WO2023076219A2 - Antagonistes de la protéine gpr39 - Google Patents

Antagonistes de la protéine gpr39 Download PDF

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WO2023076219A2
WO2023076219A2 PCT/US2022/047658 US2022047658W WO2023076219A2 WO 2023076219 A2 WO2023076219 A2 WO 2023076219A2 US 2022047658 W US2022047658 W US 2022047658W WO 2023076219 A2 WO2023076219 A2 WO 2023076219A2
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group
alkyl
compound
halogen
pharmaceutically acceptable
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PCT/US2022/047658
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WO2023076219A3 (fr
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Agostino CIANCIULLI
Fabrizio Micheli
Iuni Margaret Laura TRIST
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Vasocardea, Inc.
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Publication of WO2023076219A2 publication Critical patent/WO2023076219A2/fr
Publication of WO2023076219A3 publication Critical patent/WO2023076219A3/fr

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    • 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
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • C07D403/10—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 aromatic 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
    • C07D403/14—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
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—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
    • C07D417/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure concerns novel compounds that act as antagonists to human
  • GPR39 protein is a novel GPR39 protein. Additionally, the present disclosure relates to pharmaceutical compositions and methods of using antagonists to human GPR39 protein in the treatment of diseases or conditions including cardiovascular conditions, endocrine system and hormone disorders, cancer disorders, metabolic diseases, gastrointestinal and liver diseases, hematological disorders, neurological disorders and respiratory diseases.
  • diseases or conditions including cardiovascular conditions, endocrine system and hormone disorders, cancer disorders, metabolic diseases, gastrointestinal and liver diseases, hematological disorders, neurological disorders and respiratory diseases.
  • GPR39 antagonists have been described for methods of treating pain sensitivity, including hyperalgesia, and suppressing appetite (U.S. Pat. Publication 2009/0298756 - Jin et al.).
  • GPR39 agonists and/or antagonists in enhancing glucose regulation and treating impaired carbohydrate metabolism, including in disorders such as diabetes and metabolic syndrome are discussed in WO 2007/141322 - Moreaux et al. - Janssen Pharmaceutica N.V.
  • GPR39 receptor antagonists may be useful in disorders affecting stomach motility, including such as functional dyspepsia and diabetic gastroparesis and/or colorectal motility such as irritable bowel syndrome, diarrhea, or chronic constipation.
  • GPR39 antagonists in the treatment of various cancers is discussed in U.S.
  • Inge Depoortere discloses uses of GPR39 antagonists in treating motility disorders, such as functional dyspepsia, hypoparesis, and chronic constipation in her article, Gl functions of GPR39: novel biology, Current Opinion in Pharmacology, 2012, 12:647-652.
  • the zinc sensing receptor, ZnR/GPR39 controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon, Cohen et al., Cell Death and
  • GPR antagonists in promoting or enhancing colon epithelial function and tight junction barrier integrity, including treating ulcerative colon diseases, such as ulcerative colitis, and diarrheal pathologies.
  • X 1 is selected from the group of:
  • R a is selected from the group of hydrogen and C 1 -C 3 alkyl;
  • X 2 is selected from the group of: the wavy line in each instance represents a bond through which each X 1 and X 2 moiety is bound;
  • n c is an integer selected from the group of 1,
  • each of R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen,
  • n1 is an integer selected from the group of 0, 1, 2, and 3;
  • R 2 is selected from the group of carbocycle and a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system bound through a carbon atom and containing 3, 4, 5, 6, 7, or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O, with any of the foregoing substituted by 0, 1, 2, or 3 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -(CH 2 ) n1 -C 3 -C 6 cycloalkyl, -CF 3 , halogen, oxo, cyano, -O-(CH 2 ) n2 -C 3 -C 6 cycloalkyl,
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -O-C 1 -C 3 alkyl, with the proviso that R 2 is not pyridinyl unless substituted at least once by -(CH 2 ) n1 -C 3 -C 6 cycloalkyl or phenyl;
  • R 2 ' is selected from the group of hydrogen, OH, halogen, C 1 -C 6 alkyl, and -CF 3 ;
  • R 3 is present one or more times and is independently selected from the group of: a) hydrogen, halogen, cyano, or OH; b) -CO 2 H or -CO 2 -(C 1 -C 6 alkyl); c) C 1 -C 6 alkyl or -O-C 1 -C 6 alkyl substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF 3 , and OH; d) phenyl, benzyl, C 3 -C 6 cycloalkyl, and -CH 2 -C 3 -C 6 cycloalkyl, the rings of each of the phenyl, benzyl, C 3 -C 6 cycloalkyl, and -CH 2 -C 3 -C 6 cycloalkyl groups being substituted by
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from halogen, OH, CF 3 , and -O-C 1 - C 3 alkyl; and, when Y 2 is carbon, R 4 may also be -O-C 1 -C 6 alkyl or two R 4 may form a spirocyclic carbocycle or spirocyclic heterocycle; wherein the R 4 C 1
  • OH a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, substituted or unsubstituted phenyl, and -O-C 1 -C 3 alkyl;
  • R 5 is selected from the group of H and C 1 -C 6 alkyl, wherein the R 5 C 1 -C 6 alkyl group is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -
  • R x and R y are independently selected from the group of H and C 1 - C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -
  • R 6 is selected from the group of H, C 1 -C 6 alkyl, a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and 5, phenyl, and benzyl, wherein the R 6 C 1 -C 6 alkyl groups is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -NR x R y ,; and OH, and the rings of the R 6 phenyl and benzyl groups and the heterocyclic ring are substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, halogen, -CF 3 , and OH, wherein each of R x and R y ; are independently selected from the group of H and C 1 -C 6 alkyl, a heterocycl
  • X 1 is selected from the group of:
  • n a is an integer selected from the group of 0, 1, and 2; n b is an integer selected from the group of 0, 1, 2, 3, and 4; with the proviso that the sum of n a + n b is not less than 2 and not greater than 4; or X 1 and Z 1 together form a fused ring system of the formula (la):
  • R a is selected from the group of hydrogen and C 1 -C 3 alkyl
  • X 2 is selected from the group of: the wavy line in each instance represents a bond through which each X 1 and X 2 moiety is bound;
  • Y 1 is selected from the group of C and N;
  • Y 2 is selected from the group of C, N, S, and O, provided R 4 is not present when Y 2 is O and provided R 4 is either not present or present one or two times when Y 2 is S; with the proviso that no more than one of Y 1 and Y 2 are C;
  • n c is an integer selected from the group of 1, 2, and 3;
  • n d is an integer selected from the group of 1, 2, and 3; with the proviso that the sum of n c + n d is not less than 2 and not greater than 6;
  • Z 1 , Z 2 , and Z 3 are each independently selected from the group of C and N, with the proviso that Z 1 , Z 2 , and Z 3 , when bound to R 2 or non-hydrogen R 2 ' are C;
  • n1 is an integer selected from the group of 0, 1, 2, and 3;
  • R 2 is selected from the group of phenyl, pyridinyl bound through a carbon atom, and a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system bound through a nitrogen heteroatom and containing 3, 4, 5, 6, 7, or 8 ring carbon atoms and 0, 1, 2, 3, or 4 additional ring heteroatoms selected from the group of N, S, and O, with any of the foregoing substituted by 0, 1, 2, or 3 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -O-C 1 -C 3 alkyl, with the proviso that R 2 is not pyridinyl unless substituted at least once by -(CH 2 ) n1 -C 3 -C 6 cycloalkyl or phenyl; R 2 ' is selected from the group of OH, halogen, C 1 -C 6 alkyl, and -CF 3 ; R 3 is present one or more times and is independently selected from the group of: g
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from halogen, OH, CF 3 , and -O-C 1 - C 3 alkyl; and, when Y 2 is carbon, R 4 may also be -O-C 1 -C 6 alkyl or two R 4 may form a spirocyclic carbocycle or spirocyclic heterocycle; wherein the R 4 C 1
  • OH a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, substituted or unsubstituted phenyl, and -O-C 1 -C 3 alkyl;
  • R 5 is selected from the group of H and C 1 -C 6 alkyl, wherein the R 5 C 1 -C 6 alkyl group is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -
  • R 6 is selected from the group of H, C 1 -C 6 alkyl, a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, phenyl, and benzyl, wherein the R 6 C 1 -C 6 alkyl groups is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -NR x R y ,; and OH, and the rings of the R 6 phenyl and benzyl groups and the heterocyclic ring are substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, halogen, -CF 3 , and OH, wherein each of R x and R y ; are independently selected from the group of H and C 1
  • X 1 is selected from the group of:
  • n a is an integer selected from the group of 0, 1, and 2; n b is an integer selected from the group of 0, 1, 2, 3, and 4; with the proviso that the sum of n a + n b is not less than 2 and not greater than 4; or X 1 and Z 1 together form a fused ring system of the formula (la):
  • R a is selected from the group of hydrogen and C 1 -C 3 alkyl
  • X 2 is selected from the group of: the wavy line in each instance represents a bond through which each X 1 and X 2 moiety is bound;
  • Y 1 is selected from the group of C and N;
  • Y 2 is selected from the group of C, N, 5, and O, provided R 4 is not present when Y 2 is O and provided R 4 is either not present or present one or two times when Y 2 is 5; with the proviso that no more than one of Y 1 and Y 2 are C;
  • n c is an integer selected from the group of 1, 2, and 3;
  • n d is an integer selected from the group of 1, 2, and 3; with the proviso that the sum of n c + n d 2, 3, 5, or 6;
  • Z 1 , Z 2 , and Z 3 are each independently selected from the group of C and N, with the proviso that Z 1 , Z 2 , and Z 3 , when bound to R 2 or non-hydrogen R 2 ' are C;
  • R 1 is selected
  • each of R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen,
  • n1 is an integer selected from the group of 0, 1, 2, and 3;
  • R 2 is selected from the group of phenyl, pyridinyl bound through a carbon atom, and a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system bound through a nitrogen heteroatom and containing 3, 4, 5, 6, 7, or 8 ring carbon atoms and 0, 1, 2, 3, or 4 additional ring heteroatoms selected from the group of N, S, and O, with any of the foregoing substituted by 0, 1, 2, or 3 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -O-C 1 -C 3 alkyl, with the proviso that R 2 is not pyridinyl unless substituted at least once by -(CH 2 ) n1 -C 3 -C 6 cycloalkyl or phenyl; R 2 ' is selected from the group of hydrogen, OH, halogen, C 1 -C 6 alkyl, and -CF 3 ; R 3 is present one or more times and is independently selected from the group of:
  • OH a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, substituted or unsubstituted phenyl, and -O-C 1 -C 3 alkyl;
  • R 5 is selected from the group of H and C 1 -C 6 alkyl, wherein the R 5 C 1 -C 6 alkyl group is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -
  • R x and R y are independently selected from the group of H and C 1 - C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -
  • R 6 is selected from the group of H, C 1 -C 6 alkyl, a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, phenyl, and benzyl, wherein the R 6 C 1 -C 6 alkyl groups is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -NR x R y ,; and OH, and the rings of the R 6 phenyl and benzyl groups and the heterocyclic ring are substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, halogen, -CF 3 , and OH, wherein each of R x and R y ; are independently selected from the group of H and C 1
  • a compound of Formula (l-D), or a pharmaceutically acceptable salt thereof wherein: X 1 is selected from the group of: n a is an integer selected from the group of 0, 1, and 2; n b is an integer selected from the group of 0, 1, 2, 3, and 4; with the proviso that the sum of n a + n b is not less than 2 and not greater than 4; or X 1 and Z 1 together form a fused ring system of the formula (la):
  • R a is selected from the group of hydrogen and C 1 -C 3 alkyl
  • X 2 is selected from the group of: the wavy line in each instance represents a bond through which each X 1 and X 2 moiety is bound
  • Y 1 is selected from the group of C and N
  • Y 2 is selected from the group of C, N, S, and O, provided R 4 is not present when Y 2 is O and provided R 4 is either not present or present one or two times when Y 2 is S; with the proviso that no more than one of Y 1 and Y 2 are C
  • n c is an integer selected from the group of 1, 2, and 3
  • n d is an integer selected from the group of 1, 2, and 3; with the proviso that the sum of n c + n d is not less than 2 and not greater than 6
  • Z 1 , Z 2 , and Z 3 are each independently selected from the group of C and N, with the proviso that Z 1 , Z 2 , and Z 3 ,
  • n1 is an integer selected from the group of 0, 1, 2, and 3;
  • R 2 is selected from the group of phenyl, pyridinyl bound through a carbon atom, and a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system bound through a nitrogen heteroatom and containing 3, 4, 5, 6, 7, or 8 ring carbon atoms and 0, 1, 2, 3, or 4 additional ring heteroatoms selected from the group of N, S, and O, with any of the foregoing substituted by 0, 1, 2, or 3 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -O-C 1 -C 3 alkyl, with the proviso that R 2 is not pyridinyl unless substituted at least once by -(CH 2 ) n1 -C 3 -C 6 cycloalkyl or phenyl; R 2 ' is selected from the group of hydrogen, OH, halogen, C 1 -C 6 alkyl, and -CF 3 ; R 3 is present one or more times and is independently selected from the group of:
  • R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from halogen, OH, CF 3 , and -O-C 1 - C 3 alkyl; and, when Y 2 is carbon, R 4 may also be -O-C 1 -C 6 alkyl or two R 4 may form a spirocyclic carbocycle or spirocyclic heterocycle; wherein the R 4 C 1
  • OH a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, substituted or unsubstituted phenyl, and -O-C 1 -C 3 alkyl;
  • R 5 is selected from the group of H and C 1 -C 6 alkyl, wherein the R 5 C 1 -C 6 alkyl group is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -
  • R x and R y are independently selected from the group of H and C 1 - C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -
  • R 6 is selected from the group of H, C 1 -C 6 alkyl, a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, phenyl, and benzyl, wherein the R 6 C 1 -C 6 alkyl groups is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -NR x R y ,; and OH, and the rings of the R 6 phenyl and benzyl groups and the heterocyclic ring are substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, halogen, -CF 3 , and OH, wherein each of R x and R y ; are independently selected from the group of H and C 1
  • X 1 is selected from the group of:
  • n a is an integer selected from the group of 0, 1, and 2; n b is an integer selected from the group of 0, 1, 2, 3, and 4; with the proviso that the sum of n a + n b is not less than 2 and not greater than 4; or X 1 and Z 1 together form a fused ring system of the formula (la):
  • R a is selected from the group of hydrogen and C 1 -C 3 alkyl
  • X 2 is selected from the group of: the wavy line in each instance represents a bond through which each X 1 and X 2 moiety is bound;
  • Y 1 is selected from the group of C and N;
  • Y 2 is selected from the group of C, N, 5, and O, provided R 4 is not present when Y 2 is O and provided R 4 is either not present or present one or two times when Y 2 is 5; with the proviso that no more than one of Y 1 and Y 2 are C;
  • n c is an integer selected from the group of 1, 2, and 3;
  • n d is an integer selected from the group of 1, 2, and 3; with the proviso that the sum of n c + n d is not less than 2 and not greater than 6;
  • Z 1 , Z 2 , and Z 3 are each independently selected from the group of C and N, with the proviso that Z 1 , Z 2 , and Z 3 , when bound to R 2 or non-hydrogen R 2 ' are C;
  • each of R x and R y are independently selected from the group of H and C 1 -C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen,
  • n1 is an integer selected from the group of 0, 1, 2, and 3;
  • R 2 is selected from the group of phenyl, pyridinyl bound through a carbon atom, and a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system bound through a nitrogen heteroatom and containing 3, 4, 5, 6, 7, or 8 ring carbon atoms and 0, 1, 2, 3, or 4 additional ring heteroatoms selected from the group of N, S, and O, with any of the foregoing substituted by 0, 1, 2, or 3 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -
  • R 2 is not pyridinyl unless substituted at least once by -(CH 2 ) n1 -C 3 -C 6 cycloalkyl or phenyl;
  • R 2 ' is selected from the group of hydrogen, OH, halogen, C 1 -C 6 alkyl, and -CF 3 ;
  • R 3 is present one or more times and is independently selected from the group of: y) hydrogen, halogen, cyano, or OH; z) -CO 2 H or -CO 2 -(C 1 -C 6 alkyl); aa) C 1 -C 6 alkyl or -O-C 1 -C 6 alkyl substituted by 0,
  • R 4 is present one or two times and is halogen
  • R 5 is selected from the group of H and C 1 -C 6 alkyl, wherein the R 5 C 1 -C 6 alkyl group is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -
  • R x and R y are independently selected from the group of H and C 1 - C 6 alkyl substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF 3 , and -
  • R 6 is selected from the group of H, C 1 -C 6 alkyl, a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and 5, phenyl, and benzyl, wherein the R 6 C 1 -C 6 alkyl groups is further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF 3 , -NR x R y ,; and OH, and the rings of the R 6 phenyl and benzyl groups and the heterocyclic ring are substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group of C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, halogen, -CF 3 , and OH, wherein each of R x and R y ; are independently selected from the group of H and C 1 -C 6 alkyl, a heterocycl
  • Z 1 , Z 2 , and Z 3 are each C, and R a , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , n a , n b , n1, n2, and the provisos are as defined above for the corresponding Formulas (l-A), (l-B), (l-C), (l-D), or (l-E) through (l-ll).
  • Z 1 , Z 2 , and Z 3 are each N, and R a , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , n a , n b , n1, n2, and the provisos are as defined above for the corresponding Formulas (l-A), (l-B), (l-C), (l-D), or (l-E) through (l-ll).
  • R 7 is present one or two times and is independently selected from the group of hydrogen
  • CF 3 wherein any of the alkyl groups are further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, and wherein n1 is an integer selected from the group of 0, 1, 2, and 3.
  • R 7 is present one or two times and is independently selected from the group of hydrogen
  • CF 3 wherein any of the alkyl groups are further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, and wherein n1 is an integer selected from the group of 0, 1, 2, and 3.
  • R 2 is selected from the group of
  • R 7 and R 8 are in each instance independently selected from hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -CF 3 , and phenyl, with the proviso that only one of R 7 and R 8 may be phenyl.
  • R 7 and R 8 may be bound to any available ring carbon or nitrogen atom in either of the rings and that R 7 and R 8 may be bound to ring atoms in the same or different rings.
  • R 2 is selected from the group of:
  • R 7 and R 8 are in each instance independently selected from hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -CF 3 , and phenyl, with the proviso that only one of R 7 and R 8 may be phenyl.
  • separate embodiments comprising, respectfully, compounds for each of the Formulas (l-B), (l-C), (l-D), and (l-E), Formulas (I'), (I"), and (I'"), Formulas (1-1) through (1-7), and Formulas (l-a) through (l-ll), or a pharmaceutically acceptable salt thereof, wherein separate embodiments comprise a compound of each formula wherein R 2 is defined above.
  • R 2 is the azepane ring of group a) substituted by variable groups R 7 and R 8 .
  • Another embodiment comprises a compound of Formula (l-B), (l-C), (l-D), or (l-E), wherein R 2 is the azabicyclo[3.10.0]hexanyl ring of group b) substituted by variable groups R 7 and R 8 .
  • R 2 is the azabicyclo[3.10.0]hexanyl ring of group b) substituted by variable groups R 7 and R 8 .
  • each variable including Z 1 , Z 2 , Z 3 , R a , R 1 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , n a , n b , n1, n2, and the provisos are as defined above for the corresponding Formulas (l-B), (l-C), (l-D), and (l-E), Formulas (I'), (I"), and (I'"), Formulas (1-1) through (1-7), and Formulas (l-a) through (l-ll), and R 2 is selected from the group of: wherein R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, halogen, and -CF 3 .
  • each variable including Z 1 , Z 2 , Z 3 , R a , R 1 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , n a , n b , n1, n2, and the provisos are as defined above for the corresponding Formula (I), Formulas (1-1) through (1-7), and Formulas (l-a) through (l-ll), and R 2 is selected from the group of: wherein R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, and -CF 3 .
  • each variable including Z 1 , Z 2 , Z 3 , R a , R 1 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , n a , n b , n1, n2, and the provisos are as defined above for the corresponding Formula (I), Formulas (1-1) through (1-7), and Formulas (l-a) through (l-ll), and R 2 is selected from the group of: wherein R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, and -CF 3 .
  • R 2 is selected from the group of: wherein R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, and -CF 3 .
  • R 2 is selected from the group of:
  • R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, and -CF 3 .
  • R 7 and R 8 are selected from hydrogen, halogen, -CF 3 , C 1 -C 4 alkyl, and C 1 -C 4 alkoxy. In other embodiments, R 7 and R 8 are selected from hydrogen, halogen, -
  • CF 3 C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • R 3 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 3 - C 6 cycloalkyl, -CF 3 , -C 1 -C 4 alkyl-OH, phenyl, pyrazolyl, and thiophenyl, wherein the phenyl, pyrazolyl, and thiophenyl rings are substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, -CF 3 , C 1 -C 4 alkyl, and C 1 -C 4 alkoxy.
  • R 3 is selected from the group of phenyl, pyrazolyl, and thiophenyl, substituted by 0, 1, 2, or 3 substituents selected from the group of halogen, OH, -CF 3 , C 1 -C 4 alkyl, and C 1 -C 4 alkoxy.
  • each compound of Formulas (l-A), (l-B), (l-C), (l-D), and (l-E) and all other formulas and specifically named compounds herein are the pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, and pharmaceutically acceptable prodrugs of such compounds.
  • the compounds of the disclosure may possess an asymmetric center, and can be produced as a racemic mixture or as individual enantiomers.
  • the individual enantiomers may be obtained by asymmetric synthesis or by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis.
  • the individual enantiomers may also be obtained by resolution of the compound by conventional means, such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column.
  • HPLC high pressure liquid chromatography
  • BP blood pressure
  • TRH Treatment-resistant hypertension
  • a method of inhibiting the activity of a GPR39 protein in a subject comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (I-
  • a method of treating hypertension in a human in need thereof comprising administering to the human a pharmaceutically effective amount of a compound of
  • the hypertension to be treated is primary hypertension, which may also be referred to as essential hypertension.
  • the hypertension to be treated is secondary hypertension, including, but not limited to, hypertension caused by sleep apnea, blocked renal arteries, abnormal levels of hormones, enzymes, growth factors, or other agents controlling systemic or localized blood pressure (including, but not limited to, renin, angiotensin I and II, and aldosterone, angiotensin converting enzyme, catecholamines, thrombin, prostaglandins, natriuretic peptides, vasopressin, adreomedulin, Substance P, calcitonin gene related peptide, kallikreins, kininoogengs, kinins, kinin-degrading enzymes, phosducin, adipokines, and leptin), adrenal gland disease, thyroid abnormalities (including hyperthyroidism, hypothyroidism, Cushing's Disease,
  • the hypertension to be treated is treatment-resistant or refractory hypertension.
  • the hypertension to be treated is hypertensive urgency.
  • the hypertension to be treated is malignant hypertension, which may also be referred to as hypertensive emergency or hypertensive crisis.
  • the hypertension to be treated is isolated systolic hypertension.
  • the hypertension to be treated is salt-sensitive hypertension.
  • the hypertension to be treated is pulmonary hypertension.
  • a method of treating stroke in a human in need thereof comprising administering to the human a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (I-
  • Vascular dementia a small vessel disease in the brain compromises blood flow and oxygen delivery to brain cells, resulting in neuronal dysfunction.
  • Dementia due to small vessel disease is the second leading cause of dementia after Alzheimer's disease, and is the predominant cause in individuals over 70 and in developing countries.
  • a method of treating of dementia due to small vessel disease in a human in need thereof comprising administering to the human a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (I-
  • the compounds and compositions herein may also be used in methods of treating conditions associated with microvascular dysfunction and microvascular disease, with each method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of Formula (l-A),
  • diabetes in question is Type I diabetes mellitus.
  • diabetes in question is Type II diabetes mellitus.
  • prediabetic conditions also known as prediabetes.
  • Also provided is a method of treating heart failure in a human comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (I-
  • cSVD vascular cognitive impairment
  • VCI vascular cognitive impairment
  • Peripheral arterial disease which is mostly small vessel disease and is generally not helped by the surgical and stenting techniques that target large vessels, but do not treat small vessel disease.
  • a method of treatment of peripheral artery disease in a human comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (I-
  • the compounds herein may also be used in the treatment of preeclampsia, the pregnancy complication characterized by high blood pressure and signs of damage to another organ system, most often the liver and kidneys.
  • a method of treatment of preeclampsia in a human comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compounds herein are also useful in the treatment of myocardial infarction, particularly in cases where no-reflow phenomenon is present.
  • a no-reflow phenomenon is present when, despite restoration of the coronary flow of blood to the myocardium, breakdown of or obstruction to coronary microvasculature can markedly reduce blood flow to the infarct zone. Flow to the microcirculation in such instances may occur in one third of myocardial infarction patients.
  • a method of treatment of myocardial infarction in a human comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compounds of the present invention may also be used in situations of chronic coronary artery disease in which the large arteries are bypassed or stented and, yet, about a third of the patients continue to have angina due to microvascular dysfunction.
  • a method of treatment of chronic coronary artery disease in a human comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt of any of the foregoing.
  • Also provided is a method of treatment of microvascular dysfunction associated with chronic coronary artery disease in a human comprising administering to a mammal in need thereof a pharmaceutically effective amount a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compounds of the present invention may also be used for conditions referred to as
  • Syndrome X wherein a subject is experiencing a cardiac microvascular dysfunction or constriction causing angina despite normal epicardial coronary artery activity, such as diagnosed by angiography.
  • a method of treatment of Syndrome X in a human comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (I-
  • a method of treating breast cancer in a human in need thereof comprising administering to the human a pharmaceutically effective amount of a compound of
  • the breast cancer treated in this method is ER negative breast cancer.
  • a method of treating gastric adenocarcinomas in a human comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (I-
  • the ulcerative colon disease to be treated is ulcerative colitis.
  • the ulcerative colon disease to be treated is Crohn Disease or Crohn's Disease.
  • the ulcerative colon disease to be treated is Irritable Bowel Syndrome (IBS), which may also be referred to as colitis, enteritis, ileitis, or proctitis.
  • IBS Irritable Bowel Syndrome
  • IBD Inflammatory Bowel Disease
  • a method of treating Inflammatory Bowel Disease (IBD) in a human comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt of any of the foregoing.
  • IBD Inflammatory Bowel Disease
  • Also provided is a method of treating diarrhea in a human comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (I-
  • the compounds herein may be used in methods of distributing local, regional, or systemic delivery of anesthetics and improve their effects.
  • a method of enhancing the delivery of anesthetics to a human experiencing microvascular complications comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically effective amount of an anesthetic.
  • the compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt of any of the foregoing, is administered to the human prior to the administration of anesthetic.
  • compositions comprising a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt or co-crystal of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically effective amount of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E) a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt or co-crystal of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
  • Additional pharmaceutical compositions comprise, respectively, a pharmaceutically effective amount of a compound selected from those of Formulas (I'), (I"), (I'"), (1-1), (1-2), (1-3), (1-4), (1-5), (1-6), and (1-7), and each of the formulas from
  • carrier refers to an excipient or vehicle that includes without limitation diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, and the like with which the compound is administered.
  • Pharmaceutically acceptable carriers are generally described herein and also in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, carboxymethylcellulose sodium, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. It should be understood, however, that the carriers selected for the pharmaceutical compositions, and the amounts of such carriers in the composition, may vary depending on the method of
  • excipients in an oral formulation include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • a "pharmaceutically acceptable excipient” is a pharmaceutically acceptable vehicle that includes, without limitation, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • a pharmaceutically acceptable vehicle that includes, without limitation, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • agents having similar utilities for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • One mode for administration is parenteral, particularly by injection.
  • Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt or co-crystal thereof, may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline may also conventionally be used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • sterile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.1 to
  • compositions that include the compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), ), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt or co- crystal thereof.
  • Administration may be via capsule or enteric coated tablets, or the like.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • each dosage unit contains from 0.1 mg to 1 g, 0.1 mg to 700 mg, or 0.1 mg to 100 mg of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), ), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt or co-crystal thereof.
  • Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt thereof comprises from about 0.1 mg to about 500 mg per dose, given once or twice daily.
  • the individual dose is selected from 1 mg, 5 mg,
  • the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.
  • compositions comprising the compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), ), a compound of any subformula of Formula
  • any of the specifically named compounds herein, or a pharmaceutically acceptable salt or co-crystal thereof can be prepared and placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, provided is also an article of manufacture, such as a container comprising a unit dosage form of the compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), ), a compound of any subformula of Formula
  • the article of manufacture is a container comprising a unit dosage form of the compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), ), a compound of any subformula of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), any of the specifically named compounds herein, or a pharmaceutically acceptable salt or co-crystal thereof, and at least one pharmaceutically acceptable vehicle.
  • the article of manufacture may be a bottle, vial, ampoule, single-use disposable applicator, or the like, containing the pharmaceutical composition provided in the present disclosure.
  • the container may be formed from a variety of materials, such as glass or plastic and in one aspect also contains a label on, or associated with, the container which indicates directions for use in the treatment of cancer or inflammatory conditions.
  • the active ingredient may be packaged in any material capable of improving chemical and physical stability, such as an aluminum foil bag.
  • diseases or conditions indicated on the label can include, for example, treatment of cancer.
  • Microcirculation may be anatomically defined as blood vessels having a diameter of between about 250 ⁇ tom about 100 , ⁇ pmarticularly including those between about 200 ⁇ m to about 150 ⁇ ,m and includes arterioles, capillaries, and venules (post-capillary venules). Collectively, these vessels may be referred to as "microvessels",
  • microcirculatory vessels and the like.
  • the microcirculation is defined as blood vessels ⁇ 200 ⁇ m in diameter. In the human body approximately 90% of the volume of blood resides in these vessels that include arterioles, capillary and venules. Arterioles range in diameter of approximately from 50-200 ⁇ m.
  • Some venules contain vascular smooth muscle, and some capillaries are surrounded by pericytes, both of which are contractile cells that allow these vessels to constrict and relax, thus allowing more or less blood and oxygen to be delivered to cells, and cell waste removed.
  • pericytes both of which are contractile cells that allow these vessels to constrict and relax, thus allowing more or less blood and oxygen to be delivered to cells, and cell waste removed.
  • the size of these arterioles is tightly regulated to meet the oxygen demand of the cells they supply.
  • Coronary microvascular disease is heart disease that affects the walls and inner lining of tiny blood vessels branching from larger coronary arteries. Coronary microvascular disease may also be referred to as “Cardiac Syndrome X” or “nonobstructive coronary heart disease”. In the heart or elsewhere it may also be referred to as “small artery disease”, “small vessel disease”, or
  • kidney lesions typically involve afferent arterioles and the interlobular artery and may involve intimal thickening, vascular smooth muscle cell proliferation, and extracellular matrix deposition, increasing the media-to-lumen ration. Areas of vascular smooth muscle cells may then be replaced by fibrosis and cell loss.
  • Microvascular angina refers to a form of chest pain due to abnormalities in cardiac microvessels, including, but not limited to, faulty relaxation of or spasms therein.
  • heterocycle or “heterocyclic group” herein refers to a chemical ring containing carbon atoms and at least one ring heteroatom selected from O, S, and N, including saturated, unsaturated, partially saturated, and aromatic rings.
  • 3-membered heterocycles such as seen in the definitions of R 3 and R 4 herein, include by way of example and not limitation aziridinyl, azirinyl, oxiranyl, and thiiranyl groups.
  • Examples of 4-membered heterocycles include by way of example and not limitation azetidinyl, dihydro-1 ⁇ 4 -azetyl, azetyl, 1,3- diazetidinyl, and oxetanyl groups.
  • Examples of 5-membered heterocycles include by way of example and not limitation thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, pyrrolidinyl, 2-pyrrolidonyl, dihydropyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, triazinyl, thienyl, 2H- pyrrolyl, isothiazolyl, isoxazolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, and oxazolidinyl groups.
  • 6-membered heterocycles such as seen in the definitions of R 3 and R 4 herein, include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl
  • Examples of 7-membered heterocycles herein include by way of example and not limitation borepinyl, azepanyl, azepinyl, oxepanyl, oxepinyl, theipinyl, thiepanyl, diazepanyl, diazepinyl, and thiazepinyl groups.
  • 8-membered heterocycles herein include by way of example and not limitation azocinyl, azocinyl, oxocanyl, oxocinyl, thiocanyl, and thiocinyl groups.
  • 9-membered heterocycles herein include by way of example and not limitation monocyclic heterocycles such as azonanyl, azoninyl, oxonanyl, oxoninyl, thionanyl, and thioninyl groups and fused heterocycles, such as indolyl, indolinyl, isoindolyl, indolizinyl, indazolyl, azaindolyl, benzimidazolyl, azaindazolyl, pyrazolopyrimidinyl, purinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[c][l,2,5]thiadiazolyl, benzo[d]thiazolyl, benzisothiazolyl, adeninyl, and
  • 10-membered heterocycles herein include by way of example and not limitation decahydroisoquinolinyl, decahydroquinolinyl, tetrahydroquinolinyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, phthalazinyl, quinazolinyl, cinnolinyl, chromenyl, isochromenyl, naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, benzo[e][l,2]oxazinyl, benzo[e][l,3]oxazinyl, benzo[b][l,4]oo
  • heterocycles referenced herein include each isomeric form of the heterocycle, such as the term “dithianyl” including 1,2 dithianyl, 1,3- dithianyl, and 1,4-dithianyl groups, the term “thiadiazinyl” including 1,2,5 thiadiazineyl and 1,3,4- thiadiainyl groups, the term “azaindolyl” including 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, and 7- azaindolyl groups, and "benzothiophenyl” including benzo[b]thiophenyl and benzo[c]thiophenyl groups.
  • heterocycle names include each variance in one or more points of unsaturation.
  • dihydropyrrolyl refers to "2,3-dihydro-lH-pyrrolyl" and
  • alkyl refers to a straight or branched hydrocarbon.
  • an alkyl group can have a specified number of chain carbons, such as 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl or C 1-6 alkyl).
  • suitable alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl
  • n-butyl --CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propyl (i-Bu, i-butyl, --CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s- butyl, --CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, --C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -
  • alkoxy refers to a group having the formula "-O-alkyl,” in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have a specified number of carbon chain atoms, such as 1 to 6 carbon atoms
  • alkoxy groups include, but are not limited to, methoxy (-O-CH 3 or --OMe), ethoxy (-OCH 2 CH 3 or --OEt), t-butoxy (--O--C(CH 3 ) 3 or --OtBu) and the like.
  • Carbocycle or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated, unsaturated, partially saturated, and aromatic rings.
  • cycloalkyl refers to a saturated ring having 3 to 6 carbon atoms as a monocycle, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • halogen refers to an atom selected from the group of elements chlorine, fluorine, bromine, and iodine.
  • therapeutically effective amount and “pharmaceutically effective amount” refer to an amount that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a mammal, such as a human) in need of such treatment.
  • the therapeutically or pharmaceutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • a “therapeutically effective amount” or a “pharmaceutically effective amount” of a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), or a pharmaceutically acceptable salt or cocrystal thereof is an amount sufficient to antagonize GPR39 expression or activity, and thereby treat a subject (e.g., a human) suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication.
  • a therapeutically or pharmaceutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of GPR39 activity.
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: (i) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); (ii) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread
  • inhibiting indicates a decrease, such as a significant decrease, in the baseline activity of a biological activity or process.
  • Inhibition of GPR39 activity refers to a decrease in GPR39 activity as a direct or indirect response to the presence of a compound of
  • the decrease in activity may be due to the direct interaction of the compound with GPR39, or due to the interaction of the compound(s) described herein with one or more other factors that in turn affect GPR39 expression and/or activity.
  • the presence of the compound(s) may decrease GPR39 activity by directly binding to the GPR39, by causing (directly or indirectly) another factor to decrease GPR39 expression or activity, or by
  • the inhibition of GPR39 activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
  • the term "inhibitor” is understood to refer to a compound or agent that, upon administration to a human in need thereof at a pharmaceutically or therapeutically effective dose, provides the inhibition activity desired.
  • Delaying the development of a disease or condition means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease or condition, and/or subject being treated.
  • a method that "delays" development of a disease or condition is a method that reduces probability of disease or condition development in a given time frame and/or reduces the extent of the disease or condition in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • Disease or condition development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease or condition progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • significant is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • Examples of salts may include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesuflonate (besylate), p-toluenesulfonate
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • crystal forms and related terms herein refer to the various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. Crystal forms of a substance can be obtained by a number of methods, as known in the art.
  • Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal countermolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
  • additives such as, e.g., co-crystal countermolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
  • co-crystal or "co-crystal salt” as used herein means a crystalline material composed of two or more unique solids at room temperature, each of which has distinctive physical characteristics such as structure, melting point, and heats of fusion, hygroscopicity, solubility, and stability.
  • a co-crystal or a co-crystal salt can be produced according to a per se known co-crystallization method.
  • co-crystal or cocrystal salt
  • a host API active pharmaceutical ingredient
  • molecule or molecules such as a compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E)
  • guest or co-former
  • the pharmaceutically acceptable co-crystal of the compound of Formula (l-A), (l-B), (l-C), (l-D), or (l-E)with a co-former molecule is in a crystalline form selected from a malonic acid co-crystal, a succinic acid co-crystal, a decanoic acid co-crystal, a salicylic acid co-crystal, a vanillic acid co-crystal, a maltol co-crystal, or a glycolic acid co-crystal.
  • Co-crystals may have improved properties as compared to the parent form (i.e., the free molecule, zwitter ion, etc.) or a salt of the parent compound. Improved properties can include increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, a crystalline form of a normally amorphous compound, a crystalline form of a difficult to salt or unsalable compound, decreased form diversity, more desired morphology, and the like.
  • an isotopic compound includes a compound in which one or more hydrogen atoms (H) has been replaced with one or more deuterium atoms (D).
  • deuterium is an isotope of hydrogen, and replacing a hydrogen atom with deuterium (at one or more positions) renders the resulting compound an isotopic compound.
  • isotopic compounds of Formula (l-A), (l-B), (l-C), (l-D), or (l-E), as well as all reference to the various embodiments thereof refers to a compound having one or more isotopic substitutions, including (but not limited to) substitutions of one or more hydrogen atoms with one or more deuterium atoms and any occurrence(s) in the compound.
  • the isotopic compounds disclosed herein provide improved advantages relative to their non- isotopic forms.
  • isotopic modification provides a means of improving existing drugs and/or as a tool in the design of new drugs.
  • isotopic drug design has proven successful in the context of the deuterium (D) kinetic isotope effect.
  • H-D isosteric replacement usually retains the pharmacodynamics of the compound, while improving its pharmacokinetics with a repercussion on half-life and/or of area under the curve values and, ultimately, on dose and/or dosing regimen.
  • drug exposure may be enhanced with isotopic modification, and/or a decrease of clearance.
  • isotopic modification for example, drug exposure may be enhanced with isotopic modification, and/or a decrease of clearance.
  • Subject and patient refer to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications.
  • the subject is a mammal; in some embodiments the subject is human; and in some embodiments the subject is chosen from cats and dogs.
  • Subject in need thereof or “human in need thereof” refers to a subject, such as a human, who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example treatment with a compound of Formula (l-A),
  • prediabetes or "prediabetic condition” refers to a condition in which a subject's blood sugar levels are not high enough to be considered diabetic but may be a precursor to Type 2 diabetes.
  • a prediabetic condition may be defined in subjects having a fasting blood glucose level of 100 mg/dl or more, but less than 126 mg/dl (the level which is diagnostic for diabetes).
  • Hemoglobin A1c (HbA1c) levels are another laboratory test for diabetes. HbA1c levels of 6.5% or greater are characteristic of diabetes, while levels from 5.7% to 6.4% suggest prediabetes.
  • PC3 Human prostate adenocarcinoma (PC3) cells endogenously expressing human GPR39 receptor were seeded into black walls clear-base 384-well plates at a density of 7,500 cells per well in DM EM (Low Glucose) supplemented with 10% heat-inactivated foetal bovine serum and 1% of
  • Fluorometric Imaging Plate Reader FLIPR TETRA
  • a dual addition FLIPR protocol was used which included a first addition of compounds 200-fold diluted in Assay Buffer containing 150 ⁇ M ZnCI2 and 1.1% DMSO and then after 10 minutes a second addition of a submaximal concentration of the hGPR39 receptor agonist, C3 (Tocris, TC-G
  • f Ki IC50/(l+[L]/EC50) where IC50 is the concentration of antagonist required for 50% inhibition of the maximum response, [L] is the concentration of the agonist used (EC90) and EC50 is the concentration of agonist need to induced 50% of the maximum response (obtained in each experimental plate).
  • fpKi data is shown in Table 1 below. An fpKi less than 5.2 is reported as "+/-”. An fpKi ranging from 5.2 to 5.9 is reported as "+”. An fpKi from 6.0 to 6.5 is reported as "++”. An fpKi from 6.6 to
  • DIPEA N, N- Diisopropylethylamine
  • HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • Compound of formula II may be obtained from compound of formula I (commercially available from
  • Enamine) by SNAr substitution with pyrrolidine in a suitable aprotic solvent e.g. CH 3 CN, typically at
  • Compound of formula III may be obtained by nitro reduction of compound of formula II under catalytic hydrogenation conditions, using for example Pd/C in a suitable solvent such as acetic acid, typically at room temperature. The reaction takes about 4 hours to complete
  • Compound of formula IV may be obtained by coupling reaction between compound of formula III and a proper commercially available acyl chloride, e.g. cyclopropanecarbonyl chloride, in presence of an organic base, e.g. TEA.
  • acyl chloride e.g. cyclopropanecarbonyl chloride
  • organic base e.g. TEA
  • the reaction is carried out in a suitable solvent such as DCM, typically at room temperature. The reaction takes about 12 hours to complete.
  • Compound of formula V may be obtained from compound of formula IV by hydrolysis, e.g. using
  • LiOH in a suitable mixture of solvents such as MeOH/THF/H 2 O, typically at 50 °C.
  • the reaction takes about 36 hours to complete.
  • Compound of formula VI may be obtained from compound of formula V by coupling with the proper amine in the presence of coupling agent, e.g. HATU, and an organic base, e.g. DIPEA.
  • the reaction is carried out in a suitable solvent such as DMF, typically at room temperature. The reaction takes from about 3 hours to about 12 hours to complete.
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein 2-oxa-6-azaspiro[3.4]octane was used instead of 2- phenylpyrrolidine.
  • the title compound was obtained in a yield of 61 % (40 mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein trans-2,6-dimethylmorpholine was used instead of 2- phenylpyrrolidine.
  • the title compound was obtained in a yield of 50 % (33 mg) as a racemic mixture.
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein 2,6-dimethyl-l,4-thiazinane 1,1-dioxide hydrochloride was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained in a yield of 44 % (34 mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained in a yield of 44 % (34 mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained in a yield of 75 % (49 mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained in a yield of 78 % (50 mg).
  • Example 12 The synthesis of the title compound was effected analogously to the synthesis of the compound of
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein tert-butyl 3-[2-(trifluoromethyl)phenyl]piperazine-l- carboxylate was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained as a racemic mixture in a yield of 19% (24mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein tert-butyl 3-(3-cyanophenyl)piperazine-l-carboxylate was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained as a racemic mixture in a yield of 47% (55mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein tert-butyl 3-(4,5-dimethyl-l,3-thiazol-2-yl)piperazine- 1-carboxylate was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained as a racemic mixture in a yield of 60% (73 mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein tert-butyl 3-(4-methylphenyl)piperazine-l- carboxylate was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained as a racemic mixture in a yield of 70% (96 mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein tert-butyl 3-(3-chloro-5-methylphenyl)piperazine-l- carboxylate was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained as a racemic mixture in a yield of 90% (130 mg).
  • Example 1 N-[4-(2-phenylpyrrolidine-l-carbonyl)-3-pyrrolidin-l- ylphenyl]cyclopropanecarboxamide wherein tert-butyl 3-(3-methylphenyl)piperazine-l- carboxylate was used instead of 2-phenylpyrrolidine.
  • the title compound was obtained as a racemic mixture in a quantitative yield (150 mg).
  • Compound of formula II may be obtained from compound of formula II by SNAr substitution with pyrrolidine in a suitable aprotic solvent, e.g. DMSO, typically at 120 °C. The reaction takes about 36 hours to complete.
  • a suitable aprotic solvent e.g. DMSO
  • Compound of formula IV may be obtained from compound of formula III by Buchwald reaction with the proper heteroaryl aniline in the presence of a suitable palladium precatalyst, e.g. tBuBrettPhos Pd G3, and a suitable base, such as K 3 PO 4 .
  • a suitable palladium precatalyst e.g. tBuBrettPhos Pd G3
  • a suitable base such as K 3 PO 4
  • the reaction is carried out in a suitable solvent, e.g. 1- butanol, typically at 120 °C.
  • the reaction takes from about 12 hours to about 24 hours to complete.
  • Compound of formula V may be obtained via Suzuki coupling between compound of formula III and the appropriate commercially available boronic acid in the presence of a suitable catalyst, e.g. palladium tetrakis triphenylphosphine, suitable inorganic base Na 2 CO 3 , in a suitable solvent, 1,2- dimethoxyethane, typically at 95 °C.
  • a suitable catalyst e.g. palladium tetrakis triphenylphosphine, suitable inorganic base Na 2 CO 3
  • a suitable solvent 1,2- dimethoxyethane
  • Example 19 The synthesis of the title compound was effected analogously to the synthesis of the compound of
  • Example 18 [4-[(3-methyl-l,2-oxazol-5-yl)amino]-2-pyrrolidin-l-ylphenyl]-(4-methyl-2- phenylpiperazin-l-yl)methanone wherein 5-methyl-l,3,4-thiadiazol-2-amine was used instead of 3- methyl-5-isoxazolamine.
  • the title compound was obtained in a yield of 39 % (56 mg).
  • Example 21 A mixture of (4-bromo-2-pyrrolidin-l-ylphenyl)-(4-methyl-2-phenylpiperazin-l-yl)methanone (50.0 mg, 0.120 mmol), lH-pyrazole-4-boronic acid (14.37 mg, 0.130 mmol) and a 2M aqueous solution of Na 2 CO 3 (0.18 mL, 0.350 mmol) in 1,2-dimethoxyethane (1.052 mL) was degassed by 5 cycles of nitrogen/vacuum. Then palladium tetrakis triphenylphosphine (6.74 mg, 0.010 mmol) was added and the vessel was sealed. The reaction mixture was degassed again by 5 cycles of nitrogen/vacuum and then was heated to 95 °C for 2 days. After this time the mixture was directly purified by FC on
  • Compound of formula II may be obtained from compound of formula I (commercially available from
  • Enamine by coupling with a proper amine in the presence of coupling agent, e.g. HATU, and an organic base, e.g. DIPEA.
  • the reaction is carried out in a suitable solvent such as DMF, typically at room temperature. The reaction takes from about 3 hours to about 12 hours to complete.
  • compound of formula II may be obtained via acyl chloride formation of compound of formula I (commercially available from Enamine) by treatment with a suitable chlorinating agent, such as SOCl 2 , typically at 90 °C, followed by coupling with the proper amine in the presence of a suitable organic base, e.g. TEA.
  • a suitable chlorinating agent such as SOCl 2
  • TEA a suitable organic base
  • the reaction is carried out in a suitable solvent such as DCM, typically at room temperature. The reaction takes from about 1 hour to about 12 hours to complete.
  • Compound of formula III may be obtained by nitro reduction of compound of formula II using Zn dust in a suitable solvent, e.g. AcOH, typically at room temperature.
  • a suitable solvent e.g. AcOH
  • the compound of formula III may be obtained by reduction of compound of formula II using Tin (III) chloride dehydrate in a suitable solvent, e.g.
  • EtOH typically at 80 °C.
  • the reaction takes about 12 hours to complete.
  • Compound of formula IV may be obtained by coupling reaction between compound of formula III and a proper commercially available acyl chloride, e.g. Cyclopropanecarbonyl chloride, in presence of an organic base, e.g. TEA.
  • acyl chloride e.g. Cyclopropanecarbonyl chloride
  • organic base e.g. TEA
  • the reaction is carried out in a suitable solvent such as DCM, typically at room temperature. The reaction takes about 3 hours to complete.
  • Compound of formula V may be obtained via Suzuki coupling between compound of formula IV and the desired heteroaryl boronic ester or heteroaryl boronic acid, in the presence of a suitable precatalyst, e.g. XPhos Pd G2, a suitable base, e.g. K 3 PO 4 , in a suitable mixture of solvents, e.g. 1,2- dimethoxyethane / water, typically at 100 °C. The reaction takes about from 3 hours to 12 hours to complete.
  • a suitable precatalyst e.g. XPhos Pd G2
  • a suitable base e.g. K 3 PO 4
  • solvents e.g. 1,2- dimethoxyethane / water
  • Compound of formula VI may be obtained via Miyaura coupling between compound of formula IV, the desired Aryl Bromide, and Bis(pinacolato)diboron, in presence of a suitable catalyst, such as PdCl 2 (dppf)*CH 2 Cl 2 , a suitable base, e.g. AcOK, in a suitable solvent, e.g. 1,4 dioxane, typically at 100
  • Compound of formula V may be obtained via Suzuki coupling between compound of formula VI and commercially available heteroaryl halide in the presence of a suitable catalyst, e.g. palladium tetrakis triphenylphosphine, suitable inorganic base Na 2 CO 3 , in a suitable solvent, 1,2- dimethoxyethane, typically at 95 °C. The reaction takes about 12 hours to complete.
  • a suitable catalyst e.g. palladium tetrakis triphenylphosphine, suitable inorganic base Na 2 CO 3
  • a suitable solvent 1,2- dimethoxyethane
  • Example 22 N-[4-(4,4-difluoropiperidine-l-carbonyl)-3-(l-methylpyrazol-3- yl)phenyl]cyclopropanecarboxamide wherein 1-isopropyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole was used instead of l-methyl-lH-pyrazole-3-boronic acid pinacol ester. The title compound was obtained in a yield of 42 % (54 mg).
  • Example 22 N-[4-(4,4-difluoropiperidine-l-carbonyl)-3-(l-methylpyrazol-3- yl)phenyl]cyclopropanecarboxamide wherein N-[3-bromo-4-(4-propylpiperazine-l- carbonyl)phenyl]cyclopropanecarboxamide and l-isopropyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole were used instead of N-[3-bromo-4-(4,4-difluoropiperidine-l- carbonyl)phenyl]cyclopropanecarboxamide and l-methyl-lH-pyrazole-3-boronic acid pinacol ester respectively.
  • Example 25 N-[4-(l,l-dioxo-l,4-thiazinane-4-carbonyl)-3-(5-methylthiophen-2- yl)phenyl]cyclopropanecarboxamide wherein (5-cyanothiophen-2-yl)boronic acid was used instead of 4,4,5,5-tetramethyl-2-(5-methyl-2-thiophenyl)-l,3,2-dioxaborolane. The title compound was obtained in a yield of 11 % (11 mg).
  • Example 25 N-[4-(l,l-dioxo-l,4-thiazinane-4-carbonyl)-3-(5-methylthiophen-2- yl)phenyl]cyclopropanecarboxamide wherein [5-(trifluoromethyl)thiophen-2-yl]boronic acid was used instead of 4,4,5,5-tetramethyl-2-(5-methyl-2-thiophenyl)-l,3,2-dioxaborolane. The title compound was obtained in a yield of 11 % (12 mg).
  • Example 30 N-[4-(4-methyl-2-phenylpiperazine-l-carbonyl)-3-(l-propan-2-ylpyrazol-3- yl)phenyl]cyclopropanecarboxamide wherein [5-(trifluoromethyl)thiophen-2-yl]boronic acid was used instead of l-propan-2-yl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole.
  • the title compound was obtained in a yield of 20 % (11 mg) as a racemic mixture.
  • Example 36 The synthesis of the title compound was effected analogously to the synthesis of the compound of
  • Compound of formula II may be obtained from compound of formula I (commercially available from
  • Astatech by coupling with a proper amine in the presence of coupling agent, e.g. HATU, and an organic base, e.g. DIPEA.
  • the reaction is carried out in a suitable solvent such as DMF, typically at room temperature.
  • the reaction takes from about 3 hours to about 12 hours to complete.
  • Compound of formula III may be obtained via Suzuki coupling between compound of formula II and the desired heteroaryl boronic ester, in the presence of a suitable precatalyst, e.g. XPhos Pd G2, a suitable base, e.g. K 3 PO 4 , in a suitable mixture of solvents, e.g. 1,2-dimethoxyethane / water, typically at 100 °C.
  • a suitable precatalyst e.g. XPhos Pd G2
  • a suitable base e.g. K 3 PO 4
  • solvents e.g. 1,2-dimethoxyethane / water
  • Compound of formula IV may be obtained by nitrile cyclization of compound of formula III with ethanimidamide hydrochloride in presence of a suitable catalyst, e.g. CuBr, a suitable base, e.g.
  • Compound of formula V may be obtained by nitrile cyclization of compound of formula III with ethanimidamide hydrochloride in presence of a suitable catalyst, e.g. CuBr, a suitable base, e.g.
  • Compound of formula IV may be obtained via Suzuki coupling between compound of formula V and the desired heteroaryl boronic ester, in the presence of a suitable precatalyst, e.g. XPhos Pd G2, a suitable base, e.g. K 3 PO 4 , in a suitable mixture of solvents, e.g. 1,2-dimethoxyethane / water, typically at 100 °C.
  • a suitable precatalyst e.g. XPhos Pd G2
  • a suitable base e.g. K 3 PO 4
  • solvents e.g. 1,2-dimethoxyethane / water
  • the title compound was obtained in a yield of 52 % (186 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 4-(4-tert-butylpiperidine-l-carbonyl)-3-(l- isopropylpyrazol-3-yl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4-methoxy-4- methyl-piperidine-l-carbonyl)benzonitrile.
  • the title compound was obtained in a yield of 20 % (22 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 3-(l-isopropylpyrazol-3-yl)-4-(l-oxa-7- azaspiro[3.5]nonane-7-carbonyl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4- methoxy-4-methyl-piperidine-l-carbonyl)benzonitrile. The title compound was obtained in a yield of 50 % (37 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 4-(4-fluoro-4-methylpiperidine-l-carbonyl)-3-(l-propan-2- ylpyrazol-3-yl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl- piperidine-l-carbonyl)benzonitrile.
  • the title compound was obtained in a yield of 75 % (32 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 4-(4,4-difluoropiperidine-l-carbonyl)-3-(2-ethylpyrazol-3- yl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine- l-carbonyl)benzonitrile.
  • the title compound was obtained in a yield of 60 % (53 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-(l-propan-2- ylpyrazol-4-yl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl- piperidine-l-carbonyl)benzonitrile.
  • the title compound was obtained in a yield of 19 % (18 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-(l-propan-2- ylpyrazol-3-yl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl- piperidine-l-carbonyl)benzonitrile.
  • the title compound was obtained in a yield of 39 % (31 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 4-(4,4-difluoropiperidine-l-carbonyl)-3-(l-propan-2- ylpyrazol-3-yl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl- piperidine-l-carbonyl)benzonitrile.
  • the title compound was obtained in a yield of 48 % (50 mg).
  • Example 39 [2-(l-isopropylpyrazol-3-yl)-4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- methyl-l-piperidyl)methanone wherein 4-(6,6-difluoro-2-azaspiro[3.3]heptane-2-carbonyl)-3-(l- isopropylpyrazol-3-yl)benzonitrile was used instead of 3-(l-isopropylpyrazol-3-yl)-4-(4-methoxy-4- methyl-piperidine-l-carbonyl)benzonitrile.
  • the title compound was obtained in a yield of 35 % (21 mg).
  • 1H NMR 400 MHz, DMS0-d6) ⁇ 13.73 (s, 1H), 8.30 (d, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.33 (d, 1H),

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés qui agissent en tant qu'antagonistes de la protéine GPR39 humaine. L'invention concerne également des compositions pharmaceutiques et des procédés d'utilisation d'antagonistes de la protéine GPR39 humaine. En particulier, l'invention concerne des procédés d'utilisation des antagonistes dans le traitement de maladies ou d'états comprenant des états cardiovasculaires, des troubles du système endocrinien et hormonaux, des troubles cancéreux, des maladies métaboliques, des maladies gastro-intestinales et hépatiques, des troubles hématologiques, des troubles neurologiques et des maladies respiratoires.
PCT/US2022/047658 2021-10-26 2022-10-25 Antagonistes de la protéine gpr39 WO2023076219A2 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040071708A1 (en) 2002-09-26 2004-04-15 Immusol, Inc. GPR 39 modulators that control cancerous cell growth
WO2007141322A1 (fr) 2006-06-08 2007-12-13 Janssen Pharmaceutica N.V. Récepteur couplé à la protéine g 39 (gpr39)
US20090298756A1 (en) 2005-04-22 2009-12-03 Shanghai Institutes For Biological Sciences, Chinese Academy Of Sciences Functions and uses of gpr39 gene in mammalian central nervous system

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CA2432870A1 (fr) * 2000-12-22 2002-07-25 Ronghui Lin Derives de triazole diamine substitues inhibiteurs de kinases
US20140010783A1 (en) * 2012-07-06 2014-01-09 Hoffmann-La Roche Inc. Antiviral compounds
JP2016513112A (ja) * 2013-02-18 2016-05-12 ザ スクリプス リサーチ インスティテュート 治療的潜在能力を有するバソプレッシン受容体のモジュレーター
AR114136A1 (es) * 2017-10-10 2020-07-29 Hoffmann La Roche Compuestos heterocíclicos

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040071708A1 (en) 2002-09-26 2004-04-15 Immusol, Inc. GPR 39 modulators that control cancerous cell growth
US20090298756A1 (en) 2005-04-22 2009-12-03 Shanghai Institutes For Biological Sciences, Chinese Academy Of Sciences Functions and uses of gpr39 gene in mammalian central nervous system
WO2007141322A1 (fr) 2006-06-08 2007-12-13 Janssen Pharmaceutica N.V. Récepteur couplé à la protéine g 39 (gpr39)

Non-Patent Citations (5)

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Title
"GIfunctions of GPR39: novel biology", CURRENT OPINION IN PHARMACOLOGY, vol. 12, 2012, pages 647 - 652
ALEN ET AL., ONCOTARGET, vol. 7, 2016, pages 5957 - 5971
COHEN ET AL.: "The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon", CELL DEATH AND DISEASE, vol. 5, 2014, pages e1307
MOECHARS ET AL.: "Altered Gastrointestinal and Metabolic Function in the GPR39-Obestatin Receptor-Knockout Mouse", GASTROENTEROLOGY, vol. 131, October 2006 (2006-10-01), pages 1131 - 1141, XP005821163, DOI: 10.1053/j.gastro.2006.07.009
VENTURA-BIXENSHPANER ET AL.: "Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth", SCIENTIFIC REPORTS, vol. 8, 2018, pages 8119

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