WO2007003604A2 - Hists1mine h3 receptor antagonists - Google Patents

Hists1mine h3 receptor antagonists Download PDF

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Publication number
WO2007003604A2
WO2007003604A2 PCT/EP2006/063753 EP2006063753W WO2007003604A2 WO 2007003604 A2 WO2007003604 A2 WO 2007003604A2 EP 2006063753 W EP2006063753 W EP 2006063753W WO 2007003604 A2 WO2007003604 A2 WO 2007003604A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
formula
cycloalkyl
alkoxy
group
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PCT/EP2006/063753
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French (fr)
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WO2007003604A3 (en
Inventor
Rolf Hohlweg
Knud Erik Andersen
Jan Lindy SØRENSEN
Jane Marie Lundbeck
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Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to CA002614116A priority Critical patent/CA2614116A1/en
Priority to BRPI0613564-1A priority patent/BRPI0613564A2/en
Priority to MX2007015675A priority patent/MX2007015675A/en
Priority to US11/917,823 priority patent/US8501739B2/en
Priority to JP2008519917A priority patent/JP5121707B2/en
Priority to EP06764002A priority patent/EP1902028A2/en
Priority to KR1020087000240A priority patent/KR101286569B1/en
Priority to AU2006264966A priority patent/AU2006264966B2/en
Publication of WO2007003604A2 publication Critical patent/WO2007003604A2/en
Publication of WO2007003604A3 publication Critical patent/WO2007003604A3/en
Priority to US13/472,090 priority patent/US8846677B2/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • 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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen 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
    • C07D401/14—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
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • 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
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    • 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

Definitions

  • the present invention relates to novel compounds, to the use of these compounds in phar- maceutical compositions, to pharmaceutical compositions comprising the compounds, and to methods of treatment employing these compounds or compositions.
  • the present compounds show a high and selective binding affinity for the histamine H3 receptor, indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases or disorders related to the histamine H3 receptor.
  • histamine H3 receptor The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments. Recently, the human histamine H3 receptor has been cloned.
  • the histamine H3 receptor is a presynaptic autorecep- tor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (i.e., it is active in the absence of an agonist). Compounds acting as inverse agonists can inhibit this activity.
  • the histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine.
  • a histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain.
  • a histamine H3 receptor agonist leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine.
  • histamine H3 receptor agonists In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art.
  • Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of these are imidazole derivatives. However, recently some imidazole-free ligands of the histamine H3 receptor have been described (see e.g. Linney et al., J. Med. Chem. 2000, 43, 2362-2370; US 6,316,475, WO 01/66534 and WO 01/74810).
  • WO 00/66578 claims certain 3- or 4-(imidazol-2-yl)pyridines being substituted in the 4 position of the imidazole ring. It is mentioned that mammals having a disease or condition mediated by NPY can be treated with such a compound.
  • WO 2005/028438 claims certain piperidines being substituted in the 1 and 4 posi- tion.
  • the object of this invention is to overcome or ameliorate at lest some of the disadvantages of the prior art. Hence, not all the objects mentioned below may be fully overcome or ameliorated. Further objects of this invention are mentioned below.
  • hydroxy shall mean the radical -OH
  • oxy shall mean the radical -O-
  • nitro shall mean the radical -NO 2
  • cyano shall mean the radical -CN.
  • C 2 6 -alkenyl represents a branched or straight hydrocar- bon group having from 2 to 6 carbon atoms and at least one double bond, e.g. C 2 6 -alkenyl, C 3 6-alkenyl, and the like.
  • ethenyl or vinyl
  • propenyl e.g., prop-1 -enyl and prop-2-enyl
  • butadienyl e.g., buta-1 ,3-dienyl
  • butenyl e.g., but-1 -en-1 -yl and but-2-en-1 -yl
  • pentenyl e.g., pent-1 -en-1 -yl and pent-2-en-2-yl
  • hexenyl e.g., hex-1 - en-2-yl and hex-2-en-1 -yl
  • 1 -ethylprop-2-enyl 1 ,1 -(dimethyl)prop-2-enyl, 1 -ethylbut-3-enyl, 1 ,1 -(dimethyl)but-2-enyl, and the like.
  • C 3 8 -alkenyl represents a branched or straight hydrocarbon group having from 3 to 8 carbon atoms and at least one double bond, e.g. C 3 6-alkenyl, and the like.
  • propenyl e.g., prop-1 -enyl and prop-2-enyl
  • butadienyl e.g., buta-1 ,3-dienyl
  • butenyl e.g., but-1 -en-1 -yl and but-2-en-1 -yl
  • pentenyl e.g., pent-1 -en-1 -yl and pent-2-en-2-yl
  • hexenyl e.g., hex-1 -en-2-yl and hex-2-en- 1 -yl
  • 1 -ethylprop-2-enyl 1 ,1 -(dimethyl)prop-2-enyl, 1 -ethylbut-3-enyl, 1 ,1 -(dimethyl)but-2- enyl, and the like.
  • Ci 6 -alkoxy refers to the radical Ci 6 -alkyl-O-.
  • Representative examples are methoxy, ethoxy, propoxy (e.g., 1 -propoxy and 2-propoxy), butoxy (e.g., 1 -butoxy, 2-butoxy and 2-methyl-2-propoxy), pentoxy (1 -pentoxy and 2-pent- oxy), hexoxy (1 -hexoxy and 3-hexoxy), and the like.
  • Ci 6 -alkoxy-Ci 6 -alkyl refers to Ci 6 -alkyl substituted with
  • Ci 6 -alkoxy at any carbon atom are methoxymethyl, ethoxymethyl,
  • Ci 6 -alkoxycarbonyl refers to the radical Ci 6 -alkoxy-
  • Ci 6 -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms, e.g. Ci 3 -alkyl, Ci 4 -alkyl, C 2 6 -alkyl, C 3 6 - alkyl, and the like.
  • methyl, ethyl, propyl e.g., prop-1 -yl and prop-2-yl (or isopropyl)
  • butyl e.g., 2-methylprop-2-yl (or terf-butyl), but-1 -yl and but-2-yl
  • pentyl e.g., pent-1 -yl, pent-2-yl and pent-3-yl
  • 2-methylbut-1 -yl 3-methylbut-1 -yl
  • hexyl e.g., hex-1 -yl
  • heptyl e.g., hept-1 -yl
  • Ci 8 -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 8 carbon atoms, e.g. Ci 3 -alkyl, Ci 4 -alkyl, Ci
  • 6-alkyl C 2 6 -alkyl, C 3 6 -alkyl, Ci 8 -alkyl, and the like.
  • Representative examples are methyl, ethyl, propyl (e.g., prop-1 -yl and prop-2-yl (or isopropyl)), butyl (e.g., 2-methylprop-2-yl (or terf-butyl), but-1 -yl and but-2-yl), pentyl (e.g., pent-1 -yl, pent-2-yl and pent-3-yl), 2-methylbut- 1 -yl, 3-methylbut-1 -yl, hexyl (e.g., hex-1 -yl), heptyl (e.g., hept-1 -yl), octyl (e.g., oct-1 -yl), and the like.
  • Ci 6 -alkylcarbonylamino refers to the radical Ci 6 -alkyl-
  • Ci 6 -alkylcarbonylamino-Ci 6 -alkyl refers to Ci 6 -alkyl substituted at any carbon atom with Ci e-alkylcarbonylamino. Representative examples are acetylaminomethyl, 1 -(acetylamino)ethyl, propionylaminomethyl, and the like.
  • Ci 6 -alkylsulfanyl refers to the radical Ci 6 -alkyl-S-. Repre- sentative examples are methylthio, ethylthio, propylthio (e.g., 1 -propylthio, 2-propylthio and 3-propylthio), butylthio, pentylthio, hexylthio, and the like.
  • Representative examples are methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pen- tylsulfonyl, hexylsulfonyl, and the like.
  • C 3 8 -alkynyl represents a branched or straight hydrocarbon group having from 3 to 8 carbon atoms and at least one triple bond.
  • Representative ex- amples are propynyl (e.g., prop-1 -ynyl and prop-2-ynyl), butynyl (e.g., but-1 -ynyl and but-2-y- nyl), pentynyl (e.g., pent-1 -ynyl and pent-2-ynyl), hexynyl (e.g., hex-1 -ynyl and hex-2-ynyl), 1 - ethylprop-2-ynyl, 1 ,1 -(dimethyl)prop-2-ynyl, 1 -ethylbut-3-ynyl, 1 ,1 -(dimethyl)but-2-ynyl, and the like.
  • aryl as used herein is intended to include monocyclic, bicyclic or poly- cyclic carbocyclic aromatic rings. Representative examples are phenyl, naphthyl (e.g., naphth-1 -yl and naphth-2-yl), anthryl (e.g., anthr-1 -yl and anthr-9-yl), phenanthryl (e.g., phe- nanthr-1 -yl and phenanthr-9-yl), and the like.
  • Aryl is also intended to include monocyclic, bicyclic or polycyclic carbocyclic aromatic rings substituted with carbocyclic aromatic rings.
  • biphenyl e.g., biphenyl-2-yl, biphenyl-3-yl and biphenyl-4-yl
  • phenylnaphthyl e.g.1 -phenylnaphth-2-yl and 2-phenylnaphth-1 -yl
  • Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic rings with at least one unsaturated moiety (e.g., a benzo moiety).
  • indanyl e.g., in- dan-1 -yl, indan-5-yl
  • indenyl e.g., inden-1 -yl and inden-5-yl
  • 1 ,2,3,4-tetrahydronaphthyl e.g., 1 ,2,3,4-tetrahydronaphth-1 -yl, 1 ,2,3,4-tetrahydronaphth-2-yl and 1 ,2,3,4-tetrahydro- naphth-6-yl
  • 1 ,2-dihydronaphthyl e.g., 1 ,2-dihydronaphth-1 -yl, 1 ,2-dihydronaphth-4-yl and 1 ,2-dihydronaphth-6-yl
  • fluorenyl e.g., fluoren-1 -yl, fluoren-4-yl and fluoren-9-yl
  • Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are, benzonorbornyl (e.g., benzonorborn-3-yl and benzonorborn-6-yl), 1 ,4-ethano-1 ,2,3,4-tetrahydronapthyl (e.g., 1 ,4-ethano-1 ,2,3,4-tetrahydronapth-2-yl and 1 ,4-ethano-1 ,2,3,4-tetrahydronapth-10-yl), and the like.
  • Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or more spiro atoms.
  • Representative examples are spiro[cyclo- pentane-1 ,1 '-indane]-4-yl, spiro[cyclopentane-1 ,1 '-indene]-4-yl, spiro[piperidine-4,1 '-indane]- 1 -yl, spiro[piperidine-3,2'-indane]-1 -yl, spiro[piperidine-4,2'-indane]-1 -yl, spiro[piperidine-4,1 '- indane]-3'-yl, spiro[pyrrolidine-3,2'-indane]-1 -yl, spiro[pyrrolidine-3,1 '-(3',4'-dihydro- naphthalene)]-1 -yl, spiro[piperidine-3,1 '-(3',4'-dihydronaphthalene)]-1 -yl, s
  • Representative examples are benzyloxycarbonyl, phenylethoxycarbonyl (e.g., (2-phenylethoxy)carbonyl and (i -phenylethoxy)carbonyl), and the like.
  • Representative examples are benzoylamino, naphthylcarbonylamino, 4-phenylbenzoylamino, and the like.
  • arylcarbonylamino-Ci 6 -alkyl refers to Ci 6 -alkyl substituted at any carbon atom with arylcarbonylamino.
  • Representative examples are benzoylami- nomethyl, naphthylcarbonylaminomethyl, 2-(4-phenylbenzoylamino)ethyl, and the like.
  • cyano-C ⁇ 6 -alkyl refers to Ci 6 -alkyl, substituted at any carbon atom(s) with cyano. Representative examples are cyanomethyl, 2-cyanoethyl, and the like.
  • C 3 8 -cycloalkenyl represents a partially saturated monocyclic carbocyclic ring having from 3 to 8 carbon atoms and at least one double bond.
  • Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohep- tenyl, cyclooctenyl, cyclohex-1 ,3-dienyl, and the like.
  • C 38 -cycloalkenyl-Ci 3 -alkyl is a combination of C 38 -cyclo- alkenyl and Ci 3 -alkyl.
  • Representative examples are cyclopenten-1 -ylmethyl, 3-(cyclohexen-1 - yl)propyl, and the like.
  • C 3 8 -cycloalkyl represents a saturated monocyclic carbo- cyclic ring having from 3 to 8 carbon atoms, e.g. C 3 6 -alkyl, and the like.
  • Representative ex- amples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • C 3 8-cycloalkyl is also intended to represent a saturated bicyclic carbocyclic ring having from 4 to 8 carbon atoms. Representative examples are decahydronaphthalenyl, bicycle- [3.3.0]octanyl, and the like.
  • C 3 8-cycloalkyl is also intended to represent a saturated carbocyc- lie ring having from 3 to 8 carbon atoms and containing one or two carbon bridges. Representative examples are adamantyl, norbornanyl, nortricyclyl, bicyclo[3.2.1 ]octanyl, bicyclo- [2.2.2]octanyl, tricyclo[5.2.1 .0/2,6]decanyl, bicyclo[2.2.1 ]heptyl, and the like.
  • C 3 8 -cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 8 carbon atoms and containing one or more spiro atoms. Representative examples are spiro[2.5]octanyl, spiro- [4.5]decanyl, and the like.
  • C 38 -cycloalkyl-Ci 3 -alkyl is a combination of C 38 -cycloalkyl and Ci 3 -alkyl.
  • Representative examples are cyclopropylmethyl, 2-cyclohexylethyl, 3-cyclopentyl- prop-1 -yl, 1 -cyclohexylethyl, adamantylmethyl, and the like.
  • C 3 8 -cycloalkylcarbonylamino-Ci 6 -alkyl is cyclopentylcarbonylamino-methyl, 3-(cyclohexylcarbonylamino)propyl, and the like.
  • halo-Ci 6 -alkyl refers to Ci 6 -alkyl, substituted one or more times at any carbon atom(s) with any halogen. Representative examples are trifluoromethyl, 2,2,2-trifluoroethyl, and the like.
  • halo-Ci 6 -alkoxy refers to Ci 6 -alkoxy, substituted one or more times at any carbon atom(s) with any halogen.
  • Representative examples are trifluoro- methoxy and 2,2,2-trifluoroethoxy, and the like.
  • halogen or halo means fluorine, chlorine, bromine or iodine.
  • pyrrolyl e.g., pyrrol-1 -yl, pyrrol-2-yl and pyrrol-3-yl
  • furanyl e.g., furan-2-yl and furan-3-yl
  • thienyl e.g., thien-2-yl and thien-3-yl
  • oxazolyl e.g., oxazol-2-yl, oxazol-4-yl and oxazol-5-yl
  • thiazolyl e.g., thiazol-2-yl, thiazol-4-yl and thiazol-5- yl
  • imidazolyl e.g., imidazol-2-yl, imidazol-4-yl and imidazol-5-yl
  • pyrazolyl e.g., pyrazol-1 - yl, pyrazol-3-yl and pyrazol-5-yl
  • Representative examples are indolyl (e.g., indol-1 -yl, indol-2-yl, indol-3-yl and indol-5-yl), isoindolyl, benzofuranyl (e.g., benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo- [b]furan-5-yl, benzo[c]furan-2-yl, benzo[c]furan-3-yl and benzo[c]furan-5-yl), benzothienyl (e.g., benzo[b]thien-2-yl, benzo[b]thien-3-yl, benzo[b]thien-5-yl, benzo[c]thien-2-yl, be
  • Representative examples are car- apelolyl (e.g., carbazol-2-yl, carbazol-3-yl, carbazol-9-yl), phenoxazinyl (e.g., phenoxazin-10- yl), phenazinyl (e.g., phenazin-5-yl), acridinyl (e.g., acridin-9-yl and acridin-10-yl), phenol- thiazinyl (e.g., phenothiazin-10-yl), carbolinyl (e.g., pyrido[3,4-b]indol-1 -yl, pyrido[3,4-b]indol- 3-yl), phenanthrolinyl (e.
  • Representative examples are pyrrolinyl, pyrazolinyl, imidazolinyl (e.g., 4,5-dihydroimidazol-2-yl and 4,5- dihydroimidazol-1 -yl), indolinyl (e.g., 2,3-dihydroindol-1 -yl and 2,3-dihydroindol-5-yl), dihydro- benzofuranyl (e.g., 2,3-dihydrobenzo[b]furan-2-yl and 2,3-dihydrobenzo[b]furan-4-yl), dihydro- benzothienyl (e.g., 2,3-dihydrobenzo[b]thien-2-yl and
  • Heteroaryl is also intended to include partially saturated bicyclic or polycyclic heterocyclic rings containing one or more spiro atoms.
  • Representative examples are spiro[isoquinoline-3,1 '-cyclohexan]-1 -yl, spiro[piperidine-4,1 '-benzo- [c]thiophen]-1 -yl, spiro[piperidine-4,1 '-benzo[c]furan]-1 -yl, spiro[piperidine-4,3'-benzo[b]- furan]-1 -yl, spiro[piperidine-4,3'-coumarin]-1 -yl, and the like.
  • pyridinylcarbonyl e.g., pyridin-2-ylcarbonyl and pyridin-4- ylcarbonyl
  • quinolinylcarbonyl e.g., 2-(quinolin-2-yl)carbonyl and 1 -(quinolin-2-yl)carbonyl
  • imidazolylcarbonyl e.g., imidazol-2-ylcarbonyl and imidazol-5-ylcarbonyl
  • Representative examples are pyridinylcarbonylamino (e.g., pyridin-2-ylcarbonyl- amino and pyridin-4-ylcarbonylamino), quinolinylcarbonylamino (e.g., 2-(quinolin-2-yl)- carbonylamino and 1 -(quinolin-2-yl)carbonylamino), and the like.
  • heteroarylcarbonylamino-Ci 6 -alkyl refers to Ci 6 -alkyl substituted at any carbon atom with heteroarylcarbonylamino.
  • Representative examples are pyridinylcarbonylaminomethyl (e.g., pyridin-2-ylcarbonylaminomethyl and pyridin-4-yl- carbonylaminomethyl), 2-(quinolinylcarbonylamino)ethyl (e.g., 2-(2-(quinolin-2-yl)carbonyl- amino)ethyl and 2-(1 -(quinolin-2-yl)carbonylamino)ethyl), and the like.
  • Representative examples are aziridinyl (e.g., aziridin-1 -yl), azetidinyl
  • pyrrolidinyl e.g., pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl
  • 2-oxo-pyrrolidin-1 -yl 2,5-dioxo-pyrrolidin-1 -yl
  • imidazolidinyl e.g., imida- zolidin-1 -yl, imidazolidin-2-yl and imidazolidin-4-yl
  • 2,4-dioxo-imidazolidin-3-yl 2,4-dioxo-1 - methylimidazolidin-3-yl
  • 2,4-dioxo-1 5,5-trimethylimidazolidin-3-yl
  • 2,4-dioxo-5 5-dimethyl- imidazolidin-3-yl
  • Representative examples are octahydroindolyl (e.g., octahydroindol-1 -yl, octahydroindol-2-yl, octahydroindol-3-yl and octahydroindol-5-yl), decahydroquinolinyl (e.g., decahydroquinolin-1 -yl, decahydroquinolin-2-yl, decahydroquino- lin-3-yl, decahydroquinolin-4-yl and decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g., decahydroquinoxalin-1 -yl, decahydr
  • Representative examples are 3-azabicyclo[3.2.2]nonyl, 2-azabicycle- [2.2.1]heptyl, 3-azabicyclo[3.1 .0]hexyl, 2,5-diazabicyclo[2.2.1 ]heptyl, atropinyl, tropinyl, quinuclidinyl, 1 ,4-diazabicyclo[2.2.2]octanyl, and the like.
  • Repre- sentative examples are 1 ,4-dioxaspiro[4.5]decanyl (e.g., 1 ,4-dioxaspiro[4.5]decan-2-yl and 1 ,4-dioxaspiro[4.5]decan-7-yl), 1 ,4-dioxa-8-azaspiro[4.5]decanyl (e.g., 1 ,4-dioxa-8-azaspiro- [4.5]decan-2-yl and 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g., 8-aza- spiro[4.5]decan-1 -yl and 8-azaspiro[4.5]decan-8-yl), 2-azaspiro[5.5]undecanyl (e.g., 2-aza- spiro[5.5]undecan-2-yl), 2,8
  • heterocyclyl-Ci 6 -alkoxy refers to the radical heterocyclyl- Ci 6-alkoxy.
  • Representative examples are piperidin-1 -ylmethoxy, 2-(piperidin-1 -yl)ethoxy, 3- (piperidin-1 -yl)prop-3-oxy, piperazin-1 -ylmethoxy, 2-(piperazin-1 -yl)ethoxy, 3-(piperazin-1 -yl)- prop-3-oxy, morpholin-4-ylmethoxy, 2-(morpholin-4-yl)ethoxy, 3-(morpholin-4-yl)prop-3-oxy, and the like.
  • heterocyclyl-Ci 6 -alkyl refers to the radical heterocyclyl- Ci 6 -alkyl.
  • Representative examples are piperidin-1 -ylmethyl, 2-(piperidin-1 -yl)ethyl, 3- hydroxy-3-(piperidin-1 -yl)propyl, piperazin-1 -ylmethyl, 2-(piperazin-1 -yl)ethyl, 3-hydroxy-3- (piperazin-i -yl)propyl, morpholin-4-ylmethyl, 2-(morpholin-4-yl)ethyl, 3-hydroxy-3-(morpholin- 4-yl)propyl, and the like.
  • Representative examples are piperidinylcarbonyl (e.g., piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl and piperidin-4-ylcarbonyl), piperazinylcarbonyl (e.g., piperazin-1 -yl- carbonyl and piperazin-2-ylcarbonyl), and the like.
  • hydroxy-Ci 6 -alkyl refers to Ci 6 -alkyl substituted one or more times at any carbon atom(s) with hydroxyl. Representative examples are hydroxymethyl, hydoxyethyl (e.g., 1 -hydroxyethyl and 2-hydroxyethyl), and the like.
  • N-(Ci 6 -alkylcarbonyl)-N-(Ci 6 -alkyl)amino as used herein is an amino group with two substituents, i.e., a Ci 6 -alkylcarbonyl group and an Ci 6 -alkyl group.
  • N-(Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino-Ci 6 -alkyl N-(C 3 8-cycloalkylcarbonyl)-N-(Ci 6 -alkyl)amino-Ci 6 -alkyl and N-(C 3 8 - cycloalkyl-Ci 6-alkylcarbonyl)-N-(Ci 6 -alkyl)amino-Ci 6 -alkyl.
  • Representative examples are N- cyclohexylcarbonyl-N-methylamino, 2-(N-cyclopentylcarbonyl-N-methylamino)ethyl and the like.
  • bridge represents a connection in a saturated or partly saturated ring between two atoms of such ring that are not neighbors through a chain of 1 to 4 atoms selected from carbon, nitrogen, oxygen and sulfur.
  • connecting chains are -CH 2 -, -CH 2 CH 2 -, -CH 2 NHCH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, and the like.
  • spiro atom represents a carbon atom in a saturated or partly saturated ring that connects both ends of a chain of 3 to 8 atoms selected from carbon, nitrogen, oxygen and sulfur.
  • Representative examples are -(CH 2 ) 5 -, -(CH 2 ) 3 -, -(CH 2 J 4 -, -CH 2 NHCH 2 CH 2 -, -CH 2 CH 2 NHCH 2 CH 2 -, -CH 2 NHCH 2 CH 2 CH 2 -, -CH 2 CH 2 OCH 2 -, -OCH 2 CH 2 O- , and the like.
  • solvate as used herein is a complex of defined stoichiometry formed by a solute (in casu, a compound according to the present invention) and a solvent.
  • Solvents are those commonly used in the pharmaceutical art, by way of example, water, ethanol, acetic acid, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • disease means a state of a patient which is not the normal physiological state of man.
  • condition means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.
  • prodrug as used herein includes biohydrolyzable amides and biohydro- lyzable esters and also encompasses a) compounds in which the biohydrolyzable functional- ity in such a prodrug is encompassed in the compound according to the present invention, and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances according to the present invention.
  • these functional groups include 1 ,4-dihydropyridine, N-alkylcarbonyl-1 ,4-dihydropyridine, 1 ,4-cyclohexadiene, tert-butyl, and the like.
  • biohydrolyzable ester as used herein is an ester of a drug substance (in this invention, a compound of formula I) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • a drug substance in this invention, a compound of formula I
  • the advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) in plasma.
  • lower alkyl esters e.g., Ci 4
  • lower acyloxyalkyl esters lower alkoxyacyloxyalkyl esters
  • alkoxyacyloxy esters alkyl acylamino alkyl esters
  • choline esters e.g., KC 4
  • biohydrolyzable amide as used herein is an amide of a drug substance (in this invention, a compound of general formula I) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • the advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) in plasma.
  • Many examples of such are known in the art and include by way of example lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoal- kylcarbonyl amides.
  • pharmaceutically acceptable means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.
  • effective amount means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment.
  • terapéuticaally effective amount of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “thera-plastically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.
  • metabolite as used herein is any intermediate or product resulting from metabolism.
  • metabolism refers to the biotransformation of a drug substance (in this invention, a compound of general formula I) administered to a patient.
  • d day(s)
  • g is gram(s)
  • h hour(s)
  • Hz is hertz
  • kD is kiloDalton(s)
  • L is Ii- ter(s)
  • M is molar
  • mbar is millibar
  • mg is milligram(s)
  • min is minute(s)
  • ml_ is milliliter(s)
  • mM millimolar
  • mmol millimole(s)
  • mol mole(s)
  • N normal
  • ppm is parts per million
  • psi pounds per square inch
  • APCI atmospheric pressure chemical ionization
  • ESI electros- pray ionization
  • BOP is (1 -benzotriazolyloxy)tris(dimethylamino)phosphoniumhexafluorophosphate
  • CDI carbon- yldiimidazole
  • DCM is dichloromethane
  • CH 2 CI 2 is methylenechloride
  • DIBAL-H is diisobuty- laluminiumhydride
  • DBU is 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • DEAD is diethyl azodicar- boxylate
  • DIC is 1 ,3-diisopropylcarbodiimide
  • DIPEA is ⁇ /, ⁇ /-diisopropylethylamine
  • DMA is ⁇ /, ⁇ /-dimethylacetamide
  • DMF is ⁇ /, ⁇ /-dimethylformamide
  • DMPU is ⁇ /, ⁇ /'-dimethylpropylene- urea
  • the invention relates to compounds of the general formula I specified in the claims below.
  • the compounds of this invention differ structurally from the known compounds.
  • the invention also relates to the use of said compounds in therapy, and in particular to pharmaceutical compositions comprising said compounds.
  • the invention in another embodiment, relates to methods of treatment, the method comprising administering to a subject in need thereof an effective amount of one or more compounds according to formula I.
  • the invention relates to the use of compounds accord- ing to formula I in the manufacture of medicaments.
  • the compounds of this invention are useful in the treatment of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial.
  • the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
  • this invention relates to a compound of the general formula I:
  • R 2 is hydrogen, halogen, cyano, Ci 6 -alkyl, Ci 6 -alkoxy, halo-Ci 6 -alkyl or halo-Ci 6 -alkoxy;
  • R 1 represents the following possibilities i) and ii): where possibility i) is a group of the general formula -NR 3 R 4 , wherein R 3 is hydrogen, Ci 6 -alkyl, C 2 6 -alkenyl or C 3 8 -cycloalkyl; and R 4 is
  • Vl VII wherein the star indicates the position of the free bond (and not a methyl group), and wherein m is 0 (zero), 1 , 2 or 3; n is 1 , 2 or 3; o is 0 (zero), 1 , 2, 3 or 4; p is 0 (zero), 1 or 2; q is 1 or 2; Q represents a moiety of the formula -CH 2 -, -O-, -S- or >NR 3 , wherein R 3 is as defined above; R 7 and R 8 independent of each other is hydrogen or Ci 6 -alkyl, or R 7 and R 8 can together with the nitrogen to which they are attached form a heterocyclyl group; R 9 is Ci 6 -alkyl or C 3 8-cycloalkyl, which both may be substituted with a group of the general formula -NR 7 R 8 , wherein R 7 and R 8 are as defined above; R 10 is hydrogen or Ci 6 -alkyl; R 11 is hydrogen, Ci 8 - alkyl
  • this invention relates to a compound of the general formula I, to the extent possible according to claim 1 :
  • R 2 is hydrogen, halogen, cyano, Ci 6 -alkyl, Ci 6 -alkoxy, halo-Ci 6 -alkyl or halo-Ci 6 -alkoxy;
  • R 1 represents the following possibilities i) and ii): where possibility i) is a group of the general formula -NR 3 R 4 , wherein R 3 is hydrogen, Ci 6 -alkyl, C 2 6 -alkenyl or C 3 8 -cycloalkyl; and R 4 is C 1 6 -alkyl, C 2 6 -alkenyl or C 3 8 -cycloalkyl, each of which are substituted with a group selected from -NR 5
  • Vl VII wherein the star indicates the position of the free bond (and not a methyl group), and wherein m is 0 (zero), 1 , 2 or 3; n is 1 , 2 or 3; o is 0 (zero), 1 , 2, 3 or 4; p is 0 (zero), 1 or 2; q is 1 or 2; Q represents a moiety of the formula -CH 2 - , -O-, -S- or >NR 3 , wherein R 3 is as defined above; R 7 and R 8 independent of each other is hydrogen or Ci 6 -alkyl, or R 7 and R 8 can together with the nitrogen to which they are attached form a heterocyclyl group; R 9 is Ci 6 -alkyl or C 3 8-cycloalkyl, which both may be substituted with a group of the general formula -NR 7 R 8 , wherein R 7 and R 8 are as defined above; R 10 is hydrogen or Ci 6 -alkyl; R 11 is hydrogen, Ci 8 - alky
  • R 1 are as defined herein, and the three symbols R 2 are the same or different and each is as defined herein.
  • R 1 are as defined herein, and the two symbols R 2 are the same or different and each is as defined herein.
  • R 1 are as defined herein, and the two symbols R 2 are the same or different and each is as defined herein.
  • R 1 are as defined herein, and the two symbols R 2 are the same or different and each is as defined herein.
  • this invention relates to compounds having one of the general formulas l-6a, l-6b or l-6c:
  • this invention relates to compounds having one of the general formulas l-7a or l-7b:
  • this invention relates to compounds having the general formula I-8:
  • this invention relates to compounds having the general formula I-9:
  • this invention relates to compounds having the general formula 1-10:
  • this invention relates to compounds having the general formula 1-1 1 :
  • this invention relates to compounds having the general formula 1-12:
  • this invention relates to compounds having the general formula 1-13:
  • this invention relates to compounds having the general formula 1-14:
  • A is aryl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
  • A is phenyl, benzofuranyl, benzodioxinyl, benzo- dioxolyl, benzoxazinyl, dihydrobenzodioxinyl, indolyl, pyrazinyl, pyridinyl, oxadiazolyl, quinolyl or thienyl.
  • Q is -CH 2 - or -O-.
  • X is nitrogen
  • Y is nitrogen
  • W and Y are each nitrogen.
  • W and X are each nitrogen.
  • W and Z are each nitrogen.
  • the aromatic, divalent, 6-membered ring containing the symbols W, X, Y and Z is pyridine, pyridazine, pyrimidine or pyrazine from which hy- drogen is removed from two opposite carbon atoms (para position in relation to each other).
  • R 1 is a group of formula Il
  • R 1 is a group of formula
  • R 1 is a group of formula III wherein m is 0, 1 or 2, o is 0, 1 or 2, p is 1 or 2, and R 7 and R 8 are each hydrogen or R 7 and R 8 form together with the nitrogen atom to which they are attached a pyrrolidinyl or piperidinyl group.
  • R 1 is a group of formula IV
  • R 1 is a group of formula V
  • R 1 is a group of formula V wherein m is 2, R 9 is Ci 6-alkyl, and R 10 is hydrogen.
  • R 1 is a group of formula Vl
  • heterocyclyl is tetrahydropyranyl.
  • R 1 is a group of formula Vl wherein R 11 is hydrogen, methyl, isopropyl, propyl, cyclopentyl, cyclohexyl, propenyl, methoxyethyl, cyanoethyl, piperidinylpropyl, N-methylpiperidinylmethyl, methylcarbonylmethyl, N,N-dimethylaminoethyl, N,N-dimethylaminopropyl, N,N-diethylaminoethyl, N,N-dimethylaminocarbonylmethyl or tetrahydropyranyl.
  • R 1 is a group of formula VII
  • R 1 is a group of formula VII wherein m is 2.
  • R 1 is piperazinyl, piperidinyl, pyrrolidinyl, piperid- inylamino or diazepanyl.
  • R 2 is hydrogen, Ci 6 -alkyl or halogen. In an embodiment of this invention, R 2 is hydrogen, methyl or isopropyl.
  • R 2 is hydrogen or Ci 6 -alkyl.
  • R 7 is hydrogen or Ci 6 -alkyl.
  • R 8 is hydrogen or Ci 6 -alkyl.
  • R 7 and R 8 together with the nitrogen to which they are attached form a heterocyclyl group.
  • R 9 is Ci 6 -alkyl.
  • R 9 is pentyl, more preferred pent-3-yl.
  • R 10 is hydrogen or Ci 6 -alkyl.
  • R 10 is hydrogen.
  • R 11 is hydrogen, Ci 8 -alkyl, C 3 8 -alkenyl, C 3 8 - alkynyl, C 3 8 -cycloalkyl, C 3 8 -cycloalkenyl, C 3 8 -cycloalkyl-Ci 3 -alkyl or C 3 8 -cycloalkenyl- Ci 3 -alkyl.
  • R 11 is Ci 8 -alkyl, C 3 8 -cycloalkyl or C 3 8 -cycloalkyl- Ci 3 -alkyl.
  • R 11 is C 3 8 -alkyl, C 3 8 -cycloalkyl or C 3 8 -cycloalkyl- Ci 3 -alkyl.
  • R 11 cannot be hydrogen.
  • R 11 is piperidinylpropyl, N,N-dimethylaminopropyl,
  • the heterocyclyl group is piperidinyl.
  • R 12 is heterocyclyl-d 6 -alkyl, heterocyclyl-d 6-alkoxy, heterocyclylcarbonyl, arylcarbonylamino, arylcarbonylamino-d e-alkyl, heteroaryl- carbonylamino or heteroarylcarbonylamino-d e-alkyl, wherein each said aryl, heteroaryl and heterocyclyl may optionally be substituted with halogen, hydroxy, cyano, C 1 6 -alkyl, C 3 8 - cycloalkyl, halo-d 6 -alkyl, C 1 6 -alkoxy, halo-d 6 -alkoxy, C 1 6 -alkylsulfonyl, C 1 6 -alkylsulfinyl, C 1 6 -alkylcarbonyl, C 1 6 -alkoxycarbonyl, C 1 6 -alkylcarboxy, cyano-d 6
  • R 12 is aryl or heteroaryl, each of which may be substituted with halogen, hydroxy, carboxy, nitro, cyano, C 1 6 -alkyl, C 3 8 -cycloalkyl, C 1 6 - alkoxy, C 1 6 — alkylsulfanyl, C 1 6 -alkylsulfonyl, C 1 6 -alkylcarbonyl, C 1 6 -alkylcarbonylamino, C 1 6 - alkylcarbonylamino-d e-alkyl, C 1 6 -alkoxycarbonyl, C 1 6 -alkylcarboxy, halo-d e-alkyl, halo-d 6-alkoxy, hydroxy-d 6 -alkyl, C 1 6 -alkoxy-d 6 -alkyl, aryl, arylcarbonylamino, arylcarbonyl- amino-d 6 -alkyl, heteroary
  • r is 0 or 1
  • s is 0 or 1
  • R 13 is hydrogen or C 1 6 - alkyl
  • R 14 is hydrogen or C 1 e-alkyl
  • R 13 and R 14 form together with the adjacent nitrogen atom a heterocyclyl group, for example, piperidinyl, optionally substituted by aminocar- bonyl
  • V is a bond.
  • heterocyclyl is morpholinyl, piperazinyl, piperidinyl or tetrahydfropyranyl.
  • heteroaryl is oxadiazolyl.
  • R 12 is methoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, acetyl, acetylamino, acetylaminomethyl, cyanomethyl, ethanesulfanyl, butyl- sulfanyl, methanesulfonyl, ethanesulfonyl, ethanesulfinyl, methyloxadiazolyl, cyclopropylcarbonylamino, cyclopropylmethylcarbonylamino, methoxycyclohexylcarbonyl- amino, morpholinylmethyl, methyloxadiazolyl, chloromethylphenyl, cyanophenyl, cyclopropyl, piperidinylmethylphenyl, aminocarbonylpiperidinylmethylphenyl, N-acetyl-N-methylamino, amino, aminomethyl, cyclohexylcarbonylamin
  • R 13 is hydrogen or Ci 6 -alkyl-
  • R 14 is hydrogen or Ci 6 -alkyl-
  • R 13 and R 14 together with the attached nitrogen form a heterocyclyl group.
  • n 0, 1 or 2.
  • n is 0. In an embodiment of this invention, m is 1 or 2.
  • n 1 or 2.
  • o is 1.
  • p is 1 or 2.
  • m is 0 and p is 2. In an embodiment of this invention, m is 0, p is 2 and o is 1.
  • q is 1.
  • r is 0 or 1.
  • s is 0 or 1.
  • R 2 is hydrogen, Ci 6 -alkyl or halogen
  • R 7 is hydrogen or Ci 6 -alkyl
  • R 8 is hydrogen or Ci 6 -alkyl
  • R 9 is Ci 6-alkyl
  • R 10 is hydrogen or Ci 6 -alkyl
  • R 11 is hydrogen, Ci 8 -alkyl, C 3 8 -alkenyl, C 3 8-alkynyl, C 3 8 -cycloalkyl, C 3 8 -cycloalkenyl, C 3 8 -cycloalkyl-Ci 3 -alkyl or C 3 8 -cycloalkenyl- Ci 3 -alkyl
  • R 11 is Ci 8 -alkyl, C 3 8 -cycloalkyl or C 3 8 -cycloalkyl-C
  • the moiety V is a bond.
  • this invention relates to any one of the following compounds: 1 -[5- (4-chlorophenyl)pyridin-2-yl]-4-isopropylpiperazine; 1 -isopropyl-4-[5-(4-methoxyphenyl)- pyridin-2-yl]piperazine; 1 -isopropyl-4-[5-(4-trifluoromethoxyphenyl)pyridin-2-yl]piperazine; 1 - ⁇ 4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl ⁇ ethanone; 1 -[5-(2,6-difluorophenyl)pyridin- 2-yl]-4-isopropylpiperazine; 1 -[5-(4-fluorophenyl)pyridin-2-yl]-4-isopropylpiperazine; 1 -[5-(3- fluoropheny
  • this invention relates to any one of the following compounds: N- ⁇ 4- [6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl ⁇ acetamide; cyclopropanecarboxylic acid [4- (4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]amide; 2-cyclopropyl-N-[4-(4- isopropyl-S ⁇ -tetrahydro ⁇ H-ti ⁇ 'lbipyrazinyl- ⁇ '-yOphenyOacetamide ⁇ -methoxycyclo- hexanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]- amide; 4- ⁇ 4-[6-(4-iso
  • provisos a) through g. These provisos are defined in claim 1 below.
  • R 1 is different from possibility ii), formula VII, when the ring containing W, X, Y and Z is a pyridazine ring.
  • R 1 is different from possibility i), when the ring containing W, X, Y and Z is a pyridazine ring.
  • R 1 is different from possibility i), when the ring containing W, X, Y and Z is a pyrimidine ring.
  • R 1 is different from possibility i), i.e. R 1 is possibility ii).
  • R 11 is different from hydrogen.
  • the compounds of the present invention interact with the histamine H3 receptor and are accordingly particularly useful in the treatment of a variety of diseases or conditions in which histamine H3 interactions are beneficial.
  • the invention provides the use of a compound according to formula I in a pharmaceutical composition.
  • the pharmaceutical composition may in another aspect of the invention comprise, as an active ingredient, at least one compound according to formula I together with one or more pharmaceutically acceptable carriers or excipients.
  • the invention provides such a pharmaceutical composition in unit dosage form, comprising from about 0.05 mg to about 1000 mg, e.g., from about 0.1 mg to about 500 mg, such as from about 0.5 mg to about 200 mg of the compound according to formula I.
  • the invention provides the use of a compound of formula I as defined above for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the reduction of weight. In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the suppression of appetite or for satiety in- duction.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity, such as dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
  • disorders and diseases related to overweight or obesity such as dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders, such as bulimia or binge eating.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of IGT (Impaired glucose tolerance).
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which a stimulation of the H3 histamine receptor has a beneficial effect.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition having histamine H3 agonistic activity. In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.
  • the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease, narco- lepsy, attention deficit disorders or reduced wakefulness, or for the regulation of sleep.
  • the invention relates to the use of a compound of formula I for the preparation of a pharmaceutical preparation for the treatment of airway disorders, such as asthma, for regulation of gastric acid secretion, or for treatment of diarrhoea.
  • the invention provides a method for the treatment of disorders or diseases related to the H3 histamine receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula I as defined above, or of a pharmaceutical composition comprising such a compound.
  • the invention provides a method as described above, wherein the effective amount of the compound of the general formula I as defined above is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg, and more preferably from about 0.5 mg to about 500 mg per day.
  • the invention relates to compounds which exhibit histamine H3 receptor antagonistic activity or inverse agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.
  • the invention provides a method for reduction of weight, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I as defined above.
  • the invention provides a method for treatment of overweight or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • the invention provides a method for suppression of appetite or for satiety induction, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • the invention provides a method for prevention and/or treatment of disorders or diseases related to overweight or obesity, such as dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer, e.g. endometrial, breast, prostate or colon cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • the invention provides a method for prevention and/or treatment of eating disorders, such as bulimia and binge eating, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • the invention provides a method for the treatment of IGT (Impaired glucose tolerance), the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • IGT Paired glucose tolerance
  • the invention provides a method for the treatment of type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • the invention provides a method for the delaying or prevention of the progression from IGT to type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • the invention provides a method for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
  • the invention relates to compounds which exhibit histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.
  • Compounds of the present invention may also be used for the treatment of airway disorders (such as asthma), as anti-diarrhoeals, and for the modulation of gastric acid secretion.
  • airway disorders such as asthma
  • anti-diarrhoeals such as anti-diarrhoeals
  • gastric acid secretion such as gastric acid secretion
  • compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness, and for the treatment of narcolepsy and attention deficit disorders.
  • compounds of the invention may be used as CNS stimulants or as sedatives.
  • the present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, compounds of the invention may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypotha- lamo-hypophyseal secretion, as antidepressants, as modulators of cerebral circulation, and in the treatment of irritable bowel syndrome.
  • compounds of the present invention may be used for the treatment of dementia and Alzheimer's disease.
  • Compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcer or anorexia.
  • Compounds of the present invention may furthermore be useful for the treatment of migraine [see, e.g., McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50] and for the treatment of myocardial infarction [see Mackins et al., Expert Opinion on Investigational Drugs 9 (2000), 2537-2542].
  • treatment of a patient with a compound of the present invention is combined with diet and/or exercise.
  • one of more compounds of the present invention is/are administered in combination with one or more further active substances in any suitable ratio(s).
  • Such further active agents may, for example, be selected from antiobesity agents, antidiabetics, antidyslipidemic agents, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes, and agents for the treatment of complications and disorders resulting from or associated with obesity.
  • one or more compounds of the present in- vention may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may, for example, be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melan
  • an antiobesity agent administered in combination with one or more compounds of the invention is leptin.
  • such an antiobesity agent is dexamphetamine or amphetamine.
  • such an antiobesity agent is fenfluramine or dexfenflura- mine.
  • such an antiobesity agent is sibutramine. In a further embodiment, such an antiobesity agent is orlistat. In another embodiment, such an antiobesity agent is mazindol or phentermine. In still another embodiment, such an antiobesity agent is phendimetrazine, diethyl- propion, fluoxetine, bupropion, topiramate or ecopipam.
  • one or more compounds of the present in- vention may be administered in combination with one or more antidiabetic agents.
  • antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 0 792 290 (Novo Nordisk A/S), e.g. N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 0 214 826 and EP 0 705 275 (Novo Nordisk A/S), e.g. Asp B28 human insulin, US 5,504,188 (EIi Lilly), e.g. Lys B28 Pro 829 human insulin, EP 0 368 187 (Aventis), e.g. Lantus®, all of which are incorporated herein by reference, GLP-1 derivatives, such as those disclosed in WO
  • the orally active hypoglycaemic agents preferably comprise imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, ⁇ -glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the ⁇ - cells, e.g.
  • potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists, such as one of those disclosed in WO 99/01423 and WO 00/39088 (Novo Nord- isk A/S and Agouron Pharmaceuticals, Inc.), both of which are incorporated herein by reference, GLP-1 agonists, such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), incorporated herein by reference, DPP-IV (dipeptidyl pepti- dase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenosis
  • one or more compounds of the present inven- tion may be administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro 829 human insulin, Lantus ® , or a mix-preparation comprising one or more of these.
  • insulin or an insulin analogue or derivative such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro 829 human insulin, Lantus ® , or a mix-preparation comprising one or more of these.
  • one or compounds of the present invention may be administered in combination with a sulfonylurea, e.g. tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
  • a sulfonylurea e.g. tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
  • a biguanide e.g. metformin.
  • one or more compounds of the present invention may be administered in combination with a meglitinide, e.g. repaglinide or nateglinide.
  • a meglitinide e.g. repaglinide or nateglinide.
  • one or more compounds of the present invention may be administered in combination with a thiazolidinedione insulin sensitizer, e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 /CM 037 or T 174, or a compound disclosed in WO 97/41097, WO 97/411 19, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), all of which are incorporated herein by reference.
  • a thiazolidinedione insulin sensitizer e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 /CM 037 or T 174, or a compound disclosed in WO 97
  • one or more compounds of the present invention may be administered in combination with an insulin sensitizer, e.g. such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516, or a compound disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192 or WO 00/63193 (Dr.
  • an insulin sensitizer e.g. such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516, or a compound disclosed in WO 99/19313,
  • one or more compounds of the present invention may be administered in combination with an ⁇ -glucosidase inhibitor, e.g. voglibose, emiglitate, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor e.g. voglibose, emiglitate, miglitol or acarbose.
  • one or more compounds of the present invention may be administered in combination with an agent acting on the ATP-dependent po- tassium channel of the ⁇ -cells, e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS- 67582 or repaglinide.
  • an agent acting on the ATP-dependent po- tassium channel of the ⁇ -cells e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS- 67582 or repaglinide.
  • one or more compounds of the present invention may be administered in combination with nateglinide.
  • one or more compounds of the present invention may be administered in combination with an antihyperlipidemic agent or antilipidemic agent, e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probu- col or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probu- col or dextrothyroxine.
  • one or more compounds of the present invention may be administered in combination with an antilipidemic agent, e.g. cholestyr- amine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dex- trothyroxine.
  • an antilipidemic agent e.g. cholestyr- amine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dex- trothyroxine.
  • one or more compounds of the present invention may be administered in combination with more than one of the above-mentioned com- pounds, e.g. in combination with metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
  • metformin and a sulfonylurea such as glyburide
  • a sulfonylurea and acarbose such as glyburide
  • one or more compounds of the present invention may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ - blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro,
  • the compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention. Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly- colic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedi- sulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylam- monium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the invention also encompasses prodrugs of the present compounds which follow- ing administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds which are readily convertible in vivo into the required compound of the formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharma- ceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route, such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal or parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings, such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingredient, such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also to be understood as being within the scope of the present invention.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferably from about 0.05 to about 10 mg/kg body weight per day, administered in one or more doses, such as from 1 to 3 doses.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated, and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day, such as from 1 to 3 times per day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0.5 mg to about 200 mg of a compound (or a salt or other derivative thereof as set forth above), according to the invention.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typical doses are of the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having a free base functionality.
  • a compound of the formula I contains a free base functionality
  • such salts are prepared in a conventional manner by treating a solution or suspension of the free base form of the compound of formula I with a chemical equivalent (acid-base equivalent) of a pharmaceutically acceptable acid.
  • Physiologically acceptable salts of a compound of the invention having a hydroxy group include the anion of said compound in combination with a suitable cation, such as sodium or ammonium ion.
  • solutions of the novel compounds of the formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are par- ticularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, su- crose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylenes or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • Formulations of the present invention suitable for oral administration may be pre- sented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier may vary widely, but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques, may in the core contain 5.0 mg of a compound of the invention, 67.8 mg of lactosum Ph.
  • the pharmaceutical composition of this invention may comprise the compound of the formula I in combination with one or more further pharmacologically active substances, e.g., substances chosen among those described in the foregoing.
  • the compounds of this invention can be prepared in a manner known perse or analogous with known processes.
  • the ability of the compounds to interact with the histamine H3 receptor can be determined by the following in vitro binding assay.
  • the human H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector.
  • Cells stably expressing the H3 receptor are generated by transfecting the H3- expression vectors into HEK 293 cells and using G418 to select for H3 clones.
  • the human H3-HEK 293 clones are cultured in DMEM (GIBCO-BRL) with glutamax, 10% foetal calf serum, 1 % penicillin/streptavidin and 1 mg/ml G 418 at 37 0 C and 5% CO 2 .
  • the confluent cells are rinsed with phosphate buffered saline (hereinafter designated PBS) and incubated with Versene (proteinase, GIBCO-BRL) for approximately 5 minutes.
  • PBS phosphate buffered saline
  • Versene proteinase, GIBCO-BRL
  • the cells are flushed with PBS and DMEM and the cell suspension collected in a tube and centrifuged for 5-10 minutes at 1500 rpm in a Heraeus Sepatech Megafuge 1.0.
  • the pellet is resuspended in 10-20 volumes Hepes buffer (20 mM Hepes, 5 mM MgCI 2 , pH 7.1 (KOH)) and homogenized for 10-20 seconds using an Ultra-Turrax homogenizer.
  • the homogenate is centrifuged for 30 minutes at 23,000 g.
  • the pellet is resuspended in 5-10 ml Hepes buffer, homogenized 5-10 seconds with the Ultra-Turrax and centrifuged for 10 minutes at 23,000 g. Following this centrifugation step, the membrane pellet is resuspended in 2-4 ml Hepes buffer, homogenized with a syringe or Teflon homogenizer, and the protein concentration determined. The membranes are diluted to a protein concentration of 1 -5 mg/ml in Hepes buffer, aliquoted and kept at -80 0 C until use.
  • the compounds according to the invention have an IC 50 value as determined by one or more of the assays of less than 10 ⁇ M, more preferred of less than 1 ⁇ M, and even more preferred of less than 500 nM, such as of less than 100 nM.
  • the ability of the compounds to interact with the histamine H3 receptor as agonists, inverse agonists and/or antagonists, is determined by an in vitro functional assay utilizing membranes from HEK 293 cells expressing the human H3 receptors.
  • the H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector.
  • Cells stably expressing the H3 receptor are generated by transfecting the H3-expression vectors into HEK 293 cells and using G418 to select for H3 clones.
  • the human H3-HEK 293 clones are cultured in DMEM with glutamax, 10% foetal calf serum, 1 % penicillin/streptavidin and 1 mg/ml G 418 at 37 0 C and 5% CO 2 .
  • the H3 receptor expressing cells are washed once with PBS and harvested using versene (GIBCO-BRL). PBS is added and the cells are centrifuged for 5 minutes at 188 g. The cell pellet is resuspended in stimulation buffer to a concentration of 1 x 10 6 cells/ml. cAMP accumulation is measured using the Flash Plate ® cAMP assay (NENTM Life Science Products). The assay is generally performed as described by the manufacturer. Briefly, 50 ⁇ l cell suspension is added to each well of the Flashplate which also contained 25 ⁇ l 40 ⁇ M isoprenaline, to stimulate cAMP generation, and 25 ⁇ l of test compound (either agonists or inverse agonists alone, or agonist and antagonist in combination).
  • test compound either agonists or inverse agonists alone, or agonist and antagonist in combination.
  • the assay can be run in "agonist-mode” which means that the test compound is added, in increasing concentration, on its own, to the cells, and cAMP is measured. If cAMP goes up, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist, and if cAMP goes down, it is an agonist.
  • the assay can also be run in the "antagonist-mode” which means that a test compound is added, in increasing concentrations, together with increasing concentrations of a known H3 agonist (e.g. RAMHA). If the compound is an antagonist, increasing concentrations of it cause a right-ward shift in the H3-agonist's dose-response curves. The final volume in each well is 100 ⁇ l.
  • Test compounds are dissolved in DMSO and diluted in water. The mixture is shaken for 5 minutes, and allowed to stand for 25 minutes at room temperature. The reaction is stopped with 100 ⁇ l "Detection Mix” per well. The plates are then sealed with plastic, shaken for 30 minutes, allowed to stand overnight, and finally the radioactivity is counted in the Cobra Il auto gamma topcounter.
  • EC 50 values are calculated by non-linear regression analysis of dose response curves (6 points minimum) using GraphPad Prism.
  • Kb values are calculated by Schild plot analysis.
  • the antagonists and agonists according to the invention have an IC 5 o/EC 5 o value of less than 10 ⁇ M, more preferred of less than 1 ⁇ M, and even more preferred of less than 500 nM, such as of less than 100 nM.
  • the ability of the compounds to bind and interact with the human H3 receptor as agonists, inverse agonists and/or antagonists, is determined by a functional assay, named [ 35 S] GTP ⁇ S assay.
  • the assay measures the activation of G proteins by catalyzing the exchange of guanosine 5'-diphosphate (hereinafter designated GDP) by guanosine 5'-triphosphate (hereinafter designated GTP) at the ⁇ -subunit.
  • GDP guanosine 5'-diphosphate
  • GTP guanosine 5'-triphosphate
  • GTP is rapidly hydrolysed by the G -subunit (GTPases) and the G protein is deactivated and ready for a new GTP exchange cycle.
  • GPCR ligand induced G protein coupled receptor
  • GTP S a non-hydrolysed analogue of GTP. This process can be monitored in vitro by incubating cell membranes containing the G protein coupled receptor H3 with GDP and [ 35 S] GTP ⁇ S. Cell membranes are obtained from CHO cells stably expressing the human H3 receptor. The cells are washed twice in PBS, harvested with PBS + 1 mM EDTA, pH 7.4 and centrifuged at 1000 rpm for 5 minutes.
  • the cell pellet is homogenized in 10 ml ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA, pH 7.4 (NaOH)) using an Ultra-Turrax homogenizer for 30 seconds and centrifuged for 15 minutes at 20,000 rpm. Following this centrifugation step, the membrane pellet is resuspended in 10 ml ice-cold Hepes buffer (20 mM Hepes, 0.1 mM EDTA, pH 7.4 (NaOH)) and homogenized as describe above. This procedure is repeated twice except for the last homogenization step, the protein concentration is determined and membranes are diluted to a protein concentration at 2 mg/ml, aliquoted and kept at -80 0 C until use.
  • the H3-receptor agonist ligand R- ⁇ -methyl histamine (hereinafter designated RAMHA) is added.
  • RAMHA H3-receptor agonist ligand R- ⁇ -methyl histamine
  • test compound is diluted in the assay buffer (20 mM HEPES, 120 mM NaCI, 10 mM MgCI 2 pH 7.4 (NaOH)) at various concentrations followed by addition of 10 8 nM RAMHA (only in the case where an inverse agonist/antagonist is examined), 3 ⁇ M GDP, 2.5 ⁇ g membranes, 0.5 mg SPA beads and 0.1 nM [ 35 S] GTP ⁇ S and incubated for 2 hours by slightly shaking at room temperature. The plates are centrifuged at 1500 rpm for 10 minutes and the radioactivity is measured using a Top-counter. The results are analyzed by non linear regression and the IC 50 value is determined.
  • RAMHA and other H3 agonists stimulate the binding of [ 35 S] GTPyS to membranes expressing the H3 receptor.
  • the antagonist/inverse agonist test the ability of increasing amounts of test compound to inhibit the increased [ 35 S] GTPyS binding by 10 8 M RAMHA is measured as a decrease in radioactivity signal.
  • the IC 50 value determined for an antagonist is the ability of this compound to inhibit the effect of 10 8 M RAMHA by 50%.
  • the agonist test the ability of increasing amounts of test compound is measured as an increase in radioactivity signal.
  • the EC 50 value determined for an agonist is the ability of this compound to increase the signal by 50% of the maximal signal that is obtained by 10 5 M RAMHA.
  • the antagonists and agonists according to the invention have an IC 5 o/EC 5 o value of less than 10 ⁇ M, more preferred of less than 1 ⁇ M, and even more preferred of less than 500 nM, such as of less than 100 nM.
  • Preferred compounds are those that produce a statistically significant reduction of 3-hour cumulated food intake. More preferred compounds are those that decrease 3-hour cumulated food intake with 10-20 % and the most preferred compounds reduce 3-cumulated food intake with more than 20% without sedation of the animals.
  • Test of body weight reduction This test is carried out in rats that have become obese due to over-consumption of dietary energy, i.e. a sustained positive energy balance. Animals are being exposed to the test compound for 7 days. Preferred compounds are those that produce a statistically significant decrease of body weigh compared with control rats given vehicle. More preferred compounds are those that produce a weight reduction of at least 4%, compared with the vehicle control group, and the most preferred compounds are those that reduce body weight with more than 8% compared with vehicle control rats.
  • DRX400 or AV400 instrument equipped with 5 mm selective-inverse (SEI, 1 H and 13 C), 5 mm broad-band inverse (BBI, 1 H, broad-band) and 5 mm quadro nuclear (QNP, 1 H, 13 C) probe- heads, respectively. Shifts ( ⁇ ) are given in parts per million (ppm) down field from tetrame- thylsilane as internal reference standard. HPLC Method A.
  • HPLC Method C The RP-analyses was performed on a Shimadzu LC-20 using a YMC-ODS, 5.0 ⁇ m, 4.6 x 50 mm; gradient elution, 0 % to 30 % solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 6 min, and then kept for 2 min, 2.5 ml_/min, detection at 220 nm, temperature 30 0 C.
  • HPLC Method D The RP-analyses was performed on a Shimadzu LC-20 using a
  • YMC-ODS 5.0 ⁇ m, 4.6 x 50 mm; gradient elution, 0 % to 60 % solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 8 min, and then kept for 2 min, 2.5 ml_/min, detection at 220 nm, temperature 30 0 C.
  • HPLC Method E The RP-analyses was performed on a Shimadzu using a YMC- ODS, 5.0 ⁇ m, 4.6 x 50 mm; gradient elution, 10 % to 80 % solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 6 min, and then kept for 2 min, 2.5 ml_/min, detection at 220 nm, temperature 30 0 C.
  • HPLC Method F The RP-purification was performed on a Gilson Nebula Series system using a Luna, 5 ⁇ m, 21 .2 mm x 250 mm with gradient elution, 5% to 30% solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 15 min, 80 mL/min, detec- tion at 220 nm, temperature 25 0 C, injection volume 30 ml_. The pooled fractions were evaporated in vacuo until acetonitrile was removed, and then frozen and dried.
  • HPLC-MS Method G Column: Waters Xterra MS C-18 X 3 mm id. Buffer: Linear gradient 5% - 95% in 4 min, acetonitrile, 0.01 % TFA, flow rate 1 .0 ml/min. Detection 210 nm (analog output from diode array detector), MS-detection ionisation mode API-ES, scan 100- 1000 amu step 0.1 amu.
  • Microwave Synthesis When microwave oven synthesis was applied, the reaction was heated by microwave irradiation in sealed microwave vessels in a single mode Emrys Optimizer EXP from PersonalChemistry ® .
  • An amine of formula B-2 wherein X, Y, Z, W and R 1 each is as defined herein, and A repre- sents an aryl or heteroaryl group, may be acylated with an activated carboxylic acid derivative to give a compound of formula Ib.
  • an activated carboxylic acid derivative can be a carboxylic acid chloride or anhydride of formula B-4 or B-3, respectively.
  • This reaction may be carried out in a suitable solvent like, for example, dichloromethane or acetic acid, at a temperature of up to reflux.
  • a carboxylic acid of formula B-5 may also be reacted with an amine of formula B-2 to give an amide of formula Ib.
  • This reaction may be carried out by activation of the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent like, for example, THF and at a temperature of up to reflux.
  • Compounds of formula B-2 may be prepared by hydrogenation of a nitril of formula B-1 , wherein X, Y, Z, W and R 1 is as defined herein, and A represents an aryl or heteroaryl group.
  • This reaction may be carried out in a suitable solvent like, for example, THF, at a temperature of up to reflux in the presence of a reducing agent like, e.g., LiAIH 4 .
  • Compounds of formula B-1 may be may be prepared according to other General Procedure(s) described herein.
  • a hydroxyamidine of formula C-2 wherein X, Y, Z, W and R 1 each is as defined herein, and A represents an aryl or heteroaryl group, may be reacted with a carboxylic acid chloride or anhydride of formula C-3 to give a compound of formula Ic.
  • This reaction may be carried out in a suitable solvent like, e.g., ⁇ /, ⁇ /-dimethylacetamide or acetic acid, at a temperature of up to reflux.
  • Compounds of formula C-2 may be prepared by reaction of a nitril of formula C-1 , wherein X, Y, Z, W and R 1 is as defined herein, and A represents an aryl or heteroaryl group, with hydroxylamine.
  • This reaction may be carried out in a suitable solvent like, for example, ethanol and water, at a temperature of up to reflux in the presence of a base like, for example, potassium carbonate.
  • a suitable solvent like, for example, ethanol and water
  • a base for example, potassium carbonate.
  • Compounds of formula C-1 may be may be prepared according to other General Procedure(s) described herein.
  • a benzylhalogenide of formula E-1 wherein X, Y, Z, W and R 1 each is as defined herein, and Hal represents chlorine, bromine or iodine, may be reacted with an amine of formula E-2 to give a compound of formula Ie.
  • This reaction may be carried out in a suitable solvent like, for example, ethanol, at a temperature of up to reflux and in the presence of a base like, for example, triethylamine, or excess of the amine of formula E-2.
  • Compounds of formula E-1 may be prepared according to the General Procedure D described above.
  • a carbonyl compound of formula F-1 may be reacted with an amine of the formula F-2, wherein q, A, X, Y, Z, and W are as defined herein, in the presence of a reducing agent, to give a compound of formula If.
  • This reaction may be carried out in a suitable solvent like, for example, tetrahydrofuran or 1 ,2-dichloro- ethane, at a temperature of up to reflux.
  • the reducing agent may be, for example, NaCNBH 3 or NaBH(OAc) 3 , eventually in the presence of a acidic catalyst like, for example, acetic acid.
  • Compounds of formula F-2 may be may be prepared according to other General Proce- dure(s) described herein.
  • a cyano compound of formula G-1 wherein X,Y,Z, W and R 1 is as defined herein, and A represents an aryl or heteroaryl group, may be reacted with a organometallic compound of formula G-2 or G-3, followed by acidic hydrolysis with, for example, aqueous hydrochloric acid, to give a compound of formula Ig.
  • This reaction may be carried out in a suitable solvent like, for example, tetrahydrofuran or tetrahydrofuran/toluene, at a temperature of up to reflux.
  • Compounds of formula G-1 may be may be prepared according to other General Procedure ⁇ ) described herein.
  • a compound of formula H-1 wherein Hal represents chlorine, bromine or iodine, may be reacted with an amine of the formula H-2, wherein q, A, X, Y, Z, and W are as defined herein, to give a compound of formula Ih.
  • This reaction may be carried out in a suitable solvent like, for example, dimethylformamide, dimethylsulfoxide, acetonitril or 2-butanone, at a tempera- ture of up to reflux.
  • the reaction may be carried out in the presence of a base such as, for example, sodium hydride, potassium carbonate or ⁇ /, ⁇ /-diisopropylethylamine, and a catalyst like, for example, potassium iodide.
  • Compounds of formula H-2 may be may be prepared according to other General Procedure(s) described herein.
  • a compound of formula 1-1 wherein X, Y, W, Z and R 1 each is as defined herein, and Hal represents chlorine, bromine or iodine, may be reacted with a boronic acid derivative of the formula I-2, or a corresponding boronic acid ester derivative, wherein A is as defined herein, to give a compound of formula Ii.
  • This reaction may be carried out in a suitable solvent like, for example, acetonitrile/water, at a temperature of up to 150 0 C in the presence of a suitable catalyst like, for example, bistriphenylphosphinpalladium(ll)dichloride and sodium carbonate.
  • This reaction may also be performed in the other way round starting from reactants wherein the halogen and boronic acid moieties have been interchanged. This reaction may be carried out under similar conditions as described above.
  • a carboxylic acid of formula J-2 wherein A, X, Y, Z, W, and R 1 each is as defined herein, may be reacted with an amine of formula R'RNH to give an amide of formula Ij.
  • This reaction may be carried out by activation of the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent like, for example, THF and at a temperature of up to reflux.
  • a carboxylic acid of formula J-2 may be prepared by hydrolysis of a nitrile of formula J-1 , wherein A, X, Y, Z, W, and R 1 each is as defined herein. This reaction may be carried out under strong acidic conditions, for example, in 6 N hydrochloric acid at a temperature of up to reflux.
  • Compounds of formula J-1 may be prepared according to other General Procedure(s) described herein.
  • a carboxaldehyde of formula K-2 wherein A, X, Y, Z, W, and R 1 each is as defined herein, may be reacted with an amine of formula R'RNH under reducing conditions to give an amine of formula Ik.
  • This reaction may be carried out in a suitable solvent like, for example, tetrahy- drofuran or 1 ,2-dichloroethane, at a temperature of up to reflux.
  • the reducing agent may be, for example, NaCNBH 3 or NaBH(OAc) 3 , eventually in the presence of a acidic catalyst like, for example, acetic acid.
  • a carboxaldehyde of formula K-2 may be prepared from a nitrile of formula K- 1 , wherein A, X, Y, Z, W, and R 1 each is as defined herein. This reaction may be carried out in the presence of a reducing agent, for example, DIBAL-H or LiAIH 4 in a suitable solvent, for example, THF at a temperature from - 40 0 C up to reflux.
  • a reducing agent for example, DIBAL-H or LiAIH 4
  • suitable solvent for example, THF
  • An aromatic amine of formula L-2 may be acylated with an activated carboxylic acid derivative to give a compound of formula II.
  • an activated carboxylic acid derivative can be a carboxylic acid chloride or anhydride of formula L-4 or L-3, respectively.
  • This reaction may be carried out in a suitable solvent like, for example, dichloromethane or acetic acid, at a temperature of up to reflux.
  • a carboxylic acid of formula L-5 may also be reacted with an amine of formula L-2 to give an amide of formula II.
  • This reaction may be carried out by activation of the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent like, for ex- ample, THF and at a temperature of up to reflux.
  • Compounds of formula L-2 may be prepared by hydrogenation of a nitro compound of formula L-1 , wherein X, Y, Z, W and R 1 is as defined herein, and A represents an aryl or heteroaryl group.
  • This reaction may be carried out in a suitable solvent like, for example, ethanol and/or water, at a temperature of up to reflux in the presence of a reducing agent, for example, Fe powder.
  • Other reducing conditions may be hydrogenation with hydrogen gas in the presence a suitable catalyst, for example, Pd/C at a pressure up to 3000 psi.
  • Compounds of formula L-1 may be may be prepared according to other General Procedure(s) described herein.
  • An aromatic alcohol of formula M-1 wherein X, Y, Z, W and R 1 each is as defined herein, and A represents an aryl or heteroaryl group, may be alkylated with a compound of formula M-2, wherein LG represents a suitable leaving group such as, for example, halogen or mesy- late.
  • This reaction may be carried out in a suitable solvent like, for example, DMF, at a temperature of up to reflux and in the presence of a base like, for example, sodium hydride.
  • Compounds of formula M-1 may be may be prepared according to other General Procedure ⁇ ) described herein.
  • N-1 (N-3)
  • An aromatic amine of formula N-1 wherein X, Y, Z, W and R 1 each is as defined herein, and
  • A represents an aryl or heteroaryl group
  • an activated sulfonic acid of formula N-2 may be reacted with an activated sulfonic acid of formula N-2, wherein p is 1 -4 and LGi and LG 2 represents suitable leaving groups such as, for example, halogen, to give a compound of formula N-3.
  • This reaction may be carried out in a suitable solvent like, for example, DMF, at a temperature of up to reflux and in the pres- ence of a base like, for example, TEA.
  • a compound of formula N-3 may be ring-closed to give a compound of formula In.
  • This reaction may be carried out in a suitable solvent like, for example, DMF, at a temperature of up to reflux and in the presence of a base like, for exam- pie, NaH.
  • Compounds of formula N-1 may be may be prepared according to other General Procedure(s) described herein.
  • the free base was dissolved into a mixture of a 0.5 N hydrochloric acid solution and ethanol. When dissolved, the mixture was evaporated and then re-evaporated with ethanol. The solid residue was recrystallized from ethanol (50 ml_) to give 740 mg (81 %) of 1 -[5-(4-chloro- phenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-acetylphenyl)pyridine and 1 -isopropylpiperazine.
  • Example 8 (General procedure A) 1 -[5-(2-Fluorophenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride
  • Example 12 (General procedure A) 1 -(3-Piperidin-1 -ylpropyl)-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine, dihydrochlo- ride
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 1 -(3-piperidinopropyl)- piperazine.
  • Example 13 (General procedure A) 1 '-[6-(4-Methanesulfonylphenyl)pyridazin-3-yl]-[1 ,4']bipiperidinyl
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (3-dimethylaminoprop-1 - yl)piperazine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (1 -methylpiperidin-3-yl- methyl)piperazine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (1 -methylpiperidin-4-yl- methyl)piperazine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-cyanophenyl)pyridazine and (1 -methylpiperidin-4-ylmethyl)- piperazine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-butylsulfanylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-ethanesulfonylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-ethanesulfinylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-ethylsulfanylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-fluorophenyl)pyrimidine and 1 -isopropylpiperazine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-methoxy-3-fluorophenyl)pyridazine and 4-amino-1 -(1 -ethylpropyl)- piperidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-methanesulfonylphenyl)pyridazine and 4-amino-1 -(1 -ethylpropyl)- piperidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-(2,3-dihydrobenzo[1 ,4]dioxin-6-yl)-phenyl)pyridazine and 1 - isopropylpiperazine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-cyanophenyl)pyridazine and 4-amino-1 -(1 -ethylpropyl)piperidine.
  • the title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and (2-dimethylaminoethyl)- piperazine.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 4-chloro-tetrahydro- pyran.
  • 3-Chloro-6-(4-trifluoromethylphenyl)pyridazine (0.2 g, 0.77 mmol), 3-aminopiperidine dihy- drochloride (0.27 g, 1 .54 mmol) and potassium carbonate (0.53 g, 3.87 mmol) were mixed in acetone (4 ml_) in a 20 ml_ microwave vessel.
  • the reaction mixture was heated in a micro- wave oven for 2 h at 120 0 C.
  • the reaction mixture was filtered and the precipitate was washed with MeOH.
  • the combined organic phases were evaporated.
  • Step 1 4-(6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzylamine
  • Step 1
  • Step 1 6-(4-lsopropylpiperazin-1 -yl)nicotinonitrile, hydrochloride
  • the title compound was prepared by a similar procedure to that described in Example 41 , starting from N-hydroxy-6-(4-isopropylpiperazin-1 -yl)nicotinamidine and 4-cyanobenzoyl- chloride.
  • the title compound was prepared by a similar procedure to that described in Example 42, starting from N-hydroxy-6-(4-isopropylpiperazin-1 -yl)nicotinamidine and cyclopropylcarbonyl- chloride.
  • the title compound was prepared by a similar procedure to that described in Example 44, starting from 1 -(5-(5-(4-chloromethylphenyl)[1 ,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropyl- piperazine and isonipecotamide.
  • the title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-chloro- ⁇ /, ⁇ /-dimethyl- acetamide.
  • the title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-diethylaminoethyl- chloride.
  • the title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-methoxyethyl- bromide.
  • Step 1 4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl:
  • the title compound was prepared by a similar procedure to that described in Example 56, starting from 1 -(5-bromo-pyridin-2-yl)-4-isopropyl-piperazine and 4-acetamidophenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 176, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamine and cyclopropanecarboxylic acid.
  • the title compound was prepared by a similar procedure to that described in Example 176, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamine and cyclopropylacetic acid.
  • the title compound was prepared by a similar procedure to that described in Example 176, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamine and 4- methoxycyclohexanecarboxylic acid.
  • Step 1 1 -(5-Bromopyridin-2-yl)-piperazine
  • the title compound was prepared from 3-chloro-6-(4-cyclopropyl-piperazin-1 -yl)-pyridazine (4.6 g, 19.3 mmol), 1 M sodium carbonate solution (50 ml_, 100,5 mmol), acetonitrile (50 ml_), bis(triphenylphosphine)palladium(ll)chloride (0.68 g, 0.96 mmol) and N-[2-methoxy-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]acetamide (6.73 g, 23.1 mmol), yield 3.39 g (40 %).
  • Step 1 1 -(5-Bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine
  • the title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-3-methyl-pyridin-2-yl)-4-isopropyl-piperazine and 4-acetylamino- phenylboronic acid.
  • Step 1
  • the title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-cyclopropyl-piperazine and 3-acetylamino- phenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-cyclopropyl-piperazine and 3-(N,N-dimethyl- amino-carbonyl)-phenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-cyclopropyl-piperazine and 4-(N, N- dimethylamino-carbonyl)-phenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(6-chloro-pyridazin-3-yl)-4-isopropyl-perhydro-1 ,4-diazepine and 4-acetamido- phenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1 -yl)-pyridazine and 4-methyl-7-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1 ,4-benzoxazine.
  • the title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1 -yl)-pyridazine and 1 ,4-benzodioxane-6- boronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 4-cyanomethyl- phenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 4-acetylphenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 3-pyridylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-diisopropyl- aminocarbonylphenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and (4-methyl- piperidin-1 -yl)carbonylphenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-dimethyl- aminocarbonylphenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 2-(5-bromopyrazin-2-yl)octahydropyrido[1 ,2-a]pyrazine and 4-acetamidophenyl- boronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-hydroxy- phenylboronic acid.
  • Step 1
  • Step 2 [4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]methylcarbamic acid tert- butyl ester (0.38 g, 0.92 mmol) was dissolved in DCM (10 ml_) and TFA (10 ml_) was added. The reaction mixture was stirred at rt for 2 h and then evaporated in vacuo. The solid residue (20 mg) was purified by preparative HPLC Method B.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-morpholino- phenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-Bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-amino-3- methoxyphenylboronic acid pinacol ester.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 3,4-dimethoxy- phenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 3,4,5-tri- methoxyphenylboronic acid.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-(N-acetyl- aminomethyl)phenylboronic acid.
  • Example 104 The title compound was isolated as a by-product in Example 104.
  • the title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 2-methoxy-5- pyridineboronic acid.

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Abstract

Novel compounds which interact with the histamine H3 receptor are defined. These compounds are particularly useful in the treatment of a variety of diseases or conditions in which histamine H3 interactions are beneficial. Thus, the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system. The novel compounds have a core consisting of a 6 membered aromatic ring containing at least one nitrogen atom and two carbon atoms in the ring and, at the remaining positions in the ring, there is either a carbon or a nitrogen atom.

Description

NOVEL MEDICAMENTS
FIELD OF THIS INVENTION
The present invention relates to novel compounds, to the use of these compounds in phar- maceutical compositions, to pharmaceutical compositions comprising the compounds, and to methods of treatment employing these compounds or compositions. The present compounds show a high and selective binding affinity for the histamine H3 receptor, indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases or disorders related to the histamine H3 receptor.
BACKGROUND OF THIS INVENTION
The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments. Recently, the human histamine H3 receptor has been cloned. The histamine H3 receptor is a presynaptic autorecep- tor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (i.e., it is active in the absence of an agonist). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of these are imidazole derivatives. However, recently some imidazole-free ligands of the histamine H3 receptor have been described (see e.g. Linney et al., J. Med. Chem. 2000, 43, 2362-2370; US 6,316,475, WO 01/66534 and WO 01/74810). WO 00/66578 claims certain 3- or 4-(imidazol-2-yl)pyridines being substituted in the 4 position of the imidazole ring. It is mentioned that mammals having a disease or condition mediated by NPY can be treated with such a compound.
Our earlier application, WO 2003/066604 (our internal ref.: 6447), claims certain piperazines being substituted in the 1 and 4 positions. Our earlier application, WO 2005/009976 A1 (our internal ref. : 6739), claims certain
3-(4-isopropylpiperazin-1 -yl)-6-phenylpyrazines being substituted in the para position of the phenyl ring. In the specification, no pharmacological data are given for the compounds prepared.
WO 2005/028438 claims certain piperidines being substituted in the 1 and 4 posi- tion.
The object of this invention is to overcome or ameliorate at lest some of the disadvantages of the prior art. Hence, not all the objects mentioned below may be fully overcome or ameliorated. Further objects of this invention are mentioned below.
DEFINITIONS
In the structural formulae given herein and throughout the present specification, the following terms have the indicated meaning:
The term "hydroxy" shall mean the radical -OH, the term "oxy" shall mean the radical -O-, the term "oxo" shall mean the radical =0, the term "carbonyl" shall mean the radical - C(=O)-, the term "sulfinyl" shall mean the radical -(S=O)-, the term "sulfonyl" shall mean the radical -S(=O)2 -, the term "carboxy" shall mean the radical -(C=O)O- and -C(=O)OH, the term "amino" shall mean the radical -NH2, the term "nitro" shall mean the radical -NO2 and the term "cyano" shall mean the radical -CN.
The term "C2 6-alkenyl" as used herein represents a branched or straight hydrocar- bon group having from 2 to 6 carbon atoms and at least one double bond, e.g. C2 6-alkenyl, C36-alkenyl, and the like. Representative examples are ethenyl (or vinyl), propenyl (e.g., prop-1 -enyl and prop-2-enyl), butadienyl (e.g., buta-1 ,3-dienyl), butenyl (e.g., but-1 -en-1 -yl and but-2-en-1 -yl), pentenyl (e.g., pent-1 -en-1 -yl and pent-2-en-2-yl), hexenyl (e.g., hex-1 - en-2-yl and hex-2-en-1 -yl), 1 -ethylprop-2-enyl, 1 ,1 -(dimethyl)prop-2-enyl, 1 -ethylbut-3-enyl, 1 ,1 -(dimethyl)but-2-enyl, and the like.
Analogously, the term "C3 8-alkenyl" as used herein represents a branched or straight hydrocarbon group having from 3 to 8 carbon atoms and at least one double bond, e.g. C36-alkenyl, and the like. Representative examples are propenyl (e.g., prop-1 -enyl and prop-2-enyl), butadienyl (e.g., buta-1 ,3-dienyl), butenyl (e.g., but-1 -en-1 -yl and but-2-en-1 -yl), pentenyl (e.g., pent-1 -en-1 -yl and pent-2-en-2-yl), hexenyl (e.g., hex-1 -en-2-yl and hex-2-en- 1 -yl), 1 -ethylprop-2-enyl, 1 ,1 -(dimethyl)prop-2-enyl, 1 -ethylbut-3-enyl, 1 ,1 -(dimethyl)but-2- enyl, and the like.
The term "Ci 6-alkoxy" as used herein refers to the radical Ci 6-alkyl-O-.
Representative examples are methoxy, ethoxy, propoxy (e.g., 1 -propoxy and 2-propoxy), butoxy (e.g., 1 -butoxy, 2-butoxy and 2-methyl-2-propoxy), pentoxy (1 -pentoxy and 2-pent- oxy), hexoxy (1 -hexoxy and 3-hexoxy), and the like.
The term "Ci 6-alkoxy-Ci 6-alkyl" as used herein refers to Ci 6-alkyl substituted with
Ci 6-alkoxy at any carbon atom. Representative examples are methoxymethyl, ethoxymethyl,
2-methoxyethyl, 2-ethoxyethyl, 3-methoxyprop-1 -yl, and the like. The term "Ci 6-alkoxycarbonyl" as used herein refers to the radical Ci 6-alkoxy-
C(=O)-. Representative examples are methoxycarbonyl, ethoxycarbonyl, 1 -propoxycarbonyl,
2-propoxycarbonyl, 1 -butoxycarbonyl, 2-butoxycarbonyl, 2-methyl-2-propoxycarbonyl, 3- methylbutoxycarbonyl, 1 -hexoxycarbonyl, and the like.
The term "Ci 6-alkyl" as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms, e.g. Ci 3-alkyl, Ci 4-alkyl, C2 6-alkyl, C3 6- alkyl, and the like. Representative examples are methyl, ethyl, propyl (e.g., prop-1 -yl and prop-2-yl (or isopropyl)), butyl (e.g., 2-methylprop-2-yl (or terf-butyl), but-1 -yl and but-2-yl), pentyl (e.g., pent-1 -yl, pent-2-yl and pent-3-yl), 2-methylbut-1 -yl, 3-methylbut-1 -yl, hexyl (e.g., hex-1 -yl), heptyl (e.g., hept-1 -yl) and the like. Analogously, the term "Ci 8-alkyl" as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 8 carbon atoms, e.g. Ci 3-alkyl, Ci 4-alkyl, Ci
6-alkyl, C2 6-alkyl, C3 6-alkyl, Ci 8-alkyl, and the like. Representative examples are methyl, ethyl, propyl (e.g., prop-1 -yl and prop-2-yl (or isopropyl)), butyl (e.g., 2-methylprop-2-yl (or terf-butyl), but-1 -yl and but-2-yl), pentyl (e.g., pent-1 -yl, pent-2-yl and pent-3-yl), 2-methylbut- 1 -yl, 3-methylbut-1 -yl, hexyl (e.g., hex-1 -yl), heptyl (e.g., hept-1 -yl), octyl (e.g., oct-1 -yl), and the like.
The term "Ci 6-alkylcarbonyl" as used herein refers to the radical Ci 6-alkyl-C(=O)-.
Representative examples are acetyl (e.g., methylcarbonyl), propionyl (e.g, ethylcarbonyl), bu- tanoyl (e.g., prop-1 -ylcarbonyl and prop-2-ylcarbonyl), and the like. The term "Ci 6-alkylcarbonylamino" as used herein, refers to the radical Ci 6-alkyl-
C(=O)-NH-. Representative examples are acetylamino, propionylamino, pivaloylamino, va- leroylamino, and the like.
The term "Ci 6-alkylcarbonylamino-Ci 6-alkyl" as used herein, refers to Ci 6-alkyl substituted at any carbon atom with Ci e-alkylcarbonylamino. Representative examples are acetylaminomethyl, 1 -(acetylamino)ethyl, propionylaminomethyl, and the like. The term "Ci 6-alkylcarboxy" as used herein refers to the radical Ci 6-alkyl-C(=O)O-. Representative examples are methylcarboxy, ethylcarboxy, propylcarboxy (e.g., prop-1 -yl- carboxy, prop-2-ylcarboxy), and the like.
The term "Ci 6-alkylsulfanyl" as used herein refers to the radical Ci 6-alkyl-S-. Repre- sentative examples are methylthio, ethylthio, propylthio (e.g., 1 -propylthio, 2-propylthio and 3-propylthio), butylthio, pentylthio, hexylthio, and the like.
The term "Ci 6-alkylsulfinyl" as used herein refers to the radical Ci 6-alkyl-S(=O)-. Representative examples are methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentyl- sulfinyl, hexylsulfinyl, and the like. The term "Ci 6-alkylsulfonyl" as used herein refers to the radical Ci 6-alkyl-S(=O)2-.
Representative examples are methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pen- tylsulfonyl, hexylsulfonyl, and the like.
The term "C3 8-alkynyl" as used herein represents a branched or straight hydrocarbon group having from 3 to 8 carbon atoms and at least one triple bond. Representative ex- amples are propynyl (e.g., prop-1 -ynyl and prop-2-ynyl), butynyl (e.g., but-1 -ynyl and but-2-y- nyl), pentynyl (e.g., pent-1 -ynyl and pent-2-ynyl), hexynyl (e.g., hex-1 -ynyl and hex-2-ynyl), 1 - ethylprop-2-ynyl, 1 ,1 -(dimethyl)prop-2-ynyl, 1 -ethylbut-3-ynyl, 1 ,1 -(dimethyl)but-2-ynyl, and the like.
The term "aryl" as used herein is intended to include monocyclic, bicyclic or poly- cyclic carbocyclic aromatic rings. Representative examples are phenyl, naphthyl (e.g., naphth-1 -yl and naphth-2-yl), anthryl (e.g., anthr-1 -yl and anthr-9-yl), phenanthryl (e.g., phe- nanthr-1 -yl and phenanthr-9-yl), and the like. Aryl is also intended to include monocyclic, bicyclic or polycyclic carbocyclic aromatic rings substituted with carbocyclic aromatic rings. Representative examples are biphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl and biphenyl-4-yl), phenylnaphthyl (e.g.1 -phenylnaphth-2-yl and 2-phenylnaphth-1 -yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic rings with at least one unsaturated moiety (e.g., a benzo moiety). Representative examples are, indanyl (e.g., in- dan-1 -yl, indan-5-yl), indenyl (e.g., inden-1 -yl and inden-5-yl), 1 ,2,3,4-tetrahydronaphthyl (e.g., 1 ,2,3,4-tetrahydronaphth-1 -yl, 1 ,2,3,4-tetrahydronaphth-2-yl and 1 ,2,3,4-tetrahydro- naphth-6-yl), 1 ,2-dihydronaphthyl (e.g., 1 ,2-dihydronaphth-1 -yl, 1 ,2-dihydronaphth-4-yl and 1 ,2-dihydronaphth-6-yl), fluorenyl (e.g., fluoren-1 -yl, fluoren-4-yl and fluoren-9-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are, benzonorbornyl (e.g., benzonorborn-3-yl and benzonorborn-6-yl), 1 ,4-ethano-1 ,2,3,4-tetrahydronapthyl (e.g., 1 ,4-ethano-1 ,2,3,4-tetrahydronapth-2-yl and 1 ,4-ethano-1 ,2,3,4-tetrahydronapth-10-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or more spiro atoms. Representative examples are spiro[cyclo- pentane-1 ,1 '-indane]-4-yl, spiro[cyclopentane-1 ,1 '-indene]-4-yl, spiro[piperidine-4,1 '-indane]- 1 -yl, spiro[piperidine-3,2'-indane]-1 -yl, spiro[piperidine-4,2'-indane]-1 -yl, spiro[piperidine-4,1 '- indane]-3'-yl, spiro[pyrrolidine-3,2'-indane]-1 -yl, spiro[pyrrolidine-3,1 '-(3',4'-dihydro- naphthalene)]-1 -yl, spiro[piperidine-3,1 '-(3',4'-dihydronaphthalene)]-1 -yl, spiro[piperidine-4,1 '- (3',4'-dihydronaphthalene)]-1 -yl, spiro[imidazolidine-4,2'-indane]-1 -yl, spiro[piperidine-4,1 '- indene]-1 -yl, and the like.
The term "aryl-Ci 6-alkoxycarbonyl" as used herein refers to the radical aryl-Ci 6-alkoxy-C(=O)-. Representative examples are benzyloxycarbonyl, phenylethoxycarbonyl (e.g., (2-phenylethoxy)carbonyl and (i -phenylethoxy)carbonyl), and the like.
The term "arylcarbonyl" as used herein, refers to the radical aryl-C(=O)-. Representative examples are benzoyl, naphthylcarbonyl, 4-phenylbenzoyl, anthrylcarbonyl, phenanthryl- carbonyl, and the like. The term "arylcarbonylamino" as used herein, refers to the radical aryl-C(=O)-NH-.
Representative examples are benzoylamino, naphthylcarbonylamino, 4-phenylbenzoylamino, and the like.
The term "arylcarbonylamino-Ci 6-alkyl" as used herein, refers to Ci 6-alkyl substituted at any carbon atom with arylcarbonylamino. Representative examples are benzoylami- nomethyl, naphthylcarbonylaminomethyl, 2-(4-phenylbenzoylamino)ethyl, and the like.
The term "arylsulfonyl" as used herein refers to the radical aryl-S(=O)2- Representative examples are phenylsulfonyl, (4-methylphenyl)sulfonyl, (4-chlorophenyl)sulfonyl, naphthyl- sulfonyl, and the like.
The term "cyano-C^ 6-alkyl" as used herein refers to Ci 6-alkyl, substituted at any carbon atom(s) with cyano. Representative examples are cyanomethyl, 2-cyanoethyl, and the like.
The term "C3 8-cycloalkenyl" as used herein represents a partially saturated monocyclic carbocyclic ring having from 3 to 8 carbon atoms and at least one double bond. Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohep- tenyl, cyclooctenyl, cyclohex-1 ,3-dienyl, and the like.
Obviously, the term "C38-cycloalkenyl-Ci 3-alkyl" is a combination of C38-cyclo- alkenyl and Ci 3-alkyl. Representative examples are cyclopenten-1 -ylmethyl, 3-(cyclohexen-1 - yl)propyl, and the like.
The term "C3 8-cycloalkyl" as used herein represents a saturated monocyclic carbo- cyclic ring having from 3 to 8 carbon atoms, e.g. C3 6-alkyl, and the like. Representative ex- amples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. C38-cycloalkyl is also intended to represent a saturated bicyclic carbocyclic ring having from 4 to 8 carbon atoms. Representative examples are decahydronaphthalenyl, bicycle- [3.3.0]octanyl, and the like. C38-cycloalkyl is also intended to represent a saturated carbocyc- lie ring having from 3 to 8 carbon atoms and containing one or two carbon bridges. Representative examples are adamantyl, norbornanyl, nortricyclyl, bicyclo[3.2.1 ]octanyl, bicyclo- [2.2.2]octanyl, tricyclo[5.2.1 .0/2,6]decanyl, bicyclo[2.2.1 ]heptyl, and the like. C3 8-cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 8 carbon atoms and containing one or more spiro atoms. Representative examples are spiro[2.5]octanyl, spiro- [4.5]decanyl, and the like.
Obviously, the term "C38-cycloalkyl-Ci 3-alkyl" is a combination of C38-cycloalkyl and Ci 3-alkyl. Representative examples are cyclopropylmethyl, 2-cyclohexylethyl, 3-cyclopentyl- prop-1 -yl, 1 -cyclohexylethyl, adamantylmethyl, and the like.
Representative examples of "C3 8-cycloalkylcarbonylamino-Ci 6-alkyl" as used herein is cyclopentylcarbonylamino-methyl, 3-(cyclohexylcarbonylamino)propyl, and the like.
The term "halo-Ci 6-alkyl" as used herein refers to Ci 6-alkyl, substituted one or more times at any carbon atom(s) with any halogen. Representative examples are trifluoromethyl, 2,2,2-trifluoroethyl, and the like.
The term "halo-Ci 6-alkoxy" as used herein refers to Ci 6-alkoxy, substituted one or more times at any carbon atom(s) with any halogen. Representative examples are trifluoro- methoxy and 2,2,2-trifluoroethoxy, and the like.
The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine. The term "heteroaryl" as used herein is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, SO and S(=O)2. Representative examples are pyrrolyl (e.g., pyrrol-1 -yl, pyrrol-2-yl and pyrrol-3-yl), furanyl (e.g., furan-2-yl and furan-3-yl), thienyl (e.g., thien-2-yl and thien-3-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl and oxazol-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl and thiazol-5- yl), imidazolyl (e.g., imidazol-2-yl, imidazol-4-yl and imidazol-5-yl), pyrazolyl (e.g., pyrazol-1 - yl, pyrazol-3-yl and pyrazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl and isoxazol-5- yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl), 1 ,2,3-triazolyl (e.g., 1 ,2,3-triazol-1 -yl, 1 ,2,3-triazol-4-yl and 1 ,2,3-triazol-5-yl), 1 ,2,4-triazolyl (e.g., 1 ,2,4-triazol-1 - yl, 1 ,2,4-triazol-3-yl and 1 ,2,4-triazol-5-yl), 1 ,2,3-oxadiazolyl (e.g., 1 ,2,3-oxadiazol-4-yl and 1 ,2,3-oxadiazol-5-yl), 1 ,2,4-oxadiazolyl (e.g., 1 ,2,4-oxadiazol-3-yl and 1 ,2,4-oxadiazol-5-yl), 1 ,2,5-oxadiazolyl (e.g., 1 ,2,5-oxadiazol-3-yl and 1 ,2,5-oxadiazol-4-yl), 1 ,3,4-oxadiazolyl (e.g., 1 ,3,4-oxadiazol-2-yl and 1 ,3,4-oxadiazol-5-yl), 1 ,2,3-thiadiazolyl (e.g., 1 ,2,3-thiadiazol-4-yl and 1 ,2,3-thiadiazol-5-yl), 1 ,2,4-thiadiazolyl (e.g., 1 ,2,4-thiadiazol-3-yl and 1 ,2,4-thiadiazol-5-yl), 1 ,2,5-thiadiazolyl (e.g., 1 ,2,5-thiadiazol-3-yl and 1 ,2,5-thiadiazol-4-yl), 1 ,3,4-thiadiazolyl (e.g., 1 ,3,4-thiadiazol-2-yl and 1 ,3,4-thiadiazol-5-yl), tetrazolyl (e.g., tetrazol-1 -yl and tetrazol-5-yl), pyranyl (e.g., pyran-2-yl), pyridinyl (e.g., pyridine-2-yl, pyridine-3-yl and pyridine-4-yl), pyri- dazinyl (e.g., pyridazin-2-yl and pyridazin-3-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl), pyrazinyl, 1 ,2,3-tιϊazinyl, 1 ,2,4-tιϊazinyl, 1 ,3,5-triazinyl, thiadiazinyl, azepinyl, azecinyl, and the like. Heteroaryl is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are indolyl (e.g., indol-1 -yl, indol-2-yl, indol-3-yl and indol-5-yl), isoindolyl, benzofuranyl (e.g., benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo- [b]furan-5-yl, benzo[c]furan-2-yl, benzo[c]furan-3-yl and benzo[c]furan-5-yl), benzothienyl (e.g., benzo[b]thien-2-yl, benzo[b]thien-3-yl, benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]- thien-3-yl and benzo[c]thien-5-yl), indazolyl (e.g., indazol-1 -yl, indazol-3-yl and indazol-5-yl), indolizinyl (e.g., indolizin-1 -yl and indolizin-3-yl), benzopyranyl (e.g., benzo[b]pyran-3-yl, benzo[b]pyran-6-yl, benzo[c]pyran-1 -yl and benzo[c]pyran-7-yl), benzimidazolyl (e.g., ben- zimidazol-1 -yl, benzimidazol-2-yl and benzimidazol-5-yl), benzothiazolyl (e.g., benzothiazol- 2-yl and benzothiazol-5-yl), benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, ben- zotriazolyl, naphthyridinyl (e.g., 1 ,8-naphthyridin-2-yl, 1 ,7-naphthyridin-2-yl and 1 ,6-naphthy- ridin-2-yl), phthalazinyl (e.g., phthalazin-1 -yl and phthalazin-5-yl), pteridinyl, purinyl (e.g., pu- rin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl and purin-9-yl), quinazolinyl (e.g., quinazolin-2-yl, quinazolin-4-yl and quinazolin-6-yl), cinnolinyl, quinoliny (e.g., quinolin-2-yl, quinolin-3-yl, quinolin-4-yl and quinolin-6-yl), isoquinolinyl (e.g., isoquinolin-1 -yl, isoquinolin-3-yl and iso- quinolin-4-yl), quinoxalinyl (e.g., quinoxalin-2-yl and quinoxalin-5-yl), pyrrolopyridinyl (e.g., pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl and pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl and furo[3,2-c]pyridinyl), thienopyridinyl (e.g., thieno- [2,3-b]pyridinyl, thieno[2,3-c]pyridinyl and thieno[3,2-c]pyridinyl), imidazopyridinyl (e.g., imi- dazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[1 ,5-a]pyridinyl and imidazo[1 ,2-a]- pyridinyl), imidazopyrimidinyl (e.g., imidazo[1 ,2-a]pyrimidinyl and imidazo[3,4-a]pyrimidinyl), pyrazolopyridinyl (e.g., pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl and pyrazolo[1 ,5-a]- pyridinyl), pyrazolopyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidinyl and pyrazolo[3,4-d]pyrimidin- yl), thiazolopyridinyl (e.g., thiazolo[3,2-d]pyridinyl), thiazolopyrimidinyl (e.g., thiazolo[5,4-d]- pyrimidinyl), imidazothiazolyl (e.g., imidazo[2,1 -b]thiazolyl), triazolopyridinyl (e.g., triazolo- [4,5-b]pyridinyl), triazolopyrimidinyl (e.g., 8-azapurinyl), and the like. Heteroaryl is also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are car- bazolyl (e.g., carbazol-2-yl, carbazol-3-yl, carbazol-9-yl), phenoxazinyl (e.g., phenoxazin-10- yl), phenazinyl (e.g., phenazin-5-yl), acridinyl (e.g., acridin-9-yl and acridin-10-yl), phenol- thiazinyl (e.g., phenothiazin-10-yl), carbolinyl (e.g., pyrido[3,4-b]indol-1 -yl, pyrido[3,4-b]indol- 3-yl), phenanthrolinyl (e.g., phenanthrolin-5-yl), and the like. Heteroaryl is also intended to include partially saturated monocyclic, bicyclic or polycyclic heterocyclic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are pyrrolinyl, pyrazolinyl, imidazolinyl (e.g., 4,5-dihydroimidazol-2-yl and 4,5- dihydroimidazol-1 -yl), indolinyl (e.g., 2,3-dihydroindol-1 -yl and 2,3-dihydroindol-5-yl), dihydro- benzofuranyl (e.g., 2,3-dihydrobenzo[b]furan-2-yl and 2,3-dihydrobenzo[b]furan-4-yl), dihydro- benzothienyl (e.g., 2,3-dihydrobenzo[b]thien-2-yl and 2,3-dihydrobenzo[b]thien-5-yl), 4,5,6,7- tetrahydrobenzo[b]furan-5-yl), dihydrobenzopyranyl (e.g., 3,4-dihydrobenzo[b]pyran-3-yl, 3,4- dihydrobenzo[b]pyran-6-yl, 3,4-dihydrobenzo[c]pyran-1 -yl and dihydrobenzo[c]pyran-7-yl), oxazolinyl (e.g., 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl and 4,5-dihydrooxazol-5-yl), isoxazolinyl, oxazepinyl, 2,4-dioxodihydropyrimidin-3-yl, tetrahydroindazolyl (e.g., 4,5,6,7- tetrahydroindazol-1 -yl, 4,5,6,7-tetrahydroindazol-3-yl, 4,5,6,7-tetrahydroindazol-4-yl and 4,5,6,7-tetrahydroindazol-6-yl), tetrahydrobenzimidazolyl (e.g., 4,5,6,7-tetrahydrobenz- imidazol-1 -yl and 4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo[4,5-c]pyridyl (e.g., 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-1 -yl, 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-5-yl and 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-6-yl), tetrahydroquinolinyl (e.g., 1 ,2,3,4-tetrahydro- quinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrahydroisoquinolinyl (e.g., 1 ,2,3,4-tetrahydro- isoquinolinyl and 5,6,7, 8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g., 1 ,2,3,4-tetra- hydroquinoxalinyl and 5,6,7,8-tetrahydroquinoxalinyl), 2,3-dihydrobenzo[1 ,4]dioxin-6-yl, 2,3- dihydrobenzo[1 ,4]dioxin-5-yl, 2,3-dihydrobenzo[1 ,4]dioxin-2-yl, benzo[1 ,3]dioxol-4-yl, benzo- [1 ,3]dioxol-5-yl, benzo[1 ,3]dioxol-2-yl, 3,4-dihydro-2H-benzo[1 ,4]oxazin-7-yl, 4-methyl-3,4-di- hydro-2H-benzo[1 ,4]oxazin-7-yl and the like. Heteroaryl is also intended to include partially saturated bicyclic or polycyclic heterocyclic rings containing one or more spiro atoms. Representative examples are spiro[isoquinoline-3,1 '-cyclohexan]-1 -yl, spiro[piperidine-4,1 '-benzo- [c]thiophen]-1 -yl, spiro[piperidine-4,1 '-benzo[c]furan]-1 -yl, spiro[piperidine-4,3'-benzo[b]- furan]-1 -yl, spiro[piperidine-4,3'-coumarin]-1 -yl, and the like. The term "heteroarylcarbonyl" as used herein refers to the radical heteroaryl-C(=O)-.
Representative examples are pyridinylcarbonyl (e.g., pyridin-2-ylcarbonyl and pyridin-4- ylcarbonyl), quinolinylcarbonyl (e.g., 2-(quinolin-2-yl)carbonyl and 1 -(quinolin-2-yl)carbonyl), imidazolylcarbonyl (e.g., imidazol-2-ylcarbonyl and imidazol-5-ylcarbonyl), and the like.
The term "heteroarylcarbonylamino" as used herein, refers to the radical heteroaryl- C(=O)-NH-. Representative examples are pyridinylcarbonylamino (e.g., pyridin-2-ylcarbonyl- amino and pyridin-4-ylcarbonylamino), quinolinylcarbonylamino (e.g., 2-(quinolin-2-yl)- carbonylamino and 1 -(quinolin-2-yl)carbonylamino), and the like.
The term "heteroarylcarbonylamino-Ci 6-alkyl" as used herein, refers to Ci 6-alkyl substituted at any carbon atom with heteroarylcarbonylamino. Representative examples are pyridinylcarbonylaminomethyl (e.g., pyridin-2-ylcarbonylaminomethyl and pyridin-4-yl- carbonylaminomethyl), 2-(quinolinylcarbonylamino)ethyl (e.g., 2-(2-(quinolin-2-yl)carbonyl- amino)ethyl and 2-(1 -(quinolin-2-yl)carbonylamino)ethyl), and the like.
The term "heterocyclyl" as used herein represents a saturated 3 to 8 membered monocyclic ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are aziridinyl (e.g., aziridin-1 -yl), azetidinyl
(e.g., azetidin-1 -yl and azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g., pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl), 2-oxo-pyrrolidin-1 -yl, 2,5-dioxo-pyrrolidin-1 -yl, imidazolidinyl (e.g., imida- zolidin-1 -yl, imidazolidin-2-yl and imidazolidin-4-yl), 2,4-dioxo-imidazolidin-3-yl, 2,4-dioxo-1 - methylimidazolidin-3-yl, 2,4-dioxo-1 ,5,5-trimethylimidazolidin-3-yl, 2,4-dioxo-5,5-dimethyl- imidazolidin-3-yl, oxazolidinyl (e.g., oxazolidin-2-yl, oxazolidin-3-yl and oxazolidin-4-yl), 2- oxo-oxazolidin-3-yl, thiazolidinyl (e.g., thiazolidin-2-yl, thiazolidin-3-yl and thiazolidin-4-yl), 2,4-dioxo-thiazolidin-3-yl, isothiazolidinyl, 1 ,1 -dioxo-isothiazolidin-2-yl, 1 ,1 -dioxo-[1 ,2,5]thia- diazolidin-2-yl, piperidinyl (e.g., piperidin-1 -yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), 2-oxo-piperidin-1 -yl, 2,6-dioxo-piperidin-1 -yl, homopiperidinyl (e.g., homopiperidin-1 -yl, ho- mopiperidin-2-yl, homopiperidin-3-yl and homopiperidin-4-yl), piperazinyl (e.g., piperazin-1 -yl and piperazin-2-yl), morpholinyl (e.g., morpholin-2-yl, morpholin-3-yl and morpholin-4-yl), 2- oxo-[1 ,3]oxazinan-3-yl, thiomorpholinyl (e.g., thiomorpholin-2-yl, thiomorpholin-3-yl and thio- morpholin-4-yl), 1 -oxo-thiomorpholinyl, 1 ,1 -dioxo-thiomorpholinyl, tetrahydrofuranyl (e.g., tet- rahydrofuran-2-yl and tetrahydrofuran-3-yl), tetrahydrothienyl, tetrahydro-1 ,1 -dioxothienyl, tetrahydropyranyl (e.g., 2-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 2-tetrahydrothio- pyranyl), 1 ,4-dioxanyl, 1 ,3-dioxanyl, and the like. Heterocyclyl is also intended to represent a saturated 6 to 12 membered bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are octahydroindolyl (e.g., octahydroindol-1 -yl, octahydroindol-2-yl, octahydroindol-3-yl and octahydroindol-5-yl), decahydroquinolinyl (e.g., decahydroquinolin-1 -yl, decahydroquinolin-2-yl, decahydroquino- lin-3-yl, decahydroquinolin-4-yl and decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g., decahydroquinoxalin-1 -yl, decahydroquinoxalin-2-yl and decahydroquinoxalin-6-yl) and the like. Heterocyclyl is also intended to represent a saturated 6 to12 membered ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2 and hav- ing one or two bridges. Representative examples are 3-azabicyclo[3.2.2]nonyl, 2-azabicycle- [2.2.1]heptyl, 3-azabicyclo[3.1 .0]hexyl, 2,5-diazabicyclo[2.2.1 ]heptyl, atropinyl, tropinyl, quinuclidinyl, 1 ,4-diazabicyclo[2.2.2]octanyl, and the like. Heterocyclyl is also intended to represent a 6 to 12 membered saturated ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2 and containing one or more spiro atoms. Repre- sentative examples are 1 ,4-dioxaspiro[4.5]decanyl (e.g., 1 ,4-dioxaspiro[4.5]decan-2-yl and 1 ,4-dioxaspiro[4.5]decan-7-yl), 1 ,4-dioxa-8-azaspiro[4.5]decanyl (e.g., 1 ,4-dioxa-8-azaspiro- [4.5]decan-2-yl and 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g., 8-aza- spiro[4.5]decan-1 -yl and 8-azaspiro[4.5]decan-8-yl), 2-azaspiro[5.5]undecanyl (e.g., 2-aza- spiro[5.5]undecan-2-yl), 2,8-diazaspiro[4.5]decanyl (e.g., 2,8-diazaspiro[4.5]decan-2-yl and 2,8-diazaspiro[4.5]decan-8-yl), 2,8-diazaspiro[5.5]undecanyl (e.g., 2,8-diazaspiro[5.5]- undecan-2-yl), 1 ,3,8-triazaspiro[4.5]decanyl (e.g., 1 ,3,8-triazaspiro[4.5]decan-1 -yl and 1 ,3,8- triazaspiro[4.5]decan-3-yl, 1 ,3,8-triazaspiro[4.5]decan-8-yl), and the like.
The term "heterocyclyl-Ci 6-alkoxy" as used herein refers to the radical heterocyclyl- Ci 6-alkoxy. Representative examples are piperidin-1 -ylmethoxy, 2-(piperidin-1 -yl)ethoxy, 3- (piperidin-1 -yl)prop-3-oxy, piperazin-1 -ylmethoxy, 2-(piperazin-1 -yl)ethoxy, 3-(piperazin-1 -yl)- prop-3-oxy, morpholin-4-ylmethoxy, 2-(morpholin-4-yl)ethoxy, 3-(morpholin-4-yl)prop-3-oxy, and the like.
The term "heterocyclyl-Ci 6-alkyl" as used herein refers to the radical heterocyclyl- Ci 6-alkyl. Representative examples are piperidin-1 -ylmethyl, 2-(piperidin-1 -yl)ethyl, 3- hydroxy-3-(piperidin-1 -yl)propyl, piperazin-1 -ylmethyl, 2-(piperazin-1 -yl)ethyl, 3-hydroxy-3- (piperazin-i -yl)propyl, morpholin-4-ylmethyl, 2-(morpholin-4-yl)ethyl, 3-hydroxy-3-(morpholin- 4-yl)propyl, and the like.
The term "heterocyclylcarbonyl" as used herein refers to the radical heterocyclyl- C(=O)-. Representative examples are piperidinylcarbonyl (e.g., piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl and piperidin-4-ylcarbonyl), piperazinylcarbonyl (e.g., piperazin-1 -yl- carbonyl and piperazin-2-ylcarbonyl), and the like.
The term "hydroxy-Ci 6-alkyl" as used herein refers to Ci 6-alkyl substituted one or more times at any carbon atom(s) with hydroxyl. Representative examples are hydroxymethyl, hydoxyethyl (e.g., 1 -hydroxyethyl and 2-hydroxyethyl), and the like. The term "N-(Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino" as used herein is an amino group with two substituents, i.e., a Ci 6-alkylcarbonyl group and an Ci 6-alkyl group. Analogously, the following terms cover groups wherein an amino group has two substituents: N-(C3 8-cycloalkylcarbonyl)-N-(Ci 6-alkyl)amino and N-(C3 8-cycloalkyl-Ci 6-alkylcarbonyl)-N- (Ci 6-alkyl)amino. Analogously, the following terms cover groups wherein there are two substituents on the nitrogen atom in the amino-Ci 6-alkyl moiety: N-(Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino-Ci 6-alkyl, N-(C38-cycloalkylcarbonyl)-N-(Ci 6-alkyl)amino-Ci 6-alkyl and N-(C3 8- cycloalkyl-Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino-Ci 6-alkyl. Representative examples are N- cyclohexylcarbonyl-N-methylamino, 2-(N-cyclopentylcarbonyl-N-methylamino)ethyl and the like.
The term "bridge" as used herein represents a connection in a saturated or partly saturated ring between two atoms of such ring that are not neighbors through a chain of 1 to 4 atoms selected from carbon, nitrogen, oxygen and sulfur. Representative examples of such connecting chains are -CH2-, -CH2CH2-, -CH2NHCH2-, -CH2CH2CH2-, -CH2OCH2-, and the like.
The term "spiro atom" as used herein represents a carbon atom in a saturated or partly saturated ring that connects both ends of a chain of 3 to 8 atoms selected from carbon, nitrogen, oxygen and sulfur. Representative examples are -(CH2)5-, -(CH2)3-, -(CH2J4-, -CH2NHCH2CH2-, -CH2CH2NHCH2CH2-, -CH2NHCH2CH2CH2-, -CH2CH2OCH2-, -OCH2CH2O- , and the like.
The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the group(s) in question are substituted with more than one substituent the substituents may be the same or different.
Certain of the defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other. Certain of the defined terms may occur in combinations, and it is to be understood that the first mentioned radical is a substituent on the subsequently mentioned radical, where the point of substitution, i.e. the point of attachment to another part of the molecule, is on the last mentioned of the radicals.
The term "solvate" as used herein is a complex of defined stoichiometry formed by a solute (in casu, a compound according to the present invention) and a solvent. Solvents are those commonly used in the pharmaceutical art, by way of example, water, ethanol, acetic acid, and the like. The term "hydrate" refers to the complex where the solvent molecule is water.
The term "treatment" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular a human being.
The terms "disease", "condition" and "disorder" as used herein are used interchangeably to specify a state of a patient which is not the normal physiological state of man. The term "medicament" as used herein means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.
The term "prodrug" as used herein includes biohydrolyzable amides and biohydro- lyzable esters and also encompasses a) compounds in which the biohydrolyzable functional- ity in such a prodrug is encompassed in the compound according to the present invention, and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances according to the present invention. Examples of these functional groups include 1 ,4-dihydropyridine, N-alkylcarbonyl-1 ,4-dihydropyridine, 1 ,4-cyclohexadiene, tert-butyl, and the like. The term "biohydrolyzable ester" as used herein is an ester of a drug substance (in this invention, a compound of formula I) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl esters (e.g., Ci 4), lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
The term "biohydrolyzable amide" as used herein is an amide of a drug substance (in this invention, a compound of general formula I) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoal- kylcarbonyl amides.
The term "pharmaceutically acceptable" as used herein means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc. The term "effective amount" as used herein means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment.
The term "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as "thera- peutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary. The term "metabolite" as used herein is any intermediate or product resulting from metabolism.
The term "metabolism" as used herein refer to the biotransformation of a drug substance (in this invention, a compound of general formula I) administered to a patient.
The representative examples mentioned above are specific embodiments of this in- vention.
In the examples below, the following terms are intended to have the following, general meanings: d is day(s), g is gram(s), h is hour(s), Hz is hertz, kD is kiloDalton(s), L is Ii- ter(s), M is molar, mbar is millibar, mg is milligram(s), min is minute(s), ml_ is milliliter(s), mM is millimolar, mmol is millimole(s), mol is mole(s), N is normal, ppm is parts per million, psi is pounds per square inch, APCI is atmospheric pressure chemical ionization, ESI is electros- pray ionization, l.v. is intravenous, m/z is mass to charge ratio, mp/Mp is melting point, MS is mass spectrometry, HPLC is high pressure liquid chromatography, RP is reverse phase, HPLC-MS is high pressure liquid chromatography - mass spectrometry, NMR is nuclear magnetic resonance spectroscopy, p.o. is per oral, Rf is relative TLC mobility, rt is room tem- perature, s.c. is subcutaneous, TLC is thin layer chromatography, tr is retention time, BOP is (1 -benzotriazolyloxy)tris(dimethylamino)phosphoniumhexafluorophosphate, CDI is carbon- yldiimidazole, DCM is dichloromethane, CH2CI2 is methylenechloride, DIBAL-H is diisobuty- laluminiumhydride, DBU is 1 ,8-diazabicyclo[5.4.0]undec-7-ene, DEAD is diethyl azodicar- boxylate, DIC is 1 ,3-diisopropylcarbodiimide, DIPEA is Λ/,Λ/-diisopropylethylamine, DMA is Λ/,Λ/-dimethylacetamide, DMF is Λ/,Λ/-dimethylformamide, DMPU is Λ/,Λ/'-dimethylpropylene- urea, 1 ,3-dimethyl-2-oxohexahydropyrimidine, DMSO is dimethylsulfoxide, EDAC is 1 -ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride, Et2O is diethyl ether, EtOAc is ethyl acetate, HMPA is hexamethylphosphoric acid triamide, HOAt is 1 -hydroxy-7-azabenzotri- azole, HOBt is 1 -hydroxybenzotriazole, LAH is lithium aluminum hydride (LiAIH4), LDA is lith- ium diisopropylamide, MeCN is acetonitrile, MeOH is methanol, NMM is N-methylmorpholine (4-methylmorpholine), NMP is Λ/-methylpyrrolidin-2-one, TEA is triethylamine, TFA is tri- fluoroacetic acid, THF is tetrahydrofuran, THP is tetrahydropyranyl, TTFH is fluoro-Λ/,Λ/,Λ/',Λ/'- tetramethylformamidinium hexafluorophosphate, CDCI3 is deuterio chloroform, CD3OD is tet- radeuterio methanol and DMSO-c/6 is hexadeuterio dimethylsulfoxide. SUMMARY OF THIS INVENTION
The invention relates to compounds of the general formula I specified in the claims below. The compounds of this invention differ structurally from the known compounds.
The invention also relates to the use of said compounds in therapy, and in particular to pharmaceutical compositions comprising said compounds.
In another embodiment, the invention relates to methods of treatment, the method comprising administering to a subject in need thereof an effective amount of one or more compounds according to formula I.
In a still further embodiment, the invention relates to the use of compounds accord- ing to formula I in the manufacture of medicaments.
DETAILED DESCRIPTION OF THIS INVENTION
Due to their interaction with the histamine H3 receptor, the compounds of this invention as defined in the claims below and elsewhere in this specification are useful in the treatment of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
In an embodiment, this invention relates to a compound of the general formula I:
Figure imgf000015_0001
wherein W, X, Y, Z independent of each other is a moiety of the formula -C(R2)= or -N= (i.e. nitrogen), with the proviso that at least one of the symbols W, X, Y or Z must be the moiety -
N=; R2 is hydrogen, halogen, cyano, Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkyl or halo-Ci 6-alkoxy;
R1 represents the following possibilities i) and ii): where possibility i) is a group of the general formula -NR3R4, wherein R3 is hydrogen, Ci 6-alkyl, C2 6-alkenyl or C3 8-cycloalkyl; and R4 is
Ci 6-alkyl, C2 6-alkenyl or C3 8-cycloalkyl, each of which are substituted with a group selected from -NR5R6 and heterocyclyl; R5 and R6 independently represent hydrogen or Ci 6-alkyl; and where posibility ii) is a group of one of the general formulas Il to VII:
Figure imgf000016_0001
IV V
Figure imgf000016_0002
Vl VII wherein the star indicates the position of the free bond (and not a methyl group), and wherein m is 0 (zero), 1 , 2 or 3; n is 1 , 2 or 3; o is 0 (zero), 1 , 2, 3 or 4; p is 0 (zero), 1 or 2; q is 1 or 2; Q represents a moiety of the formula -CH2-, -O-, -S- or >NR3, wherein R3 is as defined above; R7 and R8 independent of each other is hydrogen or Ci 6-alkyl, or R7 and R8 can together with the nitrogen to which they are attached form a heterocyclyl group; R9 is Ci 6-alkyl or C38-cycloalkyl, which both may be substituted with a group of the general formula -NR7R8, wherein R7 and R8 are as defined above; R10 is hydrogen or Ci 6-alkyl; R11 is hydrogen, Ci 8- alkyl, C3 8-alkenyl, C3 8-alkynyl, C3 8-cycloalkyl, C3 8-cycloalkenyl, C3 8-cycloalkyl-Ci 3-alkyl or C3 8-cycloalkenyl-Ci 3-alkyl, or Ci 6-alkyl or C3 8-cycloalkyl, which both are substituted with at least one substituent selected from the group consisting of hydroxy, Ci 6-alkoxy, Ci 6-alkyl- carbonyl, cyano, -NR5R6, -C(=O)NR5R6, arylcarbonyl, heteroarylcarbonyl, Ci 6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, Ci 6-alkoxycarbonyl, aryl-Ci 6-alkoxycarbonyl, heteroaryl and heterocyclyl, which heterocyclyl may be substituted with Ci 6-alkyl, where applicable; R5 and R6 are as defined above; A is aryl or heteroaryl, each of which may optionally be substituted with one or more substituents independently selected from R12; R12 is halogen, hydroxy, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, -V-(CH2)s-(C=O)r-NR13R14, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl, Ci 6-alkoxy-Ci 6-alkyl, Ci 6-alkyl- carbonylamino, N-(Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino, Ci 6-alkylcarbonylamino-Ci 6-alkyl or N-(Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino-Ci 6-alkyl; or heterocyclyl-Ci 6-alkyl, heterocyclyl- Ci 6-alkoxy, heterocyclylcarbonyl, C3 8-cycloalkylcarbonylamino, N-(C3 8-cycloalkylcarbonyl)- N-(Ci 6-alkyl)amino, C3 8-cycloalkylcarbonylamino-Ci 6-alkyl or N-(C3 8-cycloalkylcarbonyl)-N- (Ci 6-alkyl)amino-Ci 6-alkyl, C3 8-cycloalkyl-Ci 6-alkylcarbonylamino, N-(C3 8-cycloalkyl-Ci 6- alkylcarbonyl)-N-(Ci 6-alkyl)amino, C3 8-cycloalkyl-Ci e-alkylcarbonylamino-Ci 6-alkyl or N-(C3 8-cycloalkyl-Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino-Ci 6-alkyl, arylcarbonylamino, aryl-Ci 6- alkylcarbonylamino, arylcarbonylamino-Ci 6-alkyl, aryl-Ci e-alkylcarbonylamino-Ci 6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-Ci 6-alkyl, wherein each of said aryl, heteroaryl, C3 8-cycloalkyl and heterocyclyl may optionally be substituted with halogen, hydroxy, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6- alkylsulfonyl, Ci 6-alkylsulfinyl, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cya- no-Ci 6-alkyl, hydroxy-Ci 6-alkyl or Ci 6-alkoxy-Ci 6-alkyl; or aryl or heteroaryl, each of which may be substituted with halogen, hydroxy, carboxy, nitro, cyano, Ci 6-alkyl, C3 8-cycloalkyl, Ci 6-alkoxy, Ci 6-alkylsulfanyl, Ci 6-alkylsulfonyl, Ci 6-alkylcarbonyl, Ci 6-alkylcarbonylamino, Ci e-alkylcarbonylamino-Ci 6-alkyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, halo-Ci 6-alkyl, halo-Ci 6-alkoxy, hydroxy-Ci 6-alkyl, Ci 6-alkoxy-Ci 6-alkyl, aryl, arylcarbonylamino, aryl- carbonylamino-Ci 6-alkyl, heteroaryl, heteroarylcarbonylamino, heteroarylcarbonylamino-Ci 6- alkyl or -(CH2)s-(C=O)r-NR13R14; r is 0 (zero) or 1 ; s is 0 (zero), 1 , 2 or 3; V represents a bond or moiety of the formula, -O-, -S- or >NR3, wherein R3 is as defined above; R13 is hydrogen, Ci 6-alkyl, C3 8-cycloalkyl or Ci 6-alkylcarbonyl; R14 is hydrogen, Ci 6-alkyl or C3 8-cycloalkyl with the proviso that R14 is hydrogen when R13 is Ci 6-alkylcarbonyl; or R13 and R14 can together with the attached nitrogen form a heterocyclyl group; and pharmaceutically acceptable salts and solvates thereof; with the following provisos a) through g): a) when R1 is a group of the formula Vl; W is -N=; X, Y and Z is each a moiety of the general formula - C(R2)=; wherein R2 is as defined above; then A cannot be imidazolyl; b) when R1 is a group of the formula Vl; q is 1 ; X is -C(R2)=; R11 is branched C4 6-alkyl, branched C4 6-alkenyl, branched C4 6-alkynyl, C3 5-cycloalkyl, C3 7-cycloalkenyl, C3 6-cycloalkyl-Ci 3-alkyl or C3 6- cycloalkenyl-Ci 3-alkyl; and W, Y, Z is each a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoro- methoxy, Ci 6-alkoxy , Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -V-(CH2)s-(C=O)r-NR13R14, wherein V is a bond, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; c) when R1 is a group of the formula VII; m is 1 , 2 or 3; X is a moiety of the formula -C(R2)=; and W, Y, Z is each a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -V-(CH2)s-(C=O)r-NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; d) when R1 is a group of the formula Vl; q is 1 ; R11 is ethyl, n-propyl or isopropyl; Y and Z is each -N=; X is a moiety of the formula -C(R2)=, and W is a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; e) when R1 is a group of the formula VII; m is 1 , 2 or 3; Y and Z is each -N=; X is a moiety of the formula -C(R2)=; and W is a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cyclo- alkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; f) when R1 is formula Vl, q is 1 , X and W is each a moiety of the general formula -C(R2)=, wherein R2 is as defined above, Y and Z is each -N=, R11 is isopropyl, and A is phenyl, then R12 can not be fluoro, bromo, iodo, hydroxy, trifluoromethoxy, C2 6-alkoxy, Ci 6-alkyl, C2 6-alkylsulfanyl, C2 6-alkylsulfinyl, C2 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; and g) when X and Z is each -C(R2)=; and one or both of W and Y are -N=; then R1 cannot be a group of the formula II, wherein m is 2.
In an embodiment, this invention relates to a compound of the general formula I, to the extent possible according to claim 1 :
Figure imgf000018_0001
wherein W, X, Y, Z independent of each other is a moiety of the formula -C(R2)= or -N= (i.e. nitrogen), with the proviso that at least one of the symbols W, X, Y or Z must be the moiety - N=; R2 is hydrogen, halogen, cyano, Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkyl or halo-Ci 6-alkoxy; R1 represents the following possibilities i) and ii): where possibility i) is a group of the general formula -NR3R4, wherein R3 is hydrogen, Ci 6-alkyl, C2 6-alkenyl or C3 8-cycloalkyl; and R4 is C1 6-alkyl, C2 6-alkenyl or C3 8-cycloalkyl, each of which are substituted with a group selected from -NR5R6 and heterocyclyl; R5 and R6 independently represent hydrogen or Ci 6-alkyl; and possibility ii) is a group of one of the general formulas Il to VII:
Figure imgf000019_0001
IV V
Figure imgf000019_0002
Vl VII wherein the star indicates the position of the free bond (and not a methyl group), and wherein m is 0 (zero), 1 , 2 or 3; n is 1 , 2 or 3; o is 0 (zero), 1 , 2, 3 or 4; p is 0 (zero), 1 or 2; q is 1 or 2; Q represents a moiety of the formula -CH2- , -O-, -S- or >NR3, wherein R3 is as defined above; R7 and R8 independent of each other is hydrogen or Ci 6-alkyl, or R7 and R8 can together with the nitrogen to which they are attached form a heterocyclyl group; R9 is Ci 6-alkyl or C38-cycloalkyl, which both may be substituted with a group of the general formula -NR7R8, wherein R7 and R8 are as defined above; R10 is hydrogen or Ci 6-alkyl; R11 is hydrogen, Ci 8- alkyl, C3 8-alkenyl, C3 8-alkynyl, C3 8-cycloalkyl, C3 8-cycloalkenyl, C3 8-cycloalkyl-Ci 3-alkyl or C3 8-cycloalkenyl-Ci 3-alkyl, or Ci 6-alkyl or C3 8-cycloalkyl, which both are substituted with at least one substituent selected from the group consisting of hydroxy, Ci 6-alkoxy, Ci 6-alkyl- carbonyl, cyano, -NR5R6, -C(=O)NR5R6, arylcarbonyl, heteroarylcarbonyl, Ci 6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, Ci 6-alkoxycarbonyl, aryl-Ci 6-alkoxycarbonyl, heteroaryl and heterocyclyl, which heterocyclyl may be substituted with Ci 6-alkyl, where applicable; R5 and R6 are as defined above; A is aryl or heteroaryl, each of which may optionally be substituted with one or more substituents independently selected from R12; R12 is halogen, hydroxy, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, C1 6-alkylsulfinyl, -(CH2)s-(C=O)r-NR13R14, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl, Ci 6-alkoxy-Ci 6-alkyl, Ci 6-alkylcarbonyl- amino or Ci 6-alkylcarbonylamino-Ci 6-alkyl; or heterocyclyl-Ci 6-alkyl, heterocyclyl-Ci 6- alkoxy, heterocyclylcarbonyl, arylcarbonylamino, arylcarbonylamino-Ci 6-alkyl, heteroaryl- carbonylamino or heteroarylcarbonylamino-Ci 6-alkyl, wherein each of said aryl, heteroaryl and heterocyclyl may optionally be substituted with halogen, hydroxy, cyano, Ci 6alkyl, C3 8- cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl or Ci 6-alkoxy-Ci 6-alkyl; or aryl or heteroaryl, each of which may be substituted with halogen, hydroxy, carboxy, nitro, cyano, Ci 6-alkyl, C38-cycloalkyl, Ci 6-alkoxy, Ci 6— alkylsulfanyl, Ci 6-alkylsulfonyl, C1 6-alkylcarbonyl, C1 6-alkylcarbonylamino, C1 6-alkylcarbonylamino-d 6-alkyl, C1 6-alkoxycarbonyl, C1 6-alkylcarboxy, halo-d 6-alkyl, halo-d 6-alkoxy, hydroxy-d 6-alkyl, C1 6-alkoxy-d 6-alkyl, aryl, arylcarbonylamino, arylcarbonylamino-d 6-alkyl, heteroaryl, hetero- arylcarbonylamino, heteroarylcarbonylamino-d 6-alkyl or -(CH2)s-(C=O)r-NR13R14; r is 0 (zero) or 1 ; s is 0 (zero), 1 , 2 or 3; R13 is hydrogen, C1 6-alkyl, C3 8-cycloalkyl or C1 6-alkyl- carbonyl; R14 is hydrogen, C1 6-alkyl or C3 8-cycloalkyl with the proviso that R14 is hydrogen when R13 is C1 6-alkylcarbonyl; or R13 and R14 can together with the attached nitrogen form a heterocyclyl group; and pharmaceutically acceptable salts and solvates thereof; with the following provisos a) through g): a) when R1 is a group of the formula Vl; W is -N=; X, Y and Z is each a moiety of the general formula -C(R2)=; wherein R2 is as defined above; then A cannot be imidazolyl; b) when R1 is a group of the formula Vl; q is 1 ; X is -C(R2)=; R11 is branched C4 6-alkyl, branched C4 6-alkenyl, branched C4 6-alkynyl, C3 5-cycloalkyl, C3 7-cyclo- alkenyl, C3 6-cycloalkyl-d 3-alkyl or C3 6-cycloalkenyl-d 3-alkyl; and W, Y, Z is each a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1 6-alkoxy , C1 6-alkyl, C1 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or C1 6-alkyl; c) when R1 is a group of the formula VII; m is 1 , 2 or 3; X is a moiety of the formula -C(R2)=; and W, Y, Z is each a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1 6-alkoxy, C1 6-alkyl, C1 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or C1 6-alkyl; d) when R1 is a group of the formula Vl; q is 1 ; R11 is ethyl, n-propyl or isopropyl; Y and Z is each -N=; X is a moiety of the formula -C(R2)=, and W is a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluorometh- oxy, C1 6-alkoxy, C1 6-alkyl, C1 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or C1 6-alkyl; e) when R1 is a group of the formula VII; m is 1 , 2 or 3; Y and Z is each -N=; X is a moiety of the formula -C(R2)=; and W is a moiety of the formula - C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, tri- fluoromethyl, trifluoromethoxy, C1 6-alkoxy, C1 6-alkyl, C1 6-alkylsulfonyl, cyano, aryl, hetero- aryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; f) when R1 is formula Vl, q is 1 , X and W is each a moiety of the general formula -C(R2)=, wherein R2 is as defined above, Y and Z is each -N=, R11 is isopropyl, and A is phenyl, then R12 can not be fluoro, bromo, iodo, hydroxy, trifluoromethoxy, C2 6-alkoxy, C1 6-alkyl, C2 6-alkylsulfanyl, C2 6-alkylsulfinyl, C2 6- alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r- NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; and g) when X and Z is each -C(R2)=; and one or both of W and Y are -N=; then R1 cannot be a group of the formula II, wherein m is 2. In an embodiment of this invention, it relates to compounds wherein W is -N=; and X,
Y and Z each is a moiety of the general formula -C(R2)=, wherein R2 is as defined herein; such compounds having the general formula I-2:
Figure imgf000021_0001
wherein A and R1 are as defined herein, and the three symbols R2 are the same or different and each is as defined herein.
In an embodiment of this invention, this invention relates to compounds wherein W and Y each is -N=; and X and Z each is a moiety of the general formula -C(R2)=, wherein R2 is as defined herein; such compounds having the general formula I-3:
Figure imgf000021_0002
wherein A and R1 are as defined herein, and the two symbols R2 are the same or different and each is as defined herein.
In an embodiment of this invention, this invention relates to compounds wherein W and X each is -N=; and Y and Z each is a moiety of the general formula -C(R2)=, wherein R2 is as defined herein; such compounds having the general formula I-4:
I - 4
Figure imgf000021_0003
wherein A and R1 are as defined herein, and the two symbols R2 are the same or different and each is as defined herein.
In an embodiment of this invention, this invention relates to compounds wherein W and Z each is -N=; and X and Y each is a moiety of the general formula -C(R2)=, wherein R2 is as defined herein; such compounds having the general formula I-5:
Figure imgf000022_0001
wherein A and R1 are as defined herein, and the two symbols R2 are the same or different and each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having one of the general formulas l-6a, l-6b or l-6c:
Figure imgf000022_0002
I - 6a I - 6b I - 6c
wherein A, m, o, p, R7, R8, R9, R10, W, X, Y, and Z each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having one of the general formulas l-7a or l-7b:
Figure imgf000022_0003
I - 7a I - 7b wherein W, X, Y, Z, m, q, R11, and A each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having the general formula I-8:
Figure imgf000023_0001
1 - 8 wherein q, R11, and A each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having the general formula I-9:
Figure imgf000023_0002
I - 9 wherein q, R11, and A each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having the general formula 1-10:
Figure imgf000023_0003
1 - 10 wherein q, R11, and A each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having the general formula 1-1 1 :
Figure imgf000023_0004
1 - 11 wherein q, R , and A each is as defined herein. In an embodiment of this invention, this invention relates to compounds having the general formula 1-12:
Figure imgf000024_0001
I - 12 wherein Q, n, m, and A each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having the general formula 1-13:
Figure imgf000024_0002
1 - 13 wherein Q, m, n, and A each is as defined herein.
In an embodiment of this invention, this invention relates to compounds having the general formula 1-14:
Figure imgf000024_0003
1 - 14 wherein m, R9, R10, and A each is as defined herein.
In an embodiment of this invention, A is aryl, 2-pyridyl, 3-pyridyl or 4-pyridyl. In an embodiment of this invention, A is phenyl, benzofuranyl, benzodioxinyl, benzo- dioxolyl, benzoxazinyl, dihydrobenzodioxinyl, indolyl, pyrazinyl, pyridinyl, oxadiazolyl, quinolyl or thienyl.
In an embodiment of this invention, Q is -CH2- or -O-. In an embodiment of this invention, W is nitrogen (-N=).
In an embodiment of this invention, W is a group of the general formula -C(R2)=, wherein R2 is hydrogen, i.e., carbon (-CH=).
In an embodiment of this invention, X is nitrogen.
In an embodiment of this invention, X is carbon (-CH=). In an embodiment of this invention, X is nitrogen (-N=) or carbon (-CH=).
In an embodiment of this invention, Y is nitrogen.
In an embodiment of this invention, Y is carbon (-CH=).
In an embodiment of this invention, Y is nitrogen (-N=) or carbon (-CH=).
In an embodiment of this invention, Z is nitrogen. In an embodiment of this invention, Z is carbon (-CH=).
In an embodiment of this invention, Z is nitrogen (-N=) or carbon (-CH=).
In an embodiment of this invention, W and Y are each nitrogen.
In an embodiment of this invention, W and X are each nitrogen.
In an embodiment of this invention, W and Z are each nitrogen. In an embodiment of this invention, one or two of the symbols W, X, Y and Z is nitrogen (-N=) and the remaining are a group of the general formula -C(R2)=, wherein R2 is as de- fiend herein.
In an embodiment of this invention, the aromatic, divalent, 6-membered ring containing the symbols W, X, Y and Z is pyridine, pyridazine, pyrimidine or pyrazine from which hy- drogen is removed from two opposite carbon atoms (para position in relation to each other).
In an embodiment of this invention, R1 is a group of formula Il
Figure imgf000025_0001
wherein m, n and Q each is as defined in the claims below.
In an embodiment of this invention, R1 is a group of formula
Figure imgf000026_0001
wherein m, o, p, R7 and R8 each is as defined in the claims below.
In an embodiment of this invention, R1 is a group of formula III wherein m is 0, 1 or 2, o is 0, 1 or 2, p is 1 or 2, and R7 and R8 are each hydrogen or R7 and R8 form together with the nitrogen atom to which they are attached a pyrrolidinyl or piperidinyl group.
In an embodiment of this invention, R1 is a group of formula IV
Figure imgf000026_0002
IV wherein R9 is as defined in the claims below.
In an embodiment of this invention, R1 is a group of formula V
Figure imgf000026_0003
V wherein m, R9 and R10 each is as defined in the claims below.
In an embodiment of this invention, R1 is a group of formula V wherein m is 2, R9 is Ci 6-alkyl, and R10 is hydrogen.
In an embodiment of this invention, R1 is a group of formula Vl
Figure imgf000026_0004
Vl wherein q and R11 each is as defined in the claims below.
In an embodiment of this invention, R1 is a group of formula Vl wherein R11 is hydrogen, Ci 8-alkyl, C3 8-alkenyl, C3 8-cycloalkyl, heterocyclyl, Ci 8-alkyl substituted by Ci 6-alkoxy, by cyano or by Ci 6-alkylcarbonyl or by piperidinyl which optionally is substituted by Ci 6-alkyl, R5R6N- wherein R5 and R6 are each 1 -6-alkyl, or R5R6N-C(=O)- wherein R5 and R6 are each Ci 6-alkyl.
In an embodiment of this invention, heterocyclyl is tetrahydropyranyl.
In an embodiment of this invention, R1 is a group of formula Vl wherein R11 is hydrogen, methyl, isopropyl, propyl, cyclopentyl, cyclohexyl, propenyl, methoxyethyl, cyanoethyl, piperidinylpropyl, N-methylpiperidinylmethyl, methylcarbonylmethyl, N,N-dimethylaminoethyl, N,N-dimethylaminopropyl, N,N-diethylaminoethyl, N,N-dimethylaminocarbonylmethyl or tetrahydropyranyl.
In an embodiment of this invention, R1 is a group of formula VII
Figure imgf000027_0001
VII wherein m is as defined in the claims below.
In an embodiment of this invention, R1 is a group of formula VII wherein m is 2.
In an embodiment of this invention, R1 is piperazinyl, piperidinyl, pyrrolidinyl, piperid- inylamino or diazepanyl.
In an embodiment of this invention, R2 is hydrogen, Ci 6-alkyl or halogen. In an embodiment of this invention, R2 is hydrogen, methyl or isopropyl.
In an embodiment of this invention, R2 is hydrogen or Ci 6-alkyl.
In an embodiment of this invention, R7 is hydrogen or Ci 6-alkyl.
In an embodiment of this invention, R8 is hydrogen or Ci 6-alkyl.
In an embodiment of this invention, R7 and R8 together with the nitrogen to which they are attached form a heterocyclyl group.
In an embodiment of this invention, R9 is Ci 6-alkyl.
In an embodiment of this invention, R9 is pentyl, more preferred pent-3-yl.
In an embodiment of this invention, R10 is hydrogen or Ci 6-alkyl.
In an embodiment of this invention, R10 is hydrogen. In an embodiment of this invention, R11 is hydrogen, Ci 8-alkyl, C3 8-alkenyl, C3 8- alkynyl, C3 8-cycloalkyl, C3 8-cycloalkenyl, C3 8-cycloalkyl-Ci 3-alkyl or C3 8-cycloalkenyl- Ci 3-alkyl.
In an embodiment of this invention, R11 is Ci 8-alkyl, C3 8-cycloalkyl or C3 8-cycloalkyl- Ci 3-alkyl.
In an embodiment of this invention, R11 is C3 8-alkyl, C3 8-cycloalkyl or C3 8-cycloalkyl- Ci 3-alkyl.
In an embodiment of this invention, R11 is Ci 6-alkyl or C3 8-cycloalkyl, which both are substituted with at least one substituent selected from the group consisting of hydroxy, Ci 6- alkoxy, Ci 6-alkylcarbonyl, cyano, -NR5R6 , -C(=O)NR5R6, arylcarbonyl, heteroarylcarbonyl, Ci 6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, Ci 6-alkoxycarbonyl, aryl-Ci 6-alkoxy- carbonyl, heteroaryl and heterocyclyl, which heterocyclyl may be substituted with Ci 6-alkyl, where applicable; and R5 and R6 are as defined herein.
In an embodiment of this invention, R11 cannot be hydrogen. In an embodiment of this invention, R11 is hydrogen, Ci 8-alkyl, C3 8-alkenyl or C3 8- cycloalkyl or Ci 6-alkyl which is substituted with at least one substituent selected from the group consisting of Ci 6-alkoxy, Ci 6-alkylcarbonyl, cyano, -NR5R6 , -C(=O)NR5R6 and heterocyclyl, which heterocyclyl may be substituted with Ci 6-alkyl; and R5 and R6 are each Ci 6- alkyl. In an embodiment of this invention, R11 is piperidinylpropyl, N,N-dimethylaminopropyl,
N-methylpiperidinylmethyl, methyl, N,N-dimethylaminoethyl, tetrahydropyranyl, hydrogen, propyl, cyclohexyl, methylcarbonylmethyl, N,N-dimethylaminocarbonylmethyl, cyanoethyl; N,N-di- ethylaminoethyl, methoxyethyl, propenyl, cyclobutyl, cyclopentyl, cyclopropyl, cyclopropyl- methyl, ethyl, hydrogen or isopropyl. In an embodiment of this invention, the heterocyclyl group is piperidinyl.
In an embodiment of this invention, R12 is halogen, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, -(CH2)S- (C=O)r-NR13R14, heterocyclyl-Ci 6-alkyl, heterocyclyl-Ci 6-alkoxy, heterocyclylcarbonyl, Ci 6- alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, Ci 6-alkylcarbonyl- amino, Ci 6-alkylcarbonylamino-Ci 6-alkyl, arylcarbonylamino, arylcarbonylamino-Ci 6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-Ci 6-alkyl.
In an embodiment of this invention, R12 is aryl or heteroaryl, each of which may be substituted with halogen, cyano, Ci 6-alkyl, C3 8-cycloalkyl, Ci 6-alkoxy, Ci 6-alkylsulfanyl, Ci 6-alkylsulfonyl, Ci 6-alkylcarbonyl, Ci 6-alkylcarbonylamino, Ci 6-alkoxycarbonyl, Ci 6-alkyl- carboxy, halo-Ci e-alkyl, halo-Ci 6-alkoxy, Ci 6-alkoxy-Ci 6-alkyl, aryl, arylcarbonylamino, het- eroaryl, heteroarylcarbonylamino or -(CH2)s-(C=O)r-NR13R14.
In an embodiment of this invention, R12 is halogen, hydroxy, cyano, Ci 6-alkyl, C3 8- cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, - (CH2)s-(C=O)r-NR13R14, C1 6-alkylcarbonyl, C1 6-alkoxycarbonyl, C1 6-alkylcarboxy, cyano-d 6- alkyl, hydroxy-d 6-alkyl, C1 6-alkoxy-d 6-alkyl, C1 6-alkylcarbonylamino or C1 6-alkylcarbonyl- amino-d 6-alkyl.
In an embodiment of this invention, R12 is heterocyclyl-d 6-alkyl, heterocyclyl-d 6-alkoxy, heterocyclylcarbonyl, arylcarbonylamino, arylcarbonylamino-d e-alkyl, heteroaryl- carbonylamino or heteroarylcarbonylamino-d e-alkyl, wherein each said aryl, heteroaryl and heterocyclyl may optionally be substituted with halogen, hydroxy, cyano, C1 6-alkyl, C3 8- cycloalkyl, halo-d 6-alkyl, C1 6-alkoxy, halo-d 6-alkoxy, C1 6-alkylsulfonyl, C1 6-alkylsulfinyl, C1 6-alkylcarbonyl, C1 6-alkoxycarbonyl, C1 6-alkylcarboxy, cyano-d 6-alkyl, hydroxy-d 6-alkyl or C1 6-alkoxy-d 6-alkyl. In an embodiment of this invention, R12 is aryl or heteroaryl, each of which may be substituted with halogen, hydroxy, carboxy, nitro, cyano, C1 6-alkyl, C3 8-cycloalkyl, C1 6- alkoxy, C1 6— alkylsulfanyl, C1 6-alkylsulfonyl, C1 6-alkylcarbonyl, C1 6-alkylcarbonylamino, C1 6- alkylcarbonylamino-d e-alkyl, C1 6-alkoxycarbonyl, C1 6-alkylcarboxy, halo-d e-alkyl, halo-d 6-alkoxy, hydroxy-d 6-alkyl, C1 6-alkoxy-d 6-alkyl, aryl, arylcarbonylamino, arylcarbonyl- amino-d 6-alkyl, heteroaryl, heteroarylcarbonylamino, heteroarylcarbonylamino-d 6-alkyl or - (CH2)s-(C=O)r-NR13R14
In an embodiment of this invention, R12 is halogen, hydroxy, cyano, C1 6-alkyl, C3 8- cycloalkyl, halo-d e-alkyl, C1 6-alkoxy, halo-d e-alkoxy, C1 6-alkylsulfanyl, C1 6-alkylsulfonyl, C1 6-alkylsulfinyl, -V-(CH2)s-(C=O)r-NR13R14, C1 6-alkoxycarbonyl, cyano-d 6-alkyl, C1 6-alkyl- carbonylamino, N-(C1 6-alkylcarbonyl)-N-(C1 6-alkyl)amino, C1 6-alkylcarbonylamino-d 6-alkyl, or heterocyclyl, heterocyclyl-d 6-alkyl, heterocyclylcarbonyl, Cs s-cycloalkylcarbonylamino, N- (C3 8-cycloalkylcarbonyl)-N-(d 6-alkyl)amino, C3 8-cycloalkyl-d 6-alkylcarbonylamino or heterocyclylcarbonylamino wherein said heterocyclyl and C3 8-cycloalkyl, optionally, is substituted by oxo, C1 6-alkyl, C1 6-alkoxy or C1 6-alkoxy-Ci 6-alkyl; or phenyl or heteroaryl substituted by cyano, by halo-d e-alkyl, by C1 6-alkyl, by halo-d e-alkyl or by -(CH2)s-(C=O)r- NR13R14, wherein s, r, R13 and R14 are as defined above.
In an embodiment of this invention, r is 0 or 1 , s is 0 or 1 , R13 is hydrogen or C1 6- alkyl, and R14 is hydrogen or C1 e-alkyl, or R13 and R14 form together with the adjacent nitrogen atom a heterocyclyl group, for example, piperidinyl, optionally substituted by aminocar- bonyl, and V is a bond. In an embodiment of this invention, heterocyclyl is morpholinyl, piperazinyl, piperidinyl or tetrahydfropyranyl.
In an embodiment of this invention, heteroaryl is oxadiazolyl.
In an embodiment of this invention, R12 is methoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, acetyl, acetylamino, acetylaminomethyl, cyanomethyl, ethanesulfanyl, butyl- sulfanyl, methanesulfonyl, ethanesulfonyl, ethanesulfinyl, methyloxadiazolyl, cyclopropylcarbonylamino, cyclopropylmethylcarbonylamino, methoxycyclohexylcarbonyl- amino, morpholinylmethyl, methyloxadiazolyl, chloromethylphenyl, cyanophenyl, cyclopropyl, piperidinylmethylphenyl, aminocarbonylpiperidinylmethylphenyl, N-acetyl-N-methylamino, amino, aminomethyl, cyclohexylcarbonylamino, N-cyclopropylcarbonyl-N-methylamino, cyclohexylcarbonylamino, dimethylaminomethyl, dimethylamino, dimethylaminocarbonyl, (2,2-dimethylpropyl)carbonylaminomethyl, diisopropylaminocarbonyl, 4-(1 ,1 - dioxoisothiazolidinyl)phenyl, ethoxy, hydroxyl, (4-hydroxymethylpiperidinyl)carbonyl, (4- hydroxymethylpiperidinyl)methyl, isopropylcarbonylaminomethyl, 4-isopropylpiperazinyl, (4- methylpiperazinyl)carbonyl, (4-methylpiperazinyl)methyl, (4-methylpiperidinyl)carbonyl, (4- methoxymethylpiperidinyl)carbonyl, methyl, methylamino, morpholinyl, morpholinylcarbonyl, piperidinylmethyl, piperidinyl, piperidinylcarbonyl, piperidinylsulfonyl, tetrahydropyranylcar- bonylamino, tert.butylcarbonylamino and tert.butylcarbonylaminomethyl.
In an embodiment of this invention, R13 is hydrogen or Ci 6-alkyl- In an embodiment of this invention, R14 is hydrogen or Ci 6-alkyl-
In an embodiment of this invention, R13 and R14 together with the attached nitrogen form a heterocyclyl group.
In an embodiment of this invention, m is 0, 1 or 2.
In an embodiment of this invention, m is 0. In an embodiment of this invention, m is 1 or 2.
In an embodiment of this invention, n is 1 or 2.
In an embodiment of this invention, o is 1.
In an embodiment of this invention, p is 1 or 2.
In an embodiment of this invention, m is 0 and p is 2. In an embodiment of this invention, m is 0, p is 2 and o is 1.
In an embodiment of this invention, q is 1.
In an embodiment of this invention, r is 0 or 1.
In an embodiment of this invention, s is 0 or 1.
In an embodiment, this invention relates to compounds wherein A is aryl, 2-pyridyl, 3- pyridyl or 4-pyridyl; and/or Q is -CH2- or -O-; and/or W is nitrogen; and/or W is a group of the general formula -C(R2)=, wherein R2 is hydrogen; and/or X is nitrogen; and/or X is a group of the general formula -C(R2)=, wherein R2 is hydrogen; and/or Y is nitrogen; and/or Y is a group of the general formula -C(R2)=, wherein R2 is hydrogen; and/or Z is nitrogen; and/or Z is a group of the general formula -C(R2)=, wherein R2 is hydrogen; and/or W and Y is nitrogen; and/or W and X is nitrogen; and/or W and Z is nitrogen; and/or R1 is a group of formula Il
Figure imgf000031_0001
wherein m, n and Q each is as defined in the claims below; and/or R1 is a group of formula
Figure imgf000031_0002
wherein m, o, p, R7 and R8 each is as defined in the claims below; and/or R1 is a group of formula IV
Figure imgf000031_0003
IV wherein R9 is as defined in the claims below; and/or R1 is a group of formula V
Figure imgf000031_0004
V wherein m, R9 and R10 each is as defined in the claims below; and/or R1 is a group of formula Vl
Figure imgf000032_0001
Vl wherein q and R11 each is as defined in the claims below; and/or R1 is a group of formula VII
Figure imgf000032_0002
VII wherein m is as defined in the claims below; and/or R2 is hydrogen, Ci 6-alkyl or halogen; and/or R7 is hydrogen or Ci 6-alkyl; and/or R8 is hydrogen or Ci 6-alkyl; and/or R7 and R8 together with the nitrogen to which they are attached form a heterocyclyl group; and/or R9 is Ci 6-alkyl; and/or R10 is hydrogen or Ci 6-alkyl; and/or R11 is hydrogen, Ci 8-alkyl, C3 8-alkenyl, C3 8-alkynyl, C3 8-cycloalkyl, C3 8-cycloalkenyl, C3 8-cycloalkyl-Ci 3-alkyl or C3 8-cycloalkenyl- Ci 3-alkyl; and/or R11 is Ci 8-alkyl, C3 8-cycloalkyl or C3 8-cycloalkyl-Ci 3-alkyl; and/or R11 is C3 8-alkyl, C3 8-cycloalkyl or C3 8-cycloalkyl-Ci 3-alkyl; and/or R11 is Ci 6-alkyl or C3 8-cycloalkyl, which both are substituted with at least one substituent selected from the group consisting of hydroxy, C1 6-alkoxy, Ci 6-alkylcarbonyl, cyano, -NR5R6 , -C(=O)NR5R6, arylcarbonyl, hetero- arylcarbonyl, Ci 6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, Ci 6-alkoxycarbonyl, aryl- Ci 6-alkoxycarbonyl, heteroaryl and heterocyclyl, which heterocyclyl may be substituted with Ci 6-alkyl, where applicable; and R5 and R6 are as defined herein; and/or R11 cannot be hydrogen; and/or R12 is halogen, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, -(CH2)s-(C=O)r-NR1JR , heterocyclyl-Ci 6-alkyl, heterocyclyl-Ci 6-alkoxy, heterocyclylcarbonyl, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, Ci 6-alkylcarbonylamino, Ci 6-alkylcarbonylamino-Ci 6- alkyl, arylcarbonylamino, arylcarbonylamino-Ci 6-alkyl, heteroarylcarbonylamino or hetero- arylcarbonylamino-Ci 6-alkyl; and/or R12 is aryl or heteroaryl, each of which may be substituted with halogen, cyano, Ci 6-alkyl, C3 8-cycloalkyl, Ci 6-alkoxy, Ci 6— alkylsulfanyl, Ci 6-alkyl- sulfonyl, Ci 6-alkylcarbonyl, Ci 6-alkylcarbonylamino, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, halo-Ci 6-alkyl, halo-Ci 6-alkoxy, Ci 6-alkoxy-Ci 6-alkyl, aryl, arylcarbonylamino, heteroaryl, heteroarylcarbonylamino or -(CH2)s-(C=O)r-NR13R14; and/or R12 is halogen, hydroxy, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6- alkylsulfinyl, -(CH2)s-(C=O)r-NR13R14, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkyl- carboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl, Ci 6-alkoxy-Ci 6-alkyl, Ci 6-alkylcarbonylamino or Ci 6-alkylcarbonylamino-Ci 6-alkyl; and/or R12 is heterocyclyl-Ci 6-alkyl, heterocyclyl-Ci 6-alkoxy, heterocyclylcarbonyl, arylcarbonylamino, arylcarbonylamino-Ci 6-alkyl, heteroaryl- carbonylamino or heteroarylcarbonylamino-Ci 6-alkyl, wherein each said aryl, heteroaryl and heterocyclyl may optionally be substituted with halogen, hydroxy, cyano, Ci 6-alkyl, C3 8- cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl or Ci 6-alkoxy-Ci 6-alkyl; and/or R12 is aryl or heteroaryl, each of which may be substituted with halogen, hydroxy, carboxy, nitro, cyano, Ci 6-alkyl, C3 8-cycloalkyl, Ci 6-alkoxy, Ci 6-alkyl- sulfanyl, Ci 6-alkylsulfonyl, Ci 6-alkylcarbonyl, Ci 6-alkylcarbonylamino, Ci 6-alkylcarbonyl- amino-Ci 6-alkyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, halo-Ci 6-alkyl, halo-Ci 6-alkoxy, hydroxy-Ci 6-alkyl, Ci 6-alkoxy-Ci 6-alkyl, aryl, arylcarbonylamino, arylcarbonylamino-Ci 6-alkyl, heteroaryl, heteroarylcarbonylamino, heteroarylcarbonylamino-Ci 6-alkyl or -V-(CH2)s-(C=O)r- NR13R14, wherein V is a bond; and/or R13 is hydrogen or Ci 6-alkyl; and/or R14 is hydrogen or Ci 6-alkyl; and/or R13 and R14 together with the attached nitrogen form a heterocyclyl group; and/or m is 0, 1 or 2; and/or m is 0; and/or m is 1 or 2; and/or n is 1 or 2; and/or o is 1 ; and/or p is 1 or 2; and/or m is 0 and p is 2; and/or m is 0, p is 2 and o is 1 ; and/or q is 1 ; and/or r is 0 or 1 ; and/or s is 0 or 1.
In an embodiment of this invention, the moiety V is a bond.
In an embodiment, this invention relates to any one of the following compounds: 1 -[5- (4-chlorophenyl)pyridin-2-yl]-4-isopropylpiperazine; 1 -isopropyl-4-[5-(4-methoxyphenyl)- pyridin-2-yl]piperazine; 1 -isopropyl-4-[5-(4-trifluoromethoxyphenyl)pyridin-2-yl]piperazine; 1 - {4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}ethanone; 1 -[5-(2,6-difluorophenyl)pyridin- 2-yl]-4-isopropylpiperazine; 1 -[5-(4-fluorophenyl)pyridin-2-yl]-4-isopropylpiperazine; 1 -[5-(3- fluorophenyl)pyridin-2-yl]-4-isopropylpiperazine; 1 -[5-(2-fluorophenyl)pyridin-2-yl]-4-isopropyl- piperazine; 1 -{4-[6-(4-cyclopentylpiperazin-1 -yl)pyridin-3-yl]phenyl}ethanone; 4-[6-(4-iso- propylpiperazin-1 -yl)pyridin-3-yl]benzonitrile; (4-(2-pyrrolidin-1 -ylethyl)piperidin-1 -yl)-5-(4-tri- fluoromethylphenyl)pyridine; 1 -(3-piperidin-1 -ylpropyl)-4-[5-(4-trifluoromethylphenyl)pyridin-2- yl]piperazine; 1 '-[6-(4-methanesulfonylphenyl)pyridazin-3-yl]-[1 ,4']bipiperidinyl; dimethyl-(3-{4- [6-(4-trifluoromethylphenyl)pyridazin-3-yl]piperazin-1 -yl}propyl)amine; 3-[4-(1 -methylpiperidin- 3-ylmethyl)piperazin-1 -yl]-6-(4-trifluoromethylphenyl)pyridazine; 3-[4-(1 -methylpiperidin-4-yl- methyl)piperazin-1 -yl]-6-(4-trifluoromethylphenyl)pyridazine; 4-{6-[4-(1 -methylpiperidin-4-yl- methyl)piperazin-1 -yl]pyridazin-3-yl}benzonitrile; 4-{6-[4-(1 -methylpiperidin-3-ylmethyl)- piperazin-1 -yl]pyridazin-3-yl}benzonitrile; (S)-3-(4-butylsulfanylphenyl)-6-(2-pyrrolidin-1 -yl- methylpyrrolidin-1 -yl)pyridazine; (S)-3-(4-ethanesulfonylphenyl)-6-(2-pyrrolidin-1 -ylmethyl- pyrrolidin-1 -yl)pyridazine; (S)-3-(4-ethanesulfinylphenyl)-6-(2-pyrrolidin-1 -ylmethylpyrrolidin- 1 -yl)pyridazine; (S)-3-(4-ethylsulfanylphenyl)-6-(2-pyrrolidin-1 -ylmethylpyrrolidin-1 -yl)- pyridazine; 5-(4-chlorophenyl)-2-(4-isopropylpiperazin-1 -yl)pyrimidine; 2-(4-isopropyl- piperazin-1 -yl)-5-(4-trifluoromethylphenyl)pyrimidine; 4-[2-(4-isopropylpiperazin-1 -yl)- pyrimidin-5-yl]benzonitrile; 5-(4-fluorophenyl)-2-(4-isopropylpiperazin-1 -yl)pyrimidine; 2-(4- isopropylpiperazin-1 -yl)-5-(4-trifluoromethoxyphenyl)pyrimidine; 2-(4-isopropylpiperazin-1 -yl)- 5-(4-methoxyphenyl)pyrimidine; (S)-3-(2-pyrrolidin-1 -ylmethylpyrrolidin-1 -yl)-6-(4-trifluoro- methylphenyl)pyridazine; N-{4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}acetamide; [1 -(1 -ethylpropyl)piperidin-4-yl]-[6-(3-fluoro-4-methoxyphenyl)pyridazin-3-yl]amine; [1 -(1 - ethylpropyl)piperidin-4-yl]-[6-(4-methanesulfonylphenyl)pyridazin-3-yl]amine; 1 -isopropyl-4- [5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine; 3-(2,3-dihydrobenzo[1 ,4]dioxin-6-yl)-6-(4- isopropylpiperazin-1 -yl)pyridazine; 4-{6-[1 -(1 -ethylpropyl)piperidin-4-ylamino]pyridazin-3-yl}- benzonitrile; dimethyl-(2-{4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}ethyl)amine; 1 -(tetrahydropyran-4-yl)-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine; 1 -[6-(4-trifluoro- methylphenyl)pyridazin-3-yl]piperidin-3-ylamine; N-{4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3- yl]benzyl}acetamide; 1 -isopropyl-4-{5-[4-(5-methyl[1 ,2,4]oxadiazol-3-yl)phenyl]pyridin-2-yl}- piperazine; 1 -(5-(5-(4-chloromethylphenyl)[1 ,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropyl- piperazine; 4-{3-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl][1 ,2,4]oxadiazol-5-yl}benzonitrile; 1 - [5-(5-cyclopropyl[1 ,2,4]oxadiazol-3-yl)pyridin-2-yl]-4-isopropylpiperazine; 1 -isopropyl-4-{5-[5- (4-piperidin-1 -ylmethylphenyl)[1 ,2,4]oxadiazol-3-yl]pyridin-2-yl}piperazine; 1 -(4-{3-[6-(4-iso- propylpiperazin-1 -yl)pyridin-3-yl][1 ,2,4]oxadiazol-5-yl}benzyl)piperidine-4-carboxylic acid amide; 1 -propyl-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine; 1 -cyclohexyl-4-[5-(4-tri- fluoromethylphenyl)pyridin-2-yl]piperazine; 1 -{4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]- phenyljethanone; 1 -{4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}propan-2-one; Λ/,Λ/-dimethyl-2-{4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}acetamide; 3-{4-[5- (4-trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}propionitrile; diethyl-(2-{4-[5-(4-trifluoro- methylphenyl)pyridin-2-yl]piperazin-1 -yl}ethyl)amine; 1 -(2-methoxyethyl)-4-[5-(4-trifluoro- methylphenyl)pyridin-2-yl]piperazine; 1 -allyl-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]- piperazine; 1 -isopropyl-4-[6-(4-trifluoromethylphenyl)pyridazin-3-yl]-[1 ,4]diazepane; N-[4-(4- isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]acetamide; [4-(4-isopropyl- 3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]acetonitrile and 5-(4-ethanesulfonyl- phenyl)-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, and salts thereof such as hydro- chlorides, dihydrochlorides, trihydrochlorides, trifluoroacetates and dimethanesulfonates. In an embodiment, this invention relates to any one of the following compounds: N-{4- [6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}acetamide; cyclopropanecarboxylic acid [4- (4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]amide; 2-cyclopropyl-N-[4-(4- isopropyl-S^^^-tetrahydro^H-ti ^'lbipyrazinyl-δ'-yOphenyOacetamide^-methoxycyclo- hexanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]- amide; 4-{4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}morpholine; 4-[2-(4-isopropyl- piperazin-1 -yl)pyrimidin-5-yl]benzonitrile and N-{4-[2-(4-isopropylpiperazin-1 -yl)pyrimidin-5- yl]benzyl}acetamide and salts thereof such as hydrochlorides, dihydrochlorides, trihydrochlo- rides, trifluoroacetates and dimethanesulfonates. In an embodiment, this invention relates to any one of the following compounds: 4-[6-
(4-cyclopropylpiperazin-1 -yl)piperidin-3-yl]-N,N-dimethylbenzamide and N-{4-[6-(4-cyclo- propylpiperazin-1 -yl)pyridazin-3-yl]-2-methoxyphenyl}acetamide, and salts thereof such as hydrochlorides, dihydrochlorides, trihydrochlorides, trifluoroacetates and dimethanesulfonates. In an embodiment, this invention relates to any one of the following compounds: N-{3-
[6-(4-isopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]phenyl}acetamide; N-{3-[6-(4-isopropyl- piperazin-1 -yl)-5-methylpyridin-3-yl]phenyl}acetamide; N-{4-[6-(4-isopropylpiperazin-1 -yl)-4- methylpyridin-3-yl]phenyl}acetamide; N-{4-[6-(4-isopropylpiperazin-1 -yl)-5-methylpyridin-3- yl]phenyl}acetamide; N-{4-[6-(4-isopropylpiperazin-1 -yl)-4-methylpyridazin-3-yl]phenyl}- acetamide; N-{3-[6-(4-cyclopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]phenyl}acetamide; 3-[6- (4-cyclopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]-N,N-dimethylbenzamide; N-{4-[6-(4-cyclo- propylpiperazin-1 -yl)-4-methylpyridin-3-yl]phenyl}acetamide; 4-[6-(4-cyclopropylpiperazin-1 - yl)-4-methylpyridin-3-yl]-N,N-dimethylbenzamide; 5-1 ,3-benzodioxol-5-yl-2-(4-cyclopropyl- piperazin-1 -yl)pyrimidine; N-{4-[6-(4-isopropylperhydro-1 ,4-diazepin-1 -yl)pyridazin-3-yl]- phenyljacetamide; 4-[6-(4-isopropylperhydro-1 ,4-diazepin-1 -yl)pyridazin-3-yl]phenylamine; N-{4-[6-(4-cyclopropyl-[1 ,4]diazepan-1 -yl)pyridazin-3-yl]phenyl}acetamide; 7-[6-(4-cyclo- propylpiperazin-1 -yl)-pyridazin-3-yl]-4-methyl-3,4-dihydro-2H-1 ,4-benzoxazine; 3-(4-cyclo- propylpiperazin-1 -yl)-6-(2,3-dihydro-1 ,4-benzodioxin-6-yl)pyridazine; 5-[6-(4-cyclopropyl- piperazin-1 -yl)pyridazin-3-yl]-1 H-indole; {4-[2-(4-isopropylpiperazin-1 -yl)pyrimidin-5-yl]- phenyljacetonitrile; N-{4-[2-(4-isopropylpiperazin-1 -yl)pyrimidin-5-yl]phenyl}acetamide; 1 -{4- [2-(4-isopropylpiperazin-1 -yl)pyrimidin-5-yl]phenyl}ethanone; 2-(4-isopropylpiperazin-1 -yl)-5- pyridin-3-ylpyrimidine; 2-(4-isopropylpiperazin-1 -yl)-5-pyridin-4-ylpyrimidine; {4-[2-(4-iso- propylpiperazin-1 -yl)pyrimidin-5-yl]phenyl}dimethylamine; 3-[2-(4-isopropylpiperazin-1 - yl)pyrimidin-5-yl]-N,N-dimethylbenzamide; N,N-diisopropyl-4-(4-isopropyl-3,4,5,6-tetrahydro- 2H-[1 ,2']bipyrazinyl-5'-yl)benzamide; [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl- 5'-yl)phenyl]-(4-methylpiperidin-1 -yl)methanone; 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']- bipyrazinyl-5'-yl)-N,N-dimethylbenzamide; [3-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bi- pyrazinyl-5'-yl)phenyl]morpholin-4-ylmethanone; N-{4-[5-(octahydropyrido[1 ,2-a]pyrazin-2- yl)pyrazin-2-yl]phenyl}acetamide; 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'- yl)phenol; N-[4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-N-methyl- amine; 4-isopropyl-5'-(4-morpholin-4-ylphenyl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl; 5'-1 ,3- benzodioxol-5-yl-4-isopropyl-3,4,5,6-tetrahydro-2H-1 ,2'-bipyrazinyl; 4-(4-isopropyl-3,4,5,6- tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-2-methoxyphenylamine; 2-chloro-4-(4-isopropyl-3,4,5,6- tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-6-methoxyphenol; 5'-(3,4-dimethoxyphenyl)-4-isopropyl- 3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl; 4-isopropyl-5'-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetra- hydro-2H-[1 ,2']bipyrazinyl; N-[4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2l]bipyrazinyl-5'-yl)- benzyl]acetamide; 4,4"'-diisopropyl-3,4,5,6,3'",4"',5"',6'"-octahydro-2H,2"'H-[1 ,2';5',2";5",r"]- quaterpyrazine; 4-isopropyl-5'-(6-methoxypyridin-3-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl; N,N-diisopropyl-4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzamide; {4-[6-(4-isopropyl- piperazin-1 -yl)pyridin-3-yl]phenyl}-(4-methylpiperidin-1 -yl)methanone; 6'-(4-isopropyl- piperazin-1 -yl)-6-methoxy-[3,3']bipyridinyl; 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bi- pyrazinyl-5'-yl)benzonitrile; 4-isopropyl-5'-(4-trifluoromethylphenyl)-3,4,5,6-tetrahydro-2H- [1 ,2']bipyrazinyl; 6'-(4-isopropylpiperazin-1 -yl)-5-trifluoromethyl-[2,3']bipyridinyl; 4-isopropyl- 5'-[4-(piperidine-1 -sulfonyl)phenyl]-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl; 4-isopropyl-5'-(4- (piperidin-1 -yl)phenyl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl; [4-(4-isopropyl-3,4,5,6-tetra- hydro-2H-[1 ,2']bipyrazinyl-5'-yl)-2-methylphenyl]dimethylamine; 5'-(6-ethoxypyridin-3-yl)-4- isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl; 5'-benzofuran-2-yl-4-isopropyl-3,4,5,6-tetra- hydro-2H-[1 ,2']bipyrazinyl; 5-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)thio- phene-2-carbonitrile; 4-isopropyl-5'-(2-methylpyridin-4-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bi- pyrazinyl; (R)-2-(6-1 ,3-benzodioxol-5-ylpyridazin-3-yl)octahydropyrido[1 ,2-a]pyrazine; 4- isopropyl-5'-(5-trifluoromethyl-pyridin-2-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl; N-{4-[6-(4- cyclobutylpiperazin-1 -yl)pyridin-3-yl]phenyl}acetamide; 4-[6-(4-cyclobutylpiperazin-1 -yl)- pyridin-3-yl]-N,N-dimethylbenzamide; N-{4-[6-(4-cyclobutylpiperazin-1 -yl)pyridazin-3-yl]-2- methoxyphenyljacetamide; {4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}piperidin-1 - ylmethanone; {4-[6-(4-cyclopropylmethylpiperazin-1 -yl)pyridazin-3-yl]phenyl}piperidin-1 -yl- methanone; {4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}morpholin-4-ylmethanone; (4-hydroxymethylpiperidin-1 -yl)-{4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}- methanone; 4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]-N,N-dimethylbenzamide; {4-[6-(4- cyclopentylpiperazin-1 -yl)pyridazin-3-yl]phenyl}piperidin-1 -ylmethanone; {4-[6-(4-isopropyl- piperazin-1 -yl)pyridazin-3-yl]phenyl}-(4-methylpiperazin-1 -yl)methanone; {4-[6-(4-isopropyl- piperazin-1 -yl)pyridin-3-yl]phenyl}morpholin-4-ylmethanone; 4-[6-(4-isopropylpiperazin-1 - yl)pyridin-3-yl]-N,N-dimethylbenzamide; {4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}- piperidin-1 -ylmethanone; (4-hydroxymethylpiperidin-1 -yl)-{4-[6-(4-isopropylpiperazin-1 -yl)- pyridin-3-yl]phenyl}-methanone; {4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}-(4- methylpiperazin-1 -yl)methanone; {4-[6-(4-cyclopropylmethylpiperazin-1 -yl)pyridin-3-yl]- phenyl}piperidin-1 -ylmethanone; {4-[6-(4-cyclopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}- piperidin-1 -ylmethanone; {4-[6-(4-cyclopentylpiperazin-1 -yl)pyridin-3-yl]phenyl}piperidin-1 -ylmethanone; {3-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}morpholin-4-ylmethanone; {3- [6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}piperidin-1 -ylmethanone; 3-[6-(4-isopropyl- piperazin-1 -yl)pyridin-3-yl]-N,N-dimethylbenzamide; {4-[6-(4-cyclopentylpiperazin-1 -yl)- pyridin-3-yl]phenyl}-(4-methylpiperazin-1 -yl)methanone; {4-[6-(4-cyclopropylpiperazin-1 -yl)- pyridin-3-yl]phenyl}-(4-methylpiperazin-1 -yl)methanone; {4-[6-(4-ilsopropylpiperazin-1 -yl)- pyridin-3-yl]phenyl}-(4-methoxymethylpiperidin-1 -yl)-ethanone; 4-[6-(4-'cyclopentylpiperazin- 1 -yl)pyridin-3-yl]-N,N-dimethylbenzamide; {4-[6-(4-cyclopentylpiperazin-1 -yl)pyridin-3-yl]- phenyl}morpholin-4-ylmethanone; 3-[6-(4-isopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]-N,N- dimethylbenzamide; 3-[6-(4-isopropylpiperazin-1 -yl)-5-methylpyridin-3-yl]-N,N-dimethyl- benzamide; 4-[6-(4-isopropylpiperazin-1 -yl)-5-methylpyridin-3-yl]-N,N-dimethylbenzamide; 4- [6-(4-isopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]-N,N-dimethylbenzamide; 4-[4-isopropyl-6- (4-isopropylpiperazin-1 -yl)pyridazin-3-yl]-N,N-dimethylbenzamide; 1 -cyclopropylmethyl-4-[5- (4-piperidin-1 -ylmethylphenyl)pyridin-2-yl]piperazine; {4-[6-(4-isopropylpiperazin-1 -yl)pyridin- 3-yl]benzyl}dimethylamine; 3-(4-cyclopentylpiperazin-1 -yl)-6-(4-piperidin-1 -ylmethylphenyl)- pyridazine; 1 -{4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-4-methylpiperazine; (1 -{4- [6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}piperidin-4-yl)methanol; 1 -isopropyl-4-[5-(4- piperidin-1 -ylmethylphenyl)pyridin-2-yl]piperazine; {4-[6-(4-isopropylpiperazin-1 -yl)pyridazin- 3-yl]benzyl}dimethylamine; 3-(4-isopropylpiperazin-1 -yl)-6-(4-piperidin-1 -ylmethylphenyl)- pyridazine; 3-(4-isopropylpiperazin-1 -yl)-6-[4-(4-methylpiperazin-1 -ylmethyl)phenyl]- pyridazine; (1 -{4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]benzyl}piperidin-4-yl)methanol; 4-{4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]benzyl}morpholine; 1 -cyclopentyl-4-[5-(4- piperidin-1 -ylmethylphenyl)pyridin-2-yl]piperazine; 1 -cyclopropyl-4-[5-(4-piperidin-1 -ylmethyl- phenyl)pyridin-2-yl]piperazine; 3-(4-cyclopropylmethylpiperazin-1 -yl)-6-(4-piperidin-1 -yl- methylphenyl)pyridazine; 3-(4-cyclopropylpiperazin-1 -yl)-6-(4-piperidin-1 -ylmethylphenyl)- pyridazine; 4-{4-[2-(4-cyclopropylpiperazin-1 -yl)pyrimidin-5-yl]benzyl}morpholine; N-{3-[6-(4- isopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}acetamide; N-{3-[6-(4-cyclopropylpiperazin-1 - yl)pyridazin-3-yl]phenyl}acetamide; cyclopropanecarboxylic acid {3-[6-(4-cyclopropyl- piperazin-1 -yl)pyridazin-3-yl]phenyl}amide; N-{4-[6-(4-cyclopropylpiperazin-1 -yl)pyridazin-3- yl]phenyl}acetamide; cyclopropanecarboxylic acid {4-[6-(4-cyclopropylpiperazin-1 -yl)- pyridazin-3-yl]phenyl}amide; cyclopropanecarboxylic acid {4-[6-(4-cyclopropylperhydro-1 ,4- diazepin-1 -yl)pyridazin-3-yl]-phenyl}amide; N-[4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']- bipyrazinyl-5'-yl)phenyl]-2,2-dimethylpropionamide; tetrahydropyran-4-carboxylic acid [4-(4- isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]amide; N-[4-(4-isopropyl-3,4,5,6- tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-N-methylacetamide; cyclopropanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]methylamide; N-[4-(4-iso- propyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-2-methoxyphenyl]acetamide; cyclo- hexanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]- amide; 2-[4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenoxy]-N,N-dimethyl- acetamide; 5'-[4-(1 ,1 -dioxoisothiazolidin-2-yl)phenyl]-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']- bipyrazinyl; 6-(4-isopropylpiperazin-1 -yl)-[3,3']bipyridinyl; 6-(4-isopropylpiperazin-1 -yl)-[3,4']- bipyridinyl; 6'-(4-isopropylpiperazin-1 -yl)-[2,3']bipyridinyl; 6'-(4-ethylpiperazin-1 -yl)-[2,3']bi- pyridinyl; 6'-(4-isopropylpiperazin-1 -yl)-6-methyl-[2,3']bipyridinyl; 6'-(4-ethylpiperazin-1 -yl)-6- methyl-[2,3']bipyridinyl; 2-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]quinoline; N-{3-[6-(4-iso- propylpiperazin-1 -yl)-4-methylpyridazin-3-yl]phenyl}acetamide; N-{3-[6-(4-isopropylpiperazin- 1 -yl)-5-methylpyridazin-3-yl]phenyl}acetamide; 3-[6-(4-isopropylpiperazin-1 -yl)-4-methyl- pyridazin-3-yl]-N,N-dimethylbenzamide; 3-[6-(4-isopropylpiperazin-1 -yl)-5-methylpyridazin-3- yl]-N,N-dimethylbenzamide; 4-[6-(4-isopropylpiperazin-1 -yl)-4-methylpyridazin-3-yl]-N,N-di- methylbenzamide; 4-[6-(4-isopropylpiperazin-1 -yl)-5-methylpyridazin-3-yl]-N,N-dimethyl- benzamide; N-{4-[6-(4-isopropylpiperazin-1 -yl)-5-methylpyridazin-3-yl]phenyl}acetamide; 1 '- (6-pyridin-4-ylpyridazin-3-yl)-[1 ,4']bipiperidinyl; 3-(pyridin-3-yl)-6-[(4-pyrrolidin-1 -yl)piperidin- 1 -yl]pyridazine; 1 '-(6-pyridin-3-ylpyridazin-3-yl)-[1 ,4']bipiperidinyl; 3-(pyridin-4-yl)-6-[(4- pyrrolidin-1 -yl)piperidin-1 -yl]pyridazine; 4-pyrrolidin-1 -yl-3,4,5,6-tetrahydro-2H-[1 ,2';5',3"]- terpyridine; 1 -isopropyl-4-(6-phenylpyridin-3-yl)piperazine; (R)-2-[6-(3,4-dimethoxyphenyl)- pyridazin-3-yl]octahydropyrido[1 ,2-a]pyrazine; N-{3-[6-(4-isopropylpiperazin-1 -yl)pyridin-3- yl]benzyl}acetamide; N-{4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-3,3-dimethyl- butyramide; N-{3-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-3,3-dimethylbutyramide; N-{4-[2-(4-isopropylpiperazin-1 -yl)pyrimidin-5-yl]benzyl}isobutyramide; N-{4-[6-(4-isopropyl- piperazin-1 -yl)pyridin-3-yl]benzyl}-2,2-dimethylpropionamide; N-{3-[6-(4-isopropylpiperazin-1 - yl)pyridin-3-yl]benzyl}-2,2-dimethylpropionamide; 4-[2-(4-cyclopropylpiperazin-1 -yl)pyrimidin- 5-yl]benzylamine; N-{4-[2-(4-cyclopropylpiperazin-1 -yl)pyrimidin-5-yl]benzyl}acetamide; N-{4- [6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]acetamide; N-[4-(4-cyclopropyl-3,4,5,6-tetrahydro- 2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]acetamide; 2-{4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]- phenoxy}-N,N-dimethylacetamide; cyclohexanecarboxylic acid {4-[6-(4-cyclopropylpiperazin- 1 -yl)pyridazin-3-yl]phenyl}amide and N-{4-[4-isopropyl-6-(4-isopropylpiperazin-1 -yl)pyridazin- 3-yl]phenyl}acetamide and salts thereof such as hydrochlorides, dihydrochlorides, trihydro- chlorides, trifluoroacetates and dimethanesulfonates.
Combining any one of the above embodiments results in further embodiments and the present invention relates to all possible combinations of the above embodiments and all possible combinations with the claims below.
Herein, the definition of compounds of formula I contains some provisos which have been designated provisos a) through g). These provisos are defined in claim 1 below.
In an embodiment of this invention, proviso a) is worded as follows: "a) when R1 is a group of any of the formula Il through VII; W is -N=; X, Y and Z is each a moiety of the general formula -C(R2)=; wherein R2 is as defined above; then A cannot be optionally substituted imidazolyl." In another embodiment of this invention, proviso a) is worded as follows: "a) when R1 is a group of any of the formula Il through VII; W is -N=; X, Y and Z is each a moiety of the general formula -C(R2)=; wherein R2 is as defined above; then A cannot be optionally substituted heteroaryl."
In an embodiment of this invention, proviso b) is worded as follows: "b) when R1 is a group of the formula Vl; X is -C(R2)=; R11 is Ci 8-alkyl, C2 8-alkenyl, C2 8-alkynyl, C3 8-cyclo- alkyl, C3 8-cycloalkenyl, C3 8-cycloalkyl-Ci 3-alkyl or C3 8-cycloalkenyl-Ci 3-alkyl; and W, Y, Z is each a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then A can not be unsubstituted aryl or substituted heteroaryl, and, if A is substituted, then R12 can not be halogen, hydroxy, halo-Ci 6-alkyl, halo-Ci 6-alkoxy, Ci 6-alkoxy , Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -V-(CH2)s-(C=O)r-NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl."
In an embodiment of this invention, proviso c) is worded as follows: "c) when R1 is a group of the formula VII; X is a moiety of the formula -C(R2)=; and W, Y, Z is each a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, halo-Ci 6-alkyl, halo-Ci 6-alkoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -V-(CH2)s-(C=O)r-NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or C1 6-alkyl."
In an embodiment of this invention, proviso d) is worded as follows: "d) when R1 is a group of the formula Vl; R11 is Ci 8-alkyl; Y and Z is each -N=; X is a moiety of the formula - C(R2)=, and W is a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, halo-Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula - V-(CH2)s-(C=O)r-NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl." In an embodiment of this invention, proviso e) is worded as follows: "e) when R1 is a group of the formula VII; Y and Z is each -N=; X is a moiety of the formula -C(R2)=; and W is a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, halo-Ci 6-alkyl, halo-Ci 6-alkoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkyl- sulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -V-(CH2)s-(C=O)r- NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl."
In an embodiment of this invention, proviso f) is worded as follows: "f) when R1 is formula Vl, q is 1 , X and W is each a moiety of the general formula -C(R2)=, wherein R2 is as defined above, Y and Z is each -N=, R11 is Ci 8-alkyl, and A is phenyl, then R12 can not be halogen, hydroxy, halo-Ci 6-alkoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfanyl, Ci 6-alkylsulfinyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -V-(CH2)S- (C=O)r-NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl."
In an embodiment of this invention, proviso g) is worded as follows: "g) when X and Z is each -C(R2)=; and one or both of W and Y are -N=; then R1 cannot be a group of the formula II."
In an embodiment of this invention, R1 is different from possibility ii), formula VII, when the ring containing W, X, Y and Z is a pyridazine ring.
In an embodiment of this invention, R1 is different from possibility i), when the ring containing W, X, Y and Z is a pyridazine ring.
In an embodiment of this invention, R1 is different from possibility i), when the ring containing W, X, Y and Z is a pyrimidine ring.
In an embodiment of this invention, R1 is different from possibility i), i.e. R1 is possibility ii). In an embodiment of this invention, R11 is different from hydrogen.
In an embodiment of this invention, R11 is different from methyl. In an embodiment of this invention, R11 is different from C1 8-alkyl. In an embodiment of this invention, R2 is different from cyano. In an embodiment of this invention, at least one of W, X, Y and Z is a moiety of the formula -C(R2)= wherein R2 is as defined herein. In an embodiment of this invention, R1 is not a group of formula Il when the ring containing W, X, Y and Z is a pyridazine ring.
In one embodiment of this invention, R1 is different from possibility ii), formula Il and III, when W and Y are each -N=; and X and Z are each -C(R2)=, wherein R2 is as defined herein.
In one embodiment of this invention, R1 is different from possibility ii), formula Il wherein m is 2, n is 1 or 2, and Q is -O-, when W and Y are each -N=; and X and Z are each -C(R2)=, wherein R2 is as defined herein.
In one embodiment of this invention, R1 is different from possibility ii), formula III wherein p is 1 , m is 2, o is 0 (zero), and -NR7R8 is heterocyclyl, when W and Y are each -N=; and X and Z are each -C(R2)=, wherein R2 is as defined herein.
In one embodiment of this invention, R1 is different from possibility ii), formula Il and III, when W and Y are each -N=; and X and Z are each -C(R2)=, wherein R2 is as defined herein, and when A is aryl or heteroaryl optionally substituted by halogen, hydroxy, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy or -V-(CH2)s-(C=O)r- NR13R14, wherein V, s, R13 and R14 are as defined herein.
The compounds of the present invention interact with the histamine H3 receptor and are accordingly particularly useful in the treatment of a variety of diseases or conditions in which histamine H3 interactions are beneficial.
In one aspect, the invention provides the use of a compound according to formula I in a pharmaceutical composition. The pharmaceutical composition may in another aspect of the invention comprise, as an active ingredient, at least one compound according to formula I together with one or more pharmaceutically acceptable carriers or excipients. In another as- pect, the invention provides such a pharmaceutical composition in unit dosage form, comprising from about 0.05 mg to about 1000 mg, e.g., from about 0.1 mg to about 500 mg, such as from about 0.5 mg to about 200 mg of the compound according to formula I.
In another aspect, the invention provides the use of a compound of formula I as defined above for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.
In another aspect the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the reduction of weight. In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the suppression of appetite or for satiety in- duction.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity, such as dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders, such as bulimia or binge eating.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of IGT (Impaired glucose tolerance).
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which a stimulation of the H3 histamine receptor has a beneficial effect.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition having histamine H3 agonistic activity. In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.
In another aspect, the invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease, narco- lepsy, attention deficit disorders or reduced wakefulness, or for the regulation of sleep. In another aspect, the invention relates to the use of a compound of formula I for the preparation of a pharmaceutical preparation for the treatment of airway disorders, such as asthma, for regulation of gastric acid secretion, or for treatment of diarrhoea.
In another aspect, the invention provides a method for the treatment of disorders or diseases related to the H3 histamine receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula I as defined above, or of a pharmaceutical composition comprising such a compound.
In another aspect, the invention provides a method as described above, wherein the effective amount of the compound of the general formula I as defined above is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg, and more preferably from about 0.5 mg to about 500 mg per day.
In one aspect, the invention relates to compounds which exhibit histamine H3 receptor antagonistic activity or inverse agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.
In another aspect, the invention provides a method for reduction of weight, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I as defined above.
In another aspect, the invention provides a method for treatment of overweight or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
In another aspect, the invention provides a method for suppression of appetite or for satiety induction, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I. In another aspect, the invention provides a method for prevention and/or treatment of disorders or diseases related to overweight or obesity, such as dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer, e.g. endometrial, breast, prostate or colon cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I. In another aspect, the invention provides a method for prevention and/or treatment of eating disorders, such as bulimia and binge eating, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
In another aspect, the invention provides a method for the treatment of IGT (Impaired glucose tolerance), the method comprising administering to a subject in need thereof an effective amount of a compound of formula I. In another aspect, the invention provides a method for the treatment of type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
In another aspect, the invention provides a method for the delaying or prevention of the progression from IGT to type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
In another aspect, the invention provides a method for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.
In another aspect, the invention relates to compounds which exhibit histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.
Compounds of the present invention may also be used for the treatment of airway disorders (such as asthma), as anti-diarrhoeals, and for the modulation of gastric acid secretion.
Furthermore, compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness, and for the treatment of narcolepsy and attention deficit disorders. Moreover, compounds of the invention may be used as CNS stimulants or as sedatives.
The present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, compounds of the invention may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypotha- lamo-hypophyseal secretion, as antidepressants, as modulators of cerebral circulation, and in the treatment of irritable bowel syndrome.
Further, compounds of the present invention may be used for the treatment of dementia and Alzheimer's disease.
Compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcer or anorexia.
Compounds of the present invention may furthermore be useful for the treatment of migraine [see, e.g., McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50] and for the treatment of myocardial infarction [see Mackins et al., Expert Opinion on Investigational Drugs 9 (2000), 2537-2542]. In a further aspect of the invention, treatment of a patient with a compound of the present invention is combined with diet and/or exercise.
In a further aspect of the invention, one of more compounds of the present invention is/are administered in combination with one or more further active substances in any suitable ratio(s). Such further active agents may, for example, be selected from antiobesity agents, antidiabetics, antidyslipidemic agents, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes, and agents for the treatment of complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention one or more compounds of the present in- vention may be administered in combination with one or more antiobesity agents or appetite regulating agents. Such agents may, for example, be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR β agonists, AGRP (Agouti related protein) inhibitors, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention, an antiobesity agent administered in combination with one or more compounds of the invention is leptin. In another embodiment, such an antiobesity agent is dexamphetamine or amphetamine.
In another embodiment, such an antiobesity agent is fenfluramine or dexfenflura- mine.
In still another embodiment, such an antiobesity agent is sibutramine. In a further embodiment, such an antiobesity agent is orlistat. In another embodiment, such an antiobesity agent is mazindol or phentermine. In still another embodiment, such an antiobesity agent is phendimetrazine, diethyl- propion, fluoxetine, bupropion, topiramate or ecopipam.
In yet a further aspect of the invention, one or more compounds of the present in- vention may be administered in combination with one or more antidiabetic agents. Relevant antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 0 792 290 (Novo Nordisk A/S), e.g. NεB29-tetradecanoyl des (B30) human insulin, EP 0 214 826 and EP 0 705 275 (Novo Nordisk A/S), e.g. AspB28 human insulin, US 5,504,188 (EIi Lilly), e.g. LysB28 Pro829 human insulin, EP 0 368 187 (Aventis), e.g. Lantus®, all of which are incorporated herein by reference, GLP-1 derivatives, such as those disclosed in WO
98/08871 (Novo Nordisk A/S), incorporated herein by reference, as well as orally active hy- poglycaemic agents.
The orally active hypoglycaemic agents preferably comprise imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, α-glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the β- cells, e.g. potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists, such as one of those disclosed in WO 99/01423 and WO 00/39088 (Novo Nord- isk A/S and Agouron Pharmaceuticals, Inc.), both of which are incorporated herein by reference, GLP-1 agonists, such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), incorporated herein by reference, DPP-IV (dipeptidyl pepti- dase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenosis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists, such as ALRT- 268, LG-1268 or LG-1069.
In one embodiment of the invention, one or more compounds of the present inven- tion may be administered in combination with insulin or an insulin analogue or derivative, such as NεB29-tetradecanoyl des (B30) human insulin, AspB28 human insulin, LysB28 Pro829 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
In a further embodiment of the invention, one or compounds of the present invention may be administered in combination with a sulfonylurea, e.g. tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide. In another embodiment of the invention, one or more compounds of the present invention may be administered in combination with a biguanide, e.g. metformin.
In yet another embodiment of the invention, one or more compounds of the present invention may be administered in combination with a meglitinide, e.g. repaglinide or nateglinide.
In still another embodiment of the invention, one or more compounds of the present invention may be administered in combination with a thiazolidinedione insulin sensitizer, e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 /CM 037 or T 174, or a compound disclosed in WO 97/41097, WO 97/411 19, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), all of which are incorporated herein by reference.
In still another embodiment of the invention, one or more compounds of the present invention may be administered in combination with an insulin sensitizer, e.g. such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516, or a compound disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192 or WO 00/63193 (Dr. Reddy's Research Foundation) or in WO 00/23425, WO 00/23415, WO 00/23451 , WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 or WO 00/63189 (Novo Nordisk A/S), all of which are incorporated herein by reference. In a further embodiment of the invention, one or more compounds of the present invention may be administered in combination with an α-glucosidase inhibitor, e.g. voglibose, emiglitate, miglitol or acarbose.
In another embodiment of the invention, one or more compounds of the present invention may be administered in combination with an agent acting on the ATP-dependent po- tassium channel of the β-cells, e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS- 67582 or repaglinide.
In yet another embodiment of the invention, one or more compounds of the present invention may be administered in combination with nateglinide.
In still another embodiment, one or more compounds of the present invention may be administered in combination with an antihyperlipidemic agent or antilipidemic agent, e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probu- col or dextrothyroxine.
In still another embodiment of the invention, one or more compounds of the present invention may be administered in combination with an antilipidemic agent, e.g. cholestyr- amine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dex- trothyroxine.
In another aspect of the invention, one or more compounds of the present invention may be administered in combination with more than one of the above-mentioned com- pounds, e.g. in combination with metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
Furthermore, one or more compounds of the present invention may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α- blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
It should be understood that any suitable combination of compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.
The compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention. Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly- colic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedi- sulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylam- monium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form.
The acid addition salts may be obtained as the direct products of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
Compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also to be understood as being within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds which follow- ing administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds which are readily convertible in vivo into the required compound of the formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
PHARMACEUTICAL COMPOSITIONS
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharma- ceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions may be specifically formulated for administration by any suitable route, such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal or parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings, such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingredient, such as sustained or prolonged release according to methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also to be understood as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferably from about 0.05 to about 10 mg/kg body weight per day, administered in one or more doses, such as from 1 to 3 doses. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated, and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day, such as from 1 to 3 times per day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0.5 mg to about 200 mg of a compound (or a salt or other derivative thereof as set forth above), according to the invention.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typical doses are of the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having a free base functionality. When a compound of the formula I contains a free base functionality, such salts are prepared in a conventional manner by treating a solution or suspension of the free base form of the compound of formula I with a chemical equivalent (acid-base equivalent) of a pharmaceutically acceptable acid. Representative examples of relevant inorganic and organic acids.are mentioned above. Physiologically acceptable salts of a compound of the invention having a hydroxy group include the anion of said compound in combination with a suitable cation, such as sodium or ammonium ion.
For parenteral administration, solutions of the novel compounds of the formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are par- ticularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, su- crose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylenes or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compo- sitions formed by combining the novel compounds of the formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be pre- sented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier may vary widely, but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution. A typical tablet, which may be prepared by conventional tabletting techniques, may in the core contain 5.0 mg of a compound of the invention, 67.8 mg of lactosum Ph. Eur., 31 .4 mg of cellulose, microcrystalline (Avicel), 1 .0 mg of Amberlite®IRP88 (i.e., Polacrillin potassium NF, tablet disintegrant, Rohm and Haas) and magnesii stearas Ph. Eur. q.s. with a coating of approximately 9 mg of hydroxypropyl methylcellulose and approximately 0.9 mg of Mywacett 9-40 T (being acylated monoglyceride used as plasticizer for film coating).
If desired, the pharmaceutical composition of this invention may comprise the compound of the formula I in combination with one or more further pharmacologically active substances, e.g., substances chosen among those described in the foregoing.
Briefly, the compounds of this invention can be prepared in a manner known perse or analogous with known processes.
TESTS
The ability of the compounds to interact with the histamine H3 receptor can be determined by the following in vitro binding assay.
Binding assay
The human H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor are generated by transfecting the H3- expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 clones are cultured in DMEM (GIBCO-BRL) with glutamax, 10% foetal calf serum, 1 % penicillin/streptavidin and 1 mg/ml G 418 at 37 0C and 5% CO2. Before harvesting, the confluent cells are rinsed with phosphate buffered saline (hereinafter designated PBS) and incubated with Versene (proteinase, GIBCO-BRL) for approximately 5 minutes. The cells are flushed with PBS and DMEM and the cell suspension collected in a tube and centrifuged for 5-10 minutes at 1500 rpm in a Heraeus Sepatech Megafuge 1.0. The pellet is resuspended in 10-20 volumes Hepes buffer (20 mM Hepes, 5 mM MgCI2, pH 7.1 (KOH)) and homogenized for 10-20 seconds using an Ultra-Turrax homogenizer. The homogenate is centrifuged for 30 minutes at 23,000 g. The pellet is resuspended in 5-10 ml Hepes buffer, homogenized 5-10 seconds with the Ultra-Turrax and centrifuged for 10 minutes at 23,000 g. Following this centrifugation step, the membrane pellet is resuspended in 2-4 ml Hepes buffer, homogenized with a syringe or Teflon homogenizer, and the protein concentration determined. The membranes are diluted to a protein concentration of 1 -5 mg/ml in Hepes buffer, aliquoted and kept at -80 0C until use.
Aliquots of the membrane suspension are incubated for 60 minutes at 25 0C with 30 pM [125l]-iodoproxifan, a known compound with high affinity for the H3 receptor, and the test compound at various concentrations. The incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through Whatman GF/B filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity retained on the filters is counted using a Cobra Il auto gamma counter. The radioactivity of the filters is indirectly proportional to the binding affinity of the tested compound. The results are analysed by nonlinear regression analysis. When tested, the present compounds of the formula (I) generally show a high binding affinity to the histamine H3 receptor.
Preferably, the compounds according to the invention have an IC50 value as determined by one or more of the assays of less than 10 μM, more preferred of less than 1 μM, and even more preferred of less than 500 nM, such as of less than 100 nM.
Functional assay I
The ability of the compounds to interact with the histamine H3 receptor as agonists, inverse agonists and/or antagonists, is determined by an in vitro functional assay utilizing membranes from HEK 293 cells expressing the human H3 receptors.
The H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor are generated by transfecting the H3-expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 clones are cultured in DMEM with glutamax, 10% foetal calf serum, 1 % penicillin/streptavidin and 1 mg/ml G 418 at 37 0C and 5% CO2.
The H3 receptor expressing cells are washed once with PBS and harvested using versene (GIBCO-BRL). PBS is added and the cells are centrifuged for 5 minutes at 188 g. The cell pellet is resuspended in stimulation buffer to a concentration of 1 x 106 cells/ml. cAMP accumulation is measured using the Flash Plate® cAMP assay (NEN™ Life Science Products). The assay is generally performed as described by the manufacturer. Briefly, 50 μl cell suspension is added to each well of the Flashplate which also contained 25 μl 40 μM isoprenaline, to stimulate cAMP generation, and 25 μl of test compound (either agonists or inverse agonists alone, or agonist and antagonist in combination). The assay can be run in "agonist-mode" which means that the test compound is added, in increasing concentration, on its own, to the cells, and cAMP is measured. If cAMP goes up, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist, and if cAMP goes down, it is an agonist. The assay can also be run in the "antagonist-mode" which means that a test compound is added, in increasing concentrations, together with increasing concentrations of a known H3 agonist (e.g. RAMHA). If the compound is an antagonist, increasing concentrations of it cause a right-ward shift in the H3-agonist's dose-response curves. The final volume in each well is 100 μl. Test compounds are dissolved in DMSO and diluted in water. The mixture is shaken for 5 minutes, and allowed to stand for 25 minutes at room temperature. The reaction is stopped with 100 μl "Detection Mix" per well. The plates are then sealed with plastic, shaken for 30 minutes, allowed to stand overnight, and finally the radioactivity is counted in the Cobra Il auto gamma topcounter. EC50 values are calculated by non-linear regression analysis of dose response curves (6 points minimum) using GraphPad Prism. Kb values are calculated by Schild plot analysis.
Preferably, the antagonists and agonists according to the invention have an IC5o/EC5o value of less than 10 μM, more preferred of less than 1 μM, and even more preferred of less than 500 nM, such as of less than 100 nM.
Functional assay Il
The ability of the compounds to bind and interact with the human H3 receptor as agonists, inverse agonists and/or antagonists, is determined by a functional assay, named [35S] GTPγS assay. The assay measures the activation of G proteins by catalyzing the exchange of guanosine 5'-diphosphate (hereinafter designated GDP) by guanosine 5'-triphosphate (hereinafter designated GTP) at the α-subunit. The GTP-bounded G proteins dissociate into two subunits, G GTP and G , which in turn regulate intracellular enzymes and ion channels. GTP is rapidly hydrolysed by the G -subunit (GTPases) and the G protein is deactivated and ready for a new GTP exchange cycle. To study the function of ligand induced G protein coupled receptor (GPCR) activation by an increase in guanine nucleotide exchange at the G proteins, the binding of [35S]-guanosine-5'-O-(3-thio) triphosphate
(hereinafter designated [35S] GTP S), a non-hydrolysed analogue of GTP, is determined. This process can be monitored in vitro by incubating cell membranes containing the G protein coupled receptor H3 with GDP and [35S] GTPγS. Cell membranes are obtained from CHO cells stably expressing the human H3 receptor. The cells are washed twice in PBS, harvested with PBS + 1 mM EDTA, pH 7.4 and centrifuged at 1000 rpm for 5 minutes. The cell pellet is homogenized in 10 ml ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA, pH 7.4 (NaOH)) using an Ultra-Turrax homogenizer for 30 seconds and centrifuged for 15 minutes at 20,000 rpm. Following this centrifugation step, the membrane pellet is resuspended in 10 ml ice-cold Hepes buffer (20 mM Hepes, 0.1 mM EDTA, pH 7.4 (NaOH)) and homogenized as describe above. This procedure is repeated twice except for the last homogenization step, the protein concentration is determined and membranes are diluted to a protein concentration at 2 mg/ml, aliquoted and kept at -80 0C until use.
In order to study the presence and the potency of an inverse agonist/antagonist, the H3-receptor agonist ligand R-α-methyl histamine (hereinafter designated RAMHA) is added. The ability of the test compound to counteract the effect of RAMHA is measured. When studying the effect of an agonist, RAMHA is not added to the assay medium. The test compound is diluted in the assay buffer (20 mM HEPES, 120 mM NaCI, 10 mM MgCI2 pH 7.4 (NaOH)) at various concentrations followed by addition of 10 8 nM RAMHA (only in the case where an inverse agonist/antagonist is examined), 3 μM GDP, 2.5 μg membranes, 0.5 mg SPA beads and 0.1 nM [35S] GTPγS and incubated for 2 hours by slightly shaking at room temperature. The plates are centrifuged at 1500 rpm for 10 minutes and the radioactivity is measured using a Top-counter. The results are analyzed by non linear regression and the IC50 value is determined. RAMHA and other H3 agonists stimulate the binding of [35S] GTPyS to membranes expressing the H3 receptor. In the antagonist/inverse agonist test, the ability of increasing amounts of test compound to inhibit the increased [35S] GTPyS binding by 10 8 M RAMHA is measured as a decrease in radioactivity signal. The IC50 value determined for an antagonist is the ability of this compound to inhibit the effect of 10 8M RAMHA by 50%. In the agonist test, the ability of increasing amounts of test compound is measured as an increase in radioactivity signal. The EC50 value determined for an agonist, is the ability of this compound to increase the signal by 50% of the maximal signal that is obtained by 10 5 M RAMHA.
Preferably, the antagonists and agonists according to the invention have an IC5o/EC5o value of less than 10 μM, more preferred of less than 1 μM, and even more preferred of less than 500 nM, such as of less than 100 nM.
Test of food intake inhibition
In this type of test rats are acclimatized to the experimental environment for 1 -2 weeks before the start of experiments. About 7-10 days before recording of food intake access to food is restricted to 5-7 hours per day. Water remains freely available. On the test day, groups (n=10) of animals receive single administrations of histamine H3 receptor antagonists shortly before presentation of food. After this, food consumption is recorded for 3 h. Preferred compounds are those that produce a statistically significant reduction of 3-hour cumulated food intake. More preferred compounds are those that decrease 3-hour cumulated food intake with 10-20 % and the most preferred compounds reduce 3-cumulated food intake with more than 20% without sedation of the animals.
Test of body weight reduction This test is carried out in rats that have become obese due to over-consumption of dietary energy, i.e. a sustained positive energy balance. Animals are being exposed to the test compound for 7 days. Preferred compounds are those that produce a statistically significant decrease of body weigh compared with control rats given vehicle. More preferred compounds are those that produce a weight reduction of at least 4%, compared with the vehicle control group, and the most preferred compounds are those that reduce body weight with more than 8% compared with vehicle control rats.
GENERAL COMMENTS
All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).
All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and/or enforceability of such patent documents. The mentioning herein of references is no admission that they constitute prior art.
Herein, the word "comprise" is to be interpreted broadly meaning "include", "contain" or "comprehend" (EPO guidelines C 4.13). This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.
GENERAL EXPERIMENTAL PROCEDURES NMR spectra were recorded at 300 and 400 MHz on a Bruker DRX300, Avance 300,
DRX400 or AV400 instrument equipped with 5 mm selective-inverse (SEI, 1H and 13C), 5 mm broad-band inverse (BBI, 1H, broad-band) and 5 mm quadro nuclear (QNP, 1H, 13C) probe- heads, respectively. Shifts (δ) are given in parts per million (ppm) down field from tetrame- thylsilane as internal reference standard. HPLC Method A. The RP-analyses was performed on a Merck-Hitachi series 7000 system (Merck-Hitachi pump L-7100 and Merck-Hitachi autosampler L-7200 or Rheodyne sample injector) using a Hibar™ RT 250-4, Lichrosorb™ RP-18, 5.0 μm, 4.0 x 250 mm; gradient elution, 20 % to 80 % solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 30 min, 1 .0 ml/min, detection at 210 nm, temperature 300C. HPLC Method B. The RP-purification was performed on a Gilson system (3 Gilson
306 pumps, Gilson 170 DAD detector and a Gilson 215 liquid handler) using a Waters XTerra® Prep RPi8 (10 μm, 30 mm x 150 mm) with gradient elution, 5% to 95% solvent B (acetonitrile) in solvent A (0.05% TFA in water) within 15 min, 40 mL/min, detection at 210 nm, temperature rt. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the acetonitrile is removed, and then frozen and freeze dried.
HPLC Method C. The RP-analyses was performed on a Shimadzu LC-20 using a YMC-ODS, 5.0 μm, 4.6 x 50 mm; gradient elution, 0 % to 30 % solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 6 min, and then kept for 2 min, 2.5 ml_/min, detection at 220 nm, temperature 300C. HPLC Method D. The RP-analyses was performed on a Shimadzu LC-20 using a
YMC-ODS, 5.0 μm, 4.6 x 50 mm; gradient elution, 0 % to 60 % solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 8 min, and then kept for 2 min, 2.5 ml_/min, detection at 220 nm, temperature 300C.
HPLC Method E. The RP-analyses was performed on a Shimadzu using a YMC- ODS, 5.0 μm, 4.6 x 50 mm; gradient elution, 10 % to 80 % solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 6 min, and then kept for 2 min, 2.5 ml_/min, detection at 220 nm, temperature 300C.
HPLC Method F. The RP-purification was performed on a Gilson Nebula Series system using a Luna, 5 μm, 21 .2 mm x 250 mm with gradient elution, 5% to 30% solvent B (0.1 % TFA in acetonitrile) in solvent A (0.1 % TFA in water) within 15 min, 80 mL/min, detec- tion at 220 nm, temperature 250C, injection volume 30 ml_. The pooled fractions were evaporated in vacuo until acetonitrile was removed, and then frozen and dried.
HPLC-MS Method G. Column: Waters Xterra MS C-18 X 3 mm id. Buffer: Linear gradient 5% - 95% in 4 min, acetonitrile, 0.01 % TFA, flow rate 1 .0 ml/min. Detection 210 nm (analog output from diode array detector), MS-detection ionisation mode API-ES, scan 100- 1000 amu step 0.1 amu.
Microwave Synthesis. When microwave oven synthesis was applied, the reaction was heated by microwave irradiation in sealed microwave vessels in a single mode Emrys Optimizer EXP from PersonalChemistry®.
The examples below and the general procedures described herein refer to intermediate compounds and final products for general formula I identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula I of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases, the reactions can be successfully performed by conventional modifications known to those skilled in the art which is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may be prepared by a person skilled in the art in analogy with the preparation of similar known compounds or by the General Procedures A through N described herein. The following examples are offered by way of illustra- tion, not by limitation.
General Procedure A
Compounds of the formula I, wherein Y and/or W is -N=, and A, X, Z, and R1 each is as defined for formula I, which compounds here are designated formula Ia, can be prepared as outlined below:
Figure imgf000058_0001
(A-1) (A-2) An amine of formula A-1 , wherein R1 is as defined herein, may be reacted with a halogen substituted heteroaryl of the formula A-2 wherein A, X, Y, Z, and W each is as defined herein, and Hal represents chlorine or bromine, to give a compound of formula Ia. This reaction may be carried out in a suitable solvent like, for example, dimethylsulfoxide, at a tem- perature of up to reflux. Compounds of formula A-2 may be prepared according to known procedures described in, for example, WO 03/066604A2, Tetrahedron 2000, 56, 9655-9662, and Tetrahedron Lett. 2001 , 42, 2779-2781.
General procedure B Compounds of the formula I, wherein A is aryl or heteroaryl optionally substituted with R- (C=O)NHCH2-, and X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula Ib, can be prepared as outlined below:
Figure imgf000059_0001
(B-1) (B-2)
An amine of formula B-2, wherein X, Y, Z, W and R1 each is as defined herein, and A repre- sents an aryl or heteroaryl group, may be acylated with an activated carboxylic acid derivative to give a compound of formula Ib. Such an activated carboxylic acid derivative can be a carboxylic acid chloride or anhydride of formula B-4 or B-3, respectively. This reaction may be carried out in a suitable solvent like, for example, dichloromethane or acetic acid, at a temperature of up to reflux. A carboxylic acid of formula B-5 may also be reacted with an amine of formula B-2 to give an amide of formula Ib. This reaction may be carried out by activation of the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent like, for example, THF and at a temperature of up to reflux. Compounds of formula B-2 may be prepared by hydrogenation of a nitril of formula B-1 , wherein X, Y, Z, W and R1 is as defined herein, and A represents an aryl or heteroaryl group. This reaction may be carried out in a suitable solvent like, for example, THF, at a temperature of up to reflux in the presence of a reducing agent like, e.g., LiAIH4. Compounds of formula B-1 may be may be prepared according to other General Procedure(s) described herein.
General procedure C Compounds of the formula I, wherein A is aryl or heteroaryl, and X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula Ic, can be prepared as outlined below:
Figure imgf000060_0001
(C-1) (C-2)
A hydroxyamidine of formula C-2, wherein X, Y, Z, W and R1 each is as defined herein, and A represents an aryl or heteroaryl group, may be reacted with a carboxylic acid chloride or anhydride of formula C-3 to give a compound of formula Ic. This reaction may be carried out in a suitable solvent like, e.g., Λ/,Λ/-dimethylacetamide or acetic acid, at a temperature of up to reflux. Compounds of formula C-2 may be prepared by reaction of a nitril of formula C-1 , wherein X, Y, Z, W and R1 is as defined herein, and A represents an aryl or heteroaryl group, with hydroxylamine. This reaction may be carried out in a suitable solvent like, for example, ethanol and water, at a temperature of up to reflux in the presence of a base like, for example, potassium carbonate. Compounds of formula C-1 may be may be prepared according to other General Procedure(s) described herein.
General procedure D
Compounds of the formula I, wherein X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula Id, can be prepared as outlined below:
Figure imgf000060_0002
(D-1) (D-2) A hydroxyamidine of formula D-2, wherein X, Y, Z, W and R1 is as defined herein, may be reacted with a carboxylic acid chloride or anhydride of formula D-3 to give a compound of formula Id. This reaction may be carried out in a suitable solvent like, for example, N,N-di- methylacetamide or acetic acid, at a temperature of up to reflux. Compounds of formula D-2 may be prepared by reaction of a nitril of formula D-1 , wherein X, Y, Z, W and R1 each is as defined herein, with hydroxylamine. This reaction may be carried out in a suitable solvent like, for example, ethanol and water, at a temperature of up to reflux in the presence of a base like, for example, potassium carbonate.
General procedure E
Compounds of the formula I, wherein X, Y, Z, W, and R1 are as defined for formula I, which compounds here are designated formula Ie, can be prepared as outlined below:
Figure imgf000061_0001
A benzylhalogenide of formula E-1 , wherein X, Y, Z, W and R1 each is as defined herein, and Hal represents chlorine, bromine or iodine, may be reacted with an amine of formula E-2 to give a compound of formula Ie. This reaction may be carried out in a suitable solvent like, for example, ethanol, at a temperature of up to reflux and in the presence of a base like, for example, triethylamine, or excess of the amine of formula E-2. Compounds of formula E-1 may be prepared according to the General Procedure D described above.
General procedure F
Compounds of the formula I, wherein R11 is represented by R11a-CH-R11 b, and q, A, X, Y, W and Z each is as defined for formula I, which compounds here are designated formula If, can be prepared as outlined below:
Figure imgf000061_0002
A carbonyl compound of formula F-1 , wherein R11a and R11 b each is as defined herein, may be reacted with an amine of the formula F-2, wherein q, A, X, Y, Z, and W are as defined herein, in the presence of a reducing agent, to give a compound of formula If. This reaction may be carried out in a suitable solvent like, for example, tetrahydrofuran or 1 ,2-dichloro- ethane, at a temperature of up to reflux. The reducing agent may be, for example, NaCNBH3 or NaBH(OAc)3, eventually in the presence of a acidic catalyst like, for example, acetic acid. Compounds of formula F-2 may be may be prepared according to other General Proce- dure(s) described herein.
General procedure G
Compounds of the formula I, wherein A is aryl or heteroaryl optionally substituted with a group of the general formula R-(C=O)-, and R, X, Y, Z, W, and R1 each is as defined for for- mula I, which compounds here are designated formula Ig, can be prepared as outlined below:
Figure imgf000062_0001
(G-1) (G"3)
A cyano compound of formula G-1 , wherein X,Y,Z, W and R1 is as defined herein, and A represents an aryl or heteroaryl group, may be reacted with a organometallic compound of formula G-2 or G-3, followed by acidic hydrolysis with, for example, aqueous hydrochloric acid, to give a compound of formula Ig. This reaction may be carried out in a suitable solvent like, for example, tetrahydrofuran or tetrahydrofuran/toluene, at a temperature of up to reflux. Compounds of formula G-1 may be may be prepared according to other General Procedure^) described herein.
General procedure H
Compounds of the formula I, wherein R11, q, A, X, Y, W and Z are as defined for formula I, which compounds here are designated formula Ih, can be prepared as outlined below:
Figure imgf000062_0002
(H-1) A compound of formula H-1 , wherein Hal represents chlorine, bromine or iodine, may be reacted with an amine of the formula H-2, wherein q, A, X, Y, Z, and W are as defined herein, to give a compound of formula Ih. This reaction may be carried out in a suitable solvent like, for example, dimethylformamide, dimethylsulfoxide, acetonitril or 2-butanone, at a tempera- ture of up to reflux. The reaction may be carried out in the presence of a base such as, for example, sodium hydride, potassium carbonate or Λ/,Λ/-diisopropylethylamine, and a catalyst like, for example, potassium iodide. Compounds of formula H-2 may be may be prepared according to other General Procedure(s) described herein.
General procedure I
Compounds of the formula I, wherein A, X, Y, W, Z and R1 each is as defined for formula I, which compounds here are designated formula Ii, can be prepared as outlined below:
Figure imgf000063_0001
(1-1) (I-2)
A compound of formula 1-1 , wherein X, Y, W, Z and R1 each is as defined herein, and Hal represents chlorine, bromine or iodine, may be reacted with a boronic acid derivative of the formula I-2, or a corresponding boronic acid ester derivative, wherein A is as defined herein, to give a compound of formula Ii. This reaction may be carried out in a suitable solvent like, for example, acetonitrile/water, at a temperature of up to 1500C in the presence of a suitable catalyst like, for example, bistriphenylphosphinpalladium(ll)dichloride and sodium carbonate. This reaction may also be performed in the other way round starting from reactants wherein the halogen and boronic acid moieties have been interchanged. This reaction may be carried out under similar conditions as described above.
General procedure J
Compounds of the formula I, wherein A is aryl or heteroaryl optionally substituted with -C(=O)-NR'R, and X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula Ij, can be prepared as outlined below:
Figure imgf000064_0001
(J-1) (J-2)
A carboxylic acid of formula J-2, wherein A, X, Y, Z, W, and R1 each is as defined herein, may be reacted with an amine of formula R'RNH to give an amide of formula Ij. This reaction may be carried out by activation of the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent like, for example, THF and at a temperature of up to reflux. A carboxylic acid of formula J-2 may be prepared by hydrolysis of a nitrile of formula J-1 , wherein A, X, Y, Z, W, and R1 each is as defined herein. This reaction may be carried out under strong acidic conditions, for example, in 6 N hydrochloric acid at a temperature of up to reflux. Compounds of formula J-1 may be prepared according to other General Procedure(s) described herein.
General procedure K
Compounds of the formula I, wherein A is aryl or heteroaryl optionally substituted with -CH2-NR1R, and X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula Ik, can be prepared as outlined below:
Figure imgf000064_0002
(K-1 ) (K-2)
A carboxaldehyde of formula K-2, wherein A, X, Y, Z, W, and R1 each is as defined herein, may be reacted with an amine of formula R'RNH under reducing conditions to give an amine of formula Ik. This reaction may be carried out in a suitable solvent like, for example, tetrahy- drofuran or 1 ,2-dichloroethane, at a temperature of up to reflux. The reducing agent may be, for example, NaCNBH3 or NaBH(OAc)3, eventually in the presence of a acidic catalyst like, for example, acetic acid. A carboxaldehyde of formula K-2 may be prepared from a nitrile of formula K- 1 , wherein A, X, Y, Z, W, and R1 each is as defined herein. This reaction may be carried out in the presence of a reducing agent, for example, DIBAL-H or LiAIH4 in a suitable solvent, for example, THF at a temperature from - 40 0C up to reflux. Compounds of formula K- 1 may be prepared according to other General Procedure(s) described herein. General procedure L
Compounds of the formula I, wherein A is aryl or heteroaryl optionally substituted with R-C(=O)NH-, and X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula II, can be prepared as outlined below:
Figure imgf000065_0001
M) (L-2)
An aromatic amine of formula L-2, wherein X, Y, Z, W and R1 each is as defined herein, and A represents an aryl or heteroaryl group, may be acylated with an activated carboxylic acid derivative to give a compound of formula II. Such an activated carboxylic acid derivative can be a carboxylic acid chloride or anhydride of formula L-4 or L-3, respectively. This reaction may be carried out in a suitable solvent like, for example, dichloromethane or acetic acid, at a temperature of up to reflux. A carboxylic acid of formula L-5 may also be reacted with an amine of formula L-2 to give an amide of formula II. This reaction may be carried out by activation of the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent like, for ex- ample, THF and at a temperature of up to reflux. Compounds of formula L-2 may be prepared by hydrogenation of a nitro compound of formula L-1 , wherein X, Y, Z, W and R1 is as defined herein, and A represents an aryl or heteroaryl group. This reaction may be carried out in a suitable solvent like, for example, ethanol and/or water, at a temperature of up to reflux in the presence of a reducing agent, for example, Fe powder. Other reducing conditions may be hydrogenation with hydrogen gas in the presence a suitable catalyst, for example, Pd/C at a pressure up to 3000 psi. Compounds of formula L-1 may be may be prepared according to other General Procedure(s) described herein.
General procedure M
Compounds of the formula I, wherein A is aryl or heteroaryl optionally substituted with R-(CH)2-O-, and X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula Im, can be prepared as outlined below:
Figure imgf000066_0001
(M-1)
An aromatic alcohol of formula M-1 , wherein X, Y, Z, W and R1 each is as defined herein, and A represents an aryl or heteroaryl group, may be alkylated with a compound of formula M-2, wherein LG represents a suitable leaving group such as, for example, halogen or mesy- late. This reaction may be carried out in a suitable solvent like, for example, DMF, at a temperature of up to reflux and in the presence of a base like, for example, sodium hydride. Compounds of formula M-1 may be may be prepared according to other General Procedure^) described herein.
General procedure N Compounds of the formula I, wherein A is aryl or heteroaryl optionally substituted with a cyclic sulphonamide and wherein p is 1 -4, and X, Y, Z, W, and R1 each is as defined for formula I, which compounds here are designated formula In, can be prepared as outlined below:
Figure imgf000066_0002
(N-1 ) (N-3) An aromatic amine of formula N-1 , wherein X, Y, Z, W and R1 each is as defined herein, and
A represents an aryl or heteroaryl group, may be reacted with an activated sulfonic acid of formula N-2, wherein p is 1 -4 and LGi and LG2 represents suitable leaving groups such as, for example, halogen, to give a compound of formula N-3. This reaction may be carried out in a suitable solvent like, for example, DMF, at a temperature of up to reflux and in the pres- ence of a base like, for example, TEA. A compound of formula N-3 may be ring-closed to give a compound of formula In. This reaction may be carried out in a suitable solvent like, for example, DMF, at a temperature of up to reflux and in the presence of a base like, for exam- pie, NaH. Compounds of formula N-1 may be may be prepared according to other General Procedure(s) described herein.
Example 1 (General procedure A)
1 -[5-(4-Chlorophenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride
Figure imgf000067_0001
A mixture of 2-chloro-5-(4-chlorophenyl)pyridine (500 mg, 2.23 mmol), DMSO (2.0 ml_) and 1 -isopropylpiperazine (3 ml_, 23.4 mmol) was stirred and heated on a 1000C oil-bath over- night. The reaction mixture was poured into water (75 ml_), and the solid was isolated by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel (Kiselgel 60, mesh 0.040-0.63) eluting with a mixture of ethyl acetate and methanol (4:1 ). Collecting the proper fractions afforded 600 mg (85 %) of 1 -[5-(4-chloro- phenyl)pyridin-2-yl]-4-isopropylpiperazine. 1H NMR (300 MHz, CDCI3) δ 1 .10 (d, 6H), 2.63-2.68 (m, 4H), 2.75 (hept, 1 H), 3.59-3.66 (m, 4H), 6.69 (d, 1 H), 7.35-7.45 (m, 4H), 7.67 (dd, 1 H), 8.40 (d, 1 H).
The free base was dissolved into a mixture of a 0.5 N hydrochloric acid solution and ethanol. When dissolved, the mixture was evaporated and then re-evaporated with ethanol. The solid residue was recrystallized from ethanol (50 ml_) to give 740 mg (81 %) of 1 -[5-(4-chloro- phenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride.
1H NMR (300 MHz, DMSO-^6) δ 1 .32 (d, 6H), 3.05-3.22 (m, 2H), 3.45-3.67 (m, 5H), 4.49- 4.61 (m, 2H), 4.9 (brs, 6H), 7.23-7.31 (m, 1 H), 7.52 (d, 2H), 7.73 (d, 2H), 8.13-8.19 (m, 1 H), 8.42-8.46 (m, 1 H), 1 1.4 (brs, 1 H). Microanalysis for C18H22CIN3, 2 x HCI, 2.5 x H2O: Calculated: C: 49.84%; H: 6.74%; N: 9.69%;
Found: C: 49.82%; H: 6.66%, N: 9.36%.
Example 2 (General procedure A) 1 -lsopropyl-4-[5-(4-methoxyphenyl)pyridin-2-yl]piperazine, dihydrochloride
Figure imgf000068_0001
A mixture of 2-chloro-5-(4-methoxyphenyl)pyridine (200 mg, 0.91 mmol), dry DMSO (2.0 ml_) and 1 -isopropylpiperazine (500 mg, 3.9 mmol) was stirred and heated on a 1300C oil-bath overnight, then at 1500C for 4 h, left 2 days at rt and finally heated at 1400C overnight. The reaction mixture was allowed to cool and then poured into water (100 ml_). The mixture was extracted with ethyl acetate (100 ml_), and the organic extract was washed with water and dried (MgSO4). The solvent was evaporated to give a solid residue which was dissolved into 0.5 N hydrochloric acid (20 ml_). A small insoluble solid was removed by filtration, and the aqueous solution was evaporated to give a residue which was re-evaporated with absolute ethanol. The resulting solid was re-crystallised from absolute ethanol to give 210 mg (60 %) of 1 -[5-(4-methoxyphenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride. 1H NMR (400 MHz, CDCI3) δ 1 .51 (d, 6H), 3.23-3.34 (m, 2H), 3.49-3.59 (m, 1 H), 3.60-3.67 (m, 2H), 3.86 (s, 3H), 4.30-4.40 (m, 2H), 4.64-4.71 (m, 2H), 7.00 (d, 2H), 7.19 (d, 1 H), 7.43 (d, 2H), 8.20 (d, 1 H), 8.31 (s, 1 H), 12.9 (brs, 1 H). Microanalysis for Ci9H25N3O, 2 x HCI, 3 x H2O: Calculated: C: 52.06%; H: 7.59%; N: 9.58%;
Found: C: 51.99%; H: 7.47%, N: 9.21 %.
Example 3 (General procedure A) 1 -lsopropyl-4-[5-(4-trifluoromethoxyphenyl)pyridin-2-yl]piperazine, dihydrochloride
Figure imgf000068_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethoxyphenyl)pyridine and 1 -isopropylpiperazine. Mp = 271 -2730C. 1H NMR (300 MHz, DMSO-Cf6) δ 1 .32 (d, 6H), 3.05-3.21 (m, 2H), 3.45-3.67 (m, 5H), 4.50- 4.61 (m, 2H), 7.28 (d, 1 H), 7.46 (d, 2H), 7.82 (d, 2H), 8.17 (d, 1 H), 8.46 (s, 1 H), 11 .4 (brs, 1 H).
Microanalysis for Ci9H22F3N3O, 2 x HCI: Calculated: C: 52.06%; H: 5.52%; N: 9.59%;
Found: C: 52.07%; H: 5.53%, N: 9.36%.
Example 4 (General procedure A)
1 -{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}ethanone, dihydrochloride
Figure imgf000069_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-acetylphenyl)pyridine and 1 -isopropylpiperazine.
Mp = 288-2900C.
1H NMR (300 MHz, DMSO-c(6) δ 1 .32 (d, 6H), 2.61 (s, 3H), 3.05-3.22 (m, 2H), 3.40-3.67 (m, 5H), 4.51 -4.62 (m, 2H), 7.27 (d, 1 H), 7.86 (d, 2H), 8.03 (d, 2H), 8.22 (d, 1 H), 8.55 (s, 1 H),
1 1 .4 (brs, 1 H).
Microanalysis for C20H25N3O, 2 x HCI, 1 .25 x H2O:
Calculated: C: 57.35%; H: 7.10%; N: 10.03%;
Found: C: 57.06%; H: 7.05%, N: 9.78%.
Example 5 (General procedure A)
1 -[5-(2,6-Difluorophenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride
Figure imgf000069_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(2,6-difluorophenyl)pyridine and 1 -isopropylpiperazine. 1H NMR (300 MHz, DMSO-Cf6) δ 1 .33 (d, 6H), 3.05-3.20 (m, 2H), 3.44-3.65 (m, 5H), 4.50- 4.60 (m, 2H), 7.19-7.31 (m, 3H), 7.43-7.54 (m, 1 H), 7.88 (d, 1 H), 8.24 (s, 1 H), 11 .4 (brs, 1 H). Microanalysis for C18H21F2N3, 2 x HCI, 0.5 x H2O: Calculated: C: 54.14%; H: 6.06%; N: 10.52%; Found: C: 54.02%; H: 6.04%, N: 10.25%.
Example 6 (General procedure A)
1 -[5-(4-Fluorophenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride
Figure imgf000070_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-fluorophenyl)pyridine and 1 -isopropylpiperazine. 1H NMR (300 MHz, DMSO-Cf6) δ 1 .32 (d, 6H), 3.06-3.20 (m, 2H), 3.45-3.67 (m, 5H), 4.49- 4.59 (m, 2H), 7.25-7.35 (m, 3H), 7.70-7.77 (m, 2H), 8.15 (d, 1 H), 8.40 (s, 1 H), 11 .4 (brs, 1 H). Microanalysis for C18H22FN3, 2 x HCI, 3.5 x H2O: Calculated: C: 49.66%; H: 7.18%; N: 9.65%;
Found: C: 50.01 %; H: 7.05%, N: 9.47%.
Example 7 (General procedure A) 1 -[5-(3-Fluorophenyl)pyridin-2-yl]-4-isopropylpiperazine, hydrochloride
Figure imgf000070_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(3-fluorophenyl)pyridine and 1 -isopropylpiperazine. 1H NMR (300 MHz, DMSO-Cf6) δ 1 .32 (d, 6H), 2.99-3.14 (m, 2H), 3.36-3.67 (m, 5H), 4.45- 4.55 (m, 2H), 7.06-7.19 (m, 2H), 7.43-7.57 (m, 3H), 8.02 (d, 1 H), 8.55 (s, 1 H), 11 .0 (brs, 1 H). Microanalysis for C18H22FN3, HCI, 0.5 x H2O:
Calculated: C: 62.69%; H: 7.01 %; N: 12.18%; Found: C: 62.93%; H: 6.88%, N: 1 1 .91 %.
Example 8 (General procedure A) 1 -[5-(2-Fluorophenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride
Figure imgf000071_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(2-fluorophenyl)pyridine and 1 -isopropylpiperazine. 1 H NMR (300 MHz, DMSO-Cf6) δ 1 .33 (d, 6H), 3.06-3.22 (m, 2H), 3.44-3.69 (m, 5H), 4.50- 4.61 (m, 2H), 7.25-7.48 (m, 4H), 7.59 (t, 1 H), 7.82 (d, 2H), 8.03 (d, 1 H), 8.31 (s, 1 H), 1 1 .4 (brs, 1 H).
Microanalysis for Ci8H22FN3, 2 x HCI:
Calculated: C: 58.07%; H: 6.50%; N: 1 1 .29%;
Found: C: 58.16%; H: 6.61 %, N: 10.94%.
Example 9 (General procedure A)
1 -{4-[6-(4-Cyclopentylpiperazin-1 -yl)pyridin-3-yl]phenyl}ethanone, dihydrochloride
Figure imgf000071_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-acetylphenyl)pyridine and 1 -cyclopentylpiperazine. 1 H NMR (300 MHz, DMSO-^6) δ 1 .47-1 .63 (m, 2H), 1 .68-1 .95 (m, 4H), 1 .96-2.09 (m, 2H),
2.61 (s, 3H), 3.03-3.19 (m, 2H), 3.44-3.65 (m, 5H), 4.47-4.57 (m, 2H), 7.23 (d, 1 H), 7.85 (d,
2H), 8.03 (d, 2H), 8.19 (d, 1 H), 8.56 (s, 1 H), 1 1 .5 (brs, 1 H).
Microanalysis for C22H27N3O, 2 x HCI, 2 x H2O:
Calculated: C: 57.64%; H: 7.26%; N: 9.17%; Found: C: 58.06%; H: 7.23%, N: 9.10%. Example 10 (General procedure A) 4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzonitrile, dihydrochloride
Figure imgf000072_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-cyanophenyl)pyridine and 1 -isopropylpiperazine. 1H NMR (300 MHz, DMSO-Cf6) δ 1 .32 (d, 6H), 3.04-3.19 (m, 2H), 3.46-3.66 (m, 5H), 4.52- 4.62 (m, 2H), 5.05 (brs, 6 H), 7.24 (d, 1 H), 7.91 (s, 4H), 8.19 (dd, 1 H), 8.56 (d, 1 H), 11 .4 (brs, 1 H).
Microanalysis for Ci9H22N4, 2 x HCI, 2.5 x H2O: Calculated: C: 53.78%; H: 6.89%; N: 13.20%;
Found: C: 53.51 %; H: 6.82%, N: 12.59%.
Example 11 (General procedure A)
(4-(2-Pyrrolidin-1 -ylethyl)piperidin-1 -yl)-5-(4-trifluoromethylphenyl)pyridine, hydrochloride
Figure imgf000072_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 4-(2-pyrrolidinoethyl)piperidine. Mp = 166-1680C.
1H NMR (300 MHz, CDCI3) δ 1 .35-2.31 (m, 11 H), 2.76-2.97 (m, 2H), 3.10-3.26 (m, 2H), 3.38 (t, 2H), 3.69-3.87 (m, 2H), 4.48-4.67 (m, 2H), 7.15 (d, 1 H), 7.64 (d, 2H), 7.73 (d, 2H), 8.09 (d, 1 H), 8.41 (s, 1 H), 12.2 (brs, 1 H), 15.5 (brs, 1 H).
Example 12 (General procedure A) 1 -(3-Piperidin-1 -ylpropyl)-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine, dihydrochlo- ride
Figure imgf000073_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 1 -(3-piperidinopropyl)- piperazine.
HPLC (Method A): tr = 12.05 min (100 %).
Example 13 (General procedure A) 1 '-[6-(4-Methanesulfonylphenyl)pyridazin-3-yl]-[1 ,4']bipiperidinyl
Figure imgf000073_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-methanesulfonylphenyl)pyridazine and 4-(piperid-1 -yl)piperidine. 1H NMR (400 MHz, CDCI3) δ 1 .24 (t, J=6.82 Hz, 1 H), 1 .38-1.51 (m, 2H), 1 .52-1 .69 (m, 5H, 1 .98 (d, J=12.63 Hz, 2H), 2.47-2.63 (m, 4H), 2.95-3.07 (m, 2H), 3.09 (s, 3H), 3.72 (q, J=7.07 Hz, 1 H), 4.56 (d, J=13.14 Hz, 2H), 7.01 (d, J=9.60 Hz, 1 H), 7.67 (d, J=9.60 Hz, 1 H), 8.02 (d, J=8.59 Hz, 2H), 8.20 (d, J=8.59 Hz, 2H). Microanalysis for C2IH28N4O2S, 0.25 x H2O: Calculated: C: 62.27%; H: 7.09%; N: 13.83%;
Found: C: 61.85%; H: 6.84%; N: 13.49%.
Example 14 (General procedure A)
Dimethyl-(3-{4-[6-(4-trifluoromethylphenyl)pyridazin-3-yl]piperazin-1 -yl}propyl)amine, dihy- drochloride
Figure imgf000074_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (3-dimethylaminoprop-1 - yl)piperazine. 1H NMR (400 MHz, D2O) δ 2.06-2.35 (m, 2H), 2.85 (s, 5H), 3.13-3.23 (m, 2H), 3.23-3.32 (m, 2H), 3.49 (s, 3H), 4.70 (s, 7H), 7.68 (d, J=10.1 1 Hz, 1 H), 7.78 (d, J=8.59 Hz, 2H), 7.90 (d, J=8.59 Hz, 2H), 8.08 (d, J=9.60 Hz, 1 H). Microanalysis for C20H26N5F3, 2 x HCI, 2.75 x H2O: Calculated: C: 46.56%; H: 6.54%; N: 13.57%; Found: C: 46.53%; H: 6.35%; N: 13.32%.
Example 15 (General procedure A) 3-[4-(1 -Methylpiperidin-3-ylmethyl)piperazin-1 -yl]-6-(4-trifluoromethylphenyl)pyridazine
Figure imgf000074_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (1 -methylpiperidin-3-yl- methyl)piperazine.
1H NMR (400 MHz, DMSO-^6) δ 1 .12-1 .31 (m, 1 H), 1 .71 -2.01 (m, 2H), 2.54-2.97 (m, 4H), 3.04-3.33 (m, 3H), 3.40 (d, J=10.61 Hz, 1 H), 3.53-3.86 (m, 9H), 4.62 (brs, 1 H), 7.78 (d, J=10.11 Hz, 1 H), 7.91 (d, J=8.08 Hz, 2H), 8.23-8.37 (m, 3H).
Example 16 (General procedure A)
3-[4-(1 -Methylpiperidin-4-ylmethyl)piperazin-1 -yl]-6-(4-trifluoromethylphenyl)pyridazine, dihy- drochloride
Figure imgf000075_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (1 -methylpiperidin-4-yl- methyl)piperazine. 1H NMR (400 MHz, DMSO-Cf6) δ 1 .48-1 .64 (m, 2H), 2.05-2.20 (m, 3H), 2.68-2.79 (m, 3H), 2.94 (t, J=11 .87 Hz, 2H) 3.06-3.25 (m, 4H) 3.69 (d, J=12.13 Hz, 4H) 4.58 (d, J=13.64 Hz, 2H) 7.65 (d, J=9.60 Hz, 1 H) 7.89 (d, J=8.59 Hz, 2H) 8.23 (d, J=9.60 Hz, 1 H) 8.29 (d, J=8.08 Hz, 2H).
Microanalysis for C22H28N5F3, 2 x HCI, 2.75 x H2O: Calculated: C: 48.85%; H: 6.43%; N: 12.95%
Found: C: 49.00%; H: 6.23%; N 12.80%.
Example 17 (General procedure A) 4-{6-[4-(1 -Methylpiperidin-4-ylmethyl)piperazin-1 -yl]pyridazin-3-yl}benzonitrile, hydrochloride
Figure imgf000075_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-cyanophenyl)pyridazine and (1 -methylpiperidin-4-ylmethyl)- piperazine.
1H NMR (400 MHz, D2O) δ 1 .45-1 .62 (m, 2H), 2.06 (d, J=14.15 Hz, 2H), 2.17-2.32 (m, 1 H), 2.74-2.84 (m, 3H), 2.98 (t, 1 H), 3.19 (d, J=7.07 Hz, 2H), 3.25-3.63 (m, 7H), 3.80-4.30 (broad m, 3H), 7.66 (d, 1 H), 7.78 (d, 2H), 7.87 (d, 2H), 8.06 (d, J=10.11 Hz, 1 H).
Example 18 (General procedure A)
4-{6-[4-(1 -Methylpiperidin-3-ylmethyl)piperazin-1 -yl]pyridazin-3-yl}benzonitrile, trihydrochlo- ride
Figure imgf000076_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-cyanophenyl)pyridazine and (1 -methylpiperidin-3-ylmethyl)- piperazine. 1H NMR (400 MHz, D2O) δ 1 .30 (m, 1 H), 1 .74 (m, 1 H), 1 .99 (m, 2H), 2.41 (dd, J=6.82, 3.28 Hz, 1 H), 2.84 (m, 5H), 3.21 (d, J=6.57 Hz, 2H), 3.49 (m, 6H), 4.03 (m, 4H), 7.81 (m, 3H) 7.91 (d, 2H), 8.17 (d, J=9.60 Hz, 1 H). Microanalysis for C22H28N6, 3 x HCI, 3.75 x H2O: Calculated: C: 47.75%; H: 7.01 %; N: 15.18% Found: C: 47.99%; H: 6.96%; N: 15.01%.
Example 19 (General procedure A)
(S)-3-(4-Butylsulfanylphenyl)-6-(2-pyrrolidin-1 -ylmethylpyrrolidin-1 -yl)pyridazine, hydrochloride
Figure imgf000076_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-butylsulfanylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
1H NMR (400 MHz, D2O) δ 0.74 (t, J=7.33 Hz, 3H), 1 .00 (t, J=7.07 Hz, 2H), 1.27 (m, 2H), 1 .49 (m, 2H), 2.04 (m, 5H) 2.88 (t, J=7.58 Hz, 2H), 3.24 (m, 6H), 3.62 (m, 3H), 4.46 (m,
J=6.06 Hz, 1 H), 7.28 (d, J=8.59 Hz, 2H), 7.47 (d, J= 10.11 Hz, 1 H), 7.55 (d, J=8.59 Hz, 2H), 8.00 (d, J=9.60 Hz, 1 H).
Example 20 (General procedure A) (S)-3-(4-Ethanesulfonylphenyl)-6-(2-pyrrolidin-1 -ylmethylpyrrolidin-1 -yl)pyridazine, hydrochloride
Figure imgf000077_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-ethanesulfonylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
1H NMR (400 MHz, D2O) δ 1 .12 (t, J=7.33 Hz, 3H), 2.10 (m, 8H), 3.16 (m, 2H), 3.27 (q,
J=7.58 Hz, 2H), 3.36 (m, 2H), 3.47 (m, 1 H), 3.67 (m, 2H), 3.82 (s, 1 H), 4.59 (m, 1 H), 7.42 (d,
J=9.60 Hz, 1 H), 7.87 (m, 2H), 7.94 (m, 2H), 8.02 (d, J=9.60 Hz, 1 H).
Example 21 (General procedure A)
(S)-3-(4-Ethanesulfinylphenyl)-6-(2-pyrrolidin-1 -ylmethylpyrrolidin-1 -yl)pyridazine, hydrochloride
Figure imgf000077_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-ethanesulfinylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
1H NMR (400 MHz, D2O) δ 1 .03 (t, J=7.33 Hz, 3H), 2.04 (m, 8H), 2.89 (m, 1 H), 3.02 (m, 3H),
3.31 (m, 3H), 3.57 (m, 2H), 3.79 (m, 1 H), 4.50 (q, J=5.73 Hz, 1 H), 7.33 (d, J=9.60 Hz, 1 H),
7.65 (d, J=7.07 Hz, 2H), 7.89 (d, J=8.08 Hz, 2H), 7.97 (d, J=9.60 Hz, 1 H).
Example 22 (General procedure A)
(S)-3-(4-Ethylsulfanylphenyl)-6-(2-pyrrolidin-1 -ylmethylpyrrolidin-1 -yl)pyridazine, hydrochloride
Figure imgf000077_0003
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-ethylsulfanylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
1H NMR (400 MHz, CD3OD) δ 1 .37 (t, J=7.33 Hz, 3H), 2.20 (m, 7H), 3.10 (q, J=7.07 Hz, 2H), 3.47 (m, 6H), 3.84 (brs, 2H), 3.97 (brs, 1 H), 4.73 (brs, 1 H), 7.52 (d, J=7.58 Hz, 2H), 7.91 (m, J=7.58 Hz, 3H), 8.41 (m, 1 H).
Example 23 (General procedure A)
5-(4-Chlorophenyl)-2-(4-isopropylpiperazin-1 -yl)pyrimidine, dihydrochloride
Figure imgf000078_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-chlorophenyl)pyrimidine and 1 -isopropylpiperazine. 1H NMR (300 MHz, DMSO-c(6) δ 1 .33 (d, J=6.41 Hz, 6H), 3.08 (m, 2H), 3.53 (m, 5H), 4.82 (d, J=13.94 Hz, 2H), 7.54 (d, J=8.67 Hz, 2H), 7.74 (d, J=8.67 Hz, 2H), 8.82 (s, 2H). Microanalysis for C17H21N4CI, 2 x HCI:
Calculated: C: 52.39%; H: 5.95%; N: 14.37%;
Found: C: 52.90%; H: 6.04%; N: 14.18%.
Example 24 (General procedure A) 2-(4-lsopropylpiperazin-1 -yl)-5-(4-trifluoromethylphenyl)pyrimidine, hydrochloride
Figure imgf000078_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethylphenyl)pyrimidine and 1 -isopropylpiperazine. 1H NMR (400 MHz, DMSO-^6) δ 1 .31 (d, J=6.57 Hz, 6H), 3.05 (m, 2H), 3.51 (m, 5H), 4.82 (d, J= 14.65 Hz, 2H), 7.81 (d, J=8.08 Hz, 2H), 7.93 (d, J=8.08 Hz, 2H), 8.89 (m, 2H), 11 .23 (brs, 1 H). Microanalysis for Ci8H2IF3N4, 1 .75 x HCI: Calculated: C: 52.20%; H: 5.54%; N: 13.53%;
Found: C: 52.41 %; H: 5.54%; N: 13.26%.
Example 25 (General procedure A)
4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]benzonitrile, dihydrochloride
Figure imgf000079_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-cyanophenyl)pyrimidine and 1 -isopropylpiperazine. 1H NMR (400 MHz, DMSO-Cf6) δ 1 .31 (d, J=6.57 Hz, 6H), 3.07 (m, 2H), 3.52 (m, 5H), 4.81 (d,
J=14.15 Hz, 2H), 7.93 (s, 4H), 8.91 (s, 2H), 1 1.34 (brs, 1 H).
Microanalysis for C18H2iN5, 2 x HCI, 0.75 x H2O:
Calculated: C: 54.90%; H: 6.27%; N: 17.78%;
Found: C: 55.23%; H: 6.45%; N: 17.54%.
Example 26 (General procedure A)
5-(4-Fluorophenyl)-2-(4-isopropylpiperazin-1 -yl)pyrimidine, dimethanesulfonate
Figure imgf000079_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-fluorophenyl)pyrimidine and 1 -isopropylpiperazine.
1H NMR (400 MHz, DMSO- 6 + D2O) δ 1.29 (d, J=7.07 Hz, 6H), 2.39 (s, 6H), 3.10 (m, 2H),
3.32 (t, J=12.38 Hz, 2H), 3.55 (m, 3H), 7.31 (t, J=8.84 Hz, 2H), 7.73 (dd, J=8.84, 5.31 Hz,
2H), 8.79 (s, 2H), 9.52 (brs, 1 H).
Microanalysis for C17H21N4F, 2 x CH3SO3H: Calculated: C: 46.33%; H: 5.93%; N: 1 1 .37%;
Found: C: 46.05%; H: 6.07%; N: 1 1 .06%. Example 27 (General procedure A) 2-(4-lsopropylpiperazin-1 -yl)-5-(4-trifluoromethoxyphenyl)pyrimidine, dimethanesulfonate
Figure imgf000080_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethoxyphenyl)pyrimidine and 1 -isopropylpiperazine. 1H NMR (400 MHz, DMSO-^6 + D2O ) δ 1.31 (d, J=6.57 Hz, 6H), 2.41 (s, 6H), 3.12 (m, 2H), 3.34 (t, J=12.13 Hz, 2H), 3.56 (m, 3H), 4.86 (d, J=14.15 Hz, 2H), 7.48 (d, J=8.08 Hz, 2H), 7.83 (d, J=8.59 Hz, 2H), 8.84 (s, 2H). Microanalysis for C18H21F3N4O, 2 x CH3SO3H, 0.75 x H2O: Calculated: C: 41.99%; H: 5.37%; N: 9.79%;
Found: C: 42.17%; H: 5.34%; N: 9.74%.
Example 28 (General procedure A)
2-(4-lsopropylpiperazin-1 -yl)-5-(4-methoxyphenyl)pyrimidine, dimethanesulfonate
Figure imgf000080_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-methoxyphenyl)pyrimidine and 1 -isopropylpiperazine. 1H NMR (400 MHz, DMSO-Cf6) δ 1 .29 (d, J=6.57 Hz, 6H), 2.40 (s, 6H), 3.07 (m, 2H), 3.31 (t, J=12.13 Hz, 2H), 3.54 (m, J= 11 .37, 11 .37 Hz, 3H), 3.79 (s, 3H), 4.81 (d, J=14.15 Hz, 2H), 7.03 (d, J=8.59 Hz, 2H), 7.61 (d, J=9.10 Hz, 2H), 8.75 (s, 2H), 9.52 (brs, 1 H).
Example 29 (General procedure A)
(S)-3-(2-Pyrrolidin-1 -ylmethylpyrrolidin-1 -yl)-6-(4-trifluoromethylphenyl)pyridazine, dihydro- chloride
Figure imgf000081_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (2S)-(pyrrolidin-1 -ylmethyl)- pyrrolidine.
1H NMR (400 MHz, CD3OD) δ 2.20 (m, 8H), 3.31 (m, 2H), 3.48 (m, 2H), 3.62 (m, 1 H), 3.86
(m, 3H), 4.80 (m, 1 H), 7.91 (m, J=8.59 Hz, 3H), 8.20 (d, J=8.08 Hz, 2H), 8.45 (d, J=9.60 Hz,
1 H).
Microanalysis for C20H23F3N4, 2 x HCI, 3 x H2O:
Calculated: C: 47.72%; H: 6.21 %; N: 1 1 .13%;
Found: C: 47.95%; H: 6.35%; N: 10.92%.
Example 30 (General procedure A) N-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}acetamide
Figure imgf000081_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-acetylaminophenyl)pyridazine and 1 -isopropylpiperazine. 1H NMR (400 MHz, CDCI3) δ 1 .10 (d, 6H), 2.20 (m, 3H), 2.68 (m, 4H), 2.75 (m, 1 H), 3.73 (m, 4H), 6.97 (d, J=9.60 Hz, 1 H), 7.38 (s, 1 H), 7.61 (dd, J=9.10, 5.05 Hz, 3H), 7.96 (d, J=8.59 Hz, 2H).
Example 31 (General procedure A) [1 -(1 -Ethylpropyl)piperidin-4-yl]-[6-(3-fluoro-4-methoxyphenyl)pyridazin-3-yl]amine
Figure imgf000081_0003
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-methoxy-3-fluorophenyl)pyridazine and 4-amino-1 -(1 -ethylpropyl)- piperidine.
1H NMR (400 MHz, CD3OD) δ 0.93 (m, 6H), 1 .47 (m, 7H), 2.07 (d, J=1 1.62 Hz, 2H), 2.20 (m, 1 H), 2.45 (m, 2H), 2.83 (d, J=12.13 Hz, 2H), 3.85 (m, 1 H), 3.91 (s, 3H), 6.90 (d, J=9.10 Hz, 1 H), 7.17 (t, J=8.59 Hz, 1 H), 7.68 (m, 3H).
Example 32 (General procedure A) [1 -(1 -Ethylpropyl)piperidin-4-yl]-[6-(4-methanesulfonylphenyl)pyridazin-3-yl]amine
Figure imgf000082_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-methanesulfonylphenyl)pyridazine and 4-amino-1 -(1 -ethylpropyl)- piperidine.
1H NMR (400 MHz, CD3OD) δ 0.93 (m, 6H), 1 .49 (m, 7H), 2.08 (d, J=1 1.62 Hz, 1 H), 2.23 (m, 1 H), 2.48 (m, 2H), 2.85 (d, J=12.13 Hz, 2H), 3.16 (s, 3H), 3.90 (m, 1 H), 6.96 (d, J=9.60 Hz,
1 H), 7.83 (d, J=9.60 Hz, 1 H), 8.03 (d, J=8.59 Hz, 2H), 8.19 (d, J=8.59 Hz, 2H).
Microanalysis for C2IH30N4O2S:
Calculated: C: 62.66%; H: 7.51 %; N: 13.92%;
Found: C: 62.38%; H: 7.58%; N: 13.31%.
Example 33 (General procedure A)
1 -lsopropyl-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine
Figure imgf000082_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 1 -isopropylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ 1 .00 (d, J=6.57 Hz, 6H), 2.52 (m, 4H), 2.69 (m, 1 H), 3.55 (m, 4H), 6.93 (d, J=9.09 Hz, 1 H), 7.75 (m, 2H), 7.85 (m, 2H), 7.93 (dd, J=8.84, 2.78 Hz, 1 H), 8.53 (d, J=2.53 Hz, 1 H). Microanalysis for C19H22F3N3: Calculated: C: 65.31 %; H: 3.35%; N: 12.03%;
Found: C: 65.08%; H: 6.23%; N: 12.05%.
Example 34 (General procedure A) 3-(2,3-Dihydrobenzo[1 ,4]dioxin-6-yl)-6-(4-isopropylpiperazin-1 -yl)pyridazine, dihydrochloride
Figure imgf000083_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-(2,3-dihydrobenzo[1 ,4]dioxin-6-yl)-phenyl)pyridazine and 1 - isopropylpiperazine.
1H NMR (400 MHz, DMSO-Cf6) δ 1 .32 (d, J=6.57 Hz, 6H), 3.18 (m, 2H), 3.53 (m, JM2.13 Hz, 3H), 3.75 (t, J=12.38 Hz, 2H), 4.32 (s, 4H), 4.60 (d, J=13.64 Hz, 2H), 7.05 (d, J=8.08 Hz,
1 H), 7.59 (m, 2H), 7.95 (d, J=10.1 1 Hz, 1 H), 8.37 (d, J=9.60 Hz, 1 H), 11 .68 (brs, 1 H).
Microanalysis for C19H24N4O2, 2 x HCI:
Calculated: C: 55.21 %; H: 6.34%; N: 13.55%;
Found: C: 55.25%; H: 6.40%; N: 13.55%.
Example 35 (General procedure A)
4-{6-[1 -(1 -Ethylpropyl)piperidin-4-ylamino]pyridazin-3-yl}benzonitrile
Figure imgf000083_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(4-cyanophenyl)pyridazine and 4-amino-1 -(1 -ethylpropyl)piperidine. 1H NMR (400 MHz, DMSO-^6) δ 0.87 (t, J=7.33 Hz, 6H), 1 .35 (m, 7H), 1 .98 (m, 2H), 2.17 (m, 1 H), 2.36 (t, J=10.36 Hz, 2H), 2.71 (m, J=12.13 Hz, 2H), 6.89 (d, J=9.60 Hz, 1 H), 7.09 (d, J=7.58 Hz, 1 H), 7.91 (m, 3H), 8.17 (d, J=8.08 Hz, 2H). Example 36 (General procedure A) Dimethyl-(2-{4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}ethyl)amine
Figure imgf000084_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and (2-dimethylaminoethyl)- piperazine.
1H NMR (400 MHz, CDCI3) δ 2.29 (s, 6H), 2.53 (m, 4H), 2.61 (m, 4H), 3.64 (m, 4H), 6.72 (d, J=9.10 Hz, 1 H), 7.64 (m, 4H), 7.72 (dd, J=9.10, 2.53 Hz, 1 H), 8.45 (d, J=2.53 Hz, 1 H).
Example 37 (General procedure H)
1 -(Tetrahydropyran-4-yl)-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine
Figure imgf000084_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 4-chloro-tetrahydro- pyran.
1H NMR (400 MHz, CDCI3) δ 1 .63 (m, 2H), 1.82 (m, 2H), 2.50 (m, 1 H), 2.70 (m, 4H), 3.40 (t,
J=10.86 Hz, 2H), 3.64 (m, 4H), 4.05 (dd, JM 1 .12, 4.04 Hz, 2H), 6.73 (d, J=9.10 Hz, 1 H),
7.64 (m, 4H), 7.73 (dd, J=9.10, 2.53 Hz, 1 H), 8.46 (d, J=2.53 Hz, 1 H).
Example 38 (General procedure A)
1 -[6-(4-Trifluoromethylphenyl)pyridazin-3-yl]piperidin-3-ylamine, hydrochloride
Figure imgf000085_0001
3-Chloro-6-(4-trifluoromethylphenyl)pyridazine (0.2 g, 0.77 mmol), 3-aminopiperidine dihy- drochloride (0.27 g, 1 .54 mmol) and potassium carbonate (0.53 g, 3.87 mmol) were mixed in acetone (4 ml_) in a 20 ml_ microwave vessel. The reaction mixture was heated in a micro- wave oven for 2 h at 1200C. The reaction mixture was filtered and the precipitate was washed with MeOH. The combined organic phases were evaporated. The crude oil was purified on a silicagel column (0.04-0.063 mesh) using dichloromethane/MeOH (9:1 ) as eluent. This afforded 110 mg of a oil that was dissolved in MeOH and acidified with concentrated HCI (5 ml_). The mixture was evaporated and the residue was dissolved in MeOH (1 ml_) and ether (100 ml_) was added with stirring. The mixture was evaporated to give 76 mg (25 %) of the title compound as a yellow solid. Mp = 97-1350C.
1H NMR (400 MHz, CD3OD) δ 1 .74 (m, 2H) 1 .93 (m, 1 H) 2.16 (m, 1 H) 3.35 (m, 3H) 3.44 (m, 1 H) 4.14 (Cj1Cl1 1 H) 4.45 (d,d, 1 H) 4.97 (s, 3H) 7.39 (d, 1 H) 7.75 (d, 2H) 7.78 (s, 2H) 7.95 (s, 1 H) 8.13 (d, 2H).
HPLC-MS (Method G): M+1 = 323; tr= 1 .1 17 min.
Example 39 (General procedure B) N-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}acetamide, dihydrochloride
Figure imgf000085_0002
Step 1 : 4-(6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzylamine
Figure imgf000086_0001
A mixture of a 1 M solution of LiAIH4 in THF (1.1 ml_, 1.1 mmol) and dry THF (10 m L) was placed under an atmosphere of nitrogen. A solution of 4-(6-(4-isopropylpiperazin-1 -yl)pyridin- 3-yl)benzonitrile (306 mg, 1 .0 mmol, prepared as described in Example 10) in dry THF (5 mL) was added dropwise. The reaction mixture was then stirred at rt for 3 h and quenced with 1 N NaOH. The mixture was filtered and the volatiles were removed. The residue was re-evaporated with THF to give 310 mg (100 %) of 4-(6-(4-isopropylpiperazin-1 -yl)pyridin-3- yl]benzylamine.
1H NMR (300 MHz, CDCI3) δ 1 .10 (d, 6H), 2.63-2.68 (m, 4H), 2.75 (hept, 1 H), 3.59-3.64 (m, 4H), 3.90 (s, 2H), 6.70 (d, 1 H), 7.37 (d, 2H), 7.48 (d, 2H), 7.71 (dd, 1 H), 8.44 (d, 1 H).
Step 2:
A mixture of the above benzylamine (310 mg, 1 .0 mmol), glacial acetic acid (15 mL) and acetic anhydride (0.2 mL, 2.1 mmol) was stirred for 2 days at rt. The reaction mixture was evapo- rated to dryness, and the residue was stirred with a mixture of ethyl acetate (200 mL) and 2 M sodium carbonate (50 mL). The phases were separated and the organic phase was dried (MgSO4). The solvent was evaporated to give a solid residue which was stirred with a small portion of acetonitril. The solid was isolated by filtration and dried to give 250 mg (71 %) of N- {4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}acetamide. Mp = 188-1900C.
1H NMR (300 MHz, CDCI3) δ 1 .10 (d, 6H), 2.03 (s, 3H), 2.64-2.68 (m, 4H), 2.75 (hept, 1 H), 3.58-3.66 (m, 4H), 4.46 (d, 2H), 5.83 (brs, 1 H), 6.72 (d, 1 H), 7.33 (d, 2H), 7.47 (d, 2H), 7.68 (dd, 1 H)1 8.43 (d, 1 H). The free base (250 mg) was dissolved into a 0.5 N hydrochloric acid solution. When dis- solved, the mixture was evaporated and then re-evaporated with acetonitril. The solid residue was stirred with ethyl acetate, filtered and dried to give 270 mg (69 %) of the title compound. 1H NMR (300 MHz, DMSO-c(6) δ 1 .32 (d, 6H), 1 .89 (s, 3H), 3.05-3.21 (m, 2H), 3.45-3.66 (m, 5H), 4.28 (d, 2H), 4.48-4.59 (m, 2H), 7.27 (d, 1 H), 7.34 (d, 2H), 7.64 (d, 2H), 8.16 (d, 1 H), 8.40 (s, 1 H), 8.45 (t, 1 H), 1 1.3 (brs, 1 H). Microanalysis for C21H28N4O, 2 x HCI, 1 .5 x H2O: Calculated: C: 55.75%; H: 7.35%; N: 12.38%; Found: C: 55.53%; H: 7.38%, N: 12.17%.
Example 40 (General procedure C)
1 -lsopropyl-4-{5-[4-(5-methyl[1 ,2,4]oxadiazol-3-yl)phenyl]pyridin-2-yl}piperazine, hydrochlo- ride
Figure imgf000087_0001
Step 1 :
N-Hydroxy-4-(6-(4-isopropylpiperazin-1 -yl)pyridine-3-yl)benzamidine
Figure imgf000087_0002
A mixture of 4-(6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl)benzonitrile (330 mg, 1.1 mmol, prepared as described in Example 10), ethanol (15 ml_), hydroxylamine hydrochloride (225 mg, 3.2 mmol), potassium carbonate (240 mg, 1 .7 mmol) and water (1 .5 ml_) was stirred at reflux temperature overnight. The reaction mixture was allowed to cool to rt, and the solid was isolated by filtration and dried. The solid was then stirred with water (10 ml_) to remove inor- ganic residues. The mixture was filtered and the solid was washed with water and a small portion of ethanol. Drying in vacuo afforded 260 mg (71 %) of N-hydroxy-4-(6-(4-isopropyl- piperazin-1 -yl)pyridine-3-yl)benzamidine.
1H NMR (300 MHz, DMSO-c(6) δ 1 .00 (d, 6H), 2.50-2.55 (m, 4H), 2.67 (hept, 1 H), 3.49-3.54 (m, 4H), 5.81 (brs, 2H), 6.88 (d, 1 H), 7.62 (d, 2H), 7.73 (d, 2H), 7.86 (dd, 1 H), 8.48 (d, 1 H), 9.65 (s, 1 H).
Step 2:
A mixture of the above N-hydroxybenzamidine (260 mg, 0.76 mmol), glacial acetic acid (10 ml_) and acetic anhydride (0.56 ml_) was stirred for 2 days at rt. The reaction mixture was then heated at reflux temperature for 45 min. The mixture was evaporated to give an oily residue which was stirred with a mixture of ethyl acetate (100 ml_) and 2 M sodium carbonate (25 ml_). The phases were separated and the organic phase was dried (MgSO4). The solvent was evaporated to give a solid residue which was boiled with acetonitril. The mixture was allowed to cool, and the solid was isolated by filtration and dried to give 110 mg (28 %) of 1 - isopropyl-4-{5-[4-(5-methyl[1 ,2,4]oxadiazol-3-yl)phenyl]pyridin-2-yl}piperazine. 1H NMR (300 MHz, CDCI3) δ 1 .11 (d, 6H), 2.64-2.69 (m, 4H), 2.67 (s, 3H), 2.75 (hept, 1 H), 3.63-3.67 (m, 4H), 6.73 (d, 1 H), 7.63 (d, 2H), 7.76 (dd, 1 H), 8.10 (d, 2H), 8.50 (d, 1 H). The free base (1 10 mg) was dissolved into a 0.5 N hydrochloric acid solution. When dis- solved, the mixture was evaporated and then re-evaporated with acetonitril. The solid residue was re-crystallised from absolute ethanol to give 120 mg (28 %) of the title compound. 1H NMR (300 MHz, DMSO-c(6) δ 1 .32 (d, 6H), 2.69 (s, 3H), 3.06-3.23 (m, 2H), 3.40-3.66 (m, 5H), 4.51 -4.63 (m, 2H), 7.29 (d, 1 H), 7.90 (d, 2H), 8.07 (d, 2H), 8.23 (d, 1 H), 8.54 (s, 1 H), 1 1 .3 (brs, 1 H).
Example 41 (General procedure D)
1 -(5-(5-(4-Chloromethylphenyl)[1 ,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropylpiperazine
Figure imgf000088_0001
Step 1 : 6-(4-lsopropylpiperazin-1 -yl)nicotinonitrile, hydrochloride
Figure imgf000088_0002
A mixture of 2-chloropyridine-5-carbonitrile (5.0 g, 36.1 mmol), DMSO (10 ml_) and 1 -iso- propylpiperazine (10.7 ml_, 75.8 mmol) was stirred under an atmosphere of nitrogen and heated on a 1000C oil-bath for 3 h. The reaction mixture was allowed to cool, and then poured into cold water (500 ml_). The solid was isolated by filtration, washed with water and dried to give 6.8 g (82 %) of 6-(4-isopropylpiperazin-1 -yl)nicotinonitrile. 1H NMR (400 MHz, CDCI3) δ 1 .08 (d, 6H), 2.59-2.64 (m, 4H), 2.75 (hept,1 H), 3.67-3.72 (m, 4H), 6.59 (d, 1 H), 7.60 (dd, 1 H), 8.40 (d, 1 H).
The free base (500 mg) was dissolved into methanol (50 ml_) and 1 N hydrochloric acid solution (3 ml_) was added. The mixture was evaporated and then re-evaporated with ethanol. The solid residue was stirred with 2-propanol, filtered and dried to give 570 mg (98 %) of 6- (4-isopropylpiperazin-1 -yl)nicotinonitrile, hydrochloride.
1H NMR (300 MHz, DMSO-c(6) δ 1 .30 (d, 6H), 2.97-3.12 (m, 2H), 3.41 -3.61 (m, 5H), 4.52- 4.63 (m, 2H), 7.06 (d, 1 H), 7.97 (dd, 1 H), 8.56 (d, 1 H), 11 .5 (brs, 1 H).
Step 2:
N-Hydroxy-6-(4-isopropylpiperazin-1 -yl)nicotinamidine
Figure imgf000089_0001
A mixture of 6-(4-isopropylpiperazin-1 -yl)nicotinonitrile (2.3 g, 10 mmol), ethanol (25 ml_), hydroxylamine hydrochloride (2.1 g, 30 mmol), potassium carbonate (2.2 g, 16 mmol) and water (5 ml_) was stirred for 30 min at rt and then at reflux temperature for 3 h. The reaction mixture was left at rt for 2 days and then the solid formed was isolated by filtration. The solid was dried, boiled with ethanol (200 ml_) and filtered hot to remove inorganic impurities. The filtrate was evaporated to give 2.0 g (76 %) of N-hydroxy-6-(4-isopropylpiperazin-1 -yl)nicotin- amidine. 1 H NMR (400 MHz, DMSO-c(6) δ 0.98 (d, 6H), 2.67 (hept, 1 H), 3.31 -3.51 (m, 8H), 5.74 (brs, 2H), 6.79 (d, 1 H), 7.75 (dd, 1 H), 8.38 (d, 1 H), 9.4 (brs, 1 H).
Step 3:
The above N-hydroxynicotinamidine (263 mg, 1 .0 mmol) was dissolved into Λ/,Λ/-dimethyl- acetamide (10 ml_) and 4-chloromethylbenzoyl chloride (190 mg, 1.0 mmol) was added. The reaction was stirred for 1 h at rt and then heated at 1050C for 2 h. The mixture was allowed to cool to rt and then filtered. The solid was washed with ethyl acetate and dried. This afforded 280 mg (65 %) of 1 -(5-(5-(4-chloromethylphenyl)[1 ,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-iso- propylpiperazine, hydrochloride. The hydrochloride (400 mg) was stirred with water (30 ml_) and a potassium carbonate solution was added until alkaline reaction. The mixture was extracted with several portions of ethyl acetate (total 100 ml_). The combined organic extracts were dried and evaporated to give 300 mg of 1 -(5-(5-(4-chloromethylphenyl)[1 ,2,4]oxadiazol- 3-yl)pyridine-2-yl)-4-isopropylpiperazine.
1H NMR (300 MHz, CDCI3) δ 1 .09 (d, 6H), 2.59-2.67 (m, 4H), 2.68-2.80 (m, 1 H), 3.66-3.72 (m, 4H), 4.66 (s, 2H), 6.71 (d, 1 H), 7.57 (d, 2H), 8.16 (dd, 1 H), 8.20 (d, 2H), 8.95 (d, 1 H).
Example 42 (General procedure D) 4-{3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl][1 ,2,4]oxadiazol-5-yl}benzonitrile, hydrochloride
Figure imgf000090_0001
The title compound was prepared by a similar procedure to that described in Example 41 , starting from N-hydroxy-6-(4-isopropylpiperazin-1 -yl)nicotinamidine and 4-cyanobenzoyl- chloride.
1H NMR (300 MHz, CDCI3) δ 1 .50 (d, 6H), 2.86-3.03 (m, 2H), 3.41 -3.55 (m, 3H), 3.97-4.10
(m, 2H), 4.49-4.60 (m, 2H), 6.78 (d, 1 H), 7.87 (d, 2H), 8.25 (dd, 1 H), 8.33 (d, 2H), 8.96 (d,
1 H), 12.9 (brs, 1 H).
Example 43 (General procedure D)
1 -[5-(5-Cyclopropyl[1 ,2,4]oxadiazol-3-yl)pyridin-2-yl]-4-isopropylpiperazine, dimethanesul- fonate
Figure imgf000090_0002
The title compound was prepared by a similar procedure to that described in Example 42, starting from N-hydroxy-6-(4-isopropylpiperazin-1 -yl)nicotinamidine and cyclopropylcarbonyl- chloride.
1H NMR (300 MHz, CDCI3) δ 1 .26-1 .32 (m, 4H), 1 .45 (d, 6H), 2.20-2.28 (m,1 H), 2.80 (s, 6H), 3.29-3.45 (m, 2H), 3.54-3.69 (m, 3H), 4.02-4.16 (m, 2H), 4.59-4.70 (m, 2H), 7.31 (d, 1 H), 8.42 (dd, 1 H), 8.72 (d, 1 H), 10.9 (brs, 1 H). Example 44 (General procedure E)
1 -lsopropyl-4-{5-[5-(4-piperidin-1 -ylmethylphenyl)[1 ,2,4]oxadiazol-3-yl]pyridin-2-yl}piperazine, dihydrochloride
Figure imgf000091_0001
A mixture of 1 -(5-(5-(4-chloromethylphenyl)[1 ,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropyl- piperazine, hydrochloride (280 mg, 0.65 mmol, prepared as described in Example 41 , 96 % ethanol (20 ml_) and piperidine (0.2 ml_, 2.1 mmol) heated at reflux temperature for 4 h. The mixture was evaporated to give a solid residue which was purified by column chromatography on silica gel (75 g, Kiselgel 60, mesh 0.040-0.63) eluting with a mixture of dichloro- methane and methanol (7:3). Collecting the proper fractions afforded 310 mg (100 %) of 1 - isopropyl-4-{5-[5-(4-piperidin-1 -ylmethylphenyl)[1 ,2,4]oxadiazol-3-yl]pyridin-2-yl}piperazine. The free base (310 mg) was dissolved into ethanol (20 ml_) and a 1 N hydrochloric acid solution (1 .5 ml_) was added. When dissolved, the mixture was evaporated and the solid residue was re-crystallised from ethanol to give 240 mg (67 %) of the title compound. 1H NMR (300 MHz, D2O) δ 1 .42 (d, 6H), 1 .61 -1 .94 (m, 6H), 3.12-3.50 (m, 8H), 3.55-3.69 (m, 1 H), 3.82-4.05 (m, 4H), 4.37 (s, 2H), 7.02 (d, 1 H), 7.73 (d, 2H), 8.12 (d, 1 H), 8.18 (d, 2H), 8.64 (s, 1 H).
Example 45 (General Procedure E) 1 -(4-{3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl][1 ,2,4]oxadiazol-5-yl}benzyl)piperidine-4- carboxylic acid amide, dihydrochloride
Figure imgf000091_0002
The title compound was prepared by a similar procedure to that described in Example 44, starting from 1 -(5-(5-(4-chloromethylphenyl)[1 ,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropyl- piperazine and isonipecotamide.
1H NMR (300 MHz, DMSO-^6) δ 1 .32 (d, 6H), 1 .85-1 .97 (m, 3H), 2.26-2.40 (m, 1 H), 2.87- 3.24 (m, 4H), 3.29-3.62 (m, 6H), 4.36-4.48 (m, 2H), 4.53-4.65 (m, 2H), 6.88-7.04 (2xbrs, 1 H), 7.17 (d, 1 H), 7.38-7.52 (2xbrs, 1 H), 7.90-8.00 (m, 2H), 8.19-8.28 (m, 3H), 8.84 (s, 1 H), 1 1.0 (brs, 1 H), 1 1.3 (brs, 1 H).
Example 46 (General procedure F) 1 -Prop-1 -yl-4-[5-(4-trif luoromethylphenyl)pyridin-2-yl]piperazine
Figure imgf000092_0001
The title compound was prepared by a similar procedure to that described in Example 213, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and propionaldehyde. 1H NMR (400 MHz,CDCI3) δ 0.95 (t, 3H), 1 .57 (m, 2H), 2.37 (m, 2H), 2.58 (m, 4H), 3.64 (m, 4H), 6.73 (d, J=9.10 Hz, 1 H), 7.64 (m, 4H), 7.72 (dd, J=9.10, 2.53 Hz, 1 H), 8.46 (d, J=2.53 Hz, 1 H).
Example 47 (General procedure F) 1 -Cyclohexyl-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine, hydrochloride
Figure imgf000092_0002
The title compound was prepared by a similar procedure to that described in Example 213, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and cyclohexanone. 1H NMR (400 MHz, DMSO-d6) δ 1 .18 (m, 3H), 1.46 (m, 2H), 1 .62 (m, 1 H), 1 .82 (m, 2H), 2.18 (m, 2H), 3.17 (m, 3H), 3.59 (m, 4H), 4.53 (d, 2H), 7.25 (d, J=9.09 Hz, 1 H), 7.81 (d, J=8.08 Hz, 2H), 7.93 (d, J=8.59 Hz, 2H), 8.18 (m, 1 H), 8.54 (d, J=2.53 Hz, 1 H), 11 .47 (brs, 1 H). Example 48 (General Procedure G) 1 -{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}ethanone
Figure imgf000093_0001
To a suspension of 4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]benzonitrile (0.36 g, 1 .17 mmol, prepared by a similar procedure to that described in Example 1 ) in dry THF (5 ml_) was added a 1 .4 M methylmagnesium bromide solution in toluene/THF. The reaction mixture was stirred at room temperature for 24 h, 1 M hydrochloric acid (7 ml_) was added and the solution stirred for 1 h. The mixture was made alkaline by addition of excess NaHCO3 solution and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, the solvent was removed and the solid was re-crystallized from ethanol to give the title compound, 163 mg (43%).
1H NMR (400 MHz, DMSO- 6) δ 1 .01 (d, J=6.57 Hz, 6H), 2.57 (m, 4H), 2.62 (s, 3H), 2.71 (m, 1 H), 3.66 (m, 4H), 7.37 (d, J=9.60 Hz, 1 H), 8.04 (m, J=9.10, 9.10 Hz, 3H), 8.19 (d, J=8.59 Hz, 2H).
Microanalysis for Ci9H24N4O:
Calculated: C: 70.34%; H: 7.46%; N: 17.27%;
Found: C: 70.07%; H: 7.37%; N: 17.18%.
Example 49 (General procedure H)
1 -{4-[5-(4-Trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}propan-2-one, hydrochloride
Figure imgf000093_0002
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and chloroacetone. 1H NMR (400 MHz, CD3OD) δ 2.29 (s, 3H), 3.79 (m, 8H), 4.49 (s, 2H), 7.59 (d, J=9.60 Hz, 1 H), 7.82 (m, 2H), 7.89 (m, 2H), 8.42 (m, 1 H), 8.50 (dd, J=9.35, 2.27 Hz, 1 H). Example 50 (General procedure H)
Λ/,Λ/-Dimethyl-2-{4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}acetamide, hydrochloride
Figure imgf000094_0001
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-chloro-Λ/,Λ/-dimethyl- acetamide.
1H NMR (400 MHz, DMSO-Cf6) δ 2.95 (m, 6H), 3.45 (m, 6H), 4.48 (m, 4H), 7.20 (d, J=9.10 Hz, 1 H), 7.80 (d, J=8.08 Hz, 2H), 7.92 (d, J=8.08 Hz, 2H), 8.16 (dd, J=9.09, 2.53 Hz, 1 H), 8.57 (d, J=2.02 Hz, 1 H), 10.37 (brs, 1 H).
Example 51 (General procedure H) 3-{4-[5-(4-Trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}propionitrile
Figure imgf000094_0002
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 3-bromopropionitrile. 1H NMR (400 MHz, DMSO-^6) δ 2.54 (m, 4H), 2.62 (t, J=6.57 Hz, 2H), 2.73 (t, J=6.32 Hz, 2H), 3.58 (m, 4H), 6.97 (d, J=8.59 Hz, 1 H), 7.76 (m, 2H), 7.86 (m, 2H), 7.94 (dd, J=8.59, 2.53 Hz, 1 H), 8.54 (d, J=2.53 Hz, 1 H).
Example 52 (General procedure H) Diethyl-(2-{4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazin-1 -yl}ethyl)amine
Figure imgf000095_0001
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-diethylaminoethyl- chloride.
1H NMR (400 MHz, CDCI3) δ 1 .05 (t, J=7.07 Hz, 6H), 2.61 (m, 12H), 3.63 (m, 4H), 6.73 (d,
J=9.10 Hz, 1 H), 7.64 (m, 4H), 7.72 (dd, J=9.10, 2.53 Hz, 1 H), 8.46 (d, J=2.53 Hz, 1 H).
Example 53 (General procedure H) 1 -(2-Methoxyethyl)-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine
Figure imgf000095_0002
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-methoxyethyl- bromide.
1H NMR (400 MHz, CDCI3) δ 2.65 (m, 6H), 3.39 (s, 3H), 3.57 (t, J=5.56 Hz, 2H), 3.66 (m,
4H), 6.73 (d, J=8.59 Hz, 1 H), 7.64 (m, 4H), 7.72 (dd, J=8.59, 2.53 Hz, 1 H), 8.46 (d, J=2.53
Hz, 1 H).
Example 54 (General procedure H) 1 -Allyl-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine, hydrochloride
Figure imgf000095_0003
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and allyliodide. 1H NMR (400 MHz, DMSO-c(6) δ 3.08 (d, J=9.10 Hz, 2H), 3.80 (d, J=3.54 Hz, 2H), 4.29 (s, 4H), 4.55 (d, J=14.15 Hz, 2H), 5.54 (m, 2H), 6.06 (m, 1 H), 7.24 (d, J=9.09 Hz, 1 H), 7.81 (d, J=8.08 Hz, 2H), 7.92 (d, J=8.08 Hz, 2H), 8.19 (dd, J=9.10, 2.53 Hz, 1 H), 8.55 (d, J=2.53 Hz, 1 H), 11 .77 (brs, 1 H).
Example 55 (General Procedure H)
1 -lsopropyl-4-[6-(4-trifluoromethylphenyl)pyridazin-3-yl]-[1 ,4]diazepane, dihydrochloride
Figure imgf000096_0001
4-[6-(4-Trifluoromethylphenyl)pyridazin-3-yl]-[1 ,4]diazepane, dihydrochloride (0.028 g, 0.071 mmol) was suspended in THF (4 ml_) and triethylamine (0.022 g, 0.21 mmol) was added. Sodium hydride (0.0085 g, 0.35 mmol) was added and the reaction mixture was stirred at rt for 20 min. Dry Λ/,Λ/-dimethylformamide (1 ml_) and 2-chloropropane (0.056 g, 0.71 mmol) was added and the reaction mixture was heated 30 min at 1600C and 30 min at 1800C in a microwave oven. The reaction mixture was purified on a silicagel column (0.04-0.063 mesh) using dichloromethane/MeOH (9:1 ) as eluent. This afforded a crude oil containing several components that was purified further by preparative HPLC using Method B. This afforded 9 mg of an oil which was dissolved into MeOH. Addition of HCI in diethyl ether afforded 6.5 mg (21 %) of the title compound as an oily dihydrochloride.
1H NMR (400 MHz, CD3OD) δ 1 .38 (d, J=6.57 Hz, 6H), 2.23-2.46 (m, 2H), 3.32-3.52 (m, 2H), 3.53-3.85 (m, 4H), 3.88-4.15 (m, 2H), 4.26-4.55 (m, 1 H), 7.60 (d, J=9.60 Hz, 1 H), 7.84 (d, J=8.08 Hz, 2H), 8.05-8.28 (m, 3H) LC-MS (Method G): M+1 = 365; tr = 1 .178 min.
Example 56 (General Procedure I)
N-[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]acetamide, trifluoroace- tate
Figure imgf000097_0001
Step 1 : 4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl:
Figure imgf000097_0002
Chloropyrazine (2.3 g, 20 mmol) and triethylamine (3 g, 30 mmol) were mixed in acetone (8 ml_) in a 20 ml_ microwave vessel. 1 -lsopropylpiperazine (2.8 g, 22 mmol) was added and the reaction mixture was heated for 3300 seconds at 1200C in a microwave oven. The reaction mixture was evaporated and the residue was purified on a silicagel column with dichloromethane/MeOH (9:1 ) as eluent. Yield: 1.64 g solid 4-isopropyl-3,4,5,6-tetrahydro-2H- [1 ,2']bipyrazinyl.
1H NMR (400 MHz, CDCI3) δ 1 .08 (d, J=6.57 Hz, 6H) 2.61 -2.65 (m, 4H) 2.68-2.77 (m, 1 H) 3.58-3.62 (m, J=4.55 Hz, 4H) 7.70-7.91 (m, 1 H) 8.03-8.08 (m, 1 H) 8.13 (s, 6H). 13C NMR (400 MHz, CDCI3) δ 18.82, 45.16, 48.66, 54.94, 77.17, 77.48, 77.80, 131 .30, 133.10, 142.00, 155.30.
Step 2:
5-Bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl:
Figure imgf000097_0003
4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl (1 .0 g, 4.8 mmol) was dissolved in di- chloromethane (30 ml_) and the solution was placed on an ice-bath and brominated according to literature (Tetrahedron 44,10,1988, 2977-2984) in very bad yield. N-Bromosuccinimide (3.45 g, 19.4 mmol) was added slowly at O0C and then left overnight at rt. No reaction was observed. An additional 3.45 g of N-bromosuccinimide was added during 8 h, and then the reaction mixture was left at rt for 2 days. Aqueous concentrated Na2CO3 was added and the mixture was extracted with dichloromethane (3 x 75 ml_). The combined organic extracts were dried (MgSO4), filtered and evaporated. The oily residue was purified on a silica gel column with dichloromethane/MeOH (9:1 ) as eluent. Yield: 196 mg (28 %) of 5-bromo-4- isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl as an oil.
1H NMR (400 MHz, CDCI3) δ 1 .09 (d, J=6.57 Hz, 6H) 2.55-2.67 (m, 4H) 2.72-2.83 (m, 1 H) 3.44-3.65 (m, 4H) 7.87 (s, 1 H) 8.12 (s, 1 H).
13C NMR (400 MHz, CDCI3) δ 18.71 , 30.05, 45.19, 48.39, 48.68, 54.92, 126.04, 130.51 , 144.16, 154.31 .
Step 3:
5-Bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl (0.196 g, 0.68 mmol), 4-acet- amidophenylboronic acid (0.123 g, 0.69 mmol), bistriphenylphosphinpalladium(ll)dichloride (0.015 g, 0.021 mmol) and Na2CO3 (0.168 g, 1 .37 mmol, dissolved in 2 ml_ H2O) were mixed in acetonitril (16 ml_) under a nitrogen atmosphere in a 20 ml_ microwave vessel. The reaction mixture was heated 400 seconds at 1500C in a microwave oven. Some debromination was observed by LC-MS of the reaction mixture. The reaction mixture was evaporated and the residue was redissolved in a mixture of dichloromethane and H2O. The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 50 ml_). The combined organic extracts were evaporated and the residue was dissolved in MeOH and purified according to preparative HPLC Method B. This afforded 49 mg (15 %) of the title compound as the trifluoroacetic acid salt.
1H NMR (400 MHz, DMSO-^6) δ 1 .30 (d, J=6.57 Hz, 6H) 2.03-2.11 (m, 3H) 3.09-3.20 (m, 2H) 3.23-3.34 (m, 2H) 3.56-3.66 (m, 5H) 4.55 (d, J=11 .62 Hz, 2H) 7.69 (d, J=8.59 Hz, 2H) 7.94 (d, J=8.59 Hz, 2H) 8.49 (s, 1 H) 8.71 (s, 1 H) 10.13 (brs, 2H).
13C NMR (400 MHz, DMSO-Cf6) 5 16.78, 24.38, 42.00, 47.27, 57.62, 119.49, 125.98, 131 .08, 131 .36, 138.06, 139.79, 141 .19, 152.67, 168.76.
Example 57 (General Procedure I) [4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]acetonitrile, trifluoroacetate
Figure imgf000098_0001
4-Cyanomethylphenylboronic acid (0.137 g, 0.85 mmol), 5-bromo-4-isopropyl-3,4,5,6-tetra- hydro-2H-[1 ,2']bipyrazinyl (0.242 g, 0.85 mmol), bistriphenylphosphinpalladium(ll)dichloride (0.035 g, 0.080 mmol) and a 1 N Na2CO3 solution in H2O (1 .7 ml_)) were mixed in acetonitril (2 ml_) under an atmosphere of nitrogen in a 5 ml_ microwave vessel. The reaction mixture was heated 600 seconds at 1200C in a microwave oven. The reaction mixture was evaporated and the residue was dissolved in a mixture of H2O and dichloromethane. The phases were separated and the aquoeus phase was extracted with dichloromethane (3 x 25 ml_). The organic extracts were combined and trifluoroacetic acid was added. The volatiles were evaporated and the residue was dissolved in MeOH and purified according to preparative HPLC Method B to give 35 mg (10 %) of the title compound.
1H NMR (400 MHz, CDCI3) δ 1 .40 (d, J=6.57 Hz, 6H) 2.92-3.03 (m, 2H) 3.54-3.65 (m, 5H) 3.81 (s, 2H) 4.48 (d, J=13.64 Hz, 2H) 7.42 (d, J=8.08 Hz, 2H) 7.91 (d, J=8.08 Hz, 2H) 8.24 (s, 1 H) 8.55 (s, 1 H) 12.43-13.00 (m, 1 H). 13C NMR (400 MHz, CDCI3) δ 16.96, 23.78, 42.43, 47.56, 58.32, 118.13, 126.86, 128.92, 130.44, 130.50, 136.78, 139.24, 142.57, 152.99.
Example 58 (General Procedure I)
5-(4-Ethanesulfonylphenyl)-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trifluoroace- tate
Figure imgf000099_0001
4-Ethansulfonylphenylboronic acid (0.182 g, 0.85 mmol), 5-bromo-4-isopropyl-3,4,5,6-tetra- hydro-2H-[1 ,2']bipyrazinyl (0.242 g, 0.85 mmol), bistriphenylphosphinpalladium(ll)dichloride (0.035 g, 0.080 mmol) and a 1 N Na2CO3 solution in H2O (1 .7 ml_)) were mixed in acetonitril (2 ml_) under an atmosphere of nitrogen in a 5 ml_ microwave vessel. The reaction mixture was heated 400 seconds at 1200C in a microwave oven. The reaction mixture was evaporated and the residue was dissolved in a mixture of H2O and dichloromethane The phases were separated and the aquoeus phase was extracted with dichloromethane (3 x 25 ml_). The organic extracts were combined and trifluoroacetic acid was added. The volatiles were evaporated and the residue was dissolved in MeOH and purified according to HPLC Method B to give 60 mg (12 %) of the title compound. 1H NMR (400 MHz, CD3OD) δ 1 .24 (t, J=7.33 Hz, 3H), 1 .42 (d, J=6.57 Hz, 6H), 3.20 (q, J=7.58 Hz, 2H), 3.28-3.39 (m, 4H), 3.56-3.68 (m, 3H), 4.60-4.79 (m, 2H), 4.86 (brs, 6H), 7.96 (d, J=8.59 Hz, 2H), 8.20 (d, 2H), 8.44 (s, 1 H), 8.76 (s, 1 H).
13C NMR (400 MHz, CD3OD) δ 8.04, 17.47, 43.47, 51.67, 60.46, 127.68, 130.30, 132.37, 139.42, 141 .14, 141.74, 143.74, 155.02.
Example 59 (General Procedure I) N-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}acetamide, dihydrochloride
Figure imgf000100_0001
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1 -(5-bromo-pyridin-2-yl)-4-isopropyl-piperazine and 4-acetamidophenylboronic acid.
1H NMR (400 MHz, DMSO-^6) δ 1 1 .25 (brs, 1 H), 10.18 (s, 1 H), 8.38 (s, 1 H), 8.16 (d, 1 H),
7.70 (d, 2H), 7.62 (d, 2H), 7.28 (d, 1 H), 4.53 (d, 2H), 3.65-3.45 (m, 5H), 3.20-3.08 (m, 2H), 2.06 (s, 3H), 1 .33 (d, 6H).
Microanalysis for C20H26N4O, 2 x HCI, 1 .5 x H2O:
Calculated: C: 54.80%; H: 7.13%; N: 12.78%;
Found: C: 54.55%; H: 6.84%, N: 12.42%.
Example 60 (General Procedure L)
Cyclopropanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)- phenyl]amide, dihydrochloride
Figure imgf000100_0002
The title compound was prepared by a similar procedure to that described in Example 176, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamine and cyclopropanecarboxylic acid.1H NMR (400 MHz, DMSO-d6) δ 1 1 .24 (brs, 1 H), 10.52 (s, 1 H), 8.70 (s, 1 H), 8.47 (s, 1 H), 7.92 (d, 2H), 7.72 (d, 2H), 4.49 (d, 2H), 3.55-3.44 (m, 5H), 3.15- 3.04 (m, 2H), 1.91 -1 .83 (m, 1 H), 1 .32 (d, 6H), 0.83-0.75 (m, 4H). Microanalysis for C21H27N5O, 2 x HCI, 2.25 x H2O: Calculated: C: 52.67%; H: 7.05%; N: 14.62%; Found: C: 52.79%; H: 7.00%, N: 14.53%.
Example 61 (General Procedure L)
2-Cyclopropyl-N-[4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]- acetamide, dihydrochloride
Figure imgf000101_0001
The title compound was prepared by a similar procedure to that described in Example 176, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamine and cyclopropylacetic acid.1H NMR (400 MHz, DMSO-d6) δ 1 1 .00 (brs, 1 H), 10.06 (s, 1 H), 8.71 (s, 1 H), 8.46 (s, 1 H), 7.92 (d, 2H), 7.71 (d, 2H), 4.49 (d, 2H), 3.52-3.42 (m, 5H), 3.15-3.04 (m, 2H), 2.23 (d, 2H), 1 .30 (d, 6H), 1.10-1 .00 (m, 1 H), 0.50-0.44 (m, 2H), 0.22-0.17 (m, 2H). Microanalysis for C22H29N5O, 2 x HCI, 0.75 x H2O: Calculated: C: 56.71 %; H: 7.03%; N: 15.05%;
Found: C: 56.51 %; H: 6.73%, N: 14.82%.
Example 62 (General Procedure L)
4-Methoxycyclohexanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl- 5'-yl)phenyl]amide, dihydrochloride
Figure imgf000101_0002
The title compound was prepared by a similar procedure to that described in Example 176, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamine and 4- methoxycyclohexanecarboxylic acid.1 H NMR (400 MHz, DMSO-Cl6) δ 11 .22 (brs, 1 H), 10.08 (d, 1 H), 8.71 (s, 1 H), 8.48 (s, 1 H), 7.93 (d, 2H), 7.71 (d, 2H), 4.51 (d, 2H), 3.55-3.38 (m, 5H), 3.25 + 3.22 (2 x s, 3H), 3.16-3.04 (m, 2H), 2.47-2.29 (m, 1 H), 2.11 -1 .06 (m, 14 H). Microanalysis for C25H35N5O2, 2 x HCI, 1 .25 x H2O: Calculated: C: 56.33%; H: 7.47%; N: 13.14%;
Found: C: 56.27%; H: 7.38%, N: 12.61%.
Example 63 (General Procedure K) 4-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}morpholine, trifluoroacetate
Figure imgf000102_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde and morpholine. 1H NMR (300 MHz, D2O) δ 8.29 (dd, 1 H), 8.21 (d, 1 H), 7.65 (d, 2H), 7.52 (d, 2H), 7.34 (d, 1 H), 4.36-4.32 (m, 4H), 4.02-3.98 (m, 2H), 3.71 -3.50 (m, 7H), 3.37-3.12 (m, 6H), 1 .28 (d , 6H).
HPLC (Method D): tr = 2.45 min (97 %).
Example 64 (General Procedure A) 4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]benzonitrile
Figure imgf000102_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 1 -isopropylpiperazine and 4-(2-chloro-pyrimidin-5-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 1 1 .34 (brs, 1 H), 8.91 (s, 2H), 7.92 (s, 4H), 4.81 (d, 2H), 3.63-3.43 (m, 5H), 3.12-3.01 (m, 2H), 1.31 (d, 6 H). Microanalysis for Ci8H21 N5, 2 x HCI, 0.75 x H2O: Calculated: C: 54.90%; H: 6.27%; N: 17.78%; Found: C: 55.23%; H: 6.45%, N: 17.54%.
Example 65
N-{4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]benzyl}acetamide, dihydrochloride
Figure imgf000103_0001
The title compound was prepared by a similar procedure to that described in Example 39, starting from 4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]benzonitrile. 1H NMR (300 MHz, CDCI3) δ 8.79 (s, 2H), 7.53 (d, 2H), 7.45 (d, 2H), 5.06 (d, 2H), 4.47 (s, 2H), 4.15-4.01 (m, 2H), 3.65-3.52 (m, 3H), 3.32-3.19 (m, 2H), 2.13 (s, 3H), 1 .48 (d, 6 H). HPLC (Method A): tr = 6.66 min (100 %). Microanalysis for C20H27N5O, 2 x HCI, 4 x H2O: Calculated: C: 48.19%; H: 7.48%; N: 14.05%;
Found: C: 48.19%; H: 7.03%, N: 13.66%.
Example 66 (General Procedure I)
4-[6-(4-Cyclopropylpiperazin-1 -yl)-piperidin-3-yl]-N,N-dimethylbenzamide, dihydrochloride
Figure imgf000103_0002
Step 1 : 1 -(5-Bromopyridin-2-yl)-piperazine
Figure imgf000103_0003
A mixture of piperazine (107 g, 1.24 mol) and 2-chloro-5-bromopyridine (30 g, 156 mmol) in toluene (150 ml_) was heated at 1300C for 2 hours, The reaction mixture was cooled to room temperature and toluene (400 ml_) and water (200 ml_) were added. The organic phase was isolated and the aqeuous phase was extracted once with toluene (100 ml_). The collected organic phases were washed with water (150 ml_) and brine (100 ml_), dried over magnesium sulphate and evaporated to dryness in vacuo to give 30.1 g (80 %) of 1 -(5-bromopyridin-2- yl)-piperazine. 1H NMR (400 MHz, CDCI3) δ 8.19 (d, 1 H), 7.52 (dd, 1 H), 6.54 (d, 1 H), 3.47 (m, 4H), 2.97 (m, 4H), 1 .77 (broad s, 1 H)
Step 2:
1 -(5-Bromopyridin-2-yl)-4-cyclopropylpiperazine:
Figure imgf000104_0001
[(i -Ethoxy-cyclopropyOoxyJtrimethylsilane (26 ml_, 129.3 mmol) was added to a solution of 1 - (5-bromopyridin-2-yl)-piperazine (15 g, 62.0 mmol) in THF (120 ml_). Water (24 ml_), acetic acid (1 1 ml_), and 1 M NaCNBH3 in THF (90 ml_, 90 mmol) were added to the reaction mixture, which was then heated at reflux temperature for 3 hours. The resulting solution was cooled to rt and evaporated to dryness in vacuo. The residue was dissolved in a mixture of dichloromethane (200 ml_) and water (50 ml_) and 4 N sodium hydroxide (20 ml_) was added to pH 8-9. The organic phase was isolated and the aqeoues phase was extracted with further dichloromethane (100 ml_). The combined organic phases were evaporated to dryness in vacuo and the residue was purified on a silica gel column (gradient: from 5 % ethyl acetate in heptane to 100 % ethyl acetate over 40 min.). This afforded 13.1 g (75 %) of 1 -(5- bromopyridin-2-yl)-4-cyclopropylpiperazine.
1H NMR (400 MHz, CDCI3) δ 8.19 (d, 1 H), 7.52 (dd, 1 H), 6.54 (d, 1 H), 3.47 (m, 4H), 2.70 (m, 4H), 1 .64 (m, 1 H), 0.48 (m, 4H).
Step 3:
A mixture of 1 -(5-bromopyridin-2-yl)-4-cyclopropylpiperazine, (2.5 g, 8.86 mmol), 4-(N, N- dimethylaminocarbonyl)-phenyl boronic acid (2.5 g, 13.0 mmol), tetrakis(triphenylphosphine)- palladium(O) (300 mg, 0.26 mmol), and anhydrous sodium carbonate (2.0 g, 18.9 mmol) was purged with nitrogen. 1 ,2-Dimethoxyethane (30 ml_) and water (7 ml_) were added and the reaction mixture was heated at 800C for 1 .5 hours and filtered upon cooling to 0-50C. The crystals were washed with water (20 ml_), dried and then dissolved in acetone (130 ml_). Ad- dition of HCI9 in methanol afforded 1 .41 g (37 %) of 4-[6-(4-cyclopropylpiperazin-1 -yl)- piperidin-3-yl]-N,N-dimethylbenzamide, dihydrochloride.
1H NMR (400 MHz, DMSO-c(6) δ 1 1 .36 (brs, 1 H), 8.50 (d, 1 H), 8.18 (dd, 1 H) 7.75 (d, 2H), 7.50 (d, 2H), 7.26 (d, 1 H), 4.51 (d, 2H), 3.56 (m, 4H), 3.53 (brs, 2H), 3.00 (s, 3H), 2.96 (s, 3H), 2.89 (brs, 1 H), 1 .20 (m, 2H), 0.82 (m, 2H).
Example 67 (General Procedure I) N-{4-[6-(4-Cyclopropylpiperazin-1 -yl)pyridazin-3-yl]-2-methoxyphenyl}acetamide
Figure imgf000105_0001
The title compound was prepared from 3-chloro-6-(4-cyclopropyl-piperazin-1 -yl)-pyridazine (4.6 g, 19.3 mmol), 1 M sodium carbonate solution (50 ml_, 100,5 mmol), acetonitrile (50 ml_), bis(triphenylphosphine)palladium(ll)chloride (0.68 g, 0.96 mmol) and N-[2-methoxy-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]acetamide (6.73 g, 23.1 mmol), yield 3.39 g (40 %). 1H NMR (400 MHz, CDCI3) δ 8.44 (d, 1 H), 7.94 (d, 1 H), 7.86 (s, 1 H), 7.66 (d, 1 H), 7.34 (dd, 1 H), 6.98 (d, 1 H), 3.98 (s, 3H), 3.69 (m, 4H), 2.77 (m, 4H), 2.23 (s, 3H), 1 .67 (m, 1 H), 0.49 (m, 4H).
Example 68 (General Procedure I) N-{3-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]phenyl}acetamide
Figure imgf000105_0002
Step 1 : 1 -(5-Bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine
Figure imgf000106_0001
To a solution of 2,5-dibromo-4-methyl-pyridine (5.0 g, 20 mmol) and isopropyl-piperazine (25.6 g, 200 mmol) were added pyridine (2.06 g, 206 mmol). The reaction mixture was re- fluxed for 5 h under a nitrogen atmosphere. Brine was added and the mixture was extracted with EtOAc. The organic extract was washed with brine and 0.5 N hydrochloric acid. The acidic layer was made alkaline with Na2CO3 to pH 8 and then extracted with CH2CI2. The organic extract was dried (Na2SO4) and concentrated to give 5.4 g (90 %) of 1 -(5-bromo-4- methyl-pyridin-2-yl)-4-isopropyl-piperazine.
1H NMR (300 MHz, CDCI3) δ 8.15 (s, 1 H), 6.51 (s, 1 H), 3.50 (t, 4H), 2.81 -2.65 (m, 1 H), 2.61 (t, 4H), 2.29 (s, 3H), 1 .08 (d, 6H).
Step 2:
To a solution of 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine (0.59 g, 2 mmol) in
1 ,4-dioxane (12 ml_) and water (3 ml_) was added 3-acetylamino-phenylboronic acid (430 mg, 2.4 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol) and TEA (404 mg, 4 mmol). The resulting mixture was degassed and heated at 1000C for 4 h under a nitrogen atmosphere. The mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with CH2CVMeOH (100:1 ). This afforded 138 mg (15 %) of the title compound.
1H NMR (300 MHz, CDCI3) δ 8.00 (s, 1 H), 7.57-7.50 (m, 2H), 7.50-7.29 (m, 2H), 7.00 (d, 1 H),
6.52 (s, 1 H), 3.59 (t, 4H), 2.79-2.70 (m, 1 H), 2.66 (t, 4H), 2.30 (s, 3H), 2.16 (s, 3H), 1.10 (d,
6H).
HPLC (Method D): tr = 3.90 min (96 %).
Example 69 (General Procedure I) N-{3-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridin-3-yl]phenyl}acetamide
Figure imgf000107_0001
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-3-methyl-pyridin-2-yl)-4-isopropyl-piperazine and 3-acetylamino- phenylboronic acid. 1H NMR (300 MHz, CDCI3) δ 8.35 (d, 1 H), 7.77 (s, 1 H), 7.58 (d, 1 H),
7.46 (d, 2H), 7.35 (t, 1 H), 3.32 (t, 4H), 2.92-2.75 (m, 5H), 2.30 (s, 3H), 2.19 (s, 3H), 1 .14 (d,
6H).
HPLC (Method D): tr = 4.49 min (97 %).
Example 70 (General Procedure I) N-{4-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000107_0002
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine and 4-acetylamino- phenylboronic acid. 1H NMR (300 MHz, CD3OD) δ 7.91 (s, 1 H), 7.67 (d, 2H), 7.28 (d, 2H), 7.18 (s, 1 H), 4.75-3.35 (m, 9H), 2.35 (s, 3H), 2.14 (s, 3H), 1 .41 (d, 6H). HPLC (Method D): tr = 2.93 min (98 %).
Example 71 (General Procedure I)
N-{4-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000107_0003
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-3-methyl-pyridin-2-yl)-4-isopropyl-piperazine and 4-acetylamino- phenylboronic acid.
1H NMR (300 MHz, CD3OD) δ 8.37 (d, 1 H), 8.06 (s, 1 H), 7.68 (d, 2H), 7.58 (d, 2H), 3.99-3.71 (m, 2H), 3.62-3.55 (m, 3H), 3.52-3.31 (m, 4H), 2.44 (s, 3H), 2.13 (s, 3H), 1.42 (d, 6H). HPLC (Method E): tr = 3.53 min (98 %).
Example 72 (General Procedure I) N-{4-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridazin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000108_0001
Step 1 :
N-[4-(6-Chloro-5-methyl-pyridazin-3-yl)-phenyl]-acetamide and N-[4-(6-chloro-4-methyl- pyridazin-3-yl)-phenyl]-acetamide
Figure imgf000108_0002
A solution of 4-acetamidophenylboronic acid (2.7 g, 15 mmol), 3,6-dichloro-4-methyl- pyridazine (1 .6 g, 10 mmol) and Pd(PPh3)4 (1 .2 g, 1 mmol) in DMF (58 ml_, degassed) was stirred at rt for 1 h. Then sodium carbonate (3.9 g in 15 ml_ water, degassed) was added and the mixture was heated with stirring at 800C overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (30 ml_), washed with brine, dried (sodium sulfate) and concentrated to give a crude product, which was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1 :1 ). This afforded 1 g (39 %) of a mixture of N-[4-(6-chloro-5-methyl-pyridazin-3-yl)-phenyl]- acetamide and N-[4-(6-chloro-4-methyl-pyridazin-3-yl)-phenyl]-acetamide, which was used directly in the next step. Step 2:
The mixture of isomers (0.85 g, 3.2 mmol) from the previous step and 1 -isopropyl-piperazine (2.1 g, 16 mmol) was heated at 2000C under a nitrogen atmosphere for 1 h. The mixture was cooled to rt and diluted with dichloromethane (15 ml_). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give a crude product, which was purified by preparative HPLC Method F to give 261 mg (8 %) of N-{4-[6-(4-isopropyl-piperazin-1 -yl)-4- methyl-pyridazin-3-yl]-phenyl}-acetamide and 74 mg (2 %) of N-{4-[6-(4-isopropyl-piperazin- 1 -yl)-5-methyl-pyridazin-3-yl]-phenyl}-acetamide as the TFA salts. N-{4-[6-(4-isopropyl-piperazin-1 -yl)-4-methyl-pyridazin-3-yl]-phenyl}-acetamide: 1H NMR (300 MHz, CD3OD) δ 7.89 (s, 1 H), 7.82 (d, 2H), 7.56 (d, 2H), 4.70-3.30 (m, 9H), 2.44 (s, 3H), 2.17 (s, 3H), 1 .42 (d, 6H). HPLC (Method D): tr = 2.88 min (99 %).
Example 73 (General Procedure I) N-{3-[6-(4-Cyclopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]phenyl}acetamide, trif luoroacetate
Figure imgf000109_0001
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-cyclopropyl-piperazine and 3-acetylamino- phenylboronic acid. 1H NMR (300 MHz, CD3OD) δ 7.92 (s, 1 H), 7.72 (d, 1 H), 7.53-7.40 (m, 2H), 7.34 (s, 1 H), 7.10-7.05 (m, 1 H), 4.05-3.92 (m, 4H), 3.68-3.58 (m, 4H), 2.95-2.85 (m, 1 H), 2.39 (s, 3H), 2.13 (s, 3H), 1 .15-0.95 (m, 4H). HPLC (Method D): tr = 2.99 min (94 %).
Example 74 (General Procedure I) 3-[6-(4-Cyclopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]-N,N-dimethylbenzamide, trif luoroacetate
Figure imgf000109_0002
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-cyclopropyl-piperazine and 3-(N,N-dimethyl- amino-carbonyl)-phenylboronic acid. 1H NMR (300 MHz, CD3OD): δ 7.96 (s, 1 H), 7.62-7.52 (m, 1 H), 7.52-7.45 (m, 2H), 7.45-7.38 (m, 1 H), 4.05-3.88 (m, 4H), 3.68-3.55 (m, 4H), 3.11 (s, 3H), 3.03 (s, 3H), 2.95-2.85 (m, 1 H), 2.37 (s, 3H), 1 .15-0.95 (m, 4H). HPLC (Method D): tr = 3.04 min (98 %).
Example 75 (General Procedure I) N-{4-[6-(4-Cyclopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000110_0001
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-cyclopropyl-piperazine and 4-acetamido- phenylboronic acid. 1H NMR (300 MHz, CD3OD): δ 7.90 (s, 1 H), 7.67 (d, 2H), 7.35-7.22 (m, 3H), 4.05-3.88 (m, 4H), 3.68-3.55 (m, 4H), 2.95-2.82 (m, 1 H), 2.37 (s, 3H), 2.14 (s, 3H), 1 .15- 0.95 (m, 4H).
HPLC (Method D): tr = 2.68 min (99 %).
Example 76 (General Procedure I)
4-[6-(4-Cyclopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]-N,N-dimethylbenzamide, trifluoroace- tate
Figure imgf000110_0002
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(5-bromo-4-methyl-pyridin-2-yl)-4-cyclopropyl-piperazine and 4-(N, N- dimethylamino-carbonyl)-phenylboronic acid. 1H NMR (300 MHz, CD3OD): δ 7.95 (s, 1 H), 7.55 (d, 2H), 7.46 (d, 2H), 7.34 (s, 1 H), 4.05-3.88 (m, 4H), 3.68-3.55 (m, 4H), 3.12 (s, 3H), 3.04 (s, 3H), 2.97-2.85 (m, 1 H), 2.39 (s, 3H), 1 .18-0.95 (m, 4H). HPLC (Method D): tr = 3.04 min (94 %).
Example 77 (General Procedure I)
5-1 ,3-Benzodioxol-5-yl-2-(4-cyclopropylpiperazin-1 -yl)pyrimidine, dihydrochloride
Figure imgf000111_0001
The title compound was prepared by a similar procedure to that described in Example 68, starting from 5-bromo-2-(4-cyclopropyl-piperazin-1 -yl)-pyrimidine and 3,4-(methylenedioxy)- phenylboronic acid. Mp = 275-2790C.
1H NMR (300 MHz, DMSOd6) δ 1 1 .0 (brs, 1 H), 8.73 (s, 2H), 7.30 (s, 1 H), 7.14 (d, 1 H), 7.01
(d, 1 H), 6.06 (s, 2H), 4.76-4.71 (m, 2H), 3.58-3.18 (m, 6H), 2.91 -2.80 (m, 1 H), 1 .20-1.12 (m,
2H), 0.86-0.78 (m, 2H).
HPLC (Method Rx): tr = 11 .49 min (100 %).
Example 78 (General Procedure I)
N-{4-[6-(4-lsopropylperhydro-1 ,4-diazepin-1 -yl)pyridazin-3-yl]phenyl}acetamide, dihydrochloride
Figure imgf000111_0002
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(6-chloro-pyridazin-3-yl)-4-isopropyl-perhydro-1 ,4-diazepine and 4-acetamido- phenylboronic acid. 1H NMR (400 MHz, CD3OD) δ 8.43 (d, 1 H), 8.03 (d, 1 H), 7.94 (m, 2H), 7.84 (m, 2H), 4.36 (m, 1 H), 4.17 (m, 1 H), 4.03 (m, 1 H), 3.73 (m, 4H), 3.42 (m, 2H), 2.50 (m, 1 H), 2.39 (m, 1 H), 2.17 (s, 3H), 1 .41 (d, 6H). HPLC-MS (Method G): M+1 = 354; tr= 0.73 min.
Example 79 (General Procedure I) 4-[6-(4-lsopropyl-perhydro-1 ,4-diazepin-1 -yl)-pyridazin-3-yl]-phenylamine
Figure imgf000112_0001
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(6-chloro-pyridazin-3-yl)-4-isopropyl-perhydro-1 ,4-diazepine and 4-amino- phenylboronic acid, pinacol cyclic ester. 1H NMR (400 MHz, CDCI3) δ 7.82 (d, 2H), 7.53 (d, 1 H), 6.76 (m, 3H), 3.86 (t, 2H), 3.77 (m, 4H), 2.93 (heptet, 1 H), 2.81 (m, 2H), 2.58 (m, 2H), 1 .95 (m, 2H), 1.00 (d, 6H). HPLC-MS (Method G): M+1 = 312; tr= 0.61 min.
Example 80 (General Procedure I)
N-{4-[6-(4-Cyclopropyl-[1 ,4]diazepan-1 -yl)pyridazin-3-yl]phenyl}acetamide, dihydrochloride
Figure imgf000112_0002
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1 -(6-chloro-pyridazin-3-yl)-4-cyclopropyl-perhydro-1 ,4-diazepine and 4-acet- amidophenylboronic acid. 1H NMR (400 MHz, CD3OD) δ 8.47 (d, 1 H), 8.08 (d,1 H), 7.94 (d,
2H), 7.85 (d, 2H), 4.33 (broad m, 1 H), 4.12 (broad m, 1 H), 3.91 (broad m, 4H), 3.62 (broad m, 2H), 2.97 (hept, 1 H), 2.55 ((broad m, 1 H), 2.43 (broad m, 1 H), 2.17 (s, 3H), 1 .24 (broad m, 2H), 1 .01 (d, 2H).
HPLC-MS (Method G): M+1 = 352; tr= 0.82 min.
Example 81 (General Procedure I)
7-[6-(4-Cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-4-methyl-3,4-dihydro-2H-1 ,4-benzoxazine, dihydrochloride
Figure imgf000113_0001
The title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1 -yl)-pyridazine and 4-methyl-7-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1 ,4-benzoxazine. 1H NMR (400 MHz, DMSO-Cf6) δ 8.47 (d, 1 H), 8.04 (d, 1 H), 7.61 (m, 1 H), 7.49 (m, 1 H), 6.85 (d, 1 H), 4.50 (broad m, 2H), 4.26 (m, 2H), 3.61 (broad m, 4H), 3.40 (m, 4H), 2.97 (s, 3H), 2.88 (broad m, 1 H), 1 .23 (m, 2H), 0.82 (m, 2H). HPLC-MS (Method G): M+1 = 352; tr= 0.83 min.
Example 82 (General Procedure I)
3-(4-Cyclopropylpiperazin-1 -yl)-6-(2,3-dihydro-1 ,4-benzodioxin-6-yl)pyridazine, dihydrochlo- ride
Figure imgf000113_0002
The title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1 -yl)-pyridazine and 1 ,4-benzodioxane-6- boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1 H), 7.95 (d, 1 H), 7.63 (m, 1 H), 7.58 (m, 1 H), 7.05 (d, 1 H), 4.57 (broad m, 2H), 4.32 (m, 4H), 3.63 (broad m, 4H), 3.39 (broad m, 2H), 2.88 (broad m, 1 H), 1 .23 (m, 2H), 0.82 (m, 2H). HPLC-MS (Method G): M+1 = 339; tr= 0.84 min.
Example 83 (General Procedure I)
5-[6-(4-Cyclopropylpiperazin-1 -yl)pyridazin-3-yl]-1 H-indole, dihydrochloride
Figure imgf000114_0001
The title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1 -yl)-pyridazine and 5-indoleboronic acid. 1H NMR (400 MHz, DMSOd6) δ 1 1 .49 (s, 1 H), 8.43 (d, 1 H), 8.28 (s, 1 H), 7.93 (d, 1 H), 7.82 (dd, 1 H), 7.57 (d, 1 H), 7.48 (t, 1 H), 6.58 (s, 1 H), 4.54 (d, 2H), 3.70-3.45 (m, 4H), 3.45-3.30 (m, 2H), 2.88 (m,1 H), 1 .21 (m, 2H), 0.83 (m, 2H). HPLC-MS (Method G): M+1 = 320; tr= 0.75 min.
Example 84 (General Procedure I) {4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]phenyl}acetonitrile, dihydrochloride
Figure imgf000114_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 4-cyanomethyl- phenylboronic acid.
Example 85 (General Procedure I) N-{4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]phenyl}acetamide, dihydrochloride
Figure imgf000114_0003
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 4-acetamidophenyl- boronic acid. Mp > 2750C.
1H-NMR (400 MHz, CD3OD) δ 8.65 (s, 2H), 7.65 (d, 2H), 7.50 (d, 2H), 5.0 (m, 2H), 3.65-3.55 (m, 3H), 3.35-3.25 (m, 2H), 3.20-3.10 (m, 2H), 2.15 (s, 3H), 1.40 (d, 6H). HPLC-MS (Method G): M+1 = 340; tr= 0.919 min.
Example 86 (General Procedure I)
1 -{4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]phenyl}ethanone, dihydrochloride
Figure imgf000115_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 4-acetylphenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.75 (s, 2H), 8.10 (d, 2H), 7.70 (d, 2H), 5.10-5.00 (m, 2H),
3.65-3.55 (m, 3H), 3.40-3.30 (m, 2H), 3.25-3.15 (m, 2H), 2.65 (s, 3H), 1 .40 (d, 6H).
HPLC-MS (Method G): M+1 = 322; tr= 1 .07min.
Example 87 (General Procedure I)
2-(4-lsopropylpiperazin-1 -yl)-5-pyridin-3-ylpyrimidine, trihydrochloride
Figure imgf000115_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 3-pyridylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 9.15 (s, 1 H), 8.85 (s, 2H), 8.80 (m, 2H), 8.05 (m, 1 H), 5.15- 5.05 (m, 2H), 3.65-3.55 (m, 3H), 3.45-3.35 (m, 2H), 3.25-3.10 (m, 2H), 1 .40 (d, 6H). HPLC-MS (Method G): M+1 = 284; tr= 0.38 min.
Example 88 (General Procedure I) 2-(4-lsopropylpiperazin-1 -yl)-5-pyridin-4-ylpyrimidine, trihydrochloride
Figure imgf000116_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 4-pyridylboronic acid. 1H-NMR (400 MHz, CD3OD) δ 9.10 (s, 2H), 8.80 (d, 2H), 8.30 (d, 2H), 5.25-5.05 (m, 2H), 3.70-3.55 (m, 3H), 3.55-3.35 (m, 2H), 3.35-3.15 (m, 2H), 1 .40 (d, 6H). HPLC-MS (Method G): M+1 = 284; tr = 0.337 min.
Example 89 (General Procedure I) {4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]phenyl}dimethylamine, trihydrochloride
Figure imgf000116_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and N,N-dimethylamino- phenylboronic acid. 1H-NMR (400 MHz, CD3OD) δ 8.70 (s, 2H), 7.75 (d, 2H), 7.55 (d, 2H), 5.10-5.00 (m, 2H), 3.65-3.55 (m, 3H), 3.40-3.30 (m, 2H), 3.25 (s, 6H), 3.22-3.10 (m, 2H), 1 .40 (d, 6H). HPLC-MS (Method G): M+1 = 326; tr= 0.729 min.
Example 90 (General Procedure I) 3-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]-N,N-dimethylbenzamide, dihydrochloride
Figure imgf000116_0003
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-2-(4-isopropylpiperazin-1 -yl)-pyrimidine and 3-(dimethylamino- carbonyl)phenylboronic acid. Mp = 217-2200C. 1H-NMR (400 MHz, CD3OD) δ 8.70 (s, 2H), 7.70 (d, 1 H), 7.65 (s, 1 H), 7.55 (d,d, 1 H), 7.40 (d, 1 H), 5.05-4.95 (m, 2H), 3.65-3.55 (m, 3H), 3.35-3.25 (m, 2H), 3.20-3.10 (m, 2H), 3.12 (s, 3H), 3.05 (s, 3H), 1.40 (d, 6H). HPLC-MS (Method G): M+1 = 354; tr= 0.938 min.
Example 91 (General Procedure I)
N,N-Diisopropyl-4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)benzamide, hydrochloride
Figure imgf000117_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-diisopropyl- aminocarbonylphenylboronic acid.
1H NMR (400 MHz, DMSOd6) δ 8.63 (s, 1 H), 8.32 (s, 1 H), 8.00 (d, 1 H), 7.91 (s, 1 H), 7.55
(dd, 1 H); 7.33 (d, 1 H), 4.60-4.50 (m, 2H), 3.95-3.85 (m, 1 H), 3.70-3.60 (m, 1 H), 3.65-3.55 (m,
3H), 3.25-3.10 (m, 4H), 1 .60-1 .50 (brs, 6H), 1 .25-1 .10 (brs, 6H). HPLC-MS (Method G): M+1 = 410; tr= 1 .32 min.
Example 92 (General Procedure I)
[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-(4-methylpiperidin-1 -yl)- methanone, hydrochloride
Figure imgf000118_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and (4-methyl- piperidin-1 -yl)carbonylphenylboronic acid. 1H-NMR (400 MHz, CD3OD) δ 8.65 (s, 1 H), 8.35 (s, 1 H), 8.02 (d, 2H), 7.50 (d, 2H), 4.65-4.55 (m, 3H), 3.80-3.70 (m, 1 H), 3.65-3.55 (m, 3H), 1 .85-1 .75 (m, 1 H), 1 .75-1 .60 (m, 2H), 1 .40 (d, 6H), 1 .25-1 .05 (m, 2H), 0.95 (d, 3H). HPLC-MS (Method G): M+1 = 408; tr= 1 .31 min.
Example 93 (General Procedure I)
4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-N,N-dimethylbenzamide, hydrochloride
Figure imgf000118_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-dimethyl- aminocarbonylphenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.65 (s, 1 H), 8.35 (s, 1 H), 8.02 (d, 2H), 7.53 (d, 2H), 4.65-4.55
(m, 2H), 3.65-3.55 (m, 3H), 3.35-3.15 (m, 4H), 3.13 (s, 3H), 3.04 (s, 3H), 1.40 (d, 6H).
HPLC-MS (Method G): M+1 = 354; tr= 0.93 min.
Example 94 (General Procedure I)
[3-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]morpholin-4-ylmethanone, hydrochloride
Figure imgf000119_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and N-(morpholin-4- yl) 3-boronobenzamide. 1H-NMR (400 MHz, CD3OD) δ 8.70 (s, 1 H), 8.45 (s, 1 H), 8.07 (d, 1 H), 8.01 (s, 1 H), 7.58 (dd, 1 H), 7.45 (d, 1 H), 4.75-4.65 (m, 2H), 3.85-3.43 (m, 11 H), 3.40-3.20 (m, 4H), 1.40 (d, 6H).
Example 95 (General Procedure I) N-{4-[5-(Octahydropyrido[1 ,2-a]pyrazin-2-yl)pyrazin-2-yl]phenyl}acetamide, hydrochloride
Figure imgf000119_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 2-(5-bromopyrazin-2-yl)octahydropyrido[1 ,2-a]pyrazine and 4-acetamidophenyl- boronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.95 (s, 1 H), 8.47 (s, 1 H), 7.85 (d, 2H), 7.80 (d, 2H), 4.80-4.60 (m, 2H), 3.60-3.50 (m, 3H), 3.45-3.29 (m, 3H), 3.15-3.00 (m, 1 H), 2.15 (s, 3H), 2.10-2.05 (m,
1 H), 2.02-1 .90 (m, 3H), 1 .79-1 .62 (m, 2H).
HPLC-MS (Method G): M+1 = 352; tr= 0.92 min.
Example 96 (General Procedure I) 4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenol, dihydrochloride
Figure imgf000119_0003
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-hydroxy- phenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 9.08 (s, 1 H), 8.45 (s, 1 H), 7.75 (d, 2H), 7.0 (d, 2H), 4.72 (d, 2H), 3.7-3.5 (m, 4H), 3.3 (m, 3H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 299; tr= 1 .045 min.
Example 97 (General Procedure I)
N-[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-N-methylamine, tritrifluoroacetate
Figure imgf000120_0001
Step 1 :
[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]methylcarbamic acid tert- butyl ester, trifluoroacetate
Figure imgf000120_0002
[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]methylcarbamic acid tert- butyl ester, trifluoroacetic acid was prepared by a similar procedure to that described in Example 59, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and tert- butyl-N-methyl-N-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-carbamate. 1H-NMR (400 MHz, CDCI3) δ 8.5 (s, 1 H), 8.15 (s, 1 H), 7.85 (d, 2H), 7.25 (d, 2H), 3.65 (m, 4H), 3.45 (s, 3H), 2.7 (hept, 1 H), 2.6 (m, 4H), 1 .45 (s, 9H), 1 .1 (d, 6H). HPLC-MS (Method G): M+1 = 412; tr= 1 .60 min.
Step 2: [4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]methylcarbamic acid tert- butyl ester (0.38 g, 0.92 mmol) was dissolved in DCM (10 ml_) and TFA (10 ml_) was added. The reaction mixture was stirred at rt for 2 h and then evaporated in vacuo. The solid residue (20 mg) was purified by preparative HPLC Method B. 1H-NMR (400 MHz, CDCI3) δ 8.5 (s, 1 H), 8.2 (s, 1 H), 8.0 (brs, 1 H), 7.8 (d, 2H), 7.35 (d, 2H), 4.45 (d, 2H), 3.7 (m, 2H), 3.65 (hept, 1 H), 3.45 (m, 4H), 3.1 (s, 3H), 3.0 (m, 2H), 1.4 (d, 6H). HPLC-MS (Method G): M+1 = 312; tr= 0.909 min.
Example 98 (General Procedure I) 4-lsopropyl-5'-(4-morpholin-4-ylphenyl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trihydrochloride
Figure imgf000121_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-morpholino- phenylboronic acid.
1 H-NMR (400 MHz, CD3OD) δ 8.90 (s, 1 H), 8.68 (s, 1 H), 8.18 (d, 2H), 8.01 (d, 2H), 4.81 -4.75 (m, 2H), 4.20 (m, 4H), 3.80 (m, 4H), 3.76-3.65 (m, 5H), 3.44-3.32 (m, 2H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 368; tr= 1 .021 min.
Example 99 (General Procedure I)
5'-1 ,3-Benzodioxol-5-yl-4-isopropyl-3,4,5,6-tetrahydro-2H-1 ,2'-bipyrazinyl, dihydrochloride.
Figure imgf000121_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 3,4-methylene- dioxyphenylboronic acid. 1 H-NMR (400 MHz, CD3OD) δ 8.70 (s, 1 H), 8.47 (s, 1 H), 7.40 (m, 2H), 6.95 (d, 1 H), 6.03 (s, 2H), 4.70-4.62 (m, 2H), 3.67-3.57 (m, 3H), 3.42-3.32 (m, 2H), 3.31 -3.21 (m, 2H), 1 .45 (d, 6H).
HPLC-MS (Method G): M+1 = 327; tr = 1 .1 15 min.
Example 100 (General Procedure I)
4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-2-methoxyphenylamine, trihydrochloride
Figure imgf000122_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-Bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-amino-3- methoxyphenylboronic acid pinacol ester.
1H-NMR (400 MHz, CD3OD) δ 8.80 (s, 1 H), 8.50 (s, 1 H), 7.80 (s, 1 H), 7.65 (d, 1 H), 7.50 (s, 1 H), 4.75-4.65 (m, 2H), 4.10 (s, 3H), 3.70-3.60 (m, 3H), 3.55-3.45 (m, 2H), 3.35-3.25 (m, 2H), 1 .45 (d, 6H).
HPLC-MS (Method G): M+1 = 328; tr= 0.676 min.
Example 101 (General Procedure I)
2-Chloro-4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-6-methoxyphenol, dihydrochloride
Figure imgf000122_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 3-chloro-4- hydroxy-5-methoxyphenylboronic acid. 1H-NMR (400 MHz, CD3OD) δ 8.85 (s, 1 H), 8.38 (s, 1 H), 7.48 (s, 1 H), 7.43 (s, 1 H), 4.73-4.65 (m, 2H), 4.00 (s, 3H), 3.70-3.60 (m, 3H), 3.58-3.46 (m, 2H), 3.35-3.25 (m, 2H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 363, rt= 1 .066 min.
Example 102 (General Procedure I)
5'-(3,4-Dimethoxyphenyl)-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, dihydrochloride
Figure imgf000123_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 3,4-dimethoxy- phenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.65 (s, 1 H), 8.3 (s, 1 H), 7.55 (brs, 1 H), 7.45 (dd, 1 H), 7.05
(dd, 1 H), 4.6 (d, 2H), 3.9 (s, 3H), 3.85 (s, 3H), 3.6 (m, 3H), 3.35 (m, 2H), 3.2 (m, 2H), 1 .45 (d,
6H).
13C-NMR (400 MHz, CD3OD) δ 154.38, 151 .64, 151.25, 143.61 , 140.62, 130.88, 130.66, 120.21 , 1 13.47, 11 1.03, 60.43, 56.92, 48.79, 43.77, 17.53.
HPLC-MS (Method G): M+1 = 343; tr= 1 .051 min.
Example 103 (General Procedure I)
4-lsopropyl-5'-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, dihydrochloride
Figure imgf000123_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 3,4,5-tri- methoxyphenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.93 (s, 1 H), 8.40 (s, 1 H), 7.20 (s, 2H), 4.73-4.68 (m, 2H), 3.95 (s, 6H), 3.81 (s, 3H), 3.70-3.60 (m, 3H), 3.57-3.47 (m, 2H), 3.35-3.25 (m, 2H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 373; tr= 1 .106 min.
Example 104 (General Procedure I) N-[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)benzyl]acetamide, dihydrochlo- ride
Figure imgf000124_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-(N-acetyl- aminomethyl)phenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.65 (s, 1 H), 8.45 (s, 1 H), 7.85 (d, 2H), 7.35 (d, 2H), 4.6 (d, 2H), 4.4 (s, 2H), 3.6 (m, 3H), 3.1 -3.4 (m, 4H), 2.05 (s, 3H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 354; tr= 0.867 min.
Example 105 (General Procedure I)
4,4"'-Diisopropyl-3,4,5,6,3"',4"',5"',6"'-octahydro-2H,2"'H-[1 ,2';5',2";5",1 "']quaterpyrazine, ditrifluoroacetate
Figure imgf000124_0002
The title compound was isolated as a by-product in Example 104.
1H-NMR (400 MHz, CD3OD) δ 8.9 (s, 1 H), 8.35 (s, 1 H), 4.65 (d, 2H), 3.65 (m, 3H), 3.15-3.4 (m, 5H), 1.4 (d, 6H).
13C-NMR (400 MHz, CD3OD) δ 155.04, 141 .60, 140.50, 131 .63, 60.40, 48.62, 43.62, 17.45.
Example 106 (General Procedure I)
4-lsopropyl-5'-(6-methoxypyridin-3-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trifluoroacetate
Figure imgf000125_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 2-methoxy-5- pyridineboronic acid.
1H NMR (400 MHz, CDCI3) δ 8.75 (dd, 1 H), 8.46 (dd, 1 H), 8.22 (s, 1 H), 8.2 (dd, 1 H), 7.42
(brs, 3 H), 6.93 (d, 1 H), 4.49 (d, 2 H), 4.08 (s, 3 H), 3.72-3.41 (m, 5H), 3.20-2.79 (m, 2H),
1 .39 (d, 6H). 13C-NMR (400 MHz, CDCI3) δ 161 .82, 150.81 , 141 .04, 137.90, 136.58, 136.12, 128.39,
124.52, 109.14, 56.50, 52.87, 48.49, 45.57, 40.21 , 14.72.
HPLC-MS (Method G): M+1 = 314; tr= 0.965 min.
Example 107 (General Procedure I) N,N-Diisopropyl-4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzamide, dihydrochloride
Figure imgf000125_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 1 -(5-bromo-pyridin-2-yl)-4-isopropyl-piperazine and 4-((N,N-diisopropylamino)- carbonyl)phenylboronic acid. 1H-NMR (400 MHz, CD3OD) δ 8.5 (dd, 1 H), 8.45 (d, 1 H), 7.75 (d, 2H), 7.15 (d, 1 H), 7.45 (d, 2H), 4.55 (d, 2H), 3.6-3.9 (m, 7H), 3.4 (t, 2H), 1.55 (m, 6H), 1 .45 (d, 6H), 1 .15 (m, 6H). HPLC-MS (Method G): M+1 = 409; tr= 1 .229 min.
Example 108 (General Procedure I)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}-(4-methylpiperidin-1 -yl)methanone, dihydrochloride
Figure imgf000126_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 1 -(5-bromo-pyridin-2-yl)-4-isopropyl-piperazine and 4-((4-methylpiperdin-1 -yl)- carbonyl)phenylboronic acid.
1H NMR (400 MHz, CDCI3) δ (d, 1 H), 7.75 (dd, 2H), 7.55 (d, 2H), 7.45 (d, 2H), 6.7 (d, 1 H),
4.65 (brs, 1 H), 3.75 (brs, 1 H), 3.6 (t, 4H), 3.0 (brs, 1 H), 2.75 (hept, 1 H), 2.7 (t, 4H), 1.85-1 .6
(m, 3H), 1.4-1.15 (m, 2H), 1 .1 (d, 6H), 0.95 (d, 3H). 13C-NMR (400 MHz, CDCI3) δ 170.10, 158.82, 147.90, 146.18, 139.50, 135.96, 134.57,
132.00, 128.42, 127.61 , 125.91 , 125.06, 106.74, 54.64, 54.55, 48.47, 48.37, 48.16, 45.38,
44.88, 42.56, 34.71 , 33.87, 31.15, 21.75, 18.50, 18.43.
HPLC-MS (Method G): M+1 = 407; tr= 1 .20 min.
Example 109 (General Procedure I)
6'-(4-lsopropylpiperazin-1 -yl)-6-methoxy-[3,3']bipyridinyl, trifluroacetate
Figure imgf000126_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 2-methoxy-5- pyridineboronic acid. 1H-NMR (400 MHz, CD3OD) δ 8.5 (d, 1 H), 8.37 (m, 2H), 8.15 (d, 1 H), 7.55 (d, 1 H), 7.05 (d, 1 H), 4.5 (m, 2H), 4.05 (s, 3H), 3.4-3.9 (m, 6H), 1 .45 (d, 6H).
13C-NMR (400 MHz, CD3OD) δ 165.51 , 154.05, 144.56, 143.82, 140.69, 137.18, 126.29, 125.93, 1 14.58, 112.86, 60.68, 55.97, 48.93, 45.24, 17.74.
Example 110 (General Procedure I) 4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)benzonitrile, ditrifluoroacetate
Figure imgf000127_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-cyanophenyl- boronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.75 (s, 1 H), 8.45 (s, 1 H), 8.1 (d, 2H), 7.75 (d, 2H), 4,7 (m, 2H), 3.6 (m, 3H), 3.2-3.5 (m, 4H), 1 .4 (d, 6H).
Example 111 (General Procedure I)
4-lsopropyl-5'-(4-trifluoromethylphenyl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trifluoroacetate
Figure imgf000127_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-(trifluoro- methyl)phenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.75 (s, 1 H), 8.45 (s, 1 H), 8.15 (d, 2H), 7.75 (d, 2H), 4.7 (m,
2H), 3.7-3.55 (m, 3H), 3.4-3.15 (m, 4H), 1 .4 (d, 6H).
13C-NMR (400 MHz, CD3OD) δ 169.07, 154.98, 142.12, 140.85, 132.28, 127.54, 127.19, 60.417, 43.55, 17.45. HPLC-MS (Method G): M+1 = 351 ; tr= 1 .523 min.
Example 112 (General Procedure I) 6'-(4-lsopropylpiperazin-1 -yl)-5-trifluoromethyl-[2,3']bipyridinyl, dihydrochloride
Figure imgf000128_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 1 -[5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-pyridin-2-yl]-4-isopropyl-piperazine and 2-bromo-5-trifluoromethylpyridine.
1H-NMR (400 MHz, CDCI3) δ 8.85 (d, 1 H), 8.8 (d, 1 H), 8.2 (dd, 1 H), 7.9 (dd, 1 H), 7.7 (d, 1 H), 6.65 (d, 1 H), 3.65 (m, 4H), 2.75 (hept, 1 H), 2.6 (m, 4H), 1.1 (d, 6H). HPLC-MS (Method G): M+1 = 351 ; tr= 1 .203 min.
Example 113 (General Procedure I)
4-lsopropyl-5'-[4-(piperidine-1 -sulfonyl)phenyl]-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, hydro- chloride
Figure imgf000128_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-(piperidine-1 - sulfonyl)phenylboronic acid. 1H-NMR (400 MHz, CD3OD) δ 8.75 (s,1 H), 8.45 (s, 1 H), 8.18 (d, 2H), 7.82 (d, 2H), 4.75-4.68 (m, 2H), 3.80-3.55 (m, 4H), 3.45-3.22 (m, 4H), 3.00 (m, 4H), 1 .68-1 .60 (m, 4H), 1 .45 (m, 7H).
Example 114 (General Procedure I) 4-lsopropyl-5'-(4-(piperidin-1 -yl)phenyl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, tri- hydrochloride
Figure imgf000129_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-(piperindin-1 -yl)phenyl- boronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.80 (s,1 H), 8.52 (s, 1 H), 8.18 (d, 2H), 7.89 (d, 2H), 4.77-4.68 (m, 2H), 3.74-3.60 (m, 7H), 3.58-3.46 (m, 2H), 3.35-3.25 (m, 2H), 2.17-2.08 (m, 4H), 1 .90- 1 .80 (m, 2H), 1.45 (d, 6H). HPLC-MS (Method G): M+1 = 366; tr= 0.798 min.
Example 115 (General Procedure I)
[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-2-methylphenyl]dimethylamine, trihydrochloride
Figure imgf000129_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 4-(dimethylamino)-3- methylphenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.80 (s, 1 H), 8.50 (s, 1 H), 8.05 (m, 2H), 7.87 (d, 1 H), 4.75- 4.68 (m, 2H), 3.70-3.58 (m, 3H), 3.54-3.43 (m, 2H), 3.37 (s, 6H), 3.33-3.22 (m, 2H), 2.65 (s,
3H),1 .45 (d, 6H).
HPLC-MS (Method G): M+1 = 340; tr= 0.718 min.
Example 116 (General Procedure I) 5'-(6-Ethoxypyridin-3-yl)-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trihydrochloride
Figure imgf000130_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-3 ,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 2-ethoxy-5-pyridineboronic acid.
1H-NMR (400 MHz, CDCI3) δ 8.62 (s, 1 H), 8.45 (s, 1 H), 8.19 (s, 1 H), 8.10 (d, 1 H), 6.80 (d, 1 H), 4.40 (q, 4H), 3.65 (m, 4H), 2.75 (m, 1 H), 2.65 (m, 4H), 1 .42 (t, 3H), 1 .10 (d, 6H). HPLC-MS (Method G): M+1 = 328; tr= 1 .122 min.
Example 117 (General Procedure I)
5'-Benzofuran-2-yl-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, dihydrochloride
Figure imgf000130_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 2-benzofuranboronic acid. 1H-NMR (400 MHz, DMSO-Cf6) δ 8.70 (s, 1 H), 8.55 (s, 1 H), 7.70-7.60 (m, 2H), 7.47 (s, 1 H), 7.46-7.25 (m, 2H), 4.63-4.55 (m, 2H), 3.60-3.45 (m, 5H), 3.18-3.06 (m, 2H), 1 .32 (d, 6H). HPLC-MS (Method G): M+1 = 323; tr= 1 .354 min.
Example 118 (General Procedure I) 5-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)thiophene-2-carbonitrile, ditrifluoro- acetate
Figure imgf000131_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 5-cyano-2-thiophene- boronic acid. 1H-NMR (400 MHz, CD3OD) δ 8.70 (s, 1 H), 8.33 (s, 1 H), 7.72 (d, 1 H), 7.61 (d, 1 H), 4.75-4.65 (m, 2H), 3.70-3.55 (m, 3H), 3.40-3.20 (m, 4H), 1 .42 (d, 6H). HPLC-MS (Method G): M+1 = 314; tr= 1 .147 min.
Example 119 (General Procedure I) 4-lsopropyl-5'-(2-methylpyridin-4-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trihydrochloride
Figure imgf000131_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 5-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl and 2-methyl-4-pyridineboronic acid. 1H-NMR (400 MHz, CD3OD) δ 9.05 (s, 1 H), 8.65 (d, 1 H), 8.60 (s, 1 H), 8.50 (s, 1 H), 8.45 (d, 1 H), 4.90-4.82 (m, 2H), 3.70-3.50 (m, 5H), 3.35-3.24 (m, 2H), 2.83 (s, 3H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 298; tr= 0.413 min.
Example 120 (General Procedure I) (R)-2-(6-1 ,3-Benzodioxol-5-ylpyridazin-3-yl)octahydropyrido[1 ,2-a]pyrazine, dihydrochloride
Figure imgf000131_0003
The title compound was prepared by a similar procedure to that described in Example 57, starting from (R)-2-(6-chloropyridazin-3-yl)octahydropyrido[1 ,2-a]pyrazine and 3,4- methylenedioxyphenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.45 (brs, 1 H), 8.20 (brs, 1 H), 7.50 (d, 1 H), 7.47 (s, 1 H), 7.10 (d, 1 H), 6.15 (s, 2H), 4.75-4.55 (m, 2H), 3.80-3.30 (m, 6H), 3.20-3.05 (m, 1 H), 2.15-1.92 (m, 4H), 1 .85-1 .65 (m, 2H). HPLC-MS (Method G): M+1 = 339; tr= 0.827 min.
Example 121 (General Procedure I) 4-lsopropyl-5'-(5-trif luoromethyl-pyridin-2-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trifluoroacetate
Figure imgf000132_0001
5-Bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl (0.50 g, 1 .75 mmol) was dissolved in dry THF and cooled to -780C under an atmosphere of nitrogen. A 1 .6 N solution of n-butyl lithium in hexanes (0.124 g, 1 .93 mmol) was added keeping the temperature below -600C. Tributyltin chloride (0.628 g, 1 .93 mmol) was added and the reaction mixture was allowed to reach rt. The reaction mixture was transferred to a 5 ml_ microwave vial and 2-bromo-5-trifluromethyl- pyridine (0.33 g, 1 .93 mmol), triphenylphosphinpalladium(ll)dichloride (0.088 g, 0.0615 mmol), caesium fluoride (0.581 g, 3.85 mmol) and TEA (0.389 g, 0.385 mmol) were added. This reaction mixture was heated 1.6 h at 1000C in a microwave oven. The reaction mixture was evaporated in vacuo and the oily residue was purified on a silica gel column with DCM/MeOH (9:1 ) as eluent. The product isolated was treated with HCI in diethyl ether followed by evaporation. This afforded 49 mg (9 %) of the title compound. HPLC-MS (Method G): M+1 = 352; tr= 1 .29 min.
Example 122 (General Procedure I) N-{4-[6-(4-Cyclobutylpiperazin-1 -yl)pyridin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000133_0001
The title compound was prepared by a similar procedure to that described in Example 59, starting from 1 -(5-bromo-pyridin-2-yl)-4-cyclobutyl-piperazine and 4-acetamidophenylboronic acid. 1H-NMR (400 MHz, DMSO-c(6) δ 8.48 (d, 1 H), 7.92 (dd, 1 H), 7.65 (d, 2H), 7.55 (d, 2H), 7.05 (d, 1 H), 4.5 (d, 2H), 3.75 (pent, 1 H), 3.45 (d, 2H), 3.15 (m, 2H), 2.9 (m, 2H), 2,2 (m, 4H), 2.05 (s, 3H), 1 .75 (m, 2H). HPLC-MS (Method G): M+1 = 351 ; tr= 0.74 min.
Example 123 (General Procedure I)
4-[6-(4-Cyclobutyl-piperazin-1 -yl)-pyridin-3-yl]-N,N-dimethyl-benzamide, trifluoroacetate
Figure imgf000133_0002
The title compound was prepared by a similar procedure to that described in Example 57, starting from 1 -(5-bromo-pyridin-2-yl)-4-cyclobutyl-piperazine and 4-(dimethylaminocarbonyl)- phenylboronic acid.
1H-NMR (400 MHz, CD3OD) δ 8.45 (d, 1 H), 8.1 (dd, 1 H), 7.65 (d, 2H), 7.5 (dd, 2H), 7.18 (d, 1 H), 3.2-4.5 (m, 8H), 3.1 (s, 3H), 3.0 (s, 3H), 2.3 (m, 4H), 1 .8-1 .95 (m, 2H). HPLC-MS (Method G): M+1 = 365; tr= 0.931 min.
Example 124 (General Procedure I)
N-{4-[6-(4-Cyclobutylpiperazin-1 -yl)pyridazin-3-yl]-2-methoxyphenyl}acetamide, dihydrochlo- ride
Figure imgf000134_0001
The title compound was prepared by a similar procedure to that described in Example 57, starting from 3-chloro-6-(4-cyclobutyl-piperazin-1 -yl)-pyridazine and N-[2-methoxy-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]acetamide.
1H-NMR (400 MHz, CD3OD) δ 8.57 (d, 1 H), 8.42 (d, 1 H), 8.20 (d, 1 H), 7.62 (s, 1 H), 7.54 (d,
1 H), 4.70-4.60 (m, 2H), 4.05 (s, 3H), 3.86-3.75 (m, 1 H), 3.74-3.60 (m, 4H), 3.20-3.10 (m,
2H), 2.50-2.32 (m, 4H), 2.23 (s, 3H), 2.00-1.81 (m, 2H).
HPLC-MS (Method G): M+1 = 382; tr= 0.787 min.
Example 125 (General Procedure J)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroace- tate
Figure imgf000134_0002
Step 1 :
4-[6-(4-lsopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzonitrile
Figure imgf000134_0003
To a solution of 4-(6-chloro-pyridazin-3-yl)-benzonitrile (20 g, 92.8 mmol) in 1 -butanol (150 ml_) was added 1 -isopropyl-piperazine hydrochloride (29.8 g, 148.5 mmol) and NH4CI (4.96 g, 92.8 mmol). The reaction mixture was heated at reflux for 48 h and then concentrated under reduced pressure. The residue was dissolved into a 10% solution of citric acid in water and filtered. Solid K2CO3 was added to the filtrate until pH 9. The precipitate was isolated and washed with water to give 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzonitrile (20 g, 70 %).
Step 2:
4-[6-(4-lsopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzoic acid, hydrochloride
Figure imgf000135_0001
4-[6-(4-lsopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzonitrile (10 g, 32.6 mmol) was dissolved in 6 N hydrochloric acid (100 ml_). The reaction mixture was heated at reflux for 6 h and con- centrated under reduced pressure to give 10.3 g (79 %) 4-[6-(4-isopropyl-piperazin-1 -yl)- pyridazin-3-yl]-benzoic acid, hydrochloride.
Step 3:
To a solution of 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzoic acid, hydrochloride (2 g, 5 mmol) in CH2CI2 was added EDAC (1 .91 g, 10 mmol) and HOBt (0.81 g, 6 mmol) followed by piperidine (2.56 g, 30 mmol). The reaction mixture was stirred for 60 h at rt and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with CH2CI2 on silica gel to give a crude product, which was further purified by HPLC (Method F) to give 850 mg (43 %) of the title compound as a TFA salt. 1H NMR (300 MHz, D2O) δ 8.25 (d, 1 H), 7.90 (d, 1 H), 7.84 (d, 2H), 7.50 (d, 2H), 4.51 -4.48 (m, 2H), 3.59-3.42 (m, 7H), 3.40-3.16 (m, 4H), 1 .57-1 .49 (m, 4H), 1 .45-1 .34 (m, 2H), 1 .34 (d, 6H). HPLC (Method D): tr = 2.94 min (98 %).
Example 126 (General Procedure J)
{4-[6-(4-Cyclopropylmethylpiperazin-1 -yl)pyridazin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroacetate
Figure imgf000136_0001
The title compound was prepared by a similar procedure to that described in Example 125 starting from 4-[6-(4-cyclopropylmethyl-piperazin-1 -yl)-pyridazin-3-yl]-benzoic acid, hydrochloride and piperidine. 1H NMR (300 MHz, CDCI3) δ 8.24 (d, 1 H), 7.91 -7.81 (m, 3H), 7.48 (d, 2H), 4.48-4.43 (m, 2H), 3.76-3.69 (m, 2H), 3.53-3.43 (m, 4H), 3.30-3.09 (m, 4H), 3.02 (d, 2H), 1 .53-1.39 (m, 6H), 1 .07-0.92 (m, 1 H), 0.63 (d, 2H), 0.27 (d, 2H). HPLC (Method D): tr = 3.04 min (98 %).
Example 127 (General Procedure J)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}morpholin-4-ylmethanone, trifluoroace- tate
Figure imgf000136_0002
To a solution of 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzoic acid, hydrochloride (2 g, 5 mmol) in CH2CI2 was added EDAC (1 .91 g, 10 mmol) and HOBt (0.81 g, 6 mmol).
Then morpholine (2.61 g, 30 mmol) was added. The reaction mixture was stirred for 60 h at rt and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the product, which was further purified by HPLC Method F. This afforded 600 mg (30 %) of the title compound as a TFA salt. 1H NMR (300 MHz, D2O) δ 8.26 (d, 1 H), 7.91 (d, 1 H), 7.84 (d, 2H), 7.53 (d, 2H), 4.56-4.46 (m, 2H), 3.76-3.63 (m, 4H), 3.57-3.41 (m, 7H), 3.36-3.35 (m, 2H), 3.22-3.14 (m, 2H), 1 .20 (d, 6H). HPLC (Method E): tr = 2.28 min (95 %).
Example 128 (General Procedure J) (4-Hydroxymethylpiperidin-1 -yl)-{4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}- methanone, trifluoroacetate
Figure imgf000137_0001
To a solution of 4-[6-(4-isopropylpiperazin-1 -yl)-pyridazin-3-yl]-benzoic acid, hydrochloride (2.0 g, 5.0 mmol) in CH2CI2 was added EDAC (1 .91 g, 10 mmol) and HOBt (0.81 g, 6 mmol). Then a solution of 4-hydroxymethyl-piperidine (2.56 g, 30 mmol) in CH2CI2 (I O ml) was added. The mixture was stirred for 60 h at rt and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with CH2CI2 to give a crude product, which was further purified by HPLC Method F. This afforded 580 mg (28 %) of the title compound as a TFA salt.
HPLC (Method D): tr = 2.32 min (95 %).
Example 129 (General Procedure J)
4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000137_0002
To a solution of 4-[6-(4-isopropylpiperazin-1 -yl)-pyridazin-3-yl]-benzoic acid, hydrochloride (2 g, 5 mmol) in CH2CI2 was added EDAC (1 .91 g, 10 mmol), HOBt (0.81 g, 6 mmol) and TEA (4.04 g, 40 mmol). Then dimethylamine, hydrochloride (1 .63 g, 20 mmol) was added. The reaction mixture was stirred for 60 h at rt and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with CH2CI2 to give a crude product, which was further purified by HPLC Method F. This afforded 800 mg (45 %) of the title compound as a TFA salt.
1H NMR (300 MHz, D2O) δ 8.26 (d, 1 H), 7.90 (d, 1 H), 7.82 (d, 2H), 7.50 (d, 2H), 4.56-4.47 (m, 2H), 3.57-3.40 (m, 5H), 3.22-3.09 (m, 2H), 2.96 (m, 3H), 2.85 (m, 3H), 1 .23 (d, 6H). HPLC (Method E): tr = 2.25 min (97 %).
Example 130 (General Procedure J)
{4-[6-(4-Cyclopentylpiperazin-1 -yl)pyridazin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroace- tate
Figure imgf000138_0001
To a solution of 4-[6-(4-cyclopentyl-piperazin-1 -yl)-pyridazin-3-yl]-benzoic acid, hydrochloride (2 g, 5 mmol) in CH2CI2 was added EDAC (1 .91 g, 10 mmol), HOBt (0.81 g, 6 mmol). Then piperidine (2.52 g, 30 mmol) was added. The reaction mixture was stirred for 60 h at rt and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with CH2CI2 to give crude product, which was further purified by HPLC Method F to give 600 mg (29 %) of the title compound as a TFA salt. 1H NMR (300 MHz, D2O) δ 8.18 (d, 1 H), 7.80-7.83 (m, 3H), 7.47 (d, 2H), 4.44 (m, 2H), 3.1 - 3.7 (m, 11 H), 2.03 (m, 2H), 1.39-1 .64 (m, 12H). HPLC (Method D): tr = 3.27 min (95 %).
Example 131 (General Procedure J)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}-(4-methylpiperazin-1 -yl)methanone, trifluoroacetate
Figure imgf000138_0002
To a solution of 4-[6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]benzoic acid, hydrochloride (2 g, 5 mmol) in CH2CI2 was added EDAC (1 .91 g, 10 mmol) and HOBt (0.81 g, 6 mmol). Then 1 -methyl-piperazine (2.0 g, 20 mmol) was added. The reaction mixture was stirred for 60 h at rt and concentrated under reduced pressure. The residue was purified by column chromatog- raphy eluting with CH2CI2 on silica gel to give crude product, which was further purified by HPLC Method F. This afforded 300 mg (15 %) of the title compound as a TFA salt. 1H NMR (300 MHz, D2O) δ 8.01 (d, 1 H), 7.85 (d, 2H), 7.59-7.49 (m, 3H), 4.47-4.43 (m, 2H), 3.90-3.84 (m, 1 H), 3.50-3.05 (m, 14H), 2.81 (m, 3H), 1 .23 (d, 6H). HPLC (Method D): tr = 3.04 min (96 %).
Example 132 (General Procedure J)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}morpholin-4-ylmethanone, trifluoroacetate
Figure imgf000139_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and morpholine.
1H NMR (300 MHz, D2O) δ 8.27 (dd, J=2.4 Hz, J=9.6 Hz, 1 H) 8.20 (d, J=2.4 Hz, 1 H), 7.62 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.32 (d, J=9.6 Hz, 1 H), 4.34-4.30 (m, 2H), 3.73-3.50 (m, 1 1 H), 3.46-3.41 (m, 2H), 3.25 (m, 2H), 1 .29 (d, J=6.6 Hz, 6H). HPLC (Method D): tr = 3.75 min (93 %).
Example 133 (General Procedure J) 4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000139_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and dimethylamine, hydrochloride. 1H NMR (300 MHz, D2O) δ 8.28 (dd, J = 2.1 Hz, J = 9.3 Hz, 1 H), 8.20 (d, J = 2.1 Hz, 1 H), 7.6 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 9.3 Hz, 1 H), 4.35-4.30 (m, 2H), 3.64-3.51 (m, 5H), 3.29-3.26 (m, 2H), 3.02 (s, 3H), 2.91 (s, 3H), 1 .23 (d, J = 7.2 Hz, 6H). HPLC (Method D): tr = 3.73 min (96 %).
Example 134 (General Procedure J) {4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroacetate
Figure imgf000140_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and piperidine.
1H NMR (300 MHz, D2O) δ 8.29 (dd, J=2.4 Hz, J=9.6 Hz, 1 H), 8.15 (d, J=1.8 Hz, 1 H), 7.58 (d, J=8.7 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.34 (d, J=9.6 Hz, 1 H), 4.32-4.27 (m, 2H), 3.62- 3.48 (m, 7H), 3.28-3.19 (m, 4H), 1 .53 (m, 4H), 1 .38 (m, 2H), 1 .26 (d, J=6.6 Hz, 6H). HPLC (Method D): tr = 4.43 min (95 %).
Example 135 (General Procedure J)
(4-Hydroxymethylpiperidin-1 -yl)-{4-[6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}- methanone, trifluoroacetate
Figure imgf000140_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and 4- hydroxymethyl-piperidine.
1H NMR (300 MHz, D2O) δ 8.29 (dd, J=2.4 Hz, J=9.6 Hz, 1 H), 8.22 (d, J= 2.1 Hz, 1 H), 7.64 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.34 (d, J=9.6 Hz, 1 H), 4.45-4.32 (m, 3H), 3.65- 3.51 (m, 6H), 3.4-3.38 (m, 2H), 3.30-3.27 (m, 2H), 3.1 1 -3.07 (m, 1 H), 2.90-2.85 (m, 1 H), 1 .80-1 .76 (m, 1 H), 1 .29 (d, J=6.6 Hz, 6H), 1 .19-1.09 (m, 2H). HPLC (Method D): tr = 3.79 min (97 %).
Example 136 (General Procedure J)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}-(4-methylpiperazin-1 -yl)methanone, trifluoroacetate
Figure imgf000141_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and 1 - methylpiperazine.
1H NMR (300 MHz, D2O) δ 8.29 (dd, J=2.4, J=9.6 Hz, 1 H), 8.16 (d, J= 2.4 Hz, 1 H), 7.61 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.34 (d, J=9.3 Hz, 1 H), 4.32-4.27 (m, 2H), 3.92-3.84 (m, 1 H), 3.61 -3.44 (m, 8H), 3.32-3.01 (m, 6H), 2.80 (s, 3H), 1.24 (d, J=6.6 Hz, 6H).
Example 137 (General Procedure J)
{4-[6-(4-Cyclopropylmethylpiperazin-1 -yl)pyridin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroacetate
Figure imgf000141_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-(cyclopropylmethyl)-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and piperidine.
1H NMR (300 MHz, D2O) δ 8.45 (d, 1 H), 8.08 (d, 1 H), 7.68 (d, 2H), 7.47 (d, 2H), 7.16 (d, 1 H), 4.72-3.34 (m, 12H), 3.12 (d, 2H), 1.77-1 .49 (m, 6H), 1 .22-1 .1 1 (m, 1 H), 0.80 (q, 2H), 0.47 (q, 2H). HPLC (Method E): tr = 3.39 min (96 %).
Example 138 (General Procedure J)
{4-[6-(4-Cyclopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroace- tate
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and piperidine. 1H NMR (300 MHz, CD3OD) δ 8.38-8.28 (m, 2H), 7.73 (d, 2H), 7.51 (d, 2H), 7.46-7.41 (m, 1 H), 4.03-3.95 (m, 2H), 3.78-3.55 (m, 6H), 3.51 -3.35 (m, 4H), 2.93-2.96 (m, 1 H), 1 .79-1.48 (m, 7H), 1.06-1 .04 (m,3 H). HPLC (Method D): tr = 4.43 min (96 %).
Example 139 (General Procedure J)
{4-[6-(4-Cyclopentylpiperazin-1 -yl)pyridin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroace- tate
Figure imgf000142_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-cyclopentyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and piperidine.
1H NMR (300 MHz, CD3OD) δ 8.46 (d, 1 H), 8.06 (dd, 1 H), 7.68 (d, 2H), 7.47 (d, 2H), 7.13
(dd, 1 H), 4.70-4.09 (m, 2H), 4.09-3.35 (m, 10H), 3.35-3.28 (m, 1 H), 2.35-2.23 (m, 2H), 1.95-
1 .55 (m, 12H). HPLC (Method E): tr = 3.46 min (98 %). Example 140 (General Procedure J) {3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}morpholin-4-ylmethanone, trifluoroacetate
Figure imgf000143_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid and morpholine. 1H NMR (300 MHz, D2O) δ 8.23 (s, 1 H), 8.15 (d, 1 H), 7.55-7.52 (t, 2H), 7.37 (d, 1 H), 7.66- 7.21 (d, 1 H), 4.36-4.26 (m, 2H), 3.78-3.40 (m, 13H), 3.30-3.17 (s, 2H), 1 .29 (d, 6H). HPLC (Method C): tr = 3.95 min (96 %).
Example 141 (General Procedure J) {3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}piperidin-1 -ylmethanone, trifluoroacetate
Figure imgf000143_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid and piperidine.
1H NMR (300 MHz, D2O) δ 8.31 (d, 1 H), 8.17 (s, 1 H), 7.64 (d, 2H), 7.52 (t, 2H), 7.37 (d, 2H), 3.65-3.55 (m, 7H), 3.34 (d, 2H), 3.29 (t, 4H), 1 .60-1 .42 (d, 6H), 1 .29 (d, 6H). HPLC (Method D): tr = 4.03 min (97 %).
Example 142 (General Procedure J)
3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000144_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid and dimethylamine, hydrochloride. 1H NMR (300 MHz, D2O) δ 8.26 (d, 2H), 8.20 (s, 1 H), 7.56-7.51 (dd, 2H), 7.65 (d, 1 H), 7.41 - 7.33 (dd, 2H), 4.33 (d, 2H), 3.64-3.54 (m, 5H), 3.29 (t, 2H), 3.02 (s, 3H), 2.92 (s, 3H), 1.29 (d, 6H). HPLC (Method D): tr = 2.52 min (97 %).
Example 143 (General Procedure J)
{4-[6-(4-Cyclopentylpiperazin-1 -yl)pyridin-3-yl]phenyl}-(4-methylpiperazin-1 -yl)methanone, trifluoroacetate
Figure imgf000144_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-cyclopentyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and
1 -methylpiperazine.
1H NMR (300 MHz, CD3OD) δ 8.41 -8.32 (m, 2H), 7.77 (d, 2H), 7.62 (d, 2H), 7.47 (d, 1 H),
4.62-4.21 (m, 2H), 4.01 -3.35 (m, 11 H), 3.25-3.05 (m, 2H), 3.05-2.78 (m, 3H), 2.52-2.12 (m,
2H), 2.12-1 .98 (m, 4H), 1 .98-1 .51 (m, 6H). HPLC (Method C): tr = 4.29 min (96 %).
Example 144 (General Procedure J)
{4-[6-(4-Cyclopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}-(4-methylpiperazin-1 -yl)methanone, trifluoroacetate
Figure imgf000145_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and 1 -methylpiperazine. 1H NMR (300 MHz, CD3OD) δ 8.41 (s, 1 H), 8.12-8.15 (m, 1 H), 7.73 (d, 2H), 7.58 (d, 2H), 7.21 -7.24 (m, 1 H), 4.03-3.95 (m, 5H), 3.78-3.31 (m, 9H), 3.09-3.30 (m, 2H), 2.84-2.96 (m, 4H), 0.92-1 .14 (m, 4H). HPLC (Method D): tr = 4.43 min (96 %).
Example 145 (General Procedure J)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]phenyl}-(4-methoxymethylpiperidin-1 -yl)- methanone, trifluoroacetate
Figure imgf000145_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid, hydrochloride and 4- methoxymethyl-piperidine, hydrochloride.
1H NMR (300 MHz, CD3OD) δ 8.45 (d, 1 H), 8.10 (dd, 1 H), 7.70 (d, 2H), 7.48 (d, 2H), 7.16 (d, 1 H), 4.72-4.45 (m, 2H), 4.22-3.35 (m, 8H), 3.32 (s, 3H), 3.29-3.27 (m, 2H), 3.21 -2.95 (m, 2H), 2.95-2.75 (m, 1 H), 1 .95-1 .82 (m, 2H), 1 .75-1 .62 (m, 1 H), 1 .42 (d, 6H), 1 .41 -1 .15 (m, 2H).
HPLC (Method D): tr = 4.34 min (97 %).
Example 146 (General Procedure J) 4-[6-(4-Cyclopentylpiperazin-1 -yl)pyridin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000146_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-cyclopentyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid and dimethylamine. 1H NMR (300 MHz, CD3OD) δ 8.50 (s, 1 H), 8.00 (dd, 1 H) 7.68 (d, 2H), 7.50 (d, 2H), 7.05 (d, 1 H), 4.75-4.50 (m, 2H), 3.85-3.45 (m, 4H), 3.25-3.17 (m, 3H), 3.15-3.02 (m, 6H), 2.33-2.15 (m, 2H), 1.90-1 .65 (m, 6H). HPLC (Method D): tr = 4.83 min (97 %).
Example 147 (General Procedure J)
{4-[6-(4-Cyclopentylpiperazin-1 -yl)pyridin-3-yl]phenyl}morpholin-4-ylmethanone, trifluoroace- tate
Figure imgf000146_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-cyclopentyl-piperazin-1 -yl)-pyridin-3-yl]-benzoic acid and morpholine. 1H NMR (300 MHz, CD3OD) δ 8.50 (s, 1 H), 8.05 (d, 1 H) 7.68 (d, 2H), 7.50 (d, 2H), 7.10 (d, 1 H), 4.80-3.30 (m, 17H), 2.30-2.15 (m, 2H), 1 .90-1.55 (m, 6H). HPLC (Method D): tr = 4.77 min (96 %).
Example 148 (General Procedure J) 3-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000146_0003
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-isopropyl-piperazin-1 -yl)-4-methyl-pyridin-3-yl]-benzoic acid and di- methylamine, hydrochloride. 1H NMR (300 MHz, CD3OD) δ 7.98 (s, 1 H), 7.58 (t, 1 H), 7.48 (t, 2H), 7.41 (s, 1 H), 7.20 (s, 1 H), 4.81 -3.35 (m, 9H), 3.12 (s, 3H), 3.04 (s, 3H), 2.36 (s, 3H), 1 .42 (d, 6H). HPLC (Method D): tr = 3.95 min (97 %).
Example 149 (General Procedure J) 3-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000147_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 3-[6-(4-isopropyl-piperazin-1 -yl)-5-methyl-pyridin-3-yl]-benzoic acid and di- methylamine, hydrochloride. 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1 H), 7.97 (s, 1 H), 7.73 (d, 1 H), 7.67 (s, 1 H), 7.56 (t, 1 H), 7.43 (d, 1 H), 3.88-3.70 (m, 2H), 3.70-3.51 (m, 3H), 3.47- 3.32 (m, 3H), 3.28-3.15 (m, 4H), 3.03 (s, 3H), 2.42 (s, 3H), 1 .43 (d, 6H). HPLC (Method D): tr = 4.14 min (98 %).
Example 150 (General Procedure J)
4-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000147_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-5-methyl-pyridin-3-yl]-benzoic acid and di- methylamine, hydrochloride. 1H NMR (300 MHz, CD3OD) δ 8.43 (d, 1 H), 8.01 (d, 1 H), 7.72 (d, 2H), 7.53 (d, 2H), 3.91 -3.72 (m, 2H), 3.70-3.51 (m, 3H), 3.47-3.32 (m, 3H), 3.21 -3.09 (m, 4H), 3.04 (s, 3H), 2.38 (s, 3H), 1.43 (d, 6H). HPLC (Method D): tr = 4.11 min (95 %).
Example 151 (General Procedure J) 4-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000148_0001
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-4-methyl-pyridin-3-yl]-benzoic acid and di- methylamine, hydrochloride. 1H NMR (300 MHz, CD3OD) δ 7.95 (s, 1 H), 7.55 (d, 2H), 7.47 (d, 2H), 7.35 (s, 1 H), 4.73-3.35 (m, 9H), 3.13 (s, 3H), 3.04 (s, 3H), 2.39 (s, 3H), 1 .42 (d, 6H). HPLC (Method D): tr = 3.93 min (98 %).
Example 152 (General Procedure J)
4-[4-lsopropyl-6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000148_0002
The title compound was prepared by a similar procedure to that described in Example 125, starting from 4-[4-isopropyl-6-(4-isopropylpiperazin-1 -yl)-pyridazin-3-yl]-benzoic acid and di- methylamine, hydrochloride.
1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1 H), 7.67 (t, 4H), 4.90-3.31 (m, 9H), 3.15 (s, 3H), 3.08-3.05 (m, 4H), 1 .44 (d, 6H), 1 .27 (d, 6H). HPLC (Method D): tr = 3.46 min (99 %).
Example 153 (General Procedure K) 1 -Cyclopropylmethyl-4-[5-(4-piperidin-1 -ylmethylphenyl)pyridin-2-yl]piperazine, trifluoroace- tate
Figure imgf000149_0001
Step 1 :
4-[6-(4-Cylopropylmethyl-piperazin-1 -yl)-pyridin-3-yl]-benzonitrile
Figure imgf000149_0002
1 -Cyclopropylmethyl-piperazine (13 g, 94 mmol) was mixed with 4-(6-cloro-pyridin-3-yl)- benzonitrile (5 g, 23 mmol). The mixture was heated at 1400C for 1 .5 hours. The mixture was cooled to rt and purified by column chromatography (EtOAc : petrolether = 1 :1 ) on silica gel to give 2.7 g (43 %) of 4-[6-(4-cylopropylmethyl-piperazin-1 -yl)-pyridin-3-yl]-benzonitrile.
Step 2:
4-[6-(4-Cyclopropylmethyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde
Figure imgf000149_0003
To a solution of 4-[6-(4-cylopropylmethyl-piperazin-1 -yl)-pyridin-3-yl]-benzonitrile (2.0 g , 6.3 mmol) dissolved in THF (40 ml_) was added DIBAL-H (25 ml_, 1 N) at -400C. The mixture was stirred 2 h at -400C and then CH3OH (15 ml_), water (100 ml_) and 1 N NaOH (15 ml_) was added at - 400C. The mixture was extracted with EtOAc (3 x 300 ml_). The combined organic extracts were washed with water (3 x 5OmL), dried (Na2SO4) and concentrated under reduced pressure to give 1 .7 g (51 %) of 4-[6-(4-cyclopropylmethyl-piperazin-1 -yl)-pyridin-3-yl]- benzaldehyde.
Step 3: To a solution of 4-[6-(4-cyclopropylmethyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde (1 .7 g, 3.18 mmol) dissolved in THF (15 ml_) was added water (0.05 ml_), piperidine (0.33 g, 3.8 mmol), acetic acid (0.01 ml_) and NaCNBH3 (400 mg, 6.4 mmol). The mixture was stirred overnight at 600C and concentrated to give a crude product, which was further purified by HPLC Method F to give 540 mg (26 %) of the title compound as a TFA salt.
1H NMR (300 MHz, D2O) δ 8.28 (d, 1 H), 8.20 (d, 1 H), 7.56(d, 2H), 7.45 (d, 2H), 7.31 (d, 1 H), 4.27-4.21 (m, 2H), 4.13 (m, 2H), 3.77-3.72 (m, 2H), 3.59-3.51 (m, 2H), 3.20-3.13 (m, 4H), 3.00 (d, 2H), 2.82-2.75 (m, 2H), 1 .77-1 .42 (m, 5H), 1 .29-1.25 (m, 1 H), 1.00-0.95 (m, 1 H), 0.62-0.58 (m, 2H), 0.26-0.24 (m, 2H). HPLC (Method D): tr = 3.76 min (96 %).
Example 154 (General Procedure K) {4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}dimethylamine, trifluoroacetate
Figure imgf000150_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde and dimethylamine, hydrochloride.
1H NMR (300 MHz, D2O) δ 8.30 (d, 1 H), 8.26 (d, 1 H), 7.62 (d, 2H), 7.48 (d, 2H), 7.33 (d, 1 H), 4.33-4.29 (m, 2H), 4.23 (m, 2H), 3.62-3.48 (m, 5H), 3.28-3.15 (m, 2H), 2.73 (s, 6H), 1 .26 (d, 6H).
HPLC (Method D): tr = 2.69 min (98 %).
Example 155 (General Procedure K)
3-(4-Cyclopentylpiperazin-1 -yl)-6-(4-piperidin-1 -ylmethylphenyl)pyridazine, trifluoroacetate
Figure imgf000150_0002
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-cyclopentyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and piperidine. 1H NMR (300 MHz, D2O) δ 8.06 (d, J=9.9 Hz, 1 H), 7.80 (d, J=8.1 Hz, 2H), 7.67 (d, J=9.6 Hz, 1 H), 7.50 (d, J=8.4 Hz, 2H), 4.44-4.38 (m, 2H), 4.18 (m, 2H), 3.65-3.61 (m, 2H), 3.51 -3.30 (m, 5H), 3.16-3.07 (m, 2H), 2.85-2.78 (m, 2H), 2.03-1 .96 (m, 2H), 1 .77-1.73 (m, 2H), 1.61 - 1 .52 (m, 9H), 1.34-4.22 (m, 1 H). HPLC (Method D): tr = 3.69 min (86 %).
Example 156 (General Procedure K) 1 -{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-4-methylpiperazine, trif luoroacetate
Figure imgf000151_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde and 1 -methyl- piperazine. 1H NMR (300 MHz, D2O) δ 8.33 (d, 1 H), 8.30 (d, 1 H), 7.66 (d, 2H), 7.53 (d, 2H), 7.35 (d, 1 H), 4.57-4.31 (m, 4H), 3.65-3.53 (m, 13H), 3.31 -3.23 (m, 2H), 2.90 (s, 3H), 1 .28 (d, 6H). HPLC (Method C): tr = 2.59 min (93 %).
Example 157 (General Procedure K) (1 -{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}piperidin-4-yl)methanol, trifluoroacetate
Figure imgf000151_0002
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde and 4-hydroxy- methylpiperidine. 1H NMR (300 MHz, D2O) δ 8.32 (d, 1 H), 8.18 (d, 1 H), 7.61 (d, 2H), 7.48 (d, 2H), 7.35 (d, 1 H), 4.34-4.29 (m, 2H), 4.21 (m , 2H), 3.62-3.22 (m, 11 H), 2.94-2.86 (m, 2H), 1.87-1 .67 (m, 3H), 1 .29-1 .25 (m, 8H).
HPLC (Method C): tr = 2.82 min (97 %).
Example 158 (General Procedure K)
1 -lsopropyl-4-[5-(4-piperidin-1 -ylmethylphenyl)pyridin-2-yl]piperazine, trifluoroacetate
Figure imgf000152_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde and piperidine.
1H NMR (300 MHz, D2O) δ 8.27 (d, 1 H), 8.16 (d, 1 H), 7.59 (d, 2H), 7.45 (d, 2H), 7.31 (d, 1 H),
4.31 -4.26 (m, 2H), 4.17 (m, 2H), 3.56-3.45 (m, 4H), 3.31 -3.17 (m, 4H), 2.84-2.76 (m, 2H),
1 .82-1 .44 (m, 6H), 1 .24 (d, 6H).
HPLC (Method D): tr = 4.45 min (87 %).
Example 159 (General Procedure K)
{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]benzyl}dimethylamine, trifluoroacetate
Figure imgf000152_0002
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and dimethyl- amine, hydrochloride.
1H NMR (300 MHz, CD3OD) δ 8.13-8.06 (m, 3 H), 7.67-7.61 (m, 3 H), 4.38(s, 2 H), 3.89-3.32
(m, 6 H), 2.88 (s, 6 H), 1 .41 (d, 6 H).
HPLC (Method C): tr = 3.79 min (96 %).
Example 160 (General Procedure K) 3-(4-lsopropylpiperazin-1 -yl)-6-(4-piperidin-1 -ylmethylphenyl)pyridazine, trifluoroacetate
Figure imgf000153_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and piperidine. 1H NMR (300 MHz, CD3OD) δ 8.12-8.05 (m, 3H), 7.67-7.60 (m, 3H), 4.35 (s, 2H), 3.89-3.35 (m, 8H), 2.98 (t, 2H), 1 .95-1 .64 (m, 5H), 1 .62-1 .48 (m, 1 H), 1 .41 (d, 6H).
Example 161 (General Procedure K)
3-(4-lsopropylpiperazin-1 -yl)-6-[4-(4-methylpiperazin-1 -ylmethyl)phenyl]pyridazine, trifluoroacetate
Figure imgf000153_0002
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and 1 -methyl- piperazine. 1H NMR (300 MHz, CD3OD) δ 8.19 (d, 1 H), 7.98 (d, 1 H), 7.76 (d, 1 H), 7.62 (d, 1 H), 4.01 (s, 2H), 3.78-3.32 (m, 10H), 3.19-3.02 (m, 4H), 2.90 (s, 3H), 1 .95-1 .64 (m, 5H), 1 .62-1 .48 (m, 1 H), 1 .41 (d, 6H). HPLC (Method C): tr = 3.74 min (97 %).
Example 162 (General Procedure K)
(1 -{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]benzyl}piperidin-4-yl)methanol, trifluoroacetate
Figure imgf000154_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and 4-hydroxy- methylpiperidine.
1H NMR (300 MHz, CD3OD) δ 8.05-8.11 (m, 3 H), 7.58-7.67 (m, 3 H), 4.36 (s, 2 H), 3.78-3.38
(m, 10 H), 2.99-3.12 (m, 4 H), 1 .46-2.05 (m, 5 H), 1.41 (d, 6 H).
HPLC (Method C): tr = 3.94 min (96 %).
Example 163 (General Procedure K) 4-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]benzyl}morpholine, trifluoroacetate
Figure imgf000154_0002
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and morpholine. 1H NMR (300 MHz, CD3OD) δ 8.12-8.06 (m, 3 H), 7.70-7.59 (m, 3 H), 4.43 (s, 2 H), 4.33-3.23 (m, 14 H), 1 .41 (d, 6 H).
Example 164 (General Procedure K)
1 -Cyclopentyl-4-[5-(4-piperidin-1 -ylmethylphenyl)pyridin-2-yl]piperazine, trifluoroacetate
Figure imgf000154_0003
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-cyclopentyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde and piperidine. 1H NMR (300 MHz, D2O) δ 8.26-8.22 (m, 2H), 7.62 (d, 2H), 7.47 (d, 2H), 7.27 (d, 1 H), 4.27 (d, 2H), 4.20 (s, 2H), 3.71 (d, 2H), 3.55-3.42 (m, 3H), 3.36 (d, 2H), 3.20 (t, 2H), 2.86 (t, 2H), 2.08 (d, 2H), 1 .85-1 .51 (m, 1 1 H), 1 .41 -1 .30 (m, 1 H). HPLC (Method D): tr = 2.43 min (98 %).
Example 165 (General Procedure K)
1 -Cyclopropyl-4-[5-(4-piperidin-1 -ylmethylphenyl)pyridin-2-yl]piperazine, trifluoroacetate
Figure imgf000155_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridin-3-yl]-benzaldehyde and piperidine.
1H NMR (300 MHz, CD3OD) δ 8.46 (s, 1 H), 8.05 (d, 1 H), 7.71 (d, 2H), 7.57 (d, 2H), 7.18-7.13 (m, 1 H), 4.87 (s, 2H), 4.18-3.72 (m, 4H), 3.65-3.35 (m, 6H), 3.08-2.82 (m, 3H), 1.99-1 .62 (m, 5H), 1 .39-1 .61 (m, 1 H), 1 .05-1 .15 (m, 2H), 1 .05-0.89 (m, 2H). HPLC (Method C): tr = 4.43 min (99 %).
Example 166 (General Procedure K)
3-(4-Cyclopropylmethylpiperazin-1 -yl)-6-(4-piperidin-1 -ylmethylphenyl)pyridazine, trifluoroacetate
Figure imgf000155_0002
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-cyclopropylmethyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and piperidine.
1H NMR (300 MHz, CD3OD) δ 8.24 (d, 1 H), 8.08 (d, 2H) 7.80 (d, 1 H), 7.70 (d, 2H), 4.89-2.85
(m, 12H), 3.22-2.92 (m, 4H), 2.05-1.89 (m, 2H), 1.89-1 .75 (m, 3H), 1 .65-1 .45 (m, 1 H), 1.25- 1 .06 (m, 1 H), 0.83-0.78 (m, 2H), 0.52-0.40 (m, 2H).
HPLC (Method D): tr = 3.04 min (98 %). Example 167 (General Procedure K)
3-(4-Cyclopropylpiperazin-1 -yl)-6-(4-piperidin-1 -ylmethylphenyl)pyridazine, trifluoroacetate
Figure imgf000156_0001
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzaldehyde and piperidine. 1H NMR (300 MHz, CDCI3): δ 12.00 (s, 1 H), 8.08 (d, 2H), 7.81 (d, 1 H) 7.62 (d, 2H), 7.15 (d, 1 H), 4.25-4.00 (m, 4H), 3.65-3.40 (m, 5H), 2.85-2.40 (m, 6H), 2.15-1.95 (m, 3H), 1 .95-1.85 (m, 3H), 1.52-1 .31 (m, 2H), 0.91 (d, 2H). HPLC (Method D): tr = 4.01 min (96 %).
Example 168 (General Procedure K) 4-{4-[2-(4-Cyclopropylpiperazin-1 -yl)pyrimidin-5-yl]benzyl}morpholine, dihydrochloride
Figure imgf000156_0002
The title compound was prepared by a similar procedure to that described in Example 153, starting from 4-[2-(4-cyclopropyl-piperazin-1 -yl)-pyrimidin-5-yl]-benzaldehyde and mor- pholine.
1 H NMR (300 MHz, DMSO-c(6) δ 1 1 .6 (brs, 1 H), 11.3 (brs, 1 H), 8.85 (s, 2H), 7.81 -7.71 (m,
4H), 4.82-4.69 (m, 2H), 4.40-4.30 (m, 2H), 4.00-3.77 (m, 4H), 3.61 -3.42 (m, 4H), 3.34-3.00
(m, 6H), 2.92-2.79 (m, 1 H), 1 .25-1.15 (m, 2H), 0.86-0.77 (m, 2H). HPLC (Method Rx): tr = 3.88 min (98 %).
Example 169 (General Procedure L) N-{3-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000157_0001
The title compound was prepared by a similar procedure to that described in Example 170, starting from 3-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine and acetylchloride. 1H NMR (300 MHz, DMSOd6) δ 10.08 (s, 1 H), 9.78 (s, 1 H), 8.33 (s, 1 H), 7.97 (d, 1 H), 7.62 (t, 2H), 7.53 (d, 1 H), 7.40 (t, 1 H), 4.60 (d, 2H), 3.61 -3.50 (m, 3H), 3.34-3.25 (m, 2H), 3.16- 3.13 (m, 2H), 2.05 (s, 3H), 1 .28 (d, 6H). HPLC (Method D): tr = 2.28 min (96 %).
Example 170 (General Procedure L) N-{3-[6-(4-Cyclopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}acetamide
Figure imgf000157_0002
Step 1 : 3-(4-Cyclopropyl-piperazin-1 -yl)-6-(3-nitro-phenyl)-pyridazine
Figure imgf000157_0003
To a solution of 3-chloro-6-(3-nitro-phenyl)-pyridazine (10.0 g, 424 mmol) in n-BuOH (150 mL) was added 1 -cyclopropyl-piperazine (8.55 g, 678 mmol) and NH4CI (2.27 g, 424 mmol) and the mixture was stirred for 48 h at 800C. The solvent was removed under reduced pressure, and the residue was diluted with water. After alkalization with ammonia, the mixture was extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated to give 7.2 g of crude 3-(4-cyclopropyl-piperazin-1 -yl)-6-(3-nitro-phenyl)-pyridazine. 1H NMR (300 MHz, DMSO-c(6) δ 8.85 (s, 1 H), 8.45 (d, 1 H), 8.22 (d, 1 H), 8.1 1 (d, 1 H), 7.89- 7.66 (m, 1 H), 7.39 (d, 1 H), 3.69-3.65 (m, 4H), 2.80-2.76 (m, 4H), 1 .78-1.65 (m, 1 H), 0.54- 0.38 (m, 4H).
Step 2:
3-[6-(4-Cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine
Figure imgf000158_0001
A solution of 3-(4-cyclopropyl-piperazin-1 -yl)-6-(3-nitro-phenyl)-pyridazine (3.60 g, 1 1 mmol) in ethanol (18 ml_) was added to water (30 ml_) and powdered Fe (1 .86 g, 33 mmol). The mixture was stirred for 3 h at 800C. The resulting mixture was filtered and the filtrate was extracted with CH2CI2. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give 2.32 g (71 %) of 3-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine.
Step 3: To a solution of 3-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine (400 mg, 1 .36 mmol) in CH2CI2 (25 ml_) was added triethylamine (275 mg, 2.72 mmol). Then acetyl chloride (171 mg, 2.18 mmol) was added dropwise and the resulting mixture was stirred overnight at rt. The reaction was quenched with water (15 ml_) and the phases were separated. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give a crude prod- uct, which was recrystallized from MeOH. This afforded 201 mg (48 %) of the title compound.
1H NMR (300 MHz, CD3OD) δ 8.09 (s, 1 H), 7.82 (d, 1 H), 7.66-7.62 (m, 2H), 7.44-7.39 (m, 1 H), 7.33 (d, 1 H), 3.69-3.65 (m, 4H), 2.80-2.76 (m, 4H), 2.15 (s, 3H), 1.74-1 .71 (m, 1 H), 0.54-0.49 (m, 4H). HPLC (Method D): tr = 2.82 min (95 %).
Example 171 (General Procedure L)
Cyclopropanecarboxylic acid {3-[6-(4-cyclopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}amide
Figure imgf000159_0001
The title compound was prepared by a similar procedure to that described in Example 170, starting from 3-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine and cyclo- propanecarbonyl chloride. 1H NMR (300 MHz, CD3OD) δ 8.08 (d, 1 H), 7.82 (d, 1 H), 7.66-7.62 (m, 2H), 7.44-7.39 (m, 1 H), 7.33 (d, 1 H), 3.69-3.65 (m, 4H), 2.80-2.77 (m, 4H), 1 .79-1 .71 (m, 2H), 0.97-0.94 (m, 2H), 0.89-0.85 (m, 2H), 0.55-0.49 (m, 4H). HPLC (Method D): tr = 3.18 min (97 %).
Example 172 (General Procedure L) N-{4-[6-(4-Cyclopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000159_0002
The title compound was prepared by a similar procedure to that described in Example 170, starting from 4-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine and acetyl chlo- ride.1H NMR (300 MHz, CD3OD) δ 8.31 (d, 1 H), 7.96-7.88 (m, 3H), 7.81 (d, 2H), 4.20-3.95 (m, 4H), 3.70-3.58 (m, 4H), 2.94-2.86 (m, 1 H), 2.16 (s, 3H), 1.14-0.96 (m, 4H). HPLC (Method D): tr = 2.74 min (98 %).
Example 173 (General Procedure L)
Cyclopropanecarboxylic acid {4-[6-(4-cyclopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}amide
Figure imgf000159_0003
The title compound was prepared by a similar procedure to that described in Example 170, starting from 4-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine and cyclopro- panecarbonyl chloride.1 H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1 H), 7.93 (d, 2H), 7.86 (d, 1 H), 7.67 (d, 2H), 7.30 (d, 1 H), 3.57-3.54 (m, 4H), 2.64-2.62 (m, 4H), 1 .79-1 .74 (m, 1 H), 1 .65-1 .62 (m, 1 H), 0.78 (d, 4H), 0.43-0.41 (m, 2H), 0.35-0.30 (m, 2H). HPLC (Method D): tr = 2.52 min (93 %).
Example 174 (General Procedure L)
Cyclopropanecarboxylic acid {4-[6-(4-cyclopropylperhydro-1 ,4-diazepin-1 -yl)pyridazin-3-yl]- phenyljamide, dihydrochloride
Figure imgf000160_0001
The title compound was prepared by a similar procedure to that described in Example 176, starting from 4-[6-(4-lsopropyl-perhydro-1 ,4-diazepin-1 -yl)-pyridazin-3-yl]-phenylamine and cyclopropanecarboxylic acid. 1H NMR (400 MHz, CD3OD) δ 8.44 (d, 1 H), 8.03 (d, 1 H), 7.94 (m, 2H), 7.85 (m, 2H), 4.22 (broad m, 2H), 3.89 (t, 2H), 3.71 (broad m, 4H), 3.30 (m, 1 H), 2.48 (broad m, 2H), 1 .82 (m, 1 H), 1 .22 (m, 2H), 1.00 (m, 4H), 0.91 (m, 2H). HPLC-MS (Method G): M+1 = 378; tr= 0.96 min.
Example 175 (General Procedure L)
N-[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-2,2-dimethylpropion- amide, hydrochloride
Figure imgf000160_0002
The title compound was prepared by a similar procedure to that described in Example 176, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamineand tert- butylcarboxylic acid.
HPLC-MS (Method G): M+1 = 382; tr= 1 .23 min.
Example 176 (General Procedure L)
Tetrahydropyran-4-carboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'- yl)phenyl]amide, dihydrochloride
Figure imgf000161_0001
A mixture of tetrahydro-2H-pyran-4-carboxylic acid (0.313 g, 2.19 mmol), HOBt (0.368 g, 2.40 mmol), EDAC (0.46 g, 2.40 mmol) and TEA (0.243 g, 2.40 mmol) in DMF (5mL) was stirred at rt for 5 min. A solution of 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'- yl)phenylamine (0.65 g, 2.19 mmol) in DMF (5 mL) was added. The reaction mixture was stirred for an additional 48 h. The reaction mixture was purified by preparative HPLC Method B to give 240 mg of a TFA salt. The TFA salt was dissolved in MeOH and HCI in diethyl ether was added. Evaporation of the volatiles in vacuo afforded 186 mg (18 %) of the title compound.
1H-NMR (400 MHz, CD3OD) δ 8.90 (s, 1 H), 8.49 (s, 1 H), 7.95 (d, 2H), 7.70 (d, 2H), 4.55-4.45 (m, 2H), 3.95-3.87 (m, 2H), 3.55-3.45 (m, 5H), 3.40-3.30 (m, 2H), 3.15-3.05 (m, 2H), 2.70- 2.60 (m, 1 H), 1.75-1 .60 (m, 4H), 1 .30 (d, 6H).
HPLC-MS (Method G): M+1 = 410; tr= 1 .037 min.
Example 177 (General Procedure L)
N-[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-N-methylacetamide, di- hydrochloride
Figure imgf000162_0001
The title compound was prepared by a similar procedure to that described in Example 170, starting from N-[4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-N-methyl- amine and acetic acid anhydride. 1H-NMR (400 MHz, CD3OD) δ 8.95 (s, 1 H), 8.60 (s, 1 H), 8.04 (d, 2H), 7.35 (d, 2H), 4.80-4.72 (m, 2H), 3.73-3.62 (m, 5H), 3.40-3.28 (m, 5H), 1 .95 (brs, 3H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 354; tr= 1 .27 min.
Example 178 (General Procedure L) Cyclopropanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)- phenyl]methylamide, dihydrochloride
Figure imgf000162_0002
The title compound was prepared by a similar procedure to that described in Example 176, starting from N-[4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]-N-methyl- amine and cyclopropanecarboxylic acid.
1H-NMR (400 MHz, CD3OD) δ 8.90 (s, 1 H), 8.55 (s, 1 H), 8.05 (d, 2H), 7.55 (d, 2H), 4.80-4.70
(m, 2H), 3.72-3.55 (m, 5H), 3.40-3.25 (m, 5H), 1 .57-1 .50 (m, 1 H), 1.45 (d, 6H), 0.95 (m, 2H),
0.72 (m, 2H).
HPLC-MS (Method G): M+1 = 380; tr= 1 .10 min.
Example 179 (General Procedure L)
N-[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-2-methoxyphenyl]acetamide, dihydrochloride
Figure imgf000163_0001
The title compound was prepared by a similar procedure to that described in Example 170, starting from 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-2-methoxyphenyl- amine and acetic acid anhydride. 1H-NMR (400 MHz, CD3OD) δ 8.75 (s, 1 H), 8.40 (s, 1 H), 8.15 (d, 1 H), 7.60 (s, 1 H), 7.45 (d, 1 H), 4.72-4.65 (m, 2H), 4.00 (s, 3H), 3.68-3.58 (m, 3H), 3.40-3.22 (m, 4H), 2.20 (s, 3H), 1.45 (d, 6H). HPLC-MS (Method G): M+1 = 370; tr= 1 .004 min.
Example 180 (General Procedure L)
Cyclohexanecarboxylic acid [4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)- phenyl]amide, hydrochloride
Figure imgf000163_0002
The title compound was prepared by a similar procedure to that described in Example 176, starting from cyclohexylcarboxylic acid and 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']- bipyrazinyl-5'-yl)phenylamine. HPLC-MS (Method G): M+1 = 408; tr= 1 .34 min.
Example 181 (General Procedure M) 2-[4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenoxy]-N,N-dimethylacet- amide, dihydrochloride
Figure imgf000164_0001
4-(4-lsopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenol (0.15 g, 0.404 mmol) was dissolved in DMF (4 ml_) in a 5 ml_ microwave vial. NaH (0.039 g, 1 .62 mmol) was added slowly and the mixture was stirred at rt for 30 min. Chloro-N,N-dimethylacetamide (0.147 g, 1 .21 mmol) was added and the reaction mixture was heated for 2.5 h at 1300C in a microwave oven. The reaction mixture was evaporated in vacuo and the residue was redissolved in a mixture of DCM and water. The phases were separated and the aqueous phase was extracted with DCM (2 x 25 ml_). The combined organic extracts were evaporated, redissolved in MeOH and purified by preparative HPLC Method B. This afforded an oil which was treated with HCI in diethyl ether to give a solid material. Recrystallization from acetone and MeOH afforded 75 mg (41 %) of the title compound. 1H-NMR (400 MHz, CD3OD) δ 8.75 (s, 1 H ), 8.35 (s, 1 H), 7.85 (d, 2H), 7.1 (d, 2H), 4.65 (d, 2H), 3.65 (m, 3H), 3.2-3.5 (m, 6H), 3.1 (s, 3H), 2.95 (s, 3H), 1.45 (d, 6H). HPLC-MS (Method G): M+1 = 384; tr= 0.995 min.
Example 182 (General Procedure N)
5'-[4-(1 ,1 -Dioxoisothiazolidin-2-yl)phenyl]-4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, dihydrochloride
Figure imgf000164_0002
A mixture of 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenylamine (0.34 g, 1 .14 mmol), 3-chloro-1 -propanesulfonyl chloride (0.20 g, 1 .14 mmol) and TEA (0.12 g, 1 .14 mmol) in DMF was stirred at rt for 1 h. NaH (0.055 g, 2.29 mmol) was added and stirring was continued for 5 h. The reaction mixture was transferred to a microwave vial (20 mL) and heated for 1000 s at 800C in a microwave oven. The reaction mixture was evaporated in vacuo and redissolved in a mixture of DCM and water. The phases were separated and the aqueoues phase was extracted with DCM (2 x 25 ml_). The combined organic extracts were evaporated in vacuo, redissolved in MeOH and purified by preparative HPLC Method B. This afforded 220 mg of a solid which was redissolved in MeOH and treated with HCI in diethyl ether. The volatiles were evaporated to give 126 mg (22 %) of the title compound.
1H-NMR (400 MHz, CD3OD) δ 9.05 (s, 1 H), 8.5 (s, 1 H), 7.86 (d, 2H), 7.4 (d, 2H), 4.75 (d, 2H), 3.85 (t, 2H), 3.65 (m, 7H), 3.5 (t, 2H), 2.55 (m, 2H), 1 .45 (d, 6H). HPLC-MS (Method G): M+1 = 402; tr= 1 .1 14 min.
Example 183 (General Procedure A)
6-(4-lsopropylpiperazin-1 -yl)-[3,3']bipyridinyl, trifluoroacetate
Figure imgf000165_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 1 -isopropylpiperazine and 6-chloro-[3,3']bipyridinyl. 1H NMR (300 MHz, CD3OD) δ 1 .25 (d, 6 H), 2.19 (t, 2 H), 3.40-3.59 (m, 5 H), 4.37 (d, 2 H), 7.26 (d, 1 H), 8.01 (t, 1 H), 8.19 (d, 1 H), 8.34 (s, 1 H), 8.71 -8.64 (m, 2H), 8.93 (s, 1 H). HPLC (Method D): tr = 2.51 min (98 %).
Example 184 (General Procedure A) 6-(4-lsopropylpiperazin-1 -yl)-[3,4']bipyridinyl, trifluoroacetate
Figure imgf000165_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 1 -isopropylpiperazine and 6-chloro-[3,4']bipyridinyl.
1H NMR (300 MHz, D2O) δ 1 .09 (d, 6H), 3.15 (t, 2H), 3.36 (t, 2H), 3. 56-3.46 (m, 3H), 4.57 (d, 2H), 7.10 (d, 1 H), 8.16 (dd, 3H), 8.58 (d, 3H). HPLC (Method D): tr = 2.53 min (99 %). Example 185 (General Procedure A) 6'-(4-lsopropylpiperazin-1 -yl)-[2,3']bipyridinyl, trifluoroacetate
Figure imgf000166_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 1 -isopropylpiperazine and 6'-chloro-[2,3']bipyridinyl.
1H NMR (300 MHz, D2O) δ 8.75-8.63 (m, 2H), 8.58-8.47 (m, 1 H), 8.28-15 (m, 2H), 7.87 (t, J=6.3, 7.2 Hz, 1 H), 7.17 (d, J=9.3 Hz, 1 H), 4.61 (d, J=14.1 Hz, 2H), 3.75-3.52 (m, 3H), 3.44- 3.53 (m, 2H), 3.20-3.43 (m, 2H), 1 .39 (d, J=6.9 Hz, 6H). HPLC (Method C): tr = 2.45 min (97 %).
Example 186 (General Procedure A) 6'-(4-Ethylpiperazin-1 -yl)-[2,3']bipyridinyl
Figure imgf000166_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 1 -ethylpiperazine and 6'-chloro-[2,3']bipyridinyl.
1H NMR (300 MHz, D2O) δ 8.70 (d, J=2.1 Hz, 1 H), 8.54 (d, J=4.2 Hz, 1 H), 8.13 (dd, J=9.0, 2.7 Hz, 1 H), 7.90-7.70 (m, 2H), 7.35-7.24 (m, 1 H), 6.92 (d, J=9 Hz, 1 H), 3.66 (t, J=5.1 Hz, 4H), 2.63 (t, J=5.1 Hz, 4H), 2.52 (q, J=7.2 Hz, 2H), 1 .16 (t, J=7.2 Hz, 3H). HPLC (Method C): tr = 2.23 min (97 %).
Example 187 (General Procedure A) 6'-(4-lsopropylpiperazin-1 -yl)-6-methyl-[2,3']bipyridinyl, trifluoroacetate
Figure imgf000167_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 1 -isopropyl-piperazine and 6'-chloro-6-methyl-[2,3']bipyridinyl.
1H NMR (300 MHz, D2O) δ 8.44 (d, 1 H), 8.26 (t, 1 H), 8.01 (dd, 1 H), 7.83 (d, 1 H), 7.60 (d,
1 H), 7.05 (d, 1 H), 4.45 (d, 2H), 3.60-3.40 (m, 3H), 3.31 (t, 2H), 3.13 (t, 2H), 2.67 (s, 3H), 1 .25
(d, 6H).
HPLC (Method C): tr = 2.70 min (100 %).
Example 188 (General Procedure A) 6'-(4-Ethylpiperazin-1 -yl)-6-methyl-[2,3']bipyridinyl
Figure imgf000167_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 1 -ethyl-piperazine and 6'-chloro-6-methyl-[2,3']bipyridinyl.
1H NMR (300 MHz, CD3OD) δ 8.66 (d, 1 H), 8.11 (dd, 1 H), 7.70 (t, 1 H), 7.51 (d, 1 H), 7.14 (d,
1 H), 6.90 (d, 1 H), 3.63 (d, 4H), 2.65-2.40 (m, 9H), 1 .15 (t, 3H).
HPLC (Method C): tr = 2.42 min (98 %).
Example 189 (General Procedure A) 2-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]quinoline, trifluoroacetate
Figure imgf000167_0003
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 2-(6-chloro-pyridin-3-yl)-quinoline and 1 -isopropyl-piperazine. 1H NMR (300 MHz, CD3OD) δ 8.87 (s, 1 H), 8.40-8.25 (m, 2H), 8.04 (d, 1 H), 7.95-7.85 (m, 2H), 7.80-7.60 (m, 1 H), 7.58-7.48 (m, 1 H), 6.96 (d, 1 H), 3.67 (t, 4H), 2.80-2.65 (m, 5H), 1.13 (d, 6H).
HPLC (Method D): tr = 3.40 min (97 %).
Example 190 (General Procedure A) N-{3-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridazin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000168_0001
Step 1 :
N-[3-(6-Chloro-5-methyl-pyridazin-3-yl)-phenyl]-acetamide and N-[3-(6-chloro-4-methyl- pyridazin-3-yl)phenyl]acetamide
Figure imgf000168_0002
A solution of 3-acetamidophenylboronic acid (6.6 g, 37 mmol), 3,6-dichloro-4-methyl- pyridazine (5 g, 31 mmol) and Pd(PPh3)4 (3.5 g, 3 mmol) in DMF (180 ml_, degassed) was stirred at rt for 1 h. Then sodium carbonate (12.3 g in 45 ml_ water, degassed) was added. The mixture was heated with stirring at 800C overnight. The mixture was filtered and the fil- trate was concentrated under reduced pressure. The residue was diluted with EtOAc (100 ml_), washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1 :1 ) to give 3 g (38 %) of a mixture of N-[3-(6-chloro-5-methyl-pyridazin-3-yl)-phenyl]-acetamide and N-[3-(6-chloro- 4-methyl-pyridazin-3-yl)-phenyl]-acetamide, which was used directly in the next step.
Step 2:
The mixture of isomers (1 .5 g, 5.9 mmol) from the previous step and 1 -isopropyl-piperazine
(3.7 g, 28.5 mmol) was heated at 2000C under a nitrogen atmosphere for 1 h. The mixture was cooled to rt and diluted with dichloromethane (30 ml_). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give a crude product, which was purified by preparative HPLC Method F to give 358 mg (1 1 %) of N-{3-[6-(4-isopropyl-piperazin-1 -yl)-4- methyl-pyridazin-3-yl]-phenyl}-acetamide and 195 mg (6 %) of N-{3-[6-(4-isopropyl-piperazin- 1 -yl)-5-methyl-pyridazin-3-yl]-phenyl}-acetamide as the TFA salts.
N-{3-[6-(4-isopropyl-piperazin-1 -yl)-4-methyl-pyridazin-3-yl]-phenyl}-acetamide, trifluoroace- tate:
1H NMR (300 MHz, D2O) δ 7.90 (s, 1 H), 7.76 (d, 1 H), 7.63-7.55 (m, 2H), 7.43-7.35 (m, 1 H), 4.61 (dd, 2H), 3.72-3.56 (m, 3H), 3.56-3.45 (m, 2H), 3.35-3.20 (m, 2H), 2.42 (s, 3H), 2.17 (s, 3H), 1 .37 (d, 6H).
HPLC (Method D): tr = 2.85 min (96 %).
Example 191 (General Procedure A) N-{3-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridazin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000169_0001
The title compound was prepared as described in Example 195.
1H NMR (300 MHz, D2O) δ 8.23 (s, 1 H), 7.98 (t, 1 H), 7.68-7.55 (m, 3H), 4.12-3.98 (m, 2H), 3.70-3.54 (m, 3H), 3.50-3.30 (m, 4H), 2.58 (s, 3H), 2.18 (s, 3H), 1 .39 (d, 6H). HPLC (Method D): tr = 3.30 min (97 %).
Example 192 (General Procedure A)
3-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridazin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000169_0002
Step 1 : 3-(6-Chloro-5-methyl-pyridazin-3-yl)-N,N-dimethyl-benzamide and 3-(6-chloro-4-methyl- pyridazin-3-yl)-N,N-dimethyl-benzamide
Figure imgf000170_0001
A solution of N,N-dimethylbenzamide-3-boronic acid (7 g, 36.5 mmol), 3,6-dichloro-4-methyl- pyridazine (5 g, 30.5 mmol) and Pd(PPh3)4 (1 .7 g, 1 .5 mmol) in DMF (180 ml_, degassed) was stirred at rt for 1 h. Then sodium carbonate (12.1 g in 45 ml_ water, degassed) was added and the mixture was heated with stirring at 800C overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (100 ml_), washed with brine, dried (sodium sulfate) and concentrated to give a crude product, which was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1 :1 ). This afforded 2.8 g (32 %) of a mixture of 3-(6-chloro-5-methyl-pyridazin-3-yl)-N,N- dimethyl-benzamide and 3-(6-chloro-4-methyl-pyridazin-3-yl)-N,N-dimethyl-benzamide, which was used directly in the next step.
Step 2:
The mixture of isomers (1 .5 g, 5.9 mmol) from the previous step and 1 -isopropyl-piperazine (3.7 g, 28.5 mmol) was heated at 2000C under a nitrogen atmosphere for 1 h. The mixture was cooled to rt and diluted with dichloromethane (30 ml_). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give a crude product, which was purified by preparative HPLC Method F to give 185 mg (6 %) 3-[6-(4-isopropyl-piperazin-1 -yl)-4-methyl- pyridazin-3-yl]-N,N-dimethyl-benzamide and 373 mg (12 %) of 3-[6-(4-isopropyl-piperazin-1 - yl)-5-methyl-pyridazin-3-yl]-N,N-dimethyl-benzamide as the TFA salts.
3-[6-(4-lsopropyl-piperazin-1 -yl)-4-methyl-pyridazin-3-yl]-N,N-dimethyl-benzamide, trifluoroacetate:
1H NMR (400 MHz, D2O) δ 7.83 (s, 1 H), 7.69-7.56 (m, 3H), 7.56 (s, 1 H), 4.53 (d, 2H), 3.63- 3.50 (m, 3H), 3.50-3.39 (m, 2H), 3.30-3.15 (m, 2H), 3.01 (s, 3H), 2.92 (s, 3H), 2.33 (s, 3H), 1 .29 (d, 6H). HPLC (Method D): tr = 3.02 min (99 %).
Example 193 (General Procedure A)
3-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridazin-3-yl]-N,N-dimethylbenzamide, trifluoroacetate
Figure imgf000171_0001
The title compound was prepared as described in Example 197.
1H NMR (400 MHz, D2O) δ 8.24 (s, 1 H), 7.90 (d, 1 H), 7.81 (s, 1 H), 7.70-7.58 (m, 2H), 4.02
(d, 2H), 3.63-3.48 (m, 3H), 3.48-3.27 (m, 4H), 3.03 (s, 3H), 2.92 (s, 3H), 2.53 (s, 3H), 1 .31 (d,
6H).
HPLC (Method D): tr = 3.49 min (98 %).
Example 194 (General Procedure A)
4-[6-(4-lsopropylpiperazin-1 -yl)-4-methylpyridazin-3-yl]-N,N-dimethylbenzamide, trifluoro- acetate
Figure imgf000171_0002
Step 1 :
4-(6-Chloro-5-methyl-pyridazin-3-yl)-N,N-dimethyl-benzamide and 4-(6-chloro-4-methyl- pyridazin-3-yl)-N,N-dimethyl-benzamide.
Figure imgf000171_0003
A solution of N,N-dimethylbenzamide-4-boronic acid (7 g, 36.5 mmol), 3,6-dichloro-4-methyl- pyridazine (5 g, 31 mmol) and Pd(PPh3)4 (1 .7 g, 1 .5 mmol) in DMF (180 ml_, degassed) was stirred at rt for 1 h. Then sodium carbonate (12.3 g in 45 ml_ water, degassed) was added and the mixture was heated with stirring at 800C overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residuel was diluted with EtOAc (100 ml_), washed with brine, dried (sodium sulfate) and concentrated to give a crude product, which was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1 :1 ). This afforded 2.5 g (28 %) of a mixture of 4-(6-chloro-5-methyl-pyridazin-3-yl)-N,N-dimethyl- benzamide and 4-(6-chloro-4-methyl-pyridazin-3-yl)-N,N-dimethyl-benzamide, which was used directly in the next step.
Step 2:
The mixture of isomers (1 .5 g, 5.9 mmol) from the previous step and 1 -isopropyl-piperazine (3.7 g, 28.5 mmol) was heated at 2000C under a nitrogen atmosphere for 1 h. The mixture was cooled to rt and diluted with dichloromethane (30 ml_). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give a crude product that was purified by preparative HPLC Method F to give 256 mg (8 %) of 4-[6-(4-isopropyl-piperazin-1 -yl)-4- methyl-pyridazin-3-yl]-N,N-dimethyl-benzamide and 278 mg (9 %) of 4-[6-(4-isopropyl- piperazin-1 -yl)-5-methyl-pyridazin-3-yl]-N,N-dimethyl-benzamide as the TFA salts.
4-[6-(4-isopropyl-piperazin-1 -yl)-4-methyl-pyridazin-3-yl]-N,N-dimethyl-benzamide: 1H NMR (300 MHz, CD3OD) δ 7.76 (s, 1 H), 7.70-7.60 (m, 4H), 4.70-3.35 (m, 9H), 3.13 (s, 3H), 3.03 (s, 3H), 2.40 (s, 3H), 1.42 (d, 6H). HPLC (Method D): tr = 2.89 min (92 %).
Example 195 (General Procedure A) 4-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridazin-3-yl]-N,N-dimethylbenzamide, trifluoro- acetate
Figure imgf000172_0001
The title compound was prepared as described in Example 194.
1H NMR (300 MHz, CD3OD) δ 8.14 (s, 1 H), 8.07 (d, 2H), 7.61 (d, 2H), 4.10-3.90 (m, 2H), 3.70-3.55 (m, 3H), 3.55-3.32 (m, 4H), 3.13 (s, 3H), 3.03 (s, 3H), 2.53 (s, 3H), 1 .43 (d, 6H). HPLC (Method D): tr = 3.38 min (91 %).
Example 196 (General Procedure A) N-{4-[6-(4-lsopropylpiperazin-1 -yl)-5-methylpyridazin-3-yl]phenyl}acetamide, trifluoroacetate
Figure imgf000173_0001
The title compound was prepared as described in Example 72.
1H NMR (300 MHz, D2O) δ 8.10 (s, 1 H), 7.95 (dd, 2H), 7.78 (d, 2H), 4.02-3.85 (m, 2H), 3.70-
3.50 (m, 3H), 3.50-3.32 (m, 4H), 2.52 (s, 3H), 2.16 (s, 3H), 1 .44 (d, 6H).
HPLC (Method D): tr = 3.26 min (94 %).
Example 197 (General Procedure A)
1 '-(6-Pyridin-4-yl-pyridazin-3-yl)-[1 ,4']bipiperidinyl
Figure imgf000173_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-pyridin-4-yl-pyridazine and 4-piperidinopiperidine. 1H NMR (400 MHz, DMSO-Cf6) δ 8.67 (dd, 2H), 8.04 (m, 3H), 7.40 (d, 1 H), 4.53 (d, 2H), 2.95 (t, 2H), 2.56 (m, 1 H), 2.45 (m, 4H), 1 .82 (d, 2H), 1 .48 (m, 6H) 1.38 (m, 2H). HPLC-MS (Method G): M+1 = 324; tr= 0.54 min.
Example 198 (General Procedure A) 3-(Pyridin-3-yl)-6-[(4-pyrrolidin-1 -yl)piperidin-1 -yl]pyridazine
Figure imgf000173_0003
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(pyridin-3-yl)-pyridazine and 4-(1 -pyrrolidinyl)piperidine. 1H NMR (400 MHz, DMSO-Cf6) δ 9.22 (d, 1 H), 8.61 (dd,1 H), 8.39 (dt, 1 H), 8.01 (d, 1 H), 7.51 (m, 1 H), 7.40 (d, 1 H), 4.34 (dt, 2H), 3.09 (m, 2H), 2.56 (s, 4H), 2.33 (m, 1 H), 1 .95 (m, 2H), 1.69 (m,
4H), 1 .44 (m, 2H).
HPLC-MS (Method G): M+1 = 310; tr= 0.38 min.
Example 199 (General Procedure A)
1 '-(6-Pyridin-3-yl-pyridazin-3-yl)-[1 ,4']bipiperidinyl
Figure imgf000174_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(pyridin-3-yl)-pyridazine and 4-piperidinopiperidine. 1H NMR (400 MHz, CD3OD) δ 9.47 (d, 1 H), 9.1 1 (dt, 1 H), 8.93 (d, 1 H), 8.40 (d, 1 H), 8.15 (q, 1 H), 7.94 (d, 1 H), 4.66(d, 2H), 3.66 (m, 1 H), 3.58 (d, 2H), 3.36 (t, 2H), 3.08 (t, 2H), 2.38 (d, 2H), 1 .80-2.00 (m, 7H), 1.54 (m, 1 H). HPLC-MS (Method G): M+1 = 324; tr= 0.55 min.
Example 200 (General Procedure A)
3-(Pyridin-4-yl)-6-[(4-pyrrolidin-1 -yl)piperidin-1 -yl]pyridazine
Figure imgf000174_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(pyridin-4-yl)-pyridazine and 4-(1 -pyrrolidinyl)piperidine. 1H NMR (400 MHz, CDCI3) δ 8.69 (d, 2H), 7.90 (d, 2H), 7.67 (d, 1 H), 7.01 (d, 1 H), 4.47 (d, 2H), 3.12 (m, 2H), 2.67 (s, 4H), 2.40 (m, 1 H), 2.07 (d, 2H), 1.83 (s, 4H), 1 .67 (m, 2H). HPLC-MS (Method G): M+1 = 310; tr= 0.46 min.
Example 201 (General Procedure A) 4-Pyrrolidin-1 -yl-3,4,5,6-tetrahydro-2H-[1 ,2';5',3"]terpyridine
Figure imgf000175_0001
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 6-chloro-[3,3']bipyridinyl and 4-(1 -pyrrolidinyl)piperidine. 1H NMR (400 MHz,
CD3OD) δ 8.74 (d, 1 H), 8.46 (dd, 1 H), 8.39 (d, 1 H), 8.03 (dt, 1 H), 7.86 (dd, 1 H), 7.49 (q, 1 H),
6.95 (d, 1 H), 4.40 (d, 2H), 2.92 (m, 2H), 2.67 (t, 4H), 2.35 (m, 1 H), 2.05 (d, 2H), 1.82 (m, 4H),
1 .51 (m, 2H).
HPLC-MS (Method G): M+1 = 309; tr= 0.28 min.
Example 202 (General Procedure A) 1 -lsopropyl-4-(6-phenylpyridin-3-yl)piperazine, dihydrochloride
Figure imgf000175_0002
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 5-bromo-2-phenylpyridine and 1 -isopropylpiperazine. 1H NMR (400 MHz, CD3OD) δ 8.41 (m, 1 H), 8.13 (m, 2H), 7.90-7.85 (m, 2H), 7.63-7.55 (m, 3H), 4.3-4.1 (m, 2H), 3.75-3.55 (m, 3H), 3.50-3.30 (m, 4H), 1.45 (d, J = 6.8 Hz, 6H). HPLC-MS (Method G): M+1 = 282; tr= 0.76 min.
Example 203 (General Procedure A)
(R)-2-[6-(3,4-Dimethoxyphenyl)pyridazin-3-yl]octahydropyrido[1 ,2-a]pyrazine, dihydrochloride
Figure imgf000175_0003
The title compound was prepared by a similar procedure to that described in Example 1 , starting from 3-chloro-6-(3,4-dimethoxy-phenyl)-pyridazine and (R)-octahydro-pyridol[1 ,2-a]- pyrazine, dihydrochloride.
1H-NMR (400 MHz, CD3OD) δ 8.55 (d, 1 H), 8.22 (d, 1 H), 7.60-7.54 (m, 2H), 7.21 (d, 1 H), 4.73-4.58 (m, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.72-3.52 (m, 3H), 3.50-3.35 (m, 3H), 3.15-3.05 (m,1 H), 2.12-2.05 (m, 1 H), 2.02-1 .93 (m, 3H), 1 .81 -1 .63 (m, 2H). HPLC-MS (Method G): M+1 = 355; tr= 0.955 min.
Example 204 (General Procedure B) N-{3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}acetamide, trif luoroacetate
Figure imgf000176_0001
The title compound was prepared by a similar procedure to that described in Example 39, starting from 3-(6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzylamine and acetyl chloride. 1H NMR (300 MHz, D2O) δ 8.27 (d, 1 H), 8.10 (s, 1 H), 7.40-7.24 (m, 5H), 4.32-4.28 (d, 4H), 3.64-3.53 (m, 5H), 3.25 (t, 2H), 1.92 (s, 2H), 1.27 (d, 6H). HPLC (Method D): tr = 2.40 min (97 %).
Example 205 (General Procedure B)
N-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-3,3-dimethylbutyramide, trifluoroace- tate
Figure imgf000176_0002
The title compound was prepared by a similar procedure to that described in Example 39, starting from 4-(6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzylamine and 3,3-dimethyl-butyryl chloride. 1H NMR (400 MHz, D2O) δ 8.29 (dd, 1 H), 8.14 (d, 1 H), 7.51 (d, 2H), 7.40-7.30 (m, 3H), 4.40- 4.25 (m, 4H), 3.70-3.48 (m, 5H), 3.34-3.15 (m, 2H), 2.06 (s, 1 H), 1 .28 (dd, 6H), 0.86 (s, 9H). HPLC (Method D): tr = 3.38 min (97 %).
Example 206 (General Procedure B)
N-{3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-3,3-dimethylbutyramide, trifluoro- acetate
Figure imgf000177_0001
The title compound was prepared by a similar procedure to that described in Example 39, starting from 3-(6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzylamine and 3,3-dimethyl-butyryl chloride.
1H NMR (300 MHz, D2O) δ 8.27 (d, 1 H), 8.12 (s, 1 H), 7.46-7.28 (m, 5H), 4.32-4.28 (d, 4H),
3.64-3.53 (m, 5H), 3.25 (t, 2H), 2.06 (s, 2H), 1.27 (d, 6H), 0.85 (s, 9H).
HPLC (Method D): tr = 3.39 min (90 %).
Example 207 (General Procedure B)
N-{4-[2-(4-lsopropylpiperazin-1 -yl)pyrimidin-5-yl]benzyl}isobutyramide, dihydrochloride
Figure imgf000177_0002
The title compound was prepared by a similar procedure to that described in Example 39, starting from 4-(6-(4-isopropylpiperazin-1 -yl)pyrimidin-5-yl]benzonitrile.
Mp = 287-2890C.
1H NMR (300 MHz, CDCI3) δ 13.06 (brs, 1 H), 8.68 (s, 2H), 7.47-7.38 (m, 4H), 6.07 (brs, 1 H),
5.12 (d, 2H), 4.52-4.47 (m, 2H), 4.25-4.12 (m, 2H), 3.60-3.44 (m, 3H), 3.11 -2.76 (m, 2H),
2.52-2.38 (m, 1 H), 1 .49 (d, 6H), 1 .21 (d, 6 H). Example 208 (General Procedure B)
N-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-2,2-dimethylpropionamide, trifluoro- acetate
Figure imgf000178_0001
The title compound was prepared by a similar procedure to that described in Example 39, starting from 4-(6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzylamine and 2,2-dimethyl- propionyl chloride.
1H NMR (300 MHz, D2O) δ 8.29 (dd, 1 H), 8.13 (d, 1 H), 7.50 (d, 2H), 7.35-7.25 (m, 3H), 4.45- 4.25 (m, 4H), 3.65-3.45 (m, 5H), 3.34-3.15 (m, 2H), 1 .28 (d, 6H), 1.07 (s, 9H). HPLC (Method D): tr = 2.84 min (98 %).
Example 209 (General Procedure B)
N-{3-[6-(4-lsopropylpiperazin-1 -yl)pyridin-3-yl]benzyl}-2,2-dimethylpropionamide, trifluoro- acetate
Figure imgf000178_0002
The title compound was prepared by a similar procedure to that described in Example 39, starting from 3-(6-(4-isopropylpiperazin-1 -yl)pyridin-3-yl]benzylamine and 2,2-dimethyl- propionyl chloride.
1H NMR (300 MHz, CDCI3) δ 8.41 (d, 1 H), 7.02 (t, 1 H), 7.43-7.27 (m, 3H), 7.21 -7.18 (m, 1 H), 6.72 (t, 1 H), 6.95-6.93 (m, 1 H), 4.49-4.46 (m, 2H), 3.78-3.62 (m, 4H), 2.90-2.65 (m, 5H), 1 .17-1 .10 (m, 15H). HPLC (Method D): tr = 3.10 min (98 %).
Example 210 (General Procedure B) 4-[2-(4-Cyclopropylpiperazin-1 -yl)pyrimidin-5-yl]benzylamine
Figure imgf000179_0001
The title compound was prepared by a similar procedure to that described in Example 39, starting from 4-[2-(4-cyclopropyl-piperazin-1 -yl)-pyrimidin-5-yl]-benzonitrile.
Mp = 150-1520C.
1H NMR (300 MHz, CDCI3) δ 8.55 (s, 2H), 7.45 (d, 2H), 7.39 (d, 2H), 3.91 (s, 2H), 3.86-3.83
(m, 4H), 2.72-2.68 (m, 4H), 1 .69-1.61 (m, 1 H), 1 .5 (brs, 2H), 0.52-0.46 (m, 4H).
HPLC (Method Rx): tr = 3.29 min (99 %).
Example 211 (General Procedure B) N-{4-[2-(4-Cyclopropylpiperazin-1 -yl)pyrimidin-5-yl]benzyl}acetamide, dihydrochloride
Figure imgf000179_0002
The title compound was prepared by a similar procedure to that described in Example 39, starting from 4-[2-(4-cyclopropyl-piperazin-1 -yl)-pyrimidin-5-yl]-benzylamine and acetic anhydride.
Mp = 235-2360C.
HPLC (Method Rx): tr = 7.11 min (100 %).
Example 212 (General Procedure B)
N N-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]acetamide, ditrifluoroacetate
Figure imgf000179_0003
The title compound was prepared by a similar procedure to that described in Example 39, starting from 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-benzonitrile. 1H NMR (400 MHz, CD3OD) δ 8.24 (d, 1 H), 7.91 (d, 2H), 7.84 (d, 1 H), 7.50 (d, 2H), 4.44 (s, 2H), 3.63 (heptet, 1 H), 3.70-3.30 (broad m, 8H), 2.02 (s, 3H), 1 .42 (d, 6H). HPLC-MS (Method G): M+1 = 354; tr= 0.66 min.
Example 213 (General Procedure F)
N-[4-(4-Cyclopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)phenyl]acetamide, hydrochloride
Figure imgf000180_0001
N-[4-(3,4,5,6-Tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-phenyl]-acetamide (125 mg, 0.42 mmol) was dissolved in methanol (2 ml_)and ethoxycyclopropoxy)trimethylsilane (0.11 g, 0.63 mmol) was added together with acetic acid (0.076 g, 1 .26 mmol). The mixture was stirred for 5 min and sodium cyanoborohydride (0.04 g, 0.63 mmol) and water (1 ml_) were added. The reaction mixture was heated at 650C for 1 h and then another equivalent of sodium cyanoborohydride was added and stirring was continued at 650C for 1 h. The reaction mixture was evaporated in vacuo and the crystalline mixture was washed with methanol. Evaporation of the volatiles afforded a residue which after treatment with HCI in diethyl ether afforded 72 mg (46 %) of the title compound. 1H-NMR (400 MHz, CD3OD) δ 8.85 (s, 1 H), 8.45 (s, 1 H), 7.85 (d, 2H), 7.75 (d, 2H), 4.6 (d, 2H), 3.7 (m, 2H), 3.5 (m, 4H), 2.95 (m, 1 H), 2.15 (s, 3H), 1 .2 (brs, 2H), 1 .05 (dd, 2H). HPLC-MS (Method G): M+1 = 338; tr= 1 .51 min.
Example 214 (General Procedure M) 2-{4-[6-(4-lsopropylpiperazin-1 -yl)pyridazin-3-yl]phenoxy}-N,N-dimethylacetamide, di- hydrochloride
Figure imgf000181_0001
Step 1 :
4-[6-(4-lsopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenol
Figure imgf000181_0002
4-[6-(4-lsopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenol was prepared by the general procedure I similar to that described in Example 71 , starting from 3-chloro-6-(4-isopropyl-piperazin- 1 -yl)-pyridazine and (4-hydroxyphenyl)boronic acid.
Step 2: A mixture of 4-[6-(4-isopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenol (1 10 mg, 0.37 mmol) and
60 % sodium hydride (58 mg, 1 .45 mmol) in dry DMF (5 ml_) was heated at 600C for 30 min.
2-Chloro-N,N-dimethylacetamide (54 mg, 0.44 mmol) was added and heating at 600C was continued for another 20 h. The reaction mixture was evaporated to dryness and partitioned between water (10 ml_) and DCM (10 ml_). The organic phase was isolated, washed with brine (5 ml_), dried over anhydrous magnesium sulphate, and evaporated to dryness in vacuo. The residue was dissolved in hot ethyl acetate and HCI9 in Et2O was added to give the title compound.
1H NMR (400 MHz, DMSO-c(6) δ 1 1 .29 (broad s, 1 H), 8.30 (d, 1 H), 8.00 (d, 2H), 7.86 (d, 1 H),
7.08 (d, 1 H), 4.93 (s, 2H), 4.58 (d, 2H), 3.65(t, 2H), 3.51 (m, 3H), 3.16 (m, 2H), 3.02 (s, 3H), 2.85 (s, 3H), 1 .32 (d, 6H).
HPLC-MS (Method G): M+1 = 384; tr= 0.72 min.
Example 215 (General Procedure L)
Cyclohexanecarboxylic acid {4-[6-(4-cyclopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}amide, trifluoroacetate
Figure imgf000182_0001
The title compound was prepared by a similar procedure to that described in Example 170, starting from 4-[6-(4-cyclopropyl-piperazin-1 -yl)-pyridazin-3-yl]-phenylamine and cyclohexyl- carbonyl chloride. 1H NMR (300 MHz, CD3OD) δ 8.34 (d, 1 H), 7.98-7.82 (m, 5H), 4.05-3.95 (m, 4H), 3.69-3.55 (m, 4H), 2.96-2.85 (m, 1 H), 2.44-2.37 (m, 1 H), 1 .91 -1 .82 (m, 4H), 1 .73 (d, 1 H), 1 .59-1 .19 (m, 5H), 1 .09-0.99 (m, 4H). HPLC (Method D): tr = 3.90 min (98 %).
Example 216
N-{4-[4-lsopropyl-6-(4-isopropylpiperazin-1 -yl)pyridazin-3-yl]phenyl}acetamide, trifluoro- acetate
Figure imgf000182_0002
A mixture of 3-(4-bromophenyl)-4-isopropyl-6-(4-isopropyl-piperazin-1 -yl)-pyridazine (500 mg, 1.24 mmol), acetamide (87.8 mg, 1.49 mmol), Pd(OAc)2 (13.9 mg, 0.062 mmol), Cs2CO3 (606 mg, 1 .86 mmol) and Xantphos (53.8 mg, 0.093 mmol) in 1 ,4-dioxane (10 ml_) was heated at reflux for 12 h. Then water (5 ml_) was added. After filtration, the mixture was extracted with EtOAc (3 x 5 ml_). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by HPLC Method F to give 196 mg (38 %) of the title compound.
1H NMR (300 MHz, CD3OD) δ 7.96 (s, 1 H), 7.89 (d, 2H), 7.57 (d, 2H), 4.90-3.314 (m, 9H), 3.19-3.15 (m, 1 H), 2.20 (s, 3H), 1 .46 (d, 6H), 1 .31 (d, 6H). HPLC (Method D): tr = 3.35 min (100 %).

Claims

What is claimed is:
1 . A compound of the general formula I:
Figure imgf000183_0001
wherein W, X, Y, Z independent of each other is a moiety of the formula -C(R2)= or -N= (i.e. nitrogen), with the proviso that at least one of the symbols W, X, Y or Z must be the moiety - N=;
R2 is hydrogen, halogen, cyano, Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkyl or halo-Ci 6-alkoxy;
R1 represents the following possibilities i) and ii):
i) a group of the general formula -NR R , wherein
R3 is hydrogen, Ci 6-alkyl, C2 6-alkenyl or C3 8-cycloalkyl; and
R4 is Ci 6-alkyl, C2 6-alkenyl or C3 8-cycloalkyl, each of which are substituted with a group selected from -NR5R6 and heterocyclyl; R5 and R6 independently represent hydrogen or Ci 6-alkyl; or
i) a group of one of the general formulas Il to VII:
Figure imgf000183_0002
IV V
Figure imgf000184_0001
Vl VII wherein the star indicates the position of the free bond (and not a methyl group), and wherein
m is 0 (zero), 1 , 2 or 3;
n is 1 , 2 or 3;
o is O (zero), 1 , 2, 3 or 4;
p is 0 (zero), 1 or 2;
q is 1 or 2;
Q represents a moiety of the formula -CH2- , -O-, -S- or >NR3, wherein R3 is as defined above;
R7 and R8 independent of each other is hydrogen or Ci 6-alkyl, or R7 and R8 can together with the nitrogen to which they are attached form a heterocyclyl group;
R9 is C1 6-alkyl or C3 8-cycloalkyl, which both may be substituted with a group of the general formula -NR7R8, wherein R7 and R8 are as defined above;
R10 is hydrogen or Ci 6-alkyl;
R11 is o hydrogen, Ci 8-alkyl, C3 8-alkenyl, C3 8-alkynyl, C3 8-cycloalkyl, C3 8-cyclo- alkenyl, C3 8-cycloalkyl-Ci 3-alkyl, C3 8-cycloalkenyl-Ci 3-alkyl or heterocyclyl, or
o Ci 6-alkyl or C3 8-cycloalkyl, which both are substituted with at least one sub- stituent selected from the group consisting of hydroxy, Ci 6-alkoxy, Ci 6-alkyl- carbonyl, cyano, -NR5R6 , -C(=O)NR5R6, arylcarbonyl, heteroarylcarbonyl, Ci 6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, Ci 6-alkoxycarbonyl, aryl-Ci 6-alkoxycarbonyl, heteroaryl and heterocyclyl, which heterocyclyl may be substituted with Ci 6-alkyl, where applicable; R5 and R6 are as defined above;
A is aryl or heteroaryl, each of which may optionally be substituted with one or more sub- stituents independently selected from R12;
R12 is
• halogen, hydroxy, cyano, C1 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfanyl, Ci 6-alkylsulfinyl, -V-
(CH2)s-(C=O)r-NR13R14, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkyl- carboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl, Ci 6-alkoxy-Ci 6-alkyl, Ci 6-alkyl- carbonylamino, N-(Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino, Ci 6-alkylcarbonyl- amino-Ci 6-alkyl or N-(Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino-Ci 6-alkyl; or
• heterocyclyl, heterocyclyl-Ci 6-alkyl, heterocyclyl-Ci 6-alkoxy, heterocyclylcarbonyl, C3 8-cycloalkylcarbonylamino, N-(C3 8-cycloalkylcarbonyl)-N-(Ci 6- alkyl)amino, C3 s-cycloalkylcarbonylamino-Ci 6-alkyl, N-(C3 8-cycloalkyl- carbonyl)-N-(Ci 6-alkyl)amino-Ci 6-alkyl, C3 8-cycloalkyl-Ci 6-alkylcarbonyl- amino, N-(C3 8-cycloalkyl-Ci 6-alkylcarbonyl)-N-(Ci 6-alkyl)amino, C3 8-cyclo- alkyl-Ci 6-alkylcarbonylamino-Ci 6-alkyl, N-(C3 8-cycloalkyl-Ci 6-alkylcarbonyl)- N-(Ci 6-alkyl)amino-Ci 6-alkyl, arylcarbonylamino, aryl-Ci 6-alkylcarbonylamino, arylcarbonylamino-Ci 6-alkyl, aryl-Ci 6-alkylcarbonylamino-Ci 6-alkyl, hetero- arylcarbonylamino, heteroarylcarbonylamino-Ci 6-alkyl, heterocyclylcarbonyl- amino or heterocyclylcarbonylamino-Ci 6-alkyl, wherein each said aryl, heteroaryl, C3 8-cycloalkyl and heterocyclyl may optionally be substituted with halogen, hydroxy, oxo, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6- alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl or Ci 6-alkoxy-Ci 6-alkyl; or
• aryl or heteroaryl, each of which may be substituted with halogen, hydroxy, oxo, carboxy, nitro, cyano, Ci 6-alkyl, C3 8-cycloalkyl, Ci 6-alkoxy, Ci 6-alkyl- sulfanyl, Ci 6-alkylsulfonyl, Ci 6-alkylcarbonyl, Ci 6-alkylcarbonylamino, Ci 6- alkylcarbonylamino-Ci 6-alkyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, halo-Ci 6-alkyl, halo-Ci 6-alkoxy, hydroxy-Ci 6-alkyl, Ci 6-alkoxy-Ci 6-alkyl, aryl, arylcar- bonylamino, arylcarbonylamino-Ci 6-alkyl, heteroaryl, heteroarylcarbonyl- amino, heteroarylcarbonylamino-Ci 6-alkyl or -(CH2)s-(C=O)r-NR13R14;
r is 0 (zero) or 1 ;
s is O (zero), 1 , 2 or 3;
V represents a bond or moiety of the formula, -O-, -S-, -S(=O)-, -S(=O)2- or >NR3, wherein R3 is as defined above;
R13 is hydrogen, Ci 6-alkyl, C3 8-cycloalkyl or Ci 6-alkylcarbonyl;
R14 is hydrogen, Ci 6-alkyl or C3 8-cycloalkyl with the proviso that R14 is hydrogen when R13 is Ci 6-alkylcarbonyl; or R13 and R14 can together with the attached nitrogen form a heterocyclyl group, which heterocyclyl group may be optionally substituted with halogen, hydroxy, cyano, Ci 6-alkyl, C3 8-cycloalkyl, halo-Ci 6-alkyl, Ci 6-alkoxy, halo-Ci 6-alkoxy, Ci 6-alkylcarbonyl, Ci 6-alkoxycarbonyl, Ci 6-alkylcarboxy, cyano-Ci 6-alkyl, hydroxy-Ci 6-alkyl or aminocarbonyl;
and pharmaceutically acceptable salts and solvates thereof;
with the following provisos a) through g):
a) when R1 is a group of the formula Vl; W is -N=; X, Y and Z is each a moiety of the general formula -C(R2)=; wherein R2 is as defined above; then A cannot be imidazolyl;
b) when R1 is a group of the formula Vl; q is 1 ; X is -C(R2)=; R11 is branched C4 6-alkyl, branched C4 6-alkenyl, branched C4 6-alkynyl, C3 5-cycloalkyl, C3 7-cycloalkenyl, C3 6-cyclo- alkyl-Ci 3-alkyl or C3 6-cycloalkenyl-Ci 3-alkyl; and W, Y, Z is each a moiety of the formula - C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, tri- fluoromethyl, trifluoromethoxy, Ci 6-alkoxy , Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -V-(CH2)s-(C=O)r-NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; c) when R1 is a group of the formula VII; m is 1 , 2 or 3; X is a moiety of the formula -C(R2)=; and W, Y, Z is each a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C38-cycloalkyl or a group of the formula -V-(CH2)S- (C=O)r-NR13R14, wherein V is a bond, r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl;
d) when R1 is a group of the formula Vl; q is 1 ; R11 is ethyl, n-propyl or isopropyl; Y and Z is each -N=; X is a moiety of the formula -C(R2)=, and W is a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Ci 6-alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, Ci 6-alkylsulfinyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl;
e) when R1 is a group of the formula VII; m is 1 , 2 or 3; Y and Z is each -N=; X is a moiety of the formula -C(R2)=; and W is a moiety of the formula -C(R2)= or -N=; wherein R2 is as defined above; then R12 can not be halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Ci 6- alkoxy, Ci 6-alkyl, Ci 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl;
f) when R1 is formula Vl, q is 1 , X and W is each a moiety of the general formula -C(R2)=, wherein R2 is as defined above , Y and Z is each -N=, R11 is isopropyl, and A is phenyl, then R12 can not be fluoro, bromo, iodo, hydroxy, trifluoromethoxy, C2 6-alkoxy, Ci 6-alkyl, C2 6- alkylsulfanyl, C2 6-alkylsulfinyl, C2 6-alkylsulfonyl, cyano, aryl, heteroaryl, C3 8-cycloalkyl or a group of the formula -(CH2)s-(C=O)r-NR13R14, wherein r and s each is 0 (zero), and R13 and R14 each is hydrogen or Ci 6-alkyl; and
g) when X and Z is each -C(R2)=; and one or both of W and Y are -N=; then R1 cannot be a group of the formula II, wherein m is 2.
2. A compound according to claim 1 with the following provisos h) - m): h) R1 is different from possibility i), when the ring containing W, X, Y and Z is a pyridazine or a pyrimidine ring, i) R11 is different from hydrogen and methyl, j) R2 is different from cyano, k) at least one of W, X, Y and Z is a moiety of the formula -C(R2)= wherein R2 is as defined herein, I) R1 is not a group of formula Il when the ring containing W, X, Y and Z is a pyridazine ring, and m) A is different from pyrazol-1 -yl when the ring containing W, X, Y and Z is a pyridazine ring.
3. The use of a compound of formula I according to any of the preceding product claims as me- dicament or in a pharmaceutical composition.
4. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the preceding product claims together with one or more pharmaceutically acceptable carriers or recipients, which composition preferably comprises from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, and especially preferred from about 0.5 mg to about 200 mg, of a compound according to any one of the preceding product claims.
5. Use of a compound according to any one of the preceding product claims for the prepara- tion of a pharmaceutical composition for the treatment of disorders and diseases related to the histamine H3 receptor.
6. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the reduction of weight.
7. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.
8. Use of a compound according to any one of the preceding product claims for the prepara- tion of a pharmaceutical composition for the suppression of appetite or for satiety induction.
9. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
10. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the treatment of IGT.
1 1 . Use of a compound according to any one of the preceding product claims for the prepa- ration of a pharmaceutical composition for the treatment of type 2 diabetes.
12. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
13. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
14. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.
15. Use of a compound according to any one of the preceding product claims for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy or attention deficit disorders.
16. A method for the treatment of any of the diseases or conditions mentioned in any of the preceding claims and/or in the above specification, the method comprising administering to a subject in need thereof an effective amount of a compound according to any of the above product claims or a pharmaceutical composition according to the above claim thereon.
17. Any novel feature or combination of features described herein.
Novo Nordisk A/S
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Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071952A1 (en) * 2005-12-21 2007-06-28 Astrazeneca Ab Piperazine compounds useful as antagonists of c-c chemokines (ccr2b and ccr5) for the treatment of inflammatory diseases
WO2008145681A2 (en) * 2007-05-31 2008-12-04 Boehringer Ingelheim International Gmbh Ccr2 receptor antagonists and uses thereof
WO2008154126A1 (en) 2007-06-11 2008-12-18 High Point Pharmaceuticals, Llc New heteocyclic h3 antagonists
JP2010520276A (en) * 2007-03-06 2010-06-10 アストラゼネカ・アクチエボラーグ Novel 2-heteroaryl-substituted benzothiophenes and benzofurans 709
WO2010107765A1 (en) * 2009-03-18 2010-09-23 Schering Corporation Bicyclic compounds as inhibitors of diacylglycerol acyltransferase
US8343989B2 (en) 2006-03-31 2013-01-01 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor
US8378097B2 (en) 2006-05-29 2013-02-19 High Point Pharmaceuticals, Llc 3-(1,3-benzodioxol-5-yl)-6-(4-cyclopropylpiperazin-1-yl)-pyridazine, its salts and solvates and its use as histamine H3 receptor antagonist
US8466183B2 (en) 2008-05-14 2013-06-18 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US8501739B2 (en) 2005-07-04 2013-08-06 High Point Pharmaceuticals, Llc Medicaments
US8653274B2 (en) 2008-08-29 2014-02-18 Astrazeneca Ab Compounds suitable as precursors to compounds that are useful for imaging amyloid deposits
WO2014028459A1 (en) * 2012-08-13 2014-02-20 Novartis Ag 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
US8765949B2 (en) 2009-12-17 2014-07-01 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists and uses thereof
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US8835440B2 (en) 2008-12-19 2014-09-16 Boehringer Ingelheim International Gmbh Cyclic pyrimidin-4-carboxamides as CCR2 receptor antagonists for treatment of inflammation, asthma and COPD
US8841313B2 (en) 2010-05-17 2014-09-23 Boehringer Ingelheim International Gmbh CCR2 antagonists and uses thereof
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
US8859575B2 (en) 2013-03-06 2014-10-14 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidine modulators of the histamine h4 receptor
US8877745B2 (en) 2010-05-12 2014-11-04 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists, method for producing the same, and use thereof as medicaments
WO2015001348A1 (en) * 2013-07-03 2015-01-08 Redx Pharma Limited Pyridazine derivatives as hedgehog pathway inhibitors
US8946218B2 (en) 2010-05-12 2015-02-03 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists, method for producing the same, and use thereof as medicaments
US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
US9018212B2 (en) 2010-05-25 2015-04-28 Boehringer Ingelheim International Gmbh Pyridazine carboxamides as CCR2 receptor antagonists
US9108958B2 (en) 2011-07-15 2015-08-18 Boehringer Ingelheim International Gmbh Selective CCR2 antagonists
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9133123B2 (en) 2010-04-23 2015-09-15 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
EP3053577A1 (en) * 2015-02-09 2016-08-10 F. Hoffmann-La Roche AG Compounds for the treatment of cancer
WO2016128343A1 (en) * 2015-02-09 2016-08-18 F. Hoffmann-La Roche Ag Compounds for the treatment of cancer
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
CN108697709A (en) * 2015-12-10 2018-10-23 Ptc医疗公司 Method for treating Huntington disease
US10213428B2 (en) 2015-07-02 2019-02-26 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
EP3373935A4 (en) * 2015-11-12 2019-04-17 Merck Sharp & Dohme Corp. Cyanopyridine derivatives as liver x receptor beta agonists, compositions, and their use
US10357493B2 (en) 2017-03-10 2019-07-23 Selenity Therapeutics (Bermuda), Ltd. Metalloenzyme inhibitor compounds
WO2022053541A1 (en) * 2020-09-10 2022-03-17 Eracal Therapeutics Ltd. Compounds for use as appetite suppressant
US11382918B2 (en) 2017-06-28 2022-07-12 Ptc Therapeutics, Inc. Methods for treating Huntington's Disease
US11395822B2 (en) 2017-06-28 2022-07-26 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11407753B2 (en) 2017-06-05 2022-08-09 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
WO2023034836A1 (en) * 2021-08-30 2023-03-09 Remix Therapeutics Inc. Compounds and methods for modulating splicing
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions
US11685746B2 (en) 2018-06-27 2023-06-27 Ptc Therapeutics, Inc. Heteroaryl compounds for treating Huntington's disease
US11780839B2 (en) 2018-03-27 2023-10-10 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11858941B2 (en) 2018-06-27 2024-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating Huntington's disease

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030236259A1 (en) * 2002-02-05 2003-12-25 Rolf Hohlweg Novel aryl- and heteroarylpiperazines
EP2038256A1 (en) * 2006-05-23 2009-03-25 TransTech Pharma, Inc 6- (4-cyclopropylpiperazin-1-yl) -2 ' -methyl- [3, 4 ']-bipyridine and its use as a medicament
JP5539230B2 (en) * 2008-01-30 2014-07-02 セファロン、インク． Substituted pyridazine derivatives having histamine H3 antagonist activity
US9371311B2 (en) 2008-06-30 2016-06-21 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidine derivatives
US8802679B2 (en) * 2009-09-16 2014-08-12 Astellas Pharma Inc. Glycine compound
TW201206901A (en) * 2010-05-11 2012-02-16 Sanofi Aventis Substituted N-heteroaryl bipyrrolidine carboxamides, preparation and therapeutic use thereof
WO2013076590A1 (en) 2011-11-23 2013-05-30 Oxygen Healthcare Research Pvt. Ltd Benzothiazine compounds as h3 receptor ligands
US11270110B2 (en) 2019-09-17 2022-03-08 Boston Polarimetrics, Inc. Systems and methods for surface modeling using polarization cues
CN114746717A (en) 2019-10-07 2022-07-12 波士顿偏振测定公司 System and method for surface normal sensing using polarization
CN114787648B (en) 2019-11-30 2023-11-10 波士顿偏振测定公司 Systems and methods for transparent object segmentation using polarization cues
US11195303B2 (en) 2020-01-29 2021-12-07 Boston Polarimetrics, Inc. Systems and methods for characterizing object pose detection and measurement systems
US11797863B2 (en) 2020-01-30 2023-10-24 Intrinsic Innovation Llc Systems and methods for synthesizing data for training statistical models on different imaging modalities including polarized images
US11953700B2 (en) 2020-05-27 2024-04-09 Intrinsic Innovation Llc Multi-aperture polarization optical systems using beam splitters
US11954886B2 (en) 2021-04-15 2024-04-09 Intrinsic Innovation Llc Systems and methods for six-degree of freedom pose estimation of deformable objects
US11290658B1 (en) 2021-04-15 2022-03-29 Boston Polarimetrics, Inc. Systems and methods for camera exposure control
US11689813B2 (en) 2021-07-01 2023-06-27 Intrinsic Innovation Llc Systems and methods for high dynamic range imaging using crossed polarizers
CN114478478B (en) * 2022-02-18 2023-06-13 厦门大学 N- (1- (6- (substituted phenyl) pyridazin-3-yl) piperidin-3-yl) amine/amide derivatives and process for preparing the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066578A1 (en) 1999-04-30 2000-11-09 Pfizer Products Inc. Compounds for the treatment of obesity
WO2001066534A2 (en) 2000-03-09 2001-09-13 Abbott Laboratories Cyclic and bicyclic diamino histamine-3 receptor antagonists
WO2001074810A2 (en) 2000-03-31 2001-10-11 Ortho Mcneil Pharmaceutical, Inc. Method for using 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzothiazoles as h3 antagonists
US6316475B1 (en) 2000-11-17 2001-11-13 Abbott Laboratories Aminoalkoxybiphenylcarboxamides as histamine-3 receptor ligands and their therapeutic applications

Family Cites Families (128)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB753166A (en) 1953-05-22 1956-07-18 Miles Lab Improvements in or relating to substituted piperazines
US2724713A (en) 1954-03-24 1955-11-22 American Cyanamid Co 1-carbobenzoxypiperazines and process of preparing same
US2993899A (en) 1958-03-31 1961-07-25 Miles Lab Acetylenically unsaturated piperazine derivatives
US3164598A (en) 1963-02-01 1965-01-05 American Home Prod Substituted 1, 4-diazabicyclo[4.3.0]nonanes and methods for their preparation
US3309370A (en) 1964-07-16 1967-03-14 Miles Lab Bicycloalkyl piperazine derivatives and process
GB1293565A (en) 1969-05-03 1972-10-18 Aspro Nicholas Ltd Aminophthalazines and pharmaceutical compositions thereof
US3886161A (en) 1970-12-14 1975-05-27 Sandoz Ag 2-Piperazino-3-cyano-5-phenyl-pyridines
GB1345880A (en) 1971-06-18 1974-02-06 Cepbepe Pyridazine derivatives
DE2516040C2 (en) 1974-06-10 1984-12-20 Dr. Karl Thomae Gmbh, 7950 Biberach Benzimidazoles, processes for their preparation and pharmaceuticals containing them
FR2306694A1 (en) 1975-04-07 1976-11-05 Parcor DERIVATIVES OF PIPERAZINE
GB1545094A (en) 1976-12-14 1979-05-02 Gist Brocades Nv Piperazine derivatives
US4144346A (en) 1977-01-31 1979-03-13 Janssen Pharmaceutica N.V. Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles
HU175471B (en) * 1977-06-13 1980-08-28 Gyogyszerkutato Intezet Process for producing new 3-bracketul-pyrazolyl-bracket closed-pyridazine derivatives
US4163849A (en) 1978-03-17 1979-08-07 Merck & Co., Inc. Piperazinylpyrazines
DE2824764A1 (en) 1978-06-06 1979-12-20 Hoechst Ag NEW PYRIDYL PIPERAZINE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION
DE3160397D1 (en) 1980-02-22 1983-07-14 Tanabe Seiyaku Co Phenoxyalkane derivative and processes for preparing same
US4339579A (en) 1980-12-29 1982-07-13 American Home Products Corporation 2,6-Bis-(pyrrolopyrazinyl)pyrazines
US4616014A (en) * 1981-10-22 1986-10-07 Fujisawa Pharmaceutical Co., Ltd. Triazine derivatives, and pharmaceutical compositions comprising the same
US5001125A (en) 1984-03-26 1991-03-19 Janssen Pharmaceutica N.V. Anti-virally active pyridazinamines
FR2573075B1 (en) 1984-09-14 1987-03-20 Innothera Lab Sa NEWS (PYRIDYL-2) -1 PIPERAZINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS
DE3526235A1 (en) 1984-11-16 1986-05-22 Bayer Ag, 5090 Leverkusen LIQUID CRYSTAL COMPOSITIONS
KR860700352A (en) 1984-11-27 1986-10-06 후지와라 도미오 2-(1-piperazinyl) -4-substituted phenylquinoline derivatives and preparation methods thereof
EP0200024B1 (en) 1985-04-30 1992-07-01 ARZNEIMITTELWERK DRESDEN GmbH 3-cyano-pyridines, process for their preparation and their pharmaceutical use
US4670505A (en) * 1985-08-23 1987-06-02 Hercules Incorporated Polyacrylate dispersions
PH25772A (en) 1985-08-30 1991-10-18 Novo Industri As Insulin analogues, process for their preparation
DK111387A (en) 1986-03-05 1987-09-06 Otsuka Pharma Co Ltd CARBOSTYRIL DERIVATIVES AND SALTS THEREOF, MEDICINE CONTAINING SUCH DERIVATIVES AND PROCEDURES FOR THE PREPARATION OF THE DERIVATIVES
DE3609596A1 (en) 1986-03-21 1987-10-01 Hoechst Ag 2-AZOLYLMETHYL-2-ARYL-1,3-DIOXOLANE AND THE SALTS THEREOF, METHOD FOR THE PRODUCTION THEREOF, MEANS CONTAINING IT AND THEIR USE
MY104343A (en) 1987-11-23 1994-03-31 Janssen Pharmaceutica Nv Novel pyridizinamine deravatives
DE3803860A1 (en) 1988-02-09 1989-08-17 Basf Ag N, N'-DISUBSTITUTED PIPERAZINE
DE3837825A1 (en) 1988-11-08 1990-05-10 Hoechst Ag NEW INSULIN DERIVATIVES, THEIR USE AND A PHARMACEUTICAL PREPARATION CONTAINING THEM
US5021421A (en) 1989-03-03 1991-06-04 Dainippon Pharmaceutical Co., Ltd. 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same
GB9012316D0 (en) 1990-06-01 1990-07-18 Wellcome Found Pharmacologically active cns compounds
JPH08504798A (en) 1992-12-18 1996-05-21 ザ ウエルカム ファウンデーション リミテッド Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors
DE4308028B4 (en) 1993-03-13 2012-08-16 Merck Patent Gmbh 1,2,2,2-tetrafluoroethyl ether and liquid crystalline medium
WO1994022846A1 (en) 1993-03-30 1994-10-13 Pfizer Inc. Compounds enhancing antitumor activity of other cytotoxic agents
JP3377826B2 (en) 1993-05-06 2003-02-17 ヘキスト・アクチェンゲゼルシャフト Novel compounds for use in liquid crystal compositions
DK0705275T3 (en) 1993-06-21 1999-09-20 Novo Nordisk As Asp B28 insulin crystals
CN1056618C (en) 1993-09-17 2000-09-20 诺沃挪第克公司 Acylated insulin
IL111730A (en) 1993-11-29 1998-12-06 Fujisawa Pharmaceutical Co Piperazine derivatives processes for the preparation thereof and pharmaceutical compositions containing the same
US5504188A (en) 1994-06-16 1996-04-02 Eli Lilly And Company Preparation of stable zinc insulin analog crystals
DE4423044A1 (en) 1994-07-01 1996-01-04 Hoechst Ag Alkyl-oxiranyl-alkyl ester(s) of mesogenic carboxylic acids useful in liquid crystal mixts.
DE4425642A1 (en) 1994-07-20 1996-01-25 Merck Patent Gmbh Stable liquid crystalline or mesogenic substd. benzyl fluoro-alkyl ether(s)
WO1997002245A1 (en) 1995-07-06 1997-01-23 Japan Tobacco Inc. Benzamidoxime derivatives and medicinal use thereof
US6130217A (en) 1995-09-20 2000-10-10 Pfizer Inc Compounds enhancing antitumor activity of other cytotoxic agents
RU2167160C2 (en) 1995-11-09 2001-05-20 Санофи-Синтелябо Derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazole- -2(3h)-one, method of their synthesis, pharmaceutical composition based on thereof and drug
AU727775B2 (en) 1996-01-17 2000-12-21 Novo Nordisk A/S Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use
WO1997041120A1 (en) 1996-07-26 1997-11-06 Dr. Reddy's Research Foundation Thiazolidinedione compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions thereof
IL128332A0 (en) 1996-08-30 2000-01-31 Novo Nordisk As GLP-1 derivatives
DZ2376A1 (en) 1996-12-19 2002-12-28 Smithkline Beecham Plc New sulfonamide derivatives process for their preparation and pharmaceutical compositions containing them.
JP4339402B2 (en) 1996-12-31 2009-10-07 ドクター・レディーズ・ラボラトリーズ・リミテッド Novel heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them, and their use in the treatment of diabetes and related diseases
EP0981526B1 (en) 1997-05-02 2004-02-25 Dr. Reddy's Laboratories Ltd. Novel antidiabetic compounds having hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US6613942B1 (en) 1997-07-01 2003-09-02 Novo Nordisk A/S Glucagon antagonists/inverse agonists
AU749271B2 (en) 1997-07-01 2002-06-20 Agouron Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
RU2215004C2 (en) 1997-07-16 2003-10-27 Ново Нордиск А/С Condensed derivative of 1,2,4-thiadiazine, pharmaceutical composition and method for preparing medicine
WO1999004390A1 (en) 1997-07-17 1999-01-28 Sony Corporation Magnetic recording medium and magnetic recorder/reproducer comprising the same
US6340759B1 (en) 1997-10-02 2002-01-22 Eisai Co., Ltd. Fused pyridine derivatives
WO1999019313A1 (en) 1997-10-27 1999-04-22 Dr. Reddy's Research Foundation Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
AP1445A (en) 1997-10-27 2005-07-10 Agouron Pharma Substituted 4-amino-thiazol-2-yl compounds as CDKs inhibitors.
US6440961B1 (en) 1997-10-27 2002-08-27 Dr. Reddy's Research Foundation Tricyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them
JP4391597B2 (en) 1997-12-02 2009-12-24 ドクター・レディーズ・ラボラトリーズ・リミテッド Thiazolinedione and oxazolidinedione derivatives with antidiabetic, hypolipidemic and antihypertensive properties
EP0978512A1 (en) 1998-07-29 2000-02-09 Societe Civile Bioprojet Non-imidazole aryloxy (or arylthio) alkylamines as histamine H3-receptor antagonists and their therapeutic applications
EP1123279A1 (en) 1998-10-21 2001-08-16 Novo Nordisk A/S New compounds, their preparation and use
JP2002527502A (en) 1998-10-21 2002-08-27 ノボ ノルディスク アクティーゼルスカブ New compounds, their preparation and use
WO2000023417A1 (en) 1998-10-21 2000-04-27 Novo Nordisk A/S New compounds, their preparation and use
EP1123267A1 (en) 1998-10-21 2001-08-16 Novo Nordisk A/S New compounds, their preparation and use
WO2000023445A1 (en) 1998-10-21 2000-04-27 Novo Nordisk A/S New compounds, their preparation and use
JP2002527520A (en) 1998-10-21 2002-08-27 ノボ ノルディスク アクティーゼルスカブ New compounds, their production and use
EP1140945B1 (en) 1998-12-18 2003-06-04 Novo Nordisk A/S Fused 1,2,4-thiadiazine derivatives, their preparation and use
WO2000041121A1 (en) 1999-01-07 2000-07-13 Ccrewards.Com Method and arrangement for issuance and management of digital coupons and sales offers
AU3033500A (en) 1999-01-15 2000-08-01 Agouron Pharmaceuticals, Inc. Non-peptide glp-1 agonists
AU2953699A (en) 1999-04-16 2000-11-02 Dr. Reddy's Research Foundation Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
AU4465200A (en) 1999-04-16 2000-11-02 Dr. Reddy's Research Foundation Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
PL351492A1 (en) 1999-04-16 2003-04-22 Reddys Lab Ltd Dr Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
JP2002542237A (en) 1999-04-20 2002-12-10 ノボ ノルディスク アクティーゼルスカブ New compounds, their production and use
WO2000063196A1 (en) 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
WO2000063153A1 (en) 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
JP2002542246A (en) 1999-04-20 2002-12-10 ノボ ノルディスク アクティーゼルスカブ New compounds, their production and use
DE19922723A1 (en) 1999-05-18 2000-11-23 Clariant Gmbh Active display matrix e.g. for flat screens contains a chiral/smectic liquid crystal mixture giving high maximum transmission, high contrast and constant threshold voltage over a wide temperature range
DE19934799B4 (en) 1999-07-28 2008-01-24 Az Electronic Materials (Germany) Gmbh Chiral smectic liquid crystal mixture and its use in high contrast active matrix displays
GB9926302D0 (en) 1999-11-05 2000-01-12 Smithkline Beecham Plc Novel compounds
GB9926303D0 (en) 1999-11-05 2000-01-12 Smithkline Beecham Plc Novel compounds
US6602872B1 (en) 1999-12-13 2003-08-05 Merck & Co., Inc. Substituted pyridazines having cytokine inhibitory activity
FR2802206B1 (en) 1999-12-14 2005-04-22 Sod Conseils Rech Applic 4-AMINOPIPERIDINE DERIVATIVES AND THEIR USE AS MEDICINAL PRODUCTS
DE60022386T2 (en) 1999-12-16 2006-06-22 Schering Corp. SUBSTITUTED IMIDAZOLE AS NEUROPEPTIDE Y Y5 RECEPTOR ANTAGONISTS
FI20000480A0 (en) 2000-03-01 2000-03-01 Orion Yhtymae Oyj Quinoline and naphthalene derivatives as alpha-2 antagonists
AU2001249672A1 (en) 2000-03-31 2001-10-15 Ortho-Mcneil Pharmaceutical, Inc. Method for using 2- or 3-aryl substituted imidazo(1,2-a) pyridines as h3 antagonists
ES2213693T3 (en) 2000-03-31 2004-09-01 Ortho-Mcneil Pharmaceutical, Inc. DERIVATIVES OF INDOLIZINE PHENYL-SUBSTITUTES AND ITS USE AS LIGANDS OF THE H3 HISTAMINE RECEIVER.
AU2001247906A1 (en) 2000-03-31 2001-10-15 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-substituted indoles and indazoles
EP1268478B1 (en) 2000-03-31 2007-05-02 Ortho-McNeil Pharmaceutical, Inc. Phenyl-substituted imidazopyridines
AU8112101A (en) 2000-08-08 2002-02-18 Ortho Mcneil Pharm Inc Non-imidazole aryloxypiperidines
US20030078271A1 (en) 2001-01-31 2003-04-24 Blackburn Thomas P. Use of GAL3 receptor antagonists for the treatment of depression and/or anxiety and compounds useful in such methods
FR2827288B1 (en) * 2001-07-12 2003-10-31 Servier Lab NOVEL OCTAHYDRO-2H-PYRIDO [1,2-A] PYRAZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US20030073672A1 (en) 2001-09-05 2003-04-17 Breitenbucher J. Guy Method for treating allergies using substituted pyrazoles
US20030236259A1 (en) 2002-02-05 2003-12-25 Rolf Hohlweg Novel aryl- and heteroarylpiperazines
MXPA04007612A (en) 2002-02-05 2004-11-10 Novo Nordisk As Novel aryl- and heteroarylpiperazines.
JP2003277755A (en) 2002-03-26 2003-10-02 Fuji Photo Film Co Ltd Liquid crystal composition and liquid crystal element
US6864261B2 (en) 2002-05-02 2005-03-08 Euro-Celtique S.A. Therapeutic agents useful for treating pain
SE0201544D0 (en) 2002-05-17 2002-05-17 Biovitrum Ab Novel compounds and thier use
US6906060B2 (en) 2002-06-06 2005-06-14 Novo Nordisk A/S Substituted hexahydropyrrolo[1,2-a]pyrazines, octahydropyrido[1,2-a]-pyrazines and decahydropyrazino[1,2-a]azepines
AU2003229535A1 (en) 2002-06-06 2003-12-22 Novo Nordisk A/S Substituted hexahydropyrrolo(1,2-a)pyrazines, octahydropyrido(1,2-a)pyrazines and decahydropyrazino(1,2-a)azepines
DE10246657A1 (en) 2002-10-07 2004-04-15 Merck Patent Gmbh Chiral phenols which induce a cholesteric phase in a nematic liquid crystal and simultaneously act as a stabilizer and are useful in electro-optical displays
US7332508B2 (en) 2002-12-18 2008-02-19 Novo Nordisk A/S Substituted homopiperidine, piperidine or pyrrolidine derivatives
WO2005009976A1 (en) 2003-07-29 2005-02-03 Novo Nordisk A/S Pyridazinyl- piperazines and their use as histamine h3 receptor ligands
US20050028438A1 (en) 2003-08-05 2005-02-10 Campana Kimberly A. Plastic lawn edging fabricated by a continuous vacuum forming process
CA2551037A1 (en) * 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
US20070032477A1 (en) 2003-10-17 2007-02-08 Waer Mark J A Pteridine derivatives useful for making pharmaceutical compositions
AU2004289304A1 (en) 2003-11-10 2005-05-26 Synta Pharmaceuticals, Corp. Pyridine compounds
FR2864080B1 (en) 2003-12-23 2006-02-03 Sanofi Synthelabo 1-PIPERAZINE-AND-1-HOMOPIPERAZINE-CARBOXYLATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
JP2007217282A (en) 2004-03-04 2007-08-30 Astellas Pharma Inc Substituted pyrimidine derivative
JP2007532558A (en) 2004-04-09 2007-11-15 メルク　エンド　カムパニー　インコーポレーテッド Inhibitor of Akt activity
EP1737845A4 (en) 2004-04-13 2010-07-21 Synta Pharmaceuticals Corp Disalt inhibitors of il-12 production
AU2005260102A1 (en) 2004-05-08 2006-01-12 Novartis International Pharmaceutical Ltd. 3-aryl-5,6-disubstituted pyridazines
CA2562315A1 (en) 2004-05-19 2005-12-01 Basf Aktiengesellschaft 2-substituted pyrimidines and their use as pesticides
WO2005117883A1 (en) 2004-05-28 2005-12-15 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
ES2543813T3 (en) 2004-11-02 2015-08-24 Northwestern University Pyridazine compounds for the treatment of inflammatory diseases
MX2007006387A (en) 2004-12-03 2007-06-20 Hoffmann La Roche 3-substituted pyridine derivatives as h3 antagonists.
WO2006090273A2 (en) 2005-02-22 2006-08-31 Warner-Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds with keto or hydroxyl linkers for the treatment of schizophrenia
US20070078135A1 (en) 2005-04-18 2007-04-05 Neurogen Corporation Substituted heteroaryl CB1 antagonists
FR2885615B1 (en) 2005-05-12 2007-06-22 Servier Lab NOVEL PHENYLPYRIDINYLPIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2006124874A2 (en) 2005-05-12 2006-11-23 Kalypsys, Inc. Inhibitors of b-raf kinase
FR2885616B1 (en) 2005-05-12 2007-06-22 Servier Lab NOVEL PHENYLPYRIDINYLPIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CN103110635A (en) 2005-07-04 2013-05-22 海波因特制药有限责任公司 Histamine H3 receptor antagonist
EP1904069B1 (en) 2005-07-15 2018-06-13 Albany Molecular Research, Inc. Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
CA2606004A1 (en) 2005-08-02 2007-02-08 Neurogen Corporation Dipiperazinyl ketones and related analogues
EA015569B1 (en) 2006-03-28 2011-10-31 ХАЙ ПОЙНТ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи Benzothiazoles having histamine h3 antagonist activity and pharmaceutical compositions, comprising thereof
EP2038256A1 (en) 2006-05-23 2009-03-25 TransTech Pharma, Inc 6- (4-cyclopropylpiperazin-1-yl) -2 ' -methyl- [3, 4 ']-bipyridine and its use as a medicament
SI2079732T1 (en) 2006-05-29 2012-03-30 High Point Pharmaceuticals Llc 3- (1, 3-benz0di0x0l-5-yl) -6- (4-cyclopropylpiperazin-1-yl) -pyridazine, its salts and solvates and its use as histamine h3 receptor antagonist
EP2014656A3 (en) 2007-06-11 2011-08-24 High Point Pharmaceuticals, LLC New heteocyclic h3 antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066578A1 (en) 1999-04-30 2000-11-09 Pfizer Products Inc. Compounds for the treatment of obesity
WO2001066534A2 (en) 2000-03-09 2001-09-13 Abbott Laboratories Cyclic and bicyclic diamino histamine-3 receptor antagonists
WO2001074810A2 (en) 2000-03-31 2001-10-11 Ortho Mcneil Pharmaceutical, Inc. Method for using 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzothiazoles as h3 antagonists
US6316475B1 (en) 2000-11-17 2001-11-13 Abbott Laboratories Aminoalkoxybiphenylcarboxamides as histamine-3 receptor ligands and their therapeutic applications

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LINNEY ET AL., J. MED. CHEM., vol. 43, 2000, pages 2362 - 2370

Cited By (98)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8846677B2 (en) 2005-07-04 2014-09-30 High Point Pharmaceuticals, Llc Medicaments
US8501739B2 (en) 2005-07-04 2013-08-06 High Point Pharmaceuticals, Llc Medicaments
US7943768B2 (en) * 2005-12-21 2011-05-17 Astrazeneca Ab Piperazine compounds useful as antagonists of C-C chemokines (Ccr2b and CcrS) for the treatment of inflammatory diseases
WO2007071952A1 (en) * 2005-12-21 2007-06-28 Astrazeneca Ab Piperazine compounds useful as antagonists of c-c chemokines (ccr2b and ccr5) for the treatment of inflammatory diseases
US8962644B2 (en) 2006-03-31 2015-02-24 Janssen Pharmaceutica, Nv Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor
US9365548B2 (en) 2006-03-31 2016-06-14 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor
US8598189B2 (en) 2006-03-31 2013-12-03 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor
US8343989B2 (en) 2006-03-31 2013-01-01 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor
US8378097B2 (en) 2006-05-29 2013-02-19 High Point Pharmaceuticals, Llc 3-(1,3-benzodioxol-5-yl)-6-(4-cyclopropylpiperazin-1-yl)-pyridazine, its salts and solvates and its use as histamine H3 receptor antagonist
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
EP2132201B1 (en) * 2007-03-06 2016-11-16 AstraZeneca AB Novel 2-heteroaryl substituted benzothiophenes and benzofuranes
KR101530392B1 (en) * 2007-03-06 2015-06-22 아스트라제네카 아베 Novel 2-heteroaryl substituted benzothiophenes and benzofuranes 709
JP2010520276A (en) * 2007-03-06 2010-06-10 アストラゼネカ・アクチエボラーグ Novel 2-heteroaryl-substituted benzothiophenes and benzofurans 709
JP2010528089A (en) * 2007-05-31 2010-08-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング CCR2 receptor antagonist and use thereof
WO2008145681A3 (en) * 2007-05-31 2009-03-05 Boehringer Ingelheim Int Ccr2 receptor antagonists and uses thereof
US8653262B2 (en) 2007-05-31 2014-02-18 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists and uses thereof
WO2008145681A2 (en) * 2007-05-31 2008-12-04 Boehringer Ingelheim International Gmbh Ccr2 receptor antagonists and uses thereof
US8344001B2 (en) 2007-06-11 2013-01-01 High Point Pharmaceuticals, Llc Heterocyclic H3 antagonists
WO2008154126A1 (en) 2007-06-11 2008-12-18 High Point Pharmaceuticals, Llc New heteocyclic h3 antagonists
EP2166850A1 (en) * 2007-06-11 2010-03-31 High Point Pharmaceuticals, LLC New heteocyclic h3 antagonists
EP2166850A4 (en) * 2007-06-11 2010-06-02 High Point Pharmaceuticals Llc New heteocyclic h3 antagonists
EP2014656A2 (en) * 2007-06-11 2009-01-14 Transtech Pharma New heteocyclic h3 antagonists
CN101795567A (en) * 2007-06-11 2010-08-04 高点制药有限责任公司 New heteocyclic H3 antagonists
EP2014656A3 (en) * 2007-06-11 2011-08-24 High Point Pharmaceuticals, LLC New heteocyclic h3 antagonists
US8481573B2 (en) 2008-05-14 2013-07-09 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US9382217B2 (en) 2008-05-14 2016-07-05 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US10544136B2 (en) 2008-05-14 2020-01-28 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US8466183B2 (en) 2008-05-14 2013-06-18 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US9975863B2 (en) 2008-05-14 2018-05-22 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US8530503B2 (en) 2008-05-14 2013-09-10 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US8796318B2 (en) 2008-05-14 2014-08-05 The Scripps Research Institute Modulators of sphingosine phosphate receptors
US8653274B2 (en) 2008-08-29 2014-02-18 Astrazeneca Ab Compounds suitable as precursors to compounds that are useful for imaging amyloid deposits
US9309267B2 (en) 2008-08-29 2016-04-12 Astrazeneca Ab Compounds suitable as precursors to compounds that are useful for imaging amyloid deposits
US8835440B2 (en) 2008-12-19 2014-09-16 Boehringer Ingelheim International Gmbh Cyclic pyrimidin-4-carboxamides as CCR2 receptor antagonists for treatment of inflammation, asthma and COPD
US9067951B2 (en) 2008-12-19 2015-06-30 Boehringer Ingelheim International Gmbh Process and intermediates for the production of CCR2 antagonists
US8637507B2 (en) 2009-03-18 2014-01-28 Merck Sharp & Dohme Corp. Bicyclic compounds as inhibitors of diacylglycerol acyltransferase
WO2010107765A1 (en) * 2009-03-18 2010-09-23 Schering Corporation Bicyclic compounds as inhibitors of diacylglycerol acyltransferase
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US8765949B2 (en) 2009-12-17 2014-07-01 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists and uses thereof
US9670222B2 (en) 2009-12-17 2017-06-06 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
US10196402B2 (en) 2009-12-17 2019-02-05 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
US11731981B2 (en) 2009-12-17 2023-08-22 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
US11046706B2 (en) 2009-12-17 2021-06-29 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9133123B2 (en) 2010-04-23 2015-09-15 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US8877745B2 (en) 2010-05-12 2014-11-04 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists, method for producing the same, and use thereof as medicaments
US8946218B2 (en) 2010-05-12 2015-02-03 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists, method for producing the same, and use thereof as medicaments
US8841313B2 (en) 2010-05-17 2014-09-23 Boehringer Ingelheim International Gmbh CCR2 antagonists and uses thereof
US9018212B2 (en) 2010-05-25 2015-04-28 Boehringer Ingelheim International Gmbh Pyridazine carboxamides as CCR2 receptor antagonists
US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
US9108958B2 (en) 2011-07-15 2015-08-18 Boehringer Ingelheim International Gmbh Selective CCR2 antagonists
TWI635083B (en) * 2012-08-13 2018-09-11 瑞士商諾華公司 1,4-disubstituted pyridazine analogs and methods for treating survival of motor neuron （smn）-deficiency-related conditions
EA032005B1 (en) * 2012-08-13 2019-03-29 Новартис Аг 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
US10758533B2 (en) 2012-08-13 2020-09-01 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
WO2014028459A1 (en) * 2012-08-13 2014-02-20 Novartis Ag 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
US10195196B2 (en) 2012-08-13 2019-02-05 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US11229648B2 (en) 2012-08-13 2022-01-25 Novartis Ag 1,4-disubstituted pyridazine analogs thereof and methods for treating SMN-deficiency-related conditions
EP4101849A1 (en) * 2012-08-13 2022-12-14 Novartis AG 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
AU2013302859B2 (en) * 2012-08-13 2016-07-14 Novartis Ag 1,4-disubstituted pyridazine analogs and methods for treating SMN-deficiency-related conditions
US9278952B2 (en) 2013-03-06 2016-03-08 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor
US8859575B2 (en) 2013-03-06 2014-10-14 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidine modulators of the histamine h4 receptor
US9663497B2 (en) 2013-03-06 2017-05-30 Janssen Pharmaceutica Nv Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor
WO2015001348A1 (en) * 2013-07-03 2015-01-08 Redx Pharma Limited Pyridazine derivatives as hedgehog pathway inhibitors
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions
EP3053577A1 (en) * 2015-02-09 2016-08-10 F. Hoffmann-La Roche AG Compounds for the treatment of cancer
WO2016128343A1 (en) * 2015-02-09 2016-08-18 F. Hoffmann-La Roche Ag Compounds for the treatment of cancer
US11066400B2 (en) 2015-02-09 2021-07-20 Hoffmann-La Roche Inc. Compounds for the treatment of cancer
US11147814B2 (en) 2015-07-02 2021-10-19 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p- tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
US10568885B2 (en) 2015-07-02 2020-02-25 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-y1)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-citrate
US10213428B2 (en) 2015-07-02 2019-02-26 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
EP3373935A4 (en) * 2015-11-12 2019-04-17 Merck Sharp & Dohme Corp. Cyanopyridine derivatives as liver x receptor beta agonists, compositions, and their use
US11638706B2 (en) 2015-12-10 2023-05-02 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US10881658B2 (en) 2015-12-10 2021-01-05 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
AU2016366694B2 (en) * 2015-12-10 2020-02-06 Ptc Therapeutics, Inc. Methods for treating huntington's disease
CN113717154A (en) * 2015-12-10 2021-11-30 Ptc医疗公司 Methods for treating huntington's disease
US10874672B2 (en) 2015-12-10 2020-12-29 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
CN108697709A (en) * 2015-12-10 2018-10-23 Ptc医疗公司 Method for treating Huntington disease
EP3386511A4 (en) * 2015-12-10 2019-01-02 PTC Therapeutics, Inc. Methods for treating huntington's disease
EP3848035A1 (en) * 2015-12-10 2021-07-14 PTC Therapeutics, Inc. 1,4-disubstituted pyridazine compounds for treating huntington's disease
AU2016366694C1 (en) * 2015-12-10 2021-03-25 Ptc Therapeutics, Inc. Methods for treating huntington's disease
US10357493B2 (en) 2017-03-10 2019-07-23 Selenity Therapeutics (Bermuda), Ltd. Metalloenzyme inhibitor compounds
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11407753B2 (en) 2017-06-05 2022-08-09 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11395822B2 (en) 2017-06-28 2022-07-26 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11382918B2 (en) 2017-06-28 2022-07-12 Ptc Therapeutics, Inc. Methods for treating Huntington's Disease
US11780839B2 (en) 2018-03-27 2023-10-10 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11685746B2 (en) 2018-06-27 2023-06-27 Ptc Therapeutics, Inc. Heteroaryl compounds for treating Huntington's disease
US11858941B2 (en) 2018-06-27 2024-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating Huntington's disease
WO2022053541A1 (en) * 2020-09-10 2022-03-17 Eracal Therapeutics Ltd. Compounds for use as appetite suppressant
WO2023034836A1 (en) * 2021-08-30 2023-03-09 Remix Therapeutics Inc. Compounds and methods for modulating splicing

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