 is -W-NR c R d .
• R 1 is
• R 1 is
• W is absent. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W is C 1 -C 2 alkylene. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W is C 1 alkylene.
• R 1 is
• R 1 is
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
• each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is hydrogen. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently C 1 -C 6 alkyl.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
• each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d are hydrogen. In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d are independently C 1 -C 6 alkyl.
• R c is hydrogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 haloalkyl.
• R d is hydrogen, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) .
• R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
• each R is independently halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• each R 1 , R 9 , R a , R b , R c , R d , the heterocycloalkyl formed when R 7 and R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is optionally and independently substituted with one, two, three, or four substituents as defined herein.
• each R 1 , R 9 , R a , R b , R c , R d , the heterocycloalkyl formed when R 7 and R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is optionally and independently substituted with one, two, or three substituents as defined herein.
• each R 1 , R 9 , R a , R b , R c , R d , the heterocycloalkyl formed when R 7 and R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is optionally and independently substituted with one or two substituents as defined herein.
• each R 1 , R 9 , R a , R b , R c , R d , the heterocycloalkyl formed when R 7 and R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is optionally and independently substituted with one substituent as defined herein.
• the abundance of deuterium in each of R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , W, R a , R b , R c , and/or R d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%of a total number of hydrogen and deuterium.
• one or more hydrogens are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , W, R a , R b , R c , and/or R d .
• the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
• Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
• mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
• the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
• dissociable complexes are preferred.
• the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
• the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
• the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
• the compounds described herein exist in their isotopically-labeled forms.
• the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
• the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
• the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H (T) , 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
• Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%of a total number of hydrogen and deuterium.
• one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
• one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
• the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
• the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
• Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
• the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and 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, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
• other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
• those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
• a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
• Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
• bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
• Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
• the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
• Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
• Disclosed herein is a method of treating a disease in which inhibition of PHD is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the method comprises administering a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• Disclosed herein is a method of treating a disease or disorder associated with PHD, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the method comprises administering a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• Disclosed herein is a method of treating a disease or disorder in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the disease or disorder is cardiovascular disorders, metabolic disorders, hematological disorders, pulmonary disorders, kidney disorders, liver disorders, wound healing disorders, or cancer.
• the method comprises administering a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• a method of treating a disease or disorder in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the disease or disorder is stroke, myocardial infarction, congestive heart failure, atherosclerosis, chronic venous insufficiency, cardiac cirrhosis, acute decompensated heart failure, heart failure following a heart attack, peripheral artery disease, occlusive artery disease, diabetes, hyperglycemia, insulin resistance, metabolic syndrome X, impaired glucose tolerance, non-alcoholic liver steatosis, chronic obstructive pulmonary disease, pulmonary embolism, pulmonary hypertension, mountain sickness, acute respiratory failure, interstitial lung disease, idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphoid interstitial
• the disease or disorder is anemia, inflammatory bowel disease (IBD) , or chronic kidney disease (CKD) .
• the disease or disorder is anemia.
• the disease or disorder is inflammatory bowel disease (IBD) .
• the disease or disorder is chronic kidney disease (CKD) .
• the disease or disorder is ulcerative colitis ( “UC” ) or Crohn’s disease ( “CD” ) .
• the disease or disorder is ulcerative colitis ( “UC” ) .
• the disease or disorder is Crohn’s disease ( “CD” ) .
• a method of treating a disease or disorder in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the disease or disorder is cancer, including leukemia (e.g., chronic myelogenous leukemia and chronic lymphocytic leukemia) ; breast cancer; genitourinary cancer; skin cancer; bone cancer; prostate cancer; liver cancer; brain cancer; cancer of the larynx, gall bladder, rectum, parathyroid, thyroid, adrenal, neural tissue, bladder, head, neck, stomach, bronchi, and kidneys; basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteosarcoma, Ewing's sarcoma, reticulum cell sarcoma, and Kaposi's sarcoma; myeloma, giant cell tumor, islet cell tumor, acute and chronic lymphocytic and granulocytic tumors;
• leukemia e.
• disclosed herein is a method of treating a disease or disorder in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the same.
• a method of modulating PHD in a subject in need thereof is a method of inhibiting PHD in a subject in need thereof.
• a method of stabilizing hypoxia inducible factor (HIF) in a subject the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the same.
• HIF hypoxia inducible factor
• the HIF is HIF-1 ⁇ .
• the method comprises administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the method comprises administering a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the subject has a disease or disorder that is cardiovascular disorders, metabolic disorders, hematological disorders, pulmonary disorders, kidney disorders, liver disorders, wound healing disorders, or cancer.
• the subject has a disease or disorder that is stroke, myocardial infarction, congestive heart failure, atherosclerosis, chronic venous insufficiency, cardiac cirrhosis, acute decompensated heart failure, heart failure following a heart attack, peripheral artery disease, occlusive artery disease, diabetes, hyperglycemia, insulin resistance, metabolic syndrome X, impaired glucose tolerance, non-alcoholic liver steatosis, chronic obstructive pulmonary disease, pulmonary embolism, pulmonary hypertension, mountain sickness, acute respiratory failure, interstitial lung disease, idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphoid interstitial pneumonia, acute kidney failure, acute kidney injury, renal ischemia reperfusion injury, hepatic ischemia reperfusion injury, diabetic foot ulcers, pressure ulcers, venous ulcers, arterial
• the disease or disorder is Parkinson's disease (PD) .
• the disease or disorder is Alzheimer's disease (AD) .
• the disease or disorder is anemia, inflammatory bowel disease (IBD) , or chronic kidney disease (CKD) .
• the disease or disorder is anemia.
• the disease or disorder is anemia resulting from chronic kidney diseases.
• the disease or disorder is inflammatory bowel disease (IBD) .
• the disease or disorder is chronic inflammation of the digestive tract.
• the disease or disorder is ulcerative colitis (UC) .
• the disease or disorder is Crohn’s disease (CD) .
• the disease or disorder is chronic kidney disease (CKD) .
• the disease or disorder is cancer, including leukemia (e.g., chronic myelogenous leukemia and chronic lymphocytic leukemia) ; breast cancer; genitourinary cancer; skin cancer; bone cancer; prostate cancer; liver cancer; brain cancer; cancer of the larynx, gall bladder, rectum, parathyroid, thyroid, adrenal, neural tissue, bladder, head, neck, stomach, bronchi, and kidneys; basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteosarcoma, Ewing's sarcoma, reticulum cell sarcoma, and Kaposi's sarcoma; myeloma, giant cell tumor, islet cell tumor, acute and chronic lymphocytic and granulocytic tumors; hairy-cell tumor, adenoma, medullary carcinoma, pheochromocytoma, mucosal neuromas
• leukemia e
• ESAs erythropoiesis stimulating agents
• IBD Inflammatory Bowel Disease
• Inflammatory bowel diseases are characterized by repeated inflammation and wounding of the mucosa and loss of the intestinal epithelial barrier function, which lead to the passage of bacteria or bacterial products from the gut lumen to the serosa and into the blood, resulting in systemic bacteremia and endotoxemia.
• PHD inhibition has been shown to reduce disease severity in murine models of colitis on several levels of clinical scoring.
• the proposed mechanism for the therapeutic activity of PHD inhibitors is through HIF-1 ⁇ stabilization, which drives epithelial barrier augmentation and healing.
• compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.
• a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition is defined to be a “prophylactically effective amount or dose. ”
• the precise amounts also depend on the patient’s state of health, weight, and the like.
• effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician.
• the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
• the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday” ) .
• the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
• the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
• the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage, or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
• Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 10 and the ED 90 .
• the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
• the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
• the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
• the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
• the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours.
• the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
• the length of the drug holiday varies from 2 days to 1 year.
• Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
• parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
• a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
• long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
• the liposomes are targeted to and taken up selectively by the organ.
• the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
• the compound described herein is administered topically.
• the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
• the compounds of this invention may be administered to animals.
• the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.
• compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
• Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
• a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
• the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
• compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular) , intranasal, buccal, topical, rectal, or transdermal administration routes.
• parenteral e.g., intravenous, subcutaneous, intramuscular
• intranasal e.g., buccal
• topical e.g., topical, rectal, or transdermal administration routes.
• the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
• compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
• compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
• disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions for parental use are formulated as infusions or injections.
• the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the pharmaceutical composition comprises a liquid carrier.
• the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like) , vegetable oils, nontoxic glyceryl esters, and any combinations thereof.
• the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.
• Disclosed herein are methods of treating a disease or disorder associated with PHD using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.
• the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.
• the additional therapeutic agent is a compound or therapy for cardiovascular disorders, metabolic disorders, hematological disorders, pulmonary disorders, kidney disorders, liver disorders, wound healing disorders, and cancer, among others.
• the additional therapeutic agent is an agent for treating metabolic disorders.
• these agents include pancreatic lipase inhibitors (e.g., orlistat) ; insulin; insulin sensitizers, including biguanides (e.g., buformin, metformin, and phenformin) and glitazones (e.g., pioglitazone and rosiglitazone) ; insulin secretagogues, including sulfonylureas (e.g., acetohexamide, chlorpropamide, tolazamide, tolbutamide, gliclazide, glimepiride, glipizide, and glyburide) , and meglitinides (e.g., nateglinide and repaglinide) ; alpha-glucosidase inhibitors (e.g., acarbose and miglitol) ; glucagon-like peptide analogs and agonists (e.g.,
• the additional therapeutic agent is an agent for treating wound healing disorders.
• the additional therapeutic agent is an anti-inflammatory agent, analgesics, an antipruritic, or an anti-infective.
• anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids.
• Representative NSAIDs include apazone, aspirin, celecoxib, diclofenac (with and without misoprostol) , diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate, and sulindac.
• NSAIDs nonsteroidal anti-inflammatory drugs
• corticosteroids include apazone, aspirin, celecoxib, diclofenac (with and without misoprostol) , diflunisal, etodolac, fenoprofen, flur
• Representative corticosteroids include betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.
• Representative analgesics include acetaminophen and morphine sulfate, as well as codeine, hydrocodone, oxycodone, propoxyphene, and tramadol, all with or without acetaminophen.
• Representative antipruritics for systemic use include cyproheptadine, diphenhydramine, gabapentin, hydroxyzine, and ondansetron.
• Example anti-infective agents may include antibacterials, antifungals, and antivirals.
• antibacterials include atovaquone, aztreonam, bacitracin, chloramphenicol, colistimethate, dalfopristin/quinupristin, daptomycin, erythromycin/sulfisoxazole, fosfomycin, metronidazole, pentamidine, rifaximin, spectinomycin, and trimetrexate.
• the additional therapeutic agent is an anti-cancer agent.
• the additional therapeutic agent is a chemotherapeutic agent (i.e., cytotoxic, or antineoplastic agents) such as alkylating agents, antibiotics, antimetabolic agents, plant-derived agents, and topoisomerase inhibitors, as well as molecularly targeted drugs which block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.
• chemotherapeutic agent i.e., cytotoxic, or antineoplastic agents
• cytotoxic, or antineoplastic agents such as alkylating agents, antibiotics, antimetabolic agents, plant-derived agents, and topoisomerase inhibitors, as well as molecularly targeted drugs which block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.
• Molecularly targeted drugs include both small molecules and biologics.
• Representative alkylating agents include bischloroethylamines (nitrogen mustards) including chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, and uracil mustard) ; aziridines, including thiotepa; alkyl alkone sulfonates, including busulfan; nitrosoureas, including carmustine, lomustine, and streptozocin; nonclassical alkylating agents, including altretamine, dacarbazine, and procarbazine; and platinum compounds, including carboplatin, cisplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.
• nitrogen mustards including chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, and uracil mustard
• aziridines including thiot
• antibiotic agents include anthracyclines, including aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin; anthracenediones, including mitoxantrone and pixantrone; and Streptomyces, including actinomycin, bleomycin, dactinomycin, mitomycin C, and plicamycin.
• anthracyclines including aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin
• anthracenediones including mitoxantrone and pixantrone
• Streptomyces including actinomycin, bleomycin, dactinomycin, mitomycin C, and plicamycin.
• Representative antimetabolic agents include dihydrofolate reductase inhibitors, including aminopterin, methotrexate, and pemetrexed; hymidylate synthase inhibitors, including raltitrexed and pemetrexed; folinic acid, including leucovorin; adenosine deaminase inhibitors, including pentostatin; halogenated/ribonucleotide reductase inhibitors, including cladribine, clofarabine, and fludarabine; thiopurines, including thioguanine and mercaptopurine; thymidylate synthase inhibitors, including fluorouracil, capecitabine, tegafur, carmofur, and floxuridine; DNA polymerase inhibitors, including cytarabine; ribonucleotide reductase inhibitors, including gemcitabine; hypomethylating agent, including azacitidine and decitabine; rib
• Representative plant-derived agents include vinca alkaloids, including vincristine, vinblastine, vindesine, vinzolidine, and vinorelbine; podophyllotoxins, including etoposide and teniposide; and taxanes, including docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel.
• cytokines include interleukin-2 (IL-2, aldesleukin) , interleukin 4 (IL-4) , interleukin 12 (IL-12) , and interferon, which includes more than 23 related subtypes.
• cytokines include granulocyte colony stimulating factor (CSF) (filgrastim) and granulocyte macrophage CSF (sargramostim) .
• immuno-modulating agents include bacillus Calmette-Guerin, levamisole, and octreotide; monoclonal antibodies against tumor antigens, such as trastruzumab and rituximab; and cancer vaccines, which induce an immune response to tumors.
• Specific molecularly targeted drugs include selective estrogen receptor modulators, such as tamoxifen, toremifene, fulvestrant, and raloxifene; antiandrogens, such as bicalutamide, nilutamide, megestrol, and flutamide; and aromatase inhibitors, such as exemestane, anastrozole, and letrozole.
• selective estrogen receptor modulators such as tamoxifen, toremifene, fulvestrant, and raloxifene
• antiandrogens such as bicalutamide, nilutamide, megestrol, and flutamide
• aromatase inhibitors such as exemestane, anastrozole, and letrozole.
• agents which inhibit signal transduction include agents which inhibit signal transduction, such as imatinib, dasatinib, nilotinib, trastuzumab, gefitinib, erlotinib, cetuximab, lapatinib, panitumumab, and temsirolimus; agents that induce apoptosis, such as bortezomib; agents that block angiogenesis, such as bevacizumab, sorafenib, and sunitinib; agents that help the immune system destroy cancel cells, such as rituximab and alemtuzumab; and monoclonal antibodies which deliver toxic molecules to cancer cells, such as gemtuzumab ozogamicin, tositumomab, 1311-tositumoab, and ibritumomab tiuxetan.
• agents which inhibit signal transduction such as imatinib, dasatinib, n
• Example 29 500 mg, 1.02 mmol, 32%yield) as a white solid.
• Example 1 (7 mg, 17.64 ⁇ mol, 5%yield) was obtained as a white solid.
• Example 6 (13.3 mg, 12%yield) as a white solid.
• Example 22 The synthesis of N- ( (6-carbamoylpyridin-3-yl) methyl) -5-hydroxy-2-morpholino-1, 7-naphthyridine-6-carboxamide
• Example 24 The synthesis of 5- ( (5-hydroxy-2-morpholino-1, 7-naphthyridine-6-carboxamido) methyl) picolinic acid
• Example 41 The synthesis of (S) -N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-2- (3- (piperazine-1-carbonyl) pyrrolidin-1-yl) -1, 7-naphthyridine-6-carboxamide
• Example 46 The synthesis of (R) -2- (4-acetyl-3- (hydroxymethyl) piperazin-1-yl) -N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-1, 7-naphthyridine-6-carboxamide
• Example 60 The synthesis of (R) -N- (2-chloro-4-cyanobenzyl) -5-hydroxy-2- (3- (hydroxymethyl) piperazin-1-yl) -1, 7-naphthyridine-6-carboxamide
• Example 59 The synthesis of (R) -N- (2-chloro-4-cyanobenzyl) -5-hydroxy-2- (3- (hydroxymethyl) -4-methylpiperazin-1-yl) -1, 7-naphthyridine-6-carboxamide
• Example 59 (13.39 mg, 0.03 mmol, 26%yield) as a pale yellow solid.
• Example 63 The synthesis of (R) -2- (4-acetyl-3- (hydroxymethyl) piperazin-1-yl) -N- (2-chloro-4-cyanobenzyl) -5-hydroxy-1, 7-naphthyridine-6-carboxamide
• Example 63 (6.75 mg, 0.01 mmol, 9%yield) as a pale yellow solid.
• Example 72 The synthesis of N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-2- (4- (3-hydroxypropanoyl) piperazin-1-yl) -1, 7-naphthyridine-6-carboxamide
• Example 72 (7.07 mg, 0.02 mmol, 12%yield) as a pale yellow solid.
• Example 93 The synthesis of 2-hydroxyethyl 6- ( ( (6-cyanopyridin-3-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridine-2-carboxylate
• example 99 100 mg, 0.29 mmol
• 2-diol 3 mL
• SOCl 2 0.031 mL, 0.43 mmol
• the reaction was stirred at room temperature overnight.
• the reaction was concentrated in vacuo.
• the residue was purified by pre-HPLC to give example 93 (14.39 mg, 13%) .
• Example 99 The synthesis of 6- ( ( (6-cyanopyridin-3-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridine-2-carboxylic acid
• example 90 200 mg, 0.55 mmol
• THF 2 mL
• H 2 O 2 mL
• LiOH 69 mg, 1.65 mmol
• the reaction was stirred at room temperature for 1 h.
• the reaction was extracted with EA (25 mL ⁇ 3) .
• the organic layer was separated, washed with further saturated NaCl solution, and concentrated in vacuo. The residue was washed by MeOH (10 mL ⁇ 3) and purified by pre-HPLC to afford example 99 (4.81 mg, 3%) .
• Example 85 The sytnhesis of N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-2- (2-oxomorpholino) -1, 7-naphthyridine-6-carboxamide and example 115: The sytnhesis of ethyl N- (6- ( ( (6-cyanopyridin-3-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridin-2-yl) -N- (2-hydroxyethyl) glycinate
• Example 90 The synthesis of methyl 6- ( ( (6-cyanopyridin-3-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridine-2-carboxylate
• Example 110 The syntheis of N 2 -butyl-N 6 - ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-1, 7-naphthyridine-2, 6-dicarboxamide
• example 90 114 mg, 0.31 mmol
• THF 3 mL
• butan-1-amine 0.153 mL, 1.55 mmol
• MgCl 2 30 mg
• the reaction was stirred at room temperature overnight.
• the reaction was poured into water (50 mL) , extrated with EA (30 mL ⁇ 3) .
• the organic layer was washed with aq. NaCl (30 mL ⁇ 3) , dried over Na 2 SO 4 , and concentrated in vacuo.
• the crude was purified by prep-HPLC to afford example 110 (16.02 mg, 13%) .
• Example 124 The synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-1, 7-naphthyridine-6-carboxamide
• example 123 100 mg, 0.198 mmol was added formic acid (3 mL, 0.225 mmol) , and the reaction was stirred at 25 °C for 3 h. The reaction was concentrated in vacuo. The residue was purified by prep-HPLC to afford example 124 (34.39 mg, 43%) .
• Example 126 The synthesis of (S) -2- (3-aminopyrrolidin-1-yl) -N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-1, 7-naphthyridine-6-carboxamide
• example 125 110 mg, 0.225 mmol
• formic acid 3 mL, 0.225 mmol
• formic acid 3 mL, 0.225 mmol
• the reaction was stirred at 25 °C for 3 h.
• the reaction was concentrated in vacuo.
• the residue was purified by prep-HPLC to afford example 126 (22.01 mg, 24%) .
• Example 130 The synthesis of isopropyl 6- ( ( (6-cyanopyridin-3-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridine-2-carboxylate
• example 99 100 mg, 0.286 mmol
• i-PrOH 5 mL
• SOCl 2 0.062 mL, 0.859 mmol
• Example 15 The synthesis of (6-cyanopyridin-3-yl) methyl (R) -5-hydroxy-2- (3-hydroxypyrrolidin-1-yl) -1, 7-naphthyridine-6-carboxylate
• Example 98 The synthesis of N- ( (6-cyanopyridin-3-yl) methyl) -2, 5-dihydroxy-1, 7-naphthyridine-6-carboxamide
• Example 102 The synthesis of N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-2- (2-oxopiperazin-1-yl) -1, 7-naphthyridine-6-carboxamide
• example 101 150 mg, 0.298 mmol
• HCl/EA 3M, 2 mL
• the mixture was filtered and concentrated.
• the crude was purified by pre-HPLC to give example 102 (24.15 mg, 19%) .
• Example 97 The synthesis of 2-amino-N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-1, 7-naphthyridine-6-carboxamide
• Example 128 2- (3-aminoazetidin-1-yl) -N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-1, 7-naphthyridine-6-carboxamide
• example 127 (28 mg, 0.059 mmol) in HCl/EA (3 M, 5 mL) was stirred at rt for 1 h, and the reaction was concentrated in vacuo. The residue was purified by pre-HPLC to afford example 128 (29.91 mg, 38%) .
• Example 134 The synthesis of tert-butyl 4- (6- ( ( (5-cyanopyrazin-2-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridin-2-yl) piperazine-1-carboxylate
• Example 147 The synthesis of tert-butyl (2- ( (6- ( ( (6-cyanopyridin-3-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridin-2-yl) thio) ethyl) carbamate
• Example 129 The synthesis of ethyl 6- ( ( (6-cyanopyridin-3-yl) methyl) carbamoyl) -5-hydroxy-1, 7-naphthyridine-2-carboxylate
• Example 163 The synthesis of N- ( (6-cyanopyridin-3-yl) methyl) -5-methoxy-2-morpholino-1, 7-naphthyridine-6-carboxamide
• example 10 100 mg, 0.256 mmol
• acetone (2 mL) 2 mL
• MeI 360 mg, 2.536 mmol
• K 2 CO 3 180 mg, 1.302 mmol
• the reaction was heated to50 °C for 2 h, and the solution was diluted with water (10 mL) and extracted with EA (5 mL ⁇ 3) , the EA layer was combined and washed with brine (5 mL) , and dried over Na 2 SO 4 , and concentrated , and the residue was purified by pre-HPLC to afford example 163 (3.76 mg, 4%) .
• Example 55 The synthesis of N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-2- ( (methyl ( (tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) -1, 7-naphthyridine-6-carboxamide
• Example 40 The synthesis of 5-hydroxy-N- ( (6-hydroxypyridin-3-yl) methyl) -2-morpholino-1, 7-naphthyridine-6-carboxamide
• example 34 129 mg, 0.33 mmol
• acetonitrile 5.0 mL
• iodotrimethylsilane 0.14 mL, 1.00 mmol
• the resulting mixture was stirred at 80 °C for 18 h.
• the residue was purified by prep-HPLC to give example 40 (50.95 mg, 41%) .
• Example 167 The synthesis of N- ( (6-cyanopyridin-3-yl) methyl) -5-hydroxy-2- (hydroxymethyl) -1, 7-naphthyridine-6-carboxamide
• example 90 750 mg, 2.06 mmol
• MeOH MeOH
• NaBH 4 1.009 mL, 30.90 mmol
• the reaction was stirred at room temperature for 16 h.
• the reaction mixture was poured into saturated NH 4 Cl (100 mL) , and extracted with EA (40 mL ⁇ 3) .
• the combined organic layer was dried over Na 2 SO 4 , filtered and evaporated.
• the residue was purified by silica gel column chromatography. The organic layer was collected, and then purified by prep-HPLC to afford the title compound example 167 (13.95 mg, 22%) .
• ALPHASCREEN signal (ALPcmpd) is calculated for each well
• Cell seeding Added 100 ⁇ l cell suspension contain 20k Hep3B cell per well.
• Preparation of compound concentration gradient Compounds at top dose of 100 ⁇ M, 3-fold dilution, 8 doses, singlet or duplicate. Prepare a solution of 200x the final concentration in a 96-well plate, dilute the compound by 200/3x with cell culture medium, and then pipette 50 ⁇ L to wells. Add 50 ⁇ L of culture medium containing DMSO to the minimum control well to make the final concentration contain 5 ⁇ DMSO, and add 50 ⁇ L of the highest concentration of reference compound to the maximum control well, and incubate at 37°C for 24h.
• %Act. (Compound signal -Min signal) / (Max signal -Min signal) *100.
• Max signal was obtained from the maximum control wells.
• Min signal was obtained from the minimum control wells.
• Cells Caco2-HIF1 ⁇ -HiBiT -clone-1 cells.
• Culture medium EMEM contain 20%FBS, 1%Penicillin-Streptomycin for Caco-2
• PHD2 (nM) 0 ⁇ A ⁇ 5; 5 ⁇ B ⁇ 20; 20 ⁇ C ⁇ 100; 100 ⁇ D ⁇ 1,000; 1,000 ⁇ E ⁇ 100,000
• Caco2-HIF1 ⁇ -HiBit assay (EC50, nM) : 0 ⁇ A ⁇ 2,500; 2,500 ⁇ B ⁇ 5,000; 5,000 ⁇ C ⁇ 7500; 7,500 ⁇ D ⁇ 10,000; 10,000 ⁇ E ⁇ 100,000

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