WO2014199164A1 - Composés hétéroaromatiques diaryle substitués - Google Patents

Composés hétéroaromatiques diaryle substitués Download PDF

Info

Publication number
WO2014199164A1
WO2014199164A1 PCT/GB2014/051810 GB2014051810W WO2014199164A1 WO 2014199164 A1 WO2014199164 A1 WO 2014199164A1 GB 2014051810 W GB2014051810 W GB 2014051810W WO 2014199164 A1 WO2014199164 A1 WO 2014199164A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
alkyl
ring
mmol
Prior art date
Application number
PCT/GB2014/051810
Other languages
English (en)
Inventor
Joseph Michael Sheridan
Richard Simon Todd
Philip Huxley
Original Assignee
Ampla Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB201310456A external-priority patent/GB201310456D0/en
Priority claimed from GB201314309A external-priority patent/GB201314309D0/en
Application filed by Ampla Pharmaceuticals, Inc. filed Critical Ampla Pharmaceuticals, Inc.
Publication of WO2014199164A1 publication Critical patent/WO2014199164A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to heterocyclic derivatives, to the use of said derivatives in treating a range of metabolic diseases and other conditions mediated by agonism of the G-protein coupled bile acid GPBAR1/TGR5 receptor, to compositions and formulations containing said derivatives, processes for their preparation and methods of delivery.
  • Bile acids consisting primarily of cholic acid and chenodeoxycholic acid and their glycine and taurine conjugates, are produced in the hepatocytes, secreted into the bile canaliculi and stored in the gall bladder (Houten et al., EMBO J. 2006, 25: 1419-1425).
  • the BAs Upon meal ingestion, the BAs are released into the duodenum and intestine where they mediate a range of physiological effects through activation of several signal transduction pathways in addition to their effects on normal digestion and absorption of lipids and vitamins.
  • BAs have been demonstrated to behave as autocrine, paracrine and endocrine factors through activation of the mitogen-activated protein (MAPK; Gupta et al.
  • MAPK mitogen-activated protein
  • mice lacking TGR5 receptors display higher body weights versus wild-type as result of significant fat accumulation upon high fat diet challenge (Maruyama et al., J.
  • TGR5 receptors were detected at high levels in the ileum and colon of male mice and medium levels in the colon of females.
  • Medium expression levels of TGR5 mRNA was measured in lung, spleen, kidney, stomach, jejunum, white adipose tissue and gonads of both sexes with low expression being observed in skeletal muscle, brain, brown adipose tissue heart and liver (Maruyama et al., J.
  • TGR5 receptors represent a novel target to treat metabolic disorders, including obesity, dyslipidaemia and diabetes mellitus and for therapies aimed at altering gastrointestinal motility.
  • WO 2013/062887 Merck Sharp and Dohme Corp
  • WO 2012/1 17000 F.Hoffmann-La Roche AG
  • CN102850321 describe a series of aroxylpyrimidine formamide or aroxylpyridine formamide compounds for preventing or treating TGR5-mediated diseases.
  • the object of the invention is to identify alternative agonists of the G-protein coupled bile acid GPBAR1/TGR5 receptor.
  • the invention provides a compound of formula (I) or a
  • n, q independently represent an integer selected from 0 to 3;
  • R 1 and R 3 independently represent Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, halogen, cyano, hydroxyl, haloCi_ 6 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, -0-C 3 . 8 cycloalkyl, -Ci_ 6 alkyl-O-Ci.6 alkyl, -NR a R b , -CONR a R b , -NR a COR b , -S0 2 NR a R b , -COR a or -COOR a ;
  • R 2 represents Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, halogen, cyano, haloCi_ 6 alkyl, Ci -6 alkoxy, haloCi_ 6 alkoxy, -0-C 3 . 8 cycloalkyl, -Ci -6 alkyl-0-Ci. 6 alkyl, -NR a R b , - CONR a R b , -NR a COR b , -S0 2 NR a R b , -COR a or -COOR a ;
  • R 4 represents Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, halogen, cyano, hydroxyl, haloCi-6 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, -0-C 3 . 8 cycloalkyl, -Ci_ 6 alkyl-0-Ci. 6 alkyl, -NR a R b , -NR a COR b or -S0 2 NR a R b , such that said R 4 groups are present on ring B at a position other than the para position relative to Het;
  • R a and R b independently represent hydrogen or Ci_ 6 alkyl or together with the nitrogen atom to which they are attached may form a 4- to 7-membered nitrogen containing non-aromatic heterocyclic ring;
  • X represents -C(R c R d )-, -0-, -0-(CH 2 ) r , -(CH 2 ) r -0-, -N(R C )-, -S-, -S(O)- or -S(0 2 )-;
  • r represents an integer selected from 1 to 6;
  • R c and R d independently represent hydrogen, Ci_ 6 alkyl or C 3 . 8 cycloalkyl
  • Ring A and Ring B independently represent a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
  • Het represents a 5-membered aromatic heterocyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and p represents an integer selected from 0 or 1 , such that when p represents 1 , R 3 is attached to a heteroatom at the 2- or 4-position of Het only when a nitrogen is present at the 3- position of Het or R 3 is attached to a carbon atom at any position of Het;
  • the compound of formula (I) is other than N-(4-methylphenyl)-2-[4-(4- methylphenyl)-4H-1 ,2,4-triazol-3-yl]-benzamine and 1-[2-(2,4-dichlorophenoxy)phenyl]-5- phenyl-1 H-1 ,2,3-triazole (E18).
  • n, q independently represent an integer selected from 0 to 3;
  • R 1 , R 2 , R 3 and R 4 independently represent Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, halogen, cyano, hydroxyl, haloCi_ 6 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, -0-C 3 . 8 cycloalkyl, -Ci_ 6 alkyl-O-Ci.6 alkyl, -NR a R b , -CONR a R b , -NR a COR b , -S0 2 NR a R b , -COR a or -COOR a ;
  • R a and R b independently represent hydrogen or Ci_ 6 alkyl or together with the nitrogen atom to which they are attached may form a 4- to 7-membered nitrogen containing non-aromatic heterocyclic ring;
  • X represents -C(R c R d )-, -0-, -0-(CH 2 ) r , -(CH 2 ) r -0-, -N(R C )-, -S-, -S(O)- or -S(0 2 )-;
  • r represents an integer selected from 1 to 6;
  • R c and R d independently represent hydrogen, Ci_ 6 alkyl or C 3 . 8 cycloalkyl
  • Ring A and Ring B independently represent a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
  • Het represents a 5-membered aromatic heterocyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and p represents an integer selected from 0 or 1 ;
  • 'halo' or 'halogen' refers to fluorine, chlorine, bromine or iodine.
  • 'Ci -6 alkyr as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
  • 'C 2 - 6 alkenyl' as used herein as a group or part of a group refers to a linear or branched hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond.
  • 'C 2 - 6 alkynyl' as used herein as a group or part of a group refers to a linear or branched hydrocarbon group having from 2 to 6 carbon atoms and containing a carbon carbon triple bond.
  • 'Ci. 6 alkoxy' refers to an -0-Ci. 6 alkyl group wherein Ci -6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.
  • 'haloCi. 6 alkyr as used herein as a group or part of a group refers to a Ci -6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term 'haloCi. 6 alkyr therefore includes monohaloCi. 6 alkyl and also polyhaloCi. 6 alkyl.
  • haloCi. 6 alkyl may have one, two, three or more halogens.
  • halogens include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
  • 'haloCi. 6 alkoxy' refers to a -O-C 1 . 6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term 'haloCi. 6 alkoxy' therefore includes monohaloCi. 6 alkoxy, and also polyhaloCi. 6 alkoxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi. 6 alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
  • 5- or 6-membered aromatic heterocyclic ring means a heterocyclyl group containing one or more carbon atoms, one or more hydrogen atoms and one or more heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring.
  • five membered aromatic heterocyclic groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • six membered aromatic heterocyclic groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • nitrogen containing non-aromatic heterocyclic ring means a non- aromatic heterocyclyl ring as defined herein wherein the ring must contain at least one ring nitrogen atom.
  • nitrogen-containing non-aromatic heterocyclyl groups include aziridine, morpholine, thiomorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • m represents an integer selected from 0 to 2. In a further embodiment, m represents an integer selected from 1 to 2. In a yet further embodiment, m represents an integer selected from 1. In a yet further embodiment, m represents an integer selected from 2. In one embodiment, R 1 represents halogen, haloCi_ 6 alkyl or -CONR a R b .
  • R 1 represents halogen (such as chlorine or fluorine), haloCi_ 6 alkyl (such as trifluoromethyl) or -CONR a R b (such as -CONH 2 ).
  • m represents 1 and R 1 represents halogen (such as chlorine, in particular 2-chloro) or haloCi_ 6 alkyl (such as trifluoromethyl), in particular 2-trifluoromethyl.
  • m represents 1 and R 1 represents haloCi_ 6 alkyl (such as trifluoromethyl), in particular 2-trifluoromethyl.
  • m represents 2 and R 1 represents halogen (such as chlorine or fluorine) or -CONR a R b (such as -CONH 2 ).
  • m represents 2 and R 1 represents 2,3-dichloro, 2,4-dichloro, 2,5-dichloro, 2-chloro-4-fluoro, 3- chloro-4-fluoro or 2-chloro-4-CONH 2 .ln a yet further embodiment, m represents 2 and R 1 represents 2,3-dichloro, 2,4-dichloro, 2,5-dichloro, 3-chloro-4-fluoro or 2-chloro-4-CONH 2 .
  • m represents 2 and R 1 represents 2,4-dichloro or 2,5-dichloro. In a yet further embodiment, m represents 2 and R 1 represents 2,5-dichloro. In one embodiment, X represents -0-.
  • Ring A represents a phenyl or pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl) ring. In a further embodiment, Ring A represents a phenyl or pyridyl (such as pyrid-2-yl or pyrid-4-yl) ring. In a yet further embodiment, Ring A represents a phenyl ring. In a yet further embodiment, Ring A represents a pyridyl (such as pyrid-4-yl) ring.
  • n represents an integer selected from 0 to 2. In a further embodiment, n represents an integer selected from 0 or 1. In a yet further embodiment, n represents an integer selected from 0.
  • Ring A represents an unsubstituted phenyl ring. In an alternative embodiment, Ring A represents an unsubstituted pyridyl (such as pyrid-4-yl) ring.
  • X and Het are attached to Ring A in an ortho arrangement.
  • Het represents a pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl or tetrazolyl ring.
  • Het represents a triazolyl, imidazolyl, pyrazolyl or oxazolyl ring.
  • Het represents a triazolyl, imidazolyl or pyrazolyl ring. In an alternative embodiment, Het represents a triazolyl, pyrazolyl or oxazolyl ring. In an alternative embodiment, Het represents a triazolyl, imidazolyl or oxazolyl ring. In an alternative embodiment, Het represents an imidazolyl, pyrazolyl or oxazolyl ring.
  • Het represents a triazolyl or imidazolyl ring. In an alternative embodiment, Het represents a triazolyl or pyrazolyl ring. In an alternative embodiment, Het represents a triazolyl or oxazolyl ring. In an alternative embodiment, Het represents an imidazolyl or pyrazolyl ring. In an alternative embodiment, Het represents an imidazolyl or oxazolyl ring. In an alternative embodiment, Het represents a pyrazolyl or oxazolyl ring.
  • Het represents a group selected from (i) to (xvi):
  • Het represents a group selected from (i) to (xii):
  • Het represents a group selected from (i) to (xi):
  • Het represents an imidazolyl ring selected from any of groups (iii) to (vi) and (xii) to (xiii), a triazolyl ring selected from selected from either of groups (i) or (ii) or a pyrazolyl ring selected from any of groups (vii), (viii) or (xiv)-(xvi).
  • Het represents an imidazolyl ring selected from any of groups (iii) to (vi) and (xii) to (xiii). In a further embodiment, Het represents an imidazolyl ring selected from any of groups (iii) to (vi) and (xii). In a further embodiment, Het represents an imidazolyl ring selected from any of groups (iii) to (vi). In a yet further embodiment, Het represents an imidazolyl ring selected from group (iii), (xii) or (xiii).
  • Het represents a pyrazolyl ring selected from any of groups (vii), (viii) or (xiv)-(xvi). In a further embodiment, Het represents a pyrazolyl ring selected from either of groups (vii) or (viii).
  • Het represents an oxazolyl ring selected from any of groups (ix) to (xi).
  • Het represents a triazolyl ring selected from either of groups (i) or (ii), such as group (i).
  • Het contains a nitrogen atom at the 3 position relative to the A and B groups, such as a ring system selected from any of groups (i)-(iii), (viii) and (xii)-(xvi).
  • Het is selected from a ring system selected from any of groups (i), (iii) and (xii).
  • said Het group represents a group other than triazolyl. In any one of the embodiments referred to herein with respect to Het, said Het group represents a group other than imidazolyl. In any one of the embodiments referred to herein with respect to Het, said Het group represents a group other than pyrazolyl. In any one of the embodiments referred to herein with respect to Het, said Het group represents a group other than oxazolyl.
  • p represents an integer selected from 0 or 1. In one embodiment, p represents an integer selected from 0. In an alternative embodiment, p represents an integer selected from 1.
  • references herein to R 3 being attached to either the 2- or 4-position of Het refer to the positioning on Het relative to the points of attachment of A and B being at the 1- and 5-positions, respectively, as shown below:
  • R 3 is present on the 2- or 4-position of Het. In one embodiment, R 3 represents Ci_ 6 alkyl (such as methyl).
  • p represents an integer selected from 1 and R 3 represents Ci_ 6 alkyl (such as methyl). In a further embodiment, p represents 1 , R 1 represents Ci_ 6 alkyl (such as methyl) and Het represents a group of formula (xii) a , (xiv) a or (xv) a :
  • p represents 1
  • R 1 represents Ci_ 6 alkyl (such as methyl)
  • Het represents a group of formula (xii) a :
  • Ring B represents a phenyl ring or a 6-membered aromatic heterocyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur. In a further embodiment, Ring B represents a phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl ring.
  • Ring B represents a phenyl or pyridinyl ring (such as 2- pyridinyl, 3-pyridinyl or 4-pyridinyl).
  • Ring B represents a phenyl ring.
  • q represents an integer selected from 0 to 2. In a further embodiment, q represents an integer selected from 1 to 2. In a yet further embodiment, q represents an integer selected from 0. In a yet further embodiment, q represents an integer selected from 1. In a yet further embodiment, q represents an integer selected from 2.
  • R 4 represents Ci_ 6 alkyl, haloCi_ 6 alkyl, d -6 alkoxy, halogen, cyano or - NR a R b .
  • R 4 represents Ci_ 6 alkyl, haloCi_ 6 alkyl, Ci_ 6 alkoxy or halogen.
  • R 4 represents Ci_ 6 alkyl (such as methyl), haloCi_ 6 alkyl (e.g. trifluoromethyl), Ci_ 6 alkoxy (such as methoxy), halogen (such as fluorine or chlorine), cyano or -NR a R b (such as -N(Me) 2 ).
  • R 4 represents Ci_ 6 alkyl (such as methyl), haloCi_ 6 alkyl (e.g. trifluoromethyl), Ci_ 6 alkoxy (such as methoxy) or halogen (such as fluorine or chlorine).
  • R 4 represents Ci_ 6 alkyl, Ci_ 6 alkoxy or halogen. In a yet further embodiment, R 4 represents Ci_ 6 alkyl (such as methyl), Ci_ 6 alkoxy (such as methoxy) or halogen (such as fluorine or chlorine).
  • q represents 1 and R 4 represents Ci_ 6 alkyl (such as methyl), Ci-6 alkoxy (such as methoxy), halogen (such as fluorine or chlorine), cyano or -NR a R b (such as -N(Me) 2 ).
  • q represents 1 and R 4 represents Ci_ 6 alkyl (such as methyl), Ci_ 6 alkoxy (such as methoxy) or halogen (such as fluorine or chlorine).
  • R 4 groups are present on ring B at a position other than the para position relative to Het.
  • R 4 is present on the ortho and/or meta positions relative to Het.
  • R 4 is present on the ortho position relative to Het.
  • q represents 1
  • Ring B represents a phenyl ring and R 4 represents Ci_ 6 alkyl (such as 2-methyl), Ci_ 6 alkoxy (such as 2-methoxy or 3-methoxy), halogen (such as 3-fluorine, 4-fluorine or 2-chlorine), cyano (such as 2-cyano) or -NR a R b (such as -2-N(Me) 2 ).
  • q represents 1 , Ring B represents a phenyl ring and R 4 represents Ci_ 6 alkyl (such as 2-methyl), Ci_ 6 alkoxy (such as 2-methoxy), halogen (such as 2-chlorine), cyano (such as 2-cyano) or -NR a R b (such as -2-N(Me) 2 ).
  • q represents 1 , Ring B represents a phenyl ring and R 4 represents Ci-6 alkyl (such as 2-methyl), Ci_ 6 alkoxy (such as 2-methoxy or 3-methoxy) or halogen (such as 3-fluorine, 4-fluorine or 2-chlorine).
  • q represents 2
  • Ring B represents a phenyl ring and R 4 represents halogen (such as 2,4-difluoro or 3,4-difluoro).
  • q represents 0 and Ring B represents a phenyl ring, such as an unsubstituted phenyl ring.
  • q represents 0 and Ring B represents a pyridyl ring, such as unsubstituted 2-pyridyl, unsubstituted 3-pyridyl or unsubstituted 4-pyridyl.
  • the invention provides a compound of formula (l) a or a pharmaceutically acceptable salt or solvate thereof:
  • the invention provides a compound of formula (l) b or a pharmaceutically acceptable salt or solvate thereof:
  • the invention provides a compound of formula (l) c or a pharmaceutically acceptable salt or solvate thereof:
  • R 1a and R 1 b both represent halogen (such as chlorine).
  • the invention provides a compound of formula (l) d or a pharmaceutically acceptable salt or solvate thereof:
  • R 1a and R 1 b both represent halogen (such as chlorine).
  • the invention provides a compound of formula (l) e or a pharmaceutically acceptable salt or solvate thereof:
  • R 1a and R 1 b both represent halogen (such as chlorine).
  • the invention provides a compound of formula (l) f or a pharmaceutically acceptable salt or solvate thereof:
  • the first proviso within the compound of formula (I) refers to a known compound, N-(4-methylphenyl)-2-[4-(4-methylphenyl)-4H-1 ,2,4-triazol-3-yl]- benzamine, the synthesis of which is described in Legrand and Lozac'h (1975) Bulletin de la Societe Chimique de France 5-6(2), 1415-1418.
  • the second proviso within the compound of formula (I) refers to a known library compound of E18 described herein which may be obtained from Maybridge (Catalogue Number 5243595).
  • the compound of formula (I) is a compound of E1-E17 or E19- E235 or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • the compound of formula (I) is a compound of E1-E17 or E19-E226 or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • the compound of formula (I) is a compound of E1-E17 or E19- E223 or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • the compound of formula (I) is a compound of E1-E17, E19, E24, E96, E119, E173 and E224-E235 or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • the compound of formula (I) is a compound of E1-E17, E19, E24 and E224-E226 or a pharmaceutically acceptable salt, solvate or free base preparation thereof. In a further embodiment, the compound of formula (I) is a compound of E1-E17 or E19 or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • the compound of formula (I) is a compound of E3-E5, E10-E12, E14, E17, E24, E96, E224-E228, E230-E231 or E234-E235 or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • References herein to pharmaceutical compositions, uses or methods of formula (I) without the proviso refer to compounds of formula (I) selected from a compound of E1-E235 (such as E1-19, E24, E96, E119, E173 and E224-E235) or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • references herein to pharmaceutical compositions, uses or methods of formula (I) without the proviso refer to compounds of formula (I) selected from a compound of E1-E226 (such as E1-E19, E24 and E224-E226) or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • references herein to pharmaceutical compositions, uses or methods of formula (I) without the proviso refer to compounds of formula (I) selected from a compound of E1-E223 (such as E1-E19) or a pharmaceutically acceptable salt, solvate or free base preparation thereof.
  • a reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as dichloromethane, 1 ,4-dioxane, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • a-oxoglutaric glycolic, hippuric
  • hydrohalic acids e.g. hydrobromic, hydrochloric, hydriodic
  • isethionic lactic (e.g.
  • salts consist of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, sulfuric, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • One particular salt is the hydrochloride salt.
  • Another particular salt is the
  • the compounds of the formula (I) may contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).
  • the compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.
  • salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al.,
  • solvates complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate”. Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof.
  • Compounds of the formula (I) containing an amine function may also form N-oxides.
  • a reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid
  • pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as 2 H (D) and 3 H (T), carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l, 125 l and 131 1, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labelled compounds of formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors.
  • the detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc.
  • the radioactive isotopes tritium, i.e. 3 H (T), and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. According to a further aspect of the invention there is provided a process for preparing a compound of formula (I) as herein defined which comprises:
  • R 4 , q and B are as defined hereinbefore;
  • R 1 , m, X, R 2 , n, A, R 4 , q and B are as defined hereinbefore;
  • R 1 , m, X, R 2 , n and A are as defined hereinbefore and L 1 represents a suitable leaving group, such as a halogen atom (e.g. bromine), with a compound of formula (VI):
  • a halogen atom e.g. bromine
  • R 4 , q and B are as defined hereinbefore;
  • R 4 , q and B are as defined hereinbefore and L 2 represents a suitable leaving group, such as a halogen atom (e.g. bromine);
  • R 1 , m, X, R 2 , n, A, B, R 4 and q are as defined hereinbefore; or
  • R 1 , m, X, R 2 , n, A, B, R 4 and q are as defined hereinbefore;
  • a process for preparing a compound of formula (I) as herein defined which comprises: (a) preparing a compound of formula (I) wherein Het represents triazolyl and p represents 0, which comprises reacting a compound of formula (II):
  • R 4 , q and B are as defined hereinbefore;
  • R 1 , m, X, R 2 , n, A, R 4 , q and B are as defined hereinbefore;
  • R 1 , m, X, R 2 , n and A are as defined hereinbefore and L 1 represents a suitable leaving group, such as a halogen atom (e.g. bromine), with a compound of formula (VI):
  • a halogen atom e.g. bromine
  • R 4 , q and B are as defined hereinbefore and L 2 represents a suitable leaving group, such as a halogen atom (e.g. bromine);
  • R 1 , m, X, R 2 , n, A, B, R 4 and q are as defined hereinbefore;
  • R 1 , m, X, R 2 , n, A, B, R 4 and q are as defined hereinbefore;
  • Process (a) typically comprises reacting a compound of formula (II) with a compound of formula (III) in the presence of a suitable solvent, such as dimethylformamide (DMF), at suitable temperature, such as ambient temperature.
  • a suitable solvent such as dimethylformamide (DMF)
  • process (b) typically comprises heating a compound of formula (IV), toluenesulfonylmethyl isocyanide (TosMIC) or 1-(isocyanomethyl)-1 H-benzo[d][1 , 2, 3] triazole and a suitable base in a suitable solvent.
  • process (b) may be conducted in an analogous manner but instead using 1-(1-isocyanoethylsulfonyl)-4- methylbenzene.
  • Process (c) typically comprises heating the compounds of formulae (V) and (VI) in the presence of a copper catalyst and a base in a suitable solvent.
  • Process (d) typically comprises heating the compounds of formulae (VII) and (VIII) in the presence of a copper catalyst and a base in a suitable solvent.
  • Process (e) typically comprises heating the compounds of formulae (IX) and (X) in dilute acid, in a suitable solvent.
  • process (f) typically comprises heating a mixture comprises a compound of formula (XI) and hydrazine in acetic acid to 100 °C for approximately 1 hour.
  • process (f) typically comprises heating a mixture comprises a compound of formula (XI) and
  • Process (g) typically comprises heating the compounds of formulae (XII) and (XIII) in the presence of a suitable acid and a suitable solvent.
  • Process (h) typically comprises heating a mixture comprising a compound of formula (XIV), formamide and paraformaldehyde to 200 °C for approximately 1 hour providing a mixture of imidazolyl and oxazolyl compounds which are then separated by HPLC.
  • Process (i) typically comprises reacting a compound of formula (XL) with a suitable reagent such as (diazomethyl)trimethylsilane in a suitable solvent, such as hexane.
  • a suitable reagent such as (diazomethyl)trimethylsilane in a suitable solvent, such as hexane.
  • Process (j) typically comprises reacting a compound of formula (XLII) with suitable reagents, such as ethanol, acetic acid and ammonium acetate.
  • suitable reagents such as ethanol, acetic acid and ammonium acetate.
  • L 3 represents a suitable leaving group, such as a halogen atom (e.g. chlorine).
  • Step (i) typically comprises reacting a compound of formula (XV) with a compound of formula (XVI) in the presence of a suitable solvent, such as dimethylformamide (DMF) in the presence of copper (I) iodide at a suitable temperature (such as room temperature).
  • a suitable solvent such as dimethylformamide (DMF)
  • copper (I) iodide at a suitable temperature (such as room temperature).
  • Step (ii) typically comprises a reduction reaction of a compound of formula (XVII) in the presence of suitable reagents, such as iron powder and ammonium chloride in the presence of a suitable solvent, such as ethanol and water at a suitable temperature, such as 85 °C.
  • suitable reagents such as iron powder and ammonium chloride
  • a suitable solvent such as ethanol and water at a suitable temperature, such as 85 °C.
  • Step (iii) typically comprises treating a compound of formula (XVIII) with a suitable acid, such as sulfuric acid in water, at a suitable temperature, such as 55 °C, followed by cooling to 0 °C and addition of a suitable reagent, such as NaN0 2 in water, followed by addition of urea and NaN 3 in water followed by stirring at a suitable temperature, such as room temperature.
  • a suitable acid such as sulfuric acid in water
  • a suitable temperature such as 55 °C
  • a suitable reagent such as NaN0 2 in water
  • urea and NaN 3 in water followed by stirring at a suitable temperature, such as room temperature.
  • Step (i) typically comprises heating a mixture of the compounds of formulae (XIX) and (XX) to reflux in a suitable solvent, in the presence of a suitable base and a copper (I) salt.
  • a suitable leaving group such as a halogen atom (e.g. chlorine).
  • Step (ii) typically comprises stirring a mixture of a compound of formula (XXI) and N,0- dimethylhydroxylamine hydrochloride with an amide coupling reagent and a suitable base, in a suitable solvent.
  • Step (iii) typically comprises treating a compound of formula (XXII) with a suitable reducing agent, followed by an aqueous work up.
  • Step (iv) typically comprises heating the compounds of formula (XXIII) and (XXIV) in a suitable solvent in the presence of a desiccant and a suitable acid catalyst.
  • L 7 represents a suitable leaving group, such as a halogen atom (e.g. fluorine).
  • Step (i) typically comprises reacting a compound of formula (XXXVI) and a compound of formula (XVI) in the presence of potassium carbonate and copper (I) iodide in a suitable solvent, such as DMF under suitable conditions, such as room temperature.
  • Step (ii) typically comprises reacting a compound of formula (XXIII) with a compound of formula (XXIV) in the presence of benzene under suitable conditions, such as Dean Stark conditions.
  • R 1 , m, X, R 2 , n, A, B, R 4 and q are as defined hereinbefore.
  • Step (i) typically comprises reacting a compound of formula (XVIII) with a compound of formula (XXXV) under suitable conditions, such as Dean Stark conditions.
  • R 2 , n, A, R 1 , m and X are as defined hereinbefore and L 5 represents a suitable leaving group, such as a halogen atom (e.g. fluorine).
  • a halogen atom e.g. fluorine
  • Step (i) typically comprises heating a mixture of compounds of formulae (XXV) and (XX) to reflux in a suitable solvent, in the presence of a suitable base and a copper (I) salt.
  • Step (ii) typically comprises heating a mixture of a compound of formula (XXVI), iron powder and ammonium chloride, in a suitable solvent.
  • step (iii) typically comprises treating a compound of formula (XXVII) with nitrous acid and potassium iodide under Sandmeyer reaction conditions.
  • R 4 , q and B are as defined hereinbefore and L 6 represents a suitable leaving group, such as a halogen atom (e.g. chlorine).
  • a suitable leaving group such as a halogen atom (e.g. chlorine).
  • Step (i) typically comprises reacting compounds of formulae (XXVIII) and (XXIX) under suitable Suzuki reaction conditions.
  • R 1 , m, X, R 2 , n, A, L 1 and L 6 are as defined hereinbefore.
  • Step (i) typically comprises treating the compound of formula (V) with butyl lithium followed by quenching with trimethyl borate, giving the boronic acid of formula (XXX) following an aqueous work up.
  • Step (ii) typically comprises reacting the compounds of formulae (XXX) and (XXIX) under suitable Suzuki conditions.
  • R 1 , m, X, R 2 , n and A are as defined hereinbefore.
  • Step (i) typically comprises a diazotisation reaction under suitable conditions followed by suitable reducing conditions.
  • Compounds of formula (X) may be prepared in accordance with Scheme 7:
  • R 4 , q and B are as defined hereinbefore.
  • Step (i) typically comprises heating a compound of formula (XXXI) in the presence of dimethylformamide dimethylacetal (DMA) in a suitable solvent, such as dimethyl formamide (DMF).
  • DMA dimethylformamide dimethylacetal
  • DMF dimethyl formamide
  • Step (i) typically comprises reacting the compounds of formula (XXXII) and (XXXIII) in the presence of a suitable base followed by suitable hydrolysis and decarboxylation conditions.
  • Step (ii) typically comprises heating a compound of formula (XXXIV) in the presence of dimethylformamide dimethylacetal (DMA) in a suitable solvent, such as dimethyl formamide (DMF).
  • DMA dimethylformamide dimethylacetal
  • DMF dimethyl formamide
  • R 1 , m, X, R 2 , n and A are as defined hereinbefore.
  • Step (i) typically comprises heating a compound of formula (XXXII) with hydrazine in a suitable solvent, such as ethanol.
  • R 4 , q and B are as defined hereinbefore.
  • Step (i) typically comprises heating a compound of formula (XXIV) in the presence of dimethylformamide dimethylacetal (DMA) in a suitable solvent, such as dimethyl formamide (DMF)
  • DMA dimethylformamide dimethylacetal
  • DMF dimethyl formamide
  • R 1 , m, X, R 2 , n, A, B, R 4 and q are as defined hereinbefore.
  • Step (i) typically comprises stirring a compound of formula (XXXIV) and N-bromo succinimide in a suitable solvent, such as DMSO, for approximately 2 days, followed by working up with water.
  • a suitable solvent such as DMSO
  • halogen atom i.e. iodine
  • Step (i) typically comprises the use of copper iodide, DIPEA in a suitable solvent, such as dimethylformamide followed by the addition of a suitable catalyst, such as
  • Step (i) typically comprises the use of formamide and TMSCI in the presence of suitable solvents, such as toluene and acetonitrile.
  • Step (ii) typically comprises reacting a compound of formula (XLV) with a suitable reagent such as 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-3-ium chloride in a suitable solvent, such as tetrahydrofuran followed by purging with nitrogen prior to addition of a compound of formula (XLVI) followed by the addition of a suitable base, such as triethylamine.
  • a suitable reagent such as 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-3-ium chloride
  • a suitable solvent such as tetrahydrofuran
  • a suitable base such as triethylamine
  • Such interconversion comprises a suitable alkylation reaction, such as treatment with iodomethane in the presence of sodium hydride and a suitable solvent, such as tetrahydrofuran. Examples of such an interconversion may be seen in Examples 233 and 234.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (- NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyl carbamate (-NHCO- OCH 2 C 6 H 5 , -NH-Cbz or NH-Z); as a t-butyl carbamate (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2- biphenyl-2-propyl carbamate (-NHCO-OCCCHs ⁇ CehUCeHs, -NH-Boc), as a 9-fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-T
  • protecting groups for amines such as cyclic amines and heterocyclic N-H groups, include toluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group.
  • tosyl toluenesulphonyl
  • methanesulphonyl methanesulphonyl
  • PMB para-methoxybenzyl
  • references herein to agonism of the G-protein coupled bile acid GPBAR1/TGR5 receptor refer to a compound exhibiting an EC50 of less than 10 ⁇ in the cell based Alpha Screen® assay described herein. In one embodiment, certain compounds of formula (I) exhibit an EC50 of less than 1 ⁇ in the cell based Alpha Screen® assay described herein. In a further embodiment, certain compounds of formula (I) exhibit an EC50 of less than 0.1 ⁇ in the cell based Alpha Screen® assay described herein.
  • compounds of the invention for use as a medicament, preferably a human medicament.
  • the invention provides the use of compounds of the invention in the manufacture of a medicament for treating or preventing a disease or condition mediated by agonism of the G-protein coupled bile acid GPBAR1/TGR5 receptor.
  • compounds of the invention may be useful in the treatment of obesity, hyperlipidaemia, atherosclerosis or type-2 diabetes mellitus, or for lowering blood glucose or enhancing insulin secretion.
  • compounds of the invention may be useful in the treatment of obesity or type-2 diabetes mellitus.
  • Compounds of the invention may also be useful in increasing GLP-1 secretion.
  • a method for increasing GLP- 1 secretion in a cell in vitro comprising contacting the cell with an effective amount of a compound of formula (I) as defined herein.
  • Compounds of the invention may also be useful in altering gastrointestinal motility or transit.
  • a method for altering gastrointestinal motility or transit in a subject in need of such treatment comprising coadministering to the subject, simultaneous or sequentially, an effective amount of a compound of formula (I) as defined herein.
  • Compounds of the invention may also be useful in treating non-alcoholic steatohepatitis or liver fibrosis/cirrhosis.
  • a method for treating non-alcoholic steatohepatitis or liver fibrosis/cirrhosis in a subject in need of such treatment comprising co-administering to the subject, simultaneous or sequentially, an effective amount of a compound of formula (I) as defined herein.
  • Compounds of the invention may also be useful in treating a disease associated with perturbed bile acid metabolism.
  • a method for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
  • the compounds of the invention may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
  • each compound may differ from that when the compound is used alone.
  • combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • either the compound of the invention or the second therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) without the proviso, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier, diluent and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;
  • non-aqueous vehicles which may include edible oils
  • edible oils for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1 % by weight, for example from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will for example contain from 5-1000 mg of the active ingredient.
  • the dosage as employed for adult human treatment may range from 10 to 3000 mg per day depending on the route and frequency of administration. For oral administration a typical dose may be in the range of 50 to 1500 mg per day, for example 120 to 1000 mg per day.
  • a method of treatment or prevention of a disease or condition mediated by agonism of the G-protein coupled bile acid GPBAR1/TGR5 receptor in a mammal comprising administering an effective amount of a compound of formula (I) without the proviso.
  • urea (0.023 g, 0.39 mmol) was added and stirred for another 20 min before adding a solution of NaN 3 (0.15 g, 2.37 mmol) in H 2 0 (1.35 ml) dropwise.
  • the reaction was stirred at RT for 1.5 h then quenched with ice cold water (10 ml) and the mixture extracted with ethyl acetate (2 x 25 ml). The organic layer was washed with brine (10 ml) then dried over Na 2 S0 4 and concentrated under reduced pressure to afford the title compound (0.38g, 69%) as a brown solid.
  • Example 1 1 -(2-(2,4-Dichlorophenoxy)phenyl)-5-(3,4-difluorophenyl)-1 H-1 ,2,3- triazole (EI )
  • Phenyl acetylene (0.274 g, 2.68 mmol) and chloro(pentamethylcyclopentadienyl)ruthenium (II) tetramer (0.057 g, 0.071 mmol) were added to a stirred solution 2-(2-azidophenoxy)-1 ,4- dichlorobenzene (which may be prepared as described in Description 5) (0.5 g, 1.79 mmol) in DMF (7 ml) at ambient temperature.
  • the reaction was irradiated by microwaves at 1 10 °C for 20 minutes then cooled to ambient temperature and quenched with ice-cold water (25 ml).
  • the mixture was extracted with ethyl acetate (2 x 50 ml), the organic extracts combined, dried (Na 2 S0 4 ) and concentrated under reduced pressure to yield the crude product.
  • Phenyl acetylene (0.197 g, 1.93 mmol) and chloro(pentamethylcyclopentadienyl)ruthenium (II) tetramer (0.041 g, 0.0516 mmol) were added to a stirred solution of 1-azido-2-(2- (trifluoromethyl) phenoxy) benzene (which may be prepared as described in Description 7) (0.36 g, 1.29 mmol) in DMF (5 ml) at ambient temperature. The reaction was irradiated by microwave, at 1 10 °C for 20 minutes then cooled to ambient temperature and quenched with ice-cold water (20 ml).
  • Phenyl acetylene (0.049 g, 0.48 mmol) and chloro (pentamethylcyclopentadienyl) ruthenium (II) tetramer (0.0102 g, 0.0129 mmol) were added to a stirred solution of 1-(2-azidophenoxy)- 2,3-dichlorobenzene (which may be prepared as described in Description 9) (0.090 g, 0.322 mmol) in DMF (1.3ml) at ambient temperature.
  • the reaction was irradiated by microwave, at 1 10 °C for 20 minutes then cooled to ambient temperature and quenched with ice-cold water (10 ml).
  • Phenyl acetylene (0.1 16 g, 1.14 mmol) and chloro (pentamethylcyclopentadienyl) ruthenium (II) tetramer (0.060 g, 0.076 mmol) were added to a stirred 1-(2-azidophenoxy)-3-chloro-4- fluoro benzene (which may be prepared as described in Description 1 1) (0.200g, 0.760 mmol) in DMF (4.0ml) at ambient temperature.
  • the reaction was irradiated by microwave, at 1 10 °C for 20 minutes then cooled to ambient temperature and quenched with ice-cold water (10 ml).
  • Example 24 from the table above was prepared in accordance with the following
  • Examples 44-67 The compounds of Examples 44-67 may be prepared in accordance with the methodology described in process (c) and Schemes 3 and 4 described hereinbefore.
  • Examples 68-91 may be prepared in accordance with the methodology described in process (d) and Scheme 5 described hereinbefore.
  • Examples 92-115 may be prepared in accordance with the methodology described in process (e) and Schemes 6 and 7 described hereinbefore.
  • Example 96 from the table above was prepared in accordance with the following
  • Step B (E)-1-(2-Chlorophenyl)-3-(dimethylamino)prop-2-en-1-one
  • ⁇ , ⁇ -Dimethylformamide dimethyl acetal (1.41 g, 1 1.88 mmol) was added to a stirred solution of 1-(2-chlorophenyl)ethanone (0.5 g, 3.24 mmol) in DMF (10 ml) at ambient temperature. The reaction was stirred for 0.5h, heated at 90 °C for 16 h then cooled to ambient temperature. The mixture was diluted with water (25 ml), extracted with ethyl acetate (2 x 50 ml), washed with brine (25 ml) and dried (Na 2 S0 4 ). The organic layer was filtered and concentrated under reduced pressure to yield the title compound (0.42 g, 61.7 % crude) as a yellow liquid.
  • Step C 5-(2-Chlorophenyl)-1-(2-(2,5-dichlorophenoxy) phenyl)-1 H-pyrazole
  • Examples 1 16-133 may be prepared in accordance with the methodology described in process (f) and Scheme 8 described hereinbefore.
  • Example 119 from the table above was prepared in accordance with he following
  • Step A 1 ,4-Dichloro-2-(2-iodophenoxy)benzene
  • Step B 1 ,4-Dichloro-2-(2-((2-chlorophenyl) ethynyDphenoxy) benzene
  • Step C 4-(2-Chlorophenyl)-3-(2-(2,5-dichlorophenoxy)phenyl)-1 H-pyrazole and 3-(2- chlorophenyl)-4-(2-(2,5-dichlorophenoxy)phenyl)-1 H-pyrazole
  • Examples 134-151 may be prepared in accordance with the methodology described in process (f) and Scheme 8 described hereinbefore.
  • Examples 152-169 may be prepared in accordance with the methodology described in process (g) and Schemes 9 and 10 described hereinbefore.
  • Examples 170-187 may be prepared in accordance with the methodology described in process (h) and Scheme 11 described hereinbefore.
  • Example 173 from the table above was prepared in accordance with the following
  • Step B 5-(2-Chlorophenyl)-4-(2-(2,5-dichlorophenoxy)phenyl)-1 H-imidazole
  • Examples 188-205 may be prepared in accordance with the methodology described in process (h) and Scheme 11 described hereinbefore.
  • Example 226 1 -(2-(2,5-Dichlorophenoxy) phenyl)-4-methyl-5-phenyl-1 H-imidazole (E226)
  • Example 227 2-(1 -(2-(2,4-Dichlorophenoxy)phenyl)-1 H-1 ,2,3-triazol-5-yl)-N,N- dimethylaniline (E227)
  • Example 229 4-(2-Chloro-4-fluorophenoxy)-3-(5-(2-chlorophenyl)-1 H-1 ,2,3-triazol-1 -yl) pyridine (E229)
  • Step B 4-(2-Chloro-4-fluorophenoxy)pyridin-3-amine
  • urea (0.018 g, 0.315 mmol) was added and stirred for another 20 minutes before adding a solution of NaN 3 (0.245 g, 3.78 mmol) in H 2 0 (2.02 ml) dropwise.
  • the reaction was stirred at ambient temperature for 1.5 h then quenched with ice cold water (20 ml).
  • the reaction mixture was extracted with ethyl acetate (2 x 40 ml). The organic layer was washed with brine (20 ml) then dried over Na 2 S0 4 and concentrated under reduced pressure to afford the title compound (0.5 g, 60%) as a brown liquid.
  • Step D 4-(2-Chloro-4-fluorophenoxy)-3-(5-(2-chlorophenyl)-1 H-1 ,2,3-triazol-1-yl)pyridine
  • 1-Chloro-2-ethynylbenzene (0.386 g, 2.84 mmol) and chloro (pentamethyl cyclopentadienyl) ruthenium (II) tetramer (15 mg, 0.0189 mmol) were added to a stirred solution of 3-azido-4- (2-chloro-4-fluorophenoxy)pyridine (which may be prepared as described in Example 229, Step C) (0.5 g, 1.89 mmol) in DMF (5 ml) at ambient temperature.
  • Example 231 1 -(2-(2-Chlorophenoxy)phenyl)-5-(2-chlorophenyl)-1 H-1 ,2,3-triazole (E231 )
  • Step D 1-(2-(2-Chlorophenoxy) phenyl)-5-(2-chlorophenyl)-1 H-1 ,2,3-triazole
  • Example 232 The compound of Example 232 was prepared exactly as described in Example 119 above.
  • Step D 3-(5-(2-Chlorophenyl)-1 H-1 ,2,3-triazol-1-yl)-4-(2,5-dichlorophenoxy) pyridine
  • the biological activity of the compounds described herein was determined in a cell based Alpha Screen® assay mediated by GPBA receptor activation (Sato et al. (2008), J. Med. Chem., 51 , 1831-1841 ; Huang et al. (201 1), Experimental Diabetes Research., 10, 1-5).
  • the Alpha Screen® cAMP assay measures intracellular cAMP release upon modulation of adenylate cyclase activity by Gai or Gas GPCRs.
  • the assay is based on the competition between intracellular and extracellular biotinylated cAMP.
  • ChemibriteTM GPBA receptor stable cells (Cat no: HTS238L; Millipore) were seeded at 25,000 numbers per well in a half area 96 well plate and the cell plate was incubated overnight at 37°C in an incubator with a supply of 5% C0 2 . Following the incubation, the overnight growth medium was aspirated and the cells were washed twice with PBS. The cells were loaded with 5 ⁇ _ of anti-cAMP acceptor beads and further treated with the reference or test compounds. The cells were incubated at room temperature for 30mins in the dark. Following the incubation, 15 ⁇ _ of biotinylated-cAMP/Streptavidin donor bead detection mix was added to the cells and incubated at room temperature for 30mins in the dark. The cAMP readout was obtained by use of an ENVISION microplate reader (PerkinElmer). The % Agonistic activity (or) % Stimulation of the test compounds was calculated using the following formula:
  • % Stimulation (Average test compound counts - Average negative control counts)/(Average positive control counts - Average negative control counts) x 100.
  • the EC 50 values of the test compounds were determined using GraphPad Prism 4 software.
  • Test compounds give rise to reduced pathology following chronic dosing in the diet induced obesity (DIP) mouse model
  • mice Three week old C57BL/6 DIO mice were maintained on a 60 kcal% fat diet (D12492, Research diets). Animals were maintained on the high fat diet from 3 to 7 weeks and then randomized according to body weight into treatment groups. All animals in the study were then maintained on the high fat diet until study termination. From week eight onwards compounds were dosed daily for 28 days with vehicle ( ⁇ in PBS/ 2% TWEEN80), sigatgliptin (1 mg/kg); Example 24 (50 mg/kg); sitagliptin + Example 24 (50 mg/kg); or rosiglitazone (10 mg/kg). The combination of test compound and sitagliptin was dosed as a single formulation. Compounds were delivered orally by gavage. Body weights were measured daily from day 0 to day 28.
  • mice were fasted overnight and then dosed orally with 3 g/kg of glucose.
  • Body weights were measured daily from day 0 to day 28.
  • Table 3 shows the cumulative change on body weight from day 0 to day 28.
  • Table 4 shows the average absolute (mg/dl) fasting blood glucose levels across treatment groups and the percent reduction in fasting blood glucose animals in the treatment arms relative to vehicle control animals.
  • test compounds show robust effects in the murine DIO model.
  • Monotherapy treatment or combination dosing gave rise to superior glycemic control and body weight reduction than current therapies (sitagliptin or rosiglitazone): OGTT responses (Table 2), body weight (Table 3), and fasting blood glucose levels (Table 4).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés hétérocycliques, l'utilisation desdits dérivés dans le traitement d'une série de maladies métaboliques et d'autres affections médiées par un agonisme du récepteur d'acide biliaire couplé à la protéine G GPBAR1/TGR5, des compositions et des formulations contenant lesdits dérivés, des procédés pour les préparer et des méthodes d'administration.
PCT/GB2014/051810 2013-06-12 2014-06-12 Composés hétéroaromatiques diaryle substitués WO2014199164A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB1310456.7 2013-06-12
GB201310456A GB201310456D0 (en) 2013-06-12 2013-06-12 Novel Compounds
GB201314309A GB201314309D0 (en) 2013-08-09 2013-08-09 Novel Compounds
GB1314309.4 2013-08-09

Publications (1)

Publication Number Publication Date
WO2014199164A1 true WO2014199164A1 (fr) 2014-12-18

Family

ID=50981567

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2014/051810 WO2014199164A1 (fr) 2013-06-12 2014-06-12 Composés hétéroaromatiques diaryle substitués

Country Status (1)

Country Link
WO (1) WO2014199164A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104592121A (zh) * 2015-02-13 2015-05-06 佛山市赛维斯医药科技有限公司 含酰肼和硝基苯类结构的化合物、其制备方法及用途
US9670172B2 (en) 2013-08-28 2017-06-06 Medivation Technologies, Inc. Heterocyclic compounds and methods of use
US10183015B2 (en) 2015-03-04 2019-01-22 Medivation Technologies Llc Heterocyclic compounds and methods of use
US10189826B2 (en) 2015-03-04 2019-01-29 Medivation Technologies Llc Heterocyclic compounds and methods of use
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2273534A1 (fr) * 1974-06-07 1976-01-02 Gruenenthal Chemie Nouveaux derives du pyrrole, leur obtention, et composition pharmaceutique qui les contient
US4474599A (en) * 1982-07-14 1984-10-02 The Dow Chemical Company 1-(Pyridyl)-1H-1,2,3-triazole derivatives, and use as herbicidal agents
JPS63230679A (ja) * 1987-03-20 1988-09-27 Kureha Chem Ind Co Ltd 新規な１，２，４−トリアゾール−３−カルボン酸アミド誘導体、その製造法及び除草剤としての利用
WO1996017841A1 (fr) * 1994-12-06 1996-06-13 Nippon Soda Co., Ltd. Composes de pyridylpyrrole, processus de production et bactericide agro-horticole
WO1999014204A1 (fr) * 1997-09-16 1999-03-25 G.D. Searle & Co. 1,2,4-triazoles substitues permettant d'inhiber l'activite proteinique de transfert d'ester de cholesteryle
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
US6423713B1 (en) * 1997-05-22 2002-07-23 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
WO2002088108A1 (fr) * 2001-04-30 2002-11-07 The Procter & Gamble Company Composes triazole convenant pour le traitement de maladies associees a l'activite indesirable des cytokines
WO2003007887A2 (fr) * 2001-07-20 2003-01-30 Merck & Co., Inc. Imidazoles substitues servant de modulateurs de recepteurs de cannabinoides
US20030185793A1 (en) * 2000-03-13 2003-10-02 Felix Kratz Therapeutic and diagnostic ligand systems comprising transport molecule binding properties and medicaments containing the same
WO2003101933A1 (fr) * 2002-05-31 2003-12-11 Personal Chemistry I Uppsala Ab Produits intermediaires, procedes permettant de les preparer et leur utilisation
WO2004056368A1 (fr) * 2002-12-19 2004-07-08 Cyclacel Limited Applications therapeutiques des 4-heteroarylryrimidines 2-substituees
WO2005095354A1 (fr) * 2004-04-03 2005-10-13 Astrazeneca Ab Agents therapeutiques
WO2006018082A1 (fr) * 2004-08-13 2006-02-23 Merck Patent Gmbh 1,5-biphenyle-pyrazoles
WO2007002559A1 (fr) * 2005-06-27 2007-01-04 Exelixis, Inc. Modulateurs des lxr a base de pyrazoles
WO2009118567A2 (fr) * 2008-03-26 2009-10-01 The University Of Nottingham Pyrimidines, triazines et leur utilisation en tant qu’agents pharmaceutiques
WO2010049302A1 (fr) * 2008-10-29 2010-05-06 F. Hoffmann-La Roche Ag Nouveaux dérivés d'amides phényliques ou d'amides pyridyliques et leur utilisation en tant agonistes de gpbar1
WO2013062887A1 (fr) * 2011-10-26 2013-05-02 Merck Sharp & Dohme Corp. Dérivés pyridines substituées utiles en tant qu'agonistes de gpr131

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2273534A1 (fr) * 1974-06-07 1976-01-02 Gruenenthal Chemie Nouveaux derives du pyrrole, leur obtention, et composition pharmaceutique qui les contient
US4474599A (en) * 1982-07-14 1984-10-02 The Dow Chemical Company 1-(Pyridyl)-1H-1,2,3-triazole derivatives, and use as herbicidal agents
JPS63230679A (ja) * 1987-03-20 1988-09-27 Kureha Chem Ind Co Ltd 新規な１，２，４−トリアゾール−３−カルボン酸アミド誘導体、その製造法及び除草剤としての利用
WO1996017841A1 (fr) * 1994-12-06 1996-06-13 Nippon Soda Co., Ltd. Composes de pyridylpyrrole, processus de production et bactericide agro-horticole
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
US6423713B1 (en) * 1997-05-22 2002-07-23 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
WO1999014204A1 (fr) * 1997-09-16 1999-03-25 G.D. Searle & Co. 1,2,4-triazoles substitues permettant d'inhiber l'activite proteinique de transfert d'ester de cholesteryle
US20030185793A1 (en) * 2000-03-13 2003-10-02 Felix Kratz Therapeutic and diagnostic ligand systems comprising transport molecule binding properties and medicaments containing the same
WO2002088108A1 (fr) * 2001-04-30 2002-11-07 The Procter & Gamble Company Composes triazole convenant pour le traitement de maladies associees a l'activite indesirable des cytokines
WO2003007887A2 (fr) * 2001-07-20 2003-01-30 Merck & Co., Inc. Imidazoles substitues servant de modulateurs de recepteurs de cannabinoides
WO2003101933A1 (fr) * 2002-05-31 2003-12-11 Personal Chemistry I Uppsala Ab Produits intermediaires, procedes permettant de les preparer et leur utilisation
WO2004056368A1 (fr) * 2002-12-19 2004-07-08 Cyclacel Limited Applications therapeutiques des 4-heteroarylryrimidines 2-substituees
WO2005095354A1 (fr) * 2004-04-03 2005-10-13 Astrazeneca Ab Agents therapeutiques
WO2006018082A1 (fr) * 2004-08-13 2006-02-23 Merck Patent Gmbh 1,5-biphenyle-pyrazoles
WO2007002559A1 (fr) * 2005-06-27 2007-01-04 Exelixis, Inc. Modulateurs des lxr a base de pyrazoles
WO2009118567A2 (fr) * 2008-03-26 2009-10-01 The University Of Nottingham Pyrimidines, triazines et leur utilisation en tant qu’agents pharmaceutiques
WO2010049302A1 (fr) * 2008-10-29 2010-05-06 F. Hoffmann-La Roche Ag Nouveaux dérivés d'amides phényliques ou d'amides pyridyliques et leur utilisation en tant agonistes de gpbar1
WO2013062887A1 (fr) * 2011-10-26 2013-05-02 Merck Sharp & Dohme Corp. Dérivés pyridines substituées utiles en tant qu'agonistes de gpr131

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
AKIO KAKEFUDA ET AL: "Discovery of 4,5-Diphenyl-1,2,4-triazole Derivatives as a Novel Class of Selective Antagonists for the Human V1page 1907, tba Receptor", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 10, 2002, PERGAMON, GB, pages 1905 - 1912, XP002410341, ISSN: 0968-0896, DOI: 10.1016/S0968-0896(02)00009-3 *
DATABASE HCAPLUS [online] ACS; XP002732042, retrieved from STN Database accession no. 158:463833 (DN) *
DATABASE HCAPLUS [online] ACS; XP002732043, retrieved from STN Database accession no. 125:114502 (DN) *
DATABASE HCAPLUS [online] ACS; XP002732056, retrieved from STN Database accession no. 111:134158 (DN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 16 February 2005 (2005-02-16), XP002732044, retrieved from STN Database accession no. 832113-71-0 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 19 March 2004 (2004-03-19), XP002732045, retrieved from STN Database accession no. 664966-03-4 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732046, retrieved from STN Database accession no. 1019090-25-5 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732047, retrieved from STN Database accession no. 1019089-72-5 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732048, retrieved from STN Database accession no. 1019089-52-1 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732049, retrieved from STN Database accession no. 1019089-32-7 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732050, retrieved from STN Database accession no. 1019088-42-6 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732051, retrieved from STN Database accession no. 1019087-88-7 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732052, retrieved from STN Database accession no. 1019087-67-2 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732053, retrieved from STN Database accession no. 1019087-46-7 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732054, retrieved from STN Database accession no. 1019089-97-4 (RN) *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 May 2008 (2008-05-04), XP002732055, retrieved from STN Database accession no. 1019088-14-2 (RN) *
MANLEY P J ET AL: "2,4-Disubstituted Pyrimidines: A Novel Class of KDR Kinase Inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 13, no. 10, 2003, PERGAMON, AMSTERDAM, NL, pages 1673 - 1677, XP002407301, ISSN: 0960-894X, DOI: 10.1016/S0960-894X(03)00244-0 *
MONIKA SHARMA ET AL: "Discovery of Novel 1,2,4-Triazol-5-Ones as Tumor Necrosis Factor-Alpha Inhibitors for the Treatment of Neuropathic Pain", CHEMICAL BIOLOGY & DRUG DESIGN, vol. 80, no. 6, 9 October 2012 (2012-10-09), pages 961 - 970, XP055146658, ISSN: 1747-0277, DOI: 10.1111/cbdd.12049 *
RZA BAYRAK ET AL: "Synthesis, characterization, spectral and electrical properties of peripherally tetratriazole-substituted phthalocyanines and its metal complexes", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 712, 10 April 2012 (2012-04-10), ELSEVIER-SEQUOIA S.A. LAUSANNE, CH, pages 57 - 66, XP028509221, ISSN: 0022-328X, [retrieved on 20120419], DOI: 10.1016/J.JORGANCHEM.2012.04.010 *
TANITAME A ET AL: "Synthesis and antibacterial activity of novel and potent DNA gyrase inhibitors with azole ring", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 12, no. 21, November 2004 (2004-11-01), PERGAMON, GB, pages 5515 - 5524, XP004588154, ISSN: 0968-0896, DOI: 10.1016/J.BMC.2004.08.010 *
YAN, YULIAN ET AL., HARBIN GONGYE DAXUE XUEBAO, vol. 44, no. 4, 2012, pages 121 - 125, ISSN: 0367-6234 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9670172B2 (en) 2013-08-28 2017-06-06 Medivation Technologies, Inc. Heterocyclic compounds and methods of use
CN104592121A (zh) * 2015-02-13 2015-05-06 佛山市赛维斯医药科技有限公司 含酰肼和硝基苯类结构的化合物、其制备方法及用途
US10183015B2 (en) 2015-03-04 2019-01-22 Medivation Technologies Llc Heterocyclic compounds and methods of use
US10189826B2 (en) 2015-03-04 2019-01-29 Medivation Technologies Llc Heterocyclic compounds and methods of use
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
US11760728B2 (en) 2019-05-31 2023-09-19 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof

Similar Documents

Publication Publication Date Title
JP6130964B2 (ja) Ａｐｊ受容体のトリアゾールアゴニスト
WO2014199164A1 (fr) Composés hétéroaromatiques diaryle substitués
TWI428338B (zh) 用於發炎及免疫相關用途之環己烯基-芳基化合物
CA2469821C (fr) Modulateurs triazole substitues par heteroaryle du recepteur metabotropique 5 du glutamate
CA2687912C (fr) Derives de piperidine/piperazine
TWI490202B (zh) 昇糖素受體調節劑
TWI429642B (zh) 用於治療與醯基coA-二醯基甘油醯基轉移酶1活性有關聯之病症之化合物，包含其之醫藥組合物及其用途
CA2519252C (fr) Triazoles substitues par biaryle utilises comme inhibiteurs des canaux sodiques
US20120196838A1 (en) Compounds for inflammation and immune-related uses
EP2308869B1 (fr) Composé azole
US8324219B2 (en) Substituted benzoimidazolyl-pyrazine compounds for inflammation and immune-related uses
WO2008039520A2 (fr) Composés cycliques condensés pour utilisations associées à l'inflammation et aux troubles immunitaires
AU2009200478A1 (en) Metabotropic glutamate receptor-5 modulators
WO2009089305A1 (fr) Composés pour des utilisations apparentées à l'inflammation et à l'immunité
JP2008528700A (ja) Ｐｐａｒモジュレーターとしての化合物および組成物
KR20100095574A (ko) 스테아로일-ｃｏａ 데새츄라제 억제제로서 사용하기 위한 1,2,3-트리아졸 유도체
WO2010039236A1 (fr) Composés pour des utilisations liées à une inflammation et au système immunitaire
AU2017217931A1 (en) Halo-substituted piperidines as orexin receptor modulators
JP2007510741A (ja) ナトリウムチャンネル遮断薬としての置換トリアゾール類
WO2013063385A1 (fr) Composés et utilisations liées aux inflammations et au système immunitaire
CN105164112A (zh) 酰胺类化合物及其制备方法、药物组合物和用途
TW201102374A (en) Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
AU2013204588A1 (en) Vinyl-Phenyl Derivatives For Inflammation and Immune-Related Uses

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14732319

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 18/02/2016)

122 Ep: pct application non-entry in european phase

Ref document number: 14732319

Country of ref document: EP

Kind code of ref document: A1