WO2010133544A1 - Piperazine and aminopyrrolidine compounds as histamine h3 receptor antagonists - Google Patents

Piperazine and aminopyrrolidine compounds as histamine h3 receptor antagonists Download PDF

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Publication number
WO2010133544A1
WO2010133544A1 PCT/EP2010/056729 EP2010056729W WO2010133544A1 WO 2010133544 A1 WO2010133544 A1 WO 2010133544A1 EP 2010056729 W EP2010056729 W EP 2010056729W WO 2010133544 A1 WO2010133544 A1 WO 2010133544A1
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alkyl
methyl
triazol
alkynyl
alkenyl
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PCT/EP2010/056729
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French (fr)
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Adam James Davenport
David James Hallett
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Evotec Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to Histamine H3 receptor antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament.
  • the histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion.
  • the H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al.
  • H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance.
  • Such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity)
  • cognition e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others
  • sleep e.g., hypersomnia and narcolepsy
  • energy homeostasis e.g. obesity
  • Histamine H3 receptor antagonists are described in the art for the treatment of the above mentioned diseases and disorders.
  • WO-A 2007/080140 cyclylhexyl piperazinyl methanone derivatives are disclosed, which are useful as H3 receptor modulators.
  • cyclo butyl derivatives are disclosed as Histamine-3 receptor antagonists.
  • WO-A 2006/089076 describes imidazole amides as histamine H3 receptor modulators.
  • histamine H3 receptor modulators are described in international patent applications with application N° PCT/EP2010/051077 and PCT/EP2009/064560 as well as WO-A 2010/026113, WO-A 2009/135842, WO-A 2009/121812 and WO-A 2009/095394.
  • an object of the present invention is to provide a new class of compounds as Histamine
  • H3 receptor antagonists which may be effective in the treatment of H3 receptor related diseases and may show improved pharmaceutically relevant properties including activity
  • X 1 , X 2 is N and the other is CH;
  • R 1 is T; Ci_ 4 alkyl; C 2 - 4 alkenyl; or C 2 - 4 alkynyl, wherein Ci_ 4 alkyl; C 2 - 4 alkenyl; and C 2 - 4 alkynyl are optionally substituted with one or more R 9 , which are the same or different;
  • R 9 is halogen; CN; C(O)OR 10 ; OR 10 ; C(O)R 10 ; C(O)N(R 10 R 10a ); S(O) 2 N(R 10 R 10a ); S(O)N(R 10 R 10a ); S(O) 2 R 10 ; S(O)R 10 ; N(R 10 )S(O) 2 N(R 10a R 10b ); SR 10 ; N(R 10 R 10a ); NO 2 ; OC(O)R 10 ; N(R 10 )C(O)R 10a ; N(R 10 )SO 2 R 10a ; N(R 10 )S(O)R 10a ; N(R 10 )C(O)N(R 10a R 10b ); N(R 10 )C(O)OR 10a ; OC(O)N(R 10 R 1 Oa ); or T;
  • R 10 , R 1Oa , R 10b are independently selected from the group consisting of H; T; Ci_ 4 alkyl; C 2 - 4 alkenyl; and C 2 - 4 alkynyl, wherein Ci_ 4 alkyl; C 2 - 4 alkenyl; and C 2 - 4 alkynyl are optionally substituted with one or more R 11 , which are the same or different;
  • R 11 is halogen; CN; C(O)OR 12 ; OR 12 ; C(O)R 12 ; C(O)N(R 12 R 12a ); S(O) 2 N(R 12 R 12a ); S(O)N(R 12 R 12a ); S(O) 2 R 12 ; S(O)R 12 ; N(R 12 )S(O) 2 N(R 12a R 12b ); SR 12 ; N(R 12 R 12a ); NO 2 ; OC(O)R 12 ; N(R 12 )C(O)R 12a ; N(R 12 )SO 2 R 12a ; N(R 12 )S(O)R 12a ; N(R 12 )C(O)N(R 12a R 12b ); N(R 12 )C(O)OR 12a ; OC(O)N(R 12 R 12a ); or T;
  • R 12 , R 12a , R 12b are independently selected from the group consisting of H; T; Ci_ 4 alkyl; C 2 - 4 alkenyl; and C 2 - 4 alkynyl, wherein Ci_ 4 alkyl; C 2 - 4 alkenyl; and C 2 - 4 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • T is phenyl; naphthyl; azulenyl; indenyl; indanyl; C 3 _ 7 cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T is optionally substituted with one or more R 13 , which are the same or different;
  • R 15 , R 16 are independently selected from the group consisting of halogen; CN; C(O)OR 17 ; OR 17 ; C(O)R 17 ; C(O)N(R 17 R 17a ); S(O) 2 N(R 17 R 17a ); S (O)N(R 17 R 17a ); S(O) 2 R 17 ; S(O)R 17 ; N(R 17 )S(O) 2 N(R 17a R 17b ); SR 17 ; N(R 17 R 17a ); NO 2 ; OC(O)R 17 ; N(R 17 )C(O)R 17a ; N(R 17 )SO 2 R 17a ; N(R 17 )S(O)R 17a ; N(R 17 )C(O)N(R 17a R 17b ); N(R 17 )C(O)OR 17a ; OC(O)N(R 17 R 17a ); and T 1 ;
  • R 17 , R 17a , R 17b are independently selected from the group consisting of H; T 1 ; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • T 1 is phenyl; C 3 _ 7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 1 is optionally substituted with one or more R 18 , which are the same or different;
  • R 19 , R 19a , R 19b are independently selected from the group consisting of H; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • R 2 , R 3 are independently selected from the group consisting of H; halogen; Ci_6 alkyl; and A, wherein Ci_6 alkyl is optionally substituted with one or more R 20 , which are the same or different, provided that at least one of R 2 , R 3 is A;
  • R 2 , R 3 are joined together with the carbon atom to which they are attached to form a ring T 3 ;
  • A is T 2 ; Ci_6 alkyl; C 2 -6 alkenyl; or C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are substituted with at least one R 20a.
  • R 20 is halogen; CN; C(O)OR 21 ; OR 21 ; C(O)R 21 ; C(O)N(R 21 R 21a ); S(O) 2 N(R 21 R 21a ); S(O)N(R 21 R 21a ); S(O) 2 R 21 ; S(O)R 21 ; N(R 21 )S(O) 2 N(R 21a R 21b ); SR 21 ; N(R 21 R 21a ); NO 2 ; OC(O)R 21 ; N(R 21 )C(O)R 21a ; N(R 2 ⁇ SO 2 R 21 '; N(R 21 )S(O)R 21a ; N(R 21 )C(O)N(R 21a R 21b ); N(R 21 )C(O)OR 21a ; or OC(O)N(R 21 R 21a );
  • R 21 , R 21a , R 21b are independently selected from the group consisting of H; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • R 20a is T 2 ; halogen; CN; C(O)OR 20b ; OR 20b ; C(O)R 20b ; C(O)N(R 20b R 20c ); S(O) 2 N(R 20b R 20c ); S(O)N(R 20b R 20c ); S(O) 2 R 20b ; S(O)R 20b ; N(R 20b )S(O) 2 N(R 20c R 20d ); SR 20b ; N(R 20b R 20c ); NO 2 ; OC(O)R 20b ; N(R 20b )C(O)R 20c ; N(R 20b )SO 2 R 20c ; N(R 20b )S(O)R 20c ; N(R 20b )C(O)N(R 20c R 20d ); N(R 20b )C(O)OR 20c ; or OC(O)N(R 20b R 20c );
  • R 20b , R 20c , R 20d are independently selected from the group consisting of H; T 2 ; Ci_ 6 alkyl; C 2 - 6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • T 2 is phenyl; naphthyl; azulenyl; indenyl; indanyl; C 3 _ 7 cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T 2 is optionally substituted with one or more R 22 , which are the same or different;
  • T is C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T is optionally substituted with one or more R 23 , which are the same or different;
  • R 24 , R 24a , R 24b are independently selected from the group consisting of H; T 4 ; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more R 26 , which are the same or different;
  • R 25 , R 26 are independently selected from the group consisting of halogen; CN; C(O)OR 27 ; OR 27 ; C(O)R 27 ; C(O)N(R 27 R 27a ); S(O) 2 N(R 27 R 27a ); S(O)N(R 27 R 27a ); S(O) 2 R 27 ; S(O)R 27 ; N(R 27 )S(O) 2 N(R 27a R 27b ); SR 27 ; N(R 27 R 27a ); NO 2 ; OC(O)R 27 ; N(R 27 )C(O)R 27a ; N(R 27 )SO 2 R 27a ; N(R 27 )S(O)R 27a ; N(R 27 )C(O)N(R 27a R 27b ); N(R 27 )C(O)OR 27a ; OC(O)N(R 27 R 27a ); and T 4 ;
  • R 27 , R 27a , R 27b are independently selected from the group consisting of H; T 4 ; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more R 28 , which are the same or different;
  • R 28 is halogen; CN; C(O)OR 29 ; OR 29 ; C(O)R 29 ; C(O)N(R 29 R 29a ); S(O) 2 N(R 29 R 29a ); S(O)N(R 29 R 29a ); S(O) 2 R 29 ; S(O)R 29 ; N(R 29 )S(O) 2 N(R 29a R 29b ); SR 29 ; N(R 29 R 29a ); NO 2 ; OC(O)R 29 ; N(R 29 )C(O)R 29a ; N(R 29 )SO 2 R 29a ; N(R 29 )S(O)R 29a ; N(R 29 )C(O)N(R 29a R 29b ); N(R 29 )C(O)OR 29a ; or OC(O)N(R 29 R 29a );
  • R 29 , R 29a , R 29b are independently selected from the group consisting of H; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • T 4 is phenyl; C 3 _ 7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 4 is optionally substituted with one or more R 30 , which are the same or different;
  • R 32 , R 33 are independently selected from the group consisting of halogen; CN; C(O)OR 34 ; OR 34 ; C(O)R 34 ; C(O)N(R 34 R 34a ); S(O) 2 N(R 34 R 34a ); S(O)N(R 34 R 34a ); S(O) 2 R 34 ; S(O)R 34 ; N(R 34 )S(O) 2 N(R 34a R 34b ); SR 34 ; N(R 34 R 34a ); NO 2 ; OC(O)R 34 ; N(R 34 )C(O)R 34a ; N(R 34 )SO 2 R 34a ; N(R 34 )S(O)R 34a ; N(R 34 )C(O)N(R 34a R 34b ); N(R 34 )C(O)OR 34a ; OC(O)N(R 34 R 34a ); and T 5 ;
  • R 34 , R 34a , R 34b are independently selected from the group consisting of H; T 5 ; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more R 35 , which are the same or different;
  • R 35 is halogen; CN; C(O)OR 36 ; OR 36 ; C(O)R 36 ; C(O)N(R 36 R 36a ); S(O) 2 N(R 36 R 36a ); S(O)N(R 36 R 36a ); S(O) 2 R 36 ; S(O)R 36 ; N(R 36 )S(O) 2 N(R 36a R 36b ); SR 36 ; N(R 36 R 36a ); NO 2 ; OC(O)R 36 ; N(R 36 )C(O)R 36a ; N(R 36 )SO 2 R 36a ; N(R 36 )S(O)R 36a ; N(R 36 )C(O)N(R 36a R 36b ); N(R 36 )C(O)OR 36a ; or OC(O)N(R 36 R 36a );
  • R 36 , R 36a , R 36b are independently selected from the group consisting of H; Ci_ 6 alkyl; C 2 -e alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • T 5 is phenyl; C 3 _ 7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 5 is optionally substituted with one or more R 37 , which are the same or different;
  • R 4 , R 4a , R 4b are independently selected from the group consisting of Ci_6 alkyl; C2-6 alkenyl; C2-6 alkynyl; C 3-6 cycloalkyl; CH2-cyclopropyl; CHF-cyclopropyl; CF2-cyclopropyl; CH 2 - cyclobutyl; CHF-cyclobutyl; CF 2 -cyclobutyl; and 4 to 5 membered saturated heterocyclyl, wherein Ci_6 alkyl; C2-6 alkenyl; C2-6 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH 3 ; OCH 2 F; OCHF 2 ; OCF 3 ; and CN, and wherein C 3 .
  • R 4a , R 4b are joined together with the nitrogen atom to which they are attached to form 3 to 7 membered saturated heterocyclyl, which is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH 3 ; OCH 2 F; OCHF 2 ; OCF 3 ; CN; CH 3 ; CH 2 F; CHF 2 ; and CF 3 ;
  • R 5 , R 5a , R 6 , R 6a , R 7 , R 8 are independently selected from the group consisting of H; Ci_ 5 alkyl; C2-5 alkenyl; and C2-5 alkynyl, wherein Ci .5 alkyl; C2-5 alkenyl; and C2-5 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; and CN;
  • R 4 /R 5 , R 4 /R 6 , R 4b /R 5 , R 4a /R 6 are joined together with the atoms to which they are attached to form 3 to 7 membered heterocyclyl, wherein 3 to 7 membered heterocyclyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH 3 ; CH 2 F; CHF 2 ; and CF 3 ;
  • R 6 /R 7 , R 5 /R 8 are joined together with the carbon atoms to which they are attached to form C 3 _ 7 cycloalkyl, wherein C 3 _ 7 cycloalkyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH 3 ; CH 2 F; CHF 2 ; and CF 3 ;
  • one or more of the pairs R 5 /R 6 , R 5 /R 7 , R 4 /R 7 , R 4a /R 7 , R 4 /R 8 , R 6 /R 8 are joined together with the respective ring X 0 to form 8 to 11 membered heterobicyclyl, wherein 8 to 11 membered heterobicyclyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH 3 ; CH 2 F; CHF 2 ; and CF 3 ;
  • variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
  • Alkyl means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified.
  • Alkenyl means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.
  • Alkynyl means a straight-chain or branched hydrocarbon chain, that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified.
  • Ci_ 4 alkyl means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g.
  • Ci_4 alkyl when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_4 alkyl carbon may be replaced by a substituent as further specified.
  • the term "C 2 _ 4 alkyl" is defined accordingly.
  • Ci_6 alkyl means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_ 4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or e.g.
  • Ci_ 6 alkyl when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified.
  • the term "Ci_ 5 alkyl" is defined accordingly.
  • Each hydrogen of a C 2 _ 6 alkenyl carbon may be replaced by a substituent as further specified.
  • the terms "C 2 _4 alkenyl” and "C 2 _ 5 alkenyl” are defined accordingly.
  • C 2 _6 alkynyl means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C ⁇ CH, -CH 2 -C ⁇ CH, CH 2 -CH 2 -C ⁇ CH, CH 2 -C ⁇ C-CH 3 , or e.g. -C ⁇ C- when two moieties of a molecule are linked by the alkynyl group.
  • Each hydrogen of a C 2 _6 alkynyl carbon may be replaced by a substituent as further specified.
  • the terms "C 2 _4 alkynyl” and "C 2 _ 5 alkynyl” are defined accordingly.
  • C 3 _ 7 cycloalkyl or "C 3 _ 7 cycloalkyl ring” means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.
  • the term "C 3 _6 cycloalkyl is defined accordingly.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • Examples for 3 to 7 membered heterocycles are azeridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydro furan, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine
  • 3 to 7 membered saturated heterocyclyl or “3 to 7 membered saturated heterocycle” means “3 to 7 membered heterocyclyl” or a “3 to 7 membered heterocycle” which is saturated.
  • the term “4 to 5 membered saturated heterocyclyl” or “4 to 5 membered saturated heterocycle” is defined accordingly.
  • Examples for 8 to 11 membered heterobicycles are imidazo[2,l-b][l,3]oxazole, imidazo[2,l-b][l,3]thiazole, indole, indoline, benzo furan, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydro isoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
  • 8 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.
  • heterocycles examples include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole.
  • Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention.
  • the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.
  • the substituents R 1 to R 3 and X 0 , X 1 , X 2 of formula (I) independently have the following meaning.
  • one or more of the substituents R 1 to R 3 and X 0 , X 1 , X 2 can have the preferred or more preferred meanings given below.
  • X 0 is
  • X 2 is N.
  • R 1 is Ci_4 alkyl substituted with one or more R 9 , which are the same or different.
  • R 1 is Ci_4 alkyl substituted with one R 9 .
  • R 1 is CH 2 -R 9 ; or CH 2 CH 2 R 9 , even more preferred is CH 2 -R 9 .
  • R 9 is T.
  • T is phenyl; naphthyl; or 5 to 6 membered aromatic heterocyclyl. Even more preferred is phenyl or a 6 membered heterocycle, even more preferred is phenyl.
  • T is unsubstituted or substituted with one or two R 13 , which are the same or different. More preferred, T is unsubstituted or substituted with one R 13 .
  • R 13 is halogen; Ci -6 alkyl (Ci -4 alkyl more preferred); OH; or 0-Ci -6 alkyl (0-Ci -4 alkyl is more preferred), wherein Ci_6 alkyl (C 1-4 alkyl) is optionally substituted with one or more halogen, which are the same or different. More preferred is R 13 F; Cl; OCH 3 ; or OCF 3 .
  • one of R 2 , R 3 is A. More preferred, one of R 2 , R 3 is A and the other is H.
  • A is T 2 .
  • T 2 is phenyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl. More preferred, T 2 is phenyl; or 3 to 7 membered heterocyclyl. Even more preferably, T 2 is phenyl; or pyridyl, even more preferred phenyl; or 3-pyridyl.
  • T 2 is unsubstituted or substituted with one or two R 22 , which are the same or different.
  • T 3 is cyclopentyl; cyclohexyl; tetrahydropyranyl; piperidinyl; pyrrolidinyl; or azetidinyl.
  • T 3 is unsubstituted or substituted with one or two R 23 , which are the same or different.
  • R 24 , R 24a are independently selected from the group consisting of H; T 4 ; Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different.
  • R 25 is halogen; T 4 ; or C(O)N(R 27 R 27a ).
  • T 4 is phenyl; or 5- to 6 membered heterocyclyl.
  • T 4 is unsubstituted or substituted with one or two R 30 , which are the same or different and selected from the group consisting of halogen; OH; O-Ci_6 alkyl; Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different.
  • R 4 is cyclobutyl; cyclopentyl; or C2-4 alkyl, optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH 3 ; OCH 2 F; OCHF 2 ; OCF 3 ; and CN. More preferably, R 4 is cyclobutyl.
  • R 4a , R 4b are independently selected from the group consisting of Ci_4 alkyl, optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH 3 ; OCH 2 F; OCHF 2 ; OCF 3 ; and CN.
  • R 4a , R 4b are together with the nitrogen atom to which they are attached to form a substituted or unsubstituted (more preferably unsubstituted) pyrrolidine ring.
  • R 5 , R 5a , R 6 , R 6a , R 7 , R 8 are H or CH 3 .
  • Preferred specific compounds of the present invention are selected from the group consisting of
  • Prodrugs of the compounds of the invention are also within the scope of the present invention.
  • “Prodrug” means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated.
  • These compounds can be produced from compounds of the present invention according to well-known methods.
  • Metabolites of compounds of formula (I) are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • the individual forms like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio.
  • stereoisomers like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • each pure form separately and any mixture of at least two of the pure forms in any ratio is comprised by formula (I) and is a subject of the present invention.
  • Iso topic labeled compounds of formula (I) are also within the scope of the present invention.
  • Methods for isotope labeling are known in the art.
  • Preferred isotopes are those of the elements H, C, N, O and S.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials, reagents and/or catalysts.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the present invention provides compounds of general formula (I) as Histamine H3 receptor antagonists.
  • the histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion.
  • the H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al.
  • H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance.
  • Such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity)
  • cognition e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others
  • sleep e.g., hypersomnia and narcolepsy
  • energy homeostasis e.g. obesity
  • the pharmacology of the H3 receptor seems not only to be determined by its localization but appears also to be regulated by differential splicing.
  • the H3 receptor is localized primarily to the central nervous system (CNS), with highest expression, in rodents, in the cerebral cortex, hippocampal formations, striatum, and hypothalamus (Drutel et al. (2001) MoI Pharmacol: 59; 1 - 8).
  • H3 receptor expression is prominent in the basal ganglia, globus pallidus, hippocampus, and cortex (Martinez-Mir et al. (1990) Brain Res: 526; 322 327). Notably, many of these brain regions are critical for cognition (cortex and hippocampus) and sleep and homeostatic regulation (hypothalamus).
  • the H3 receptor has been shown also to localize to regions which might be involved in pain sensation or transmission and therefore might offer treatment opportunities for different pain states (Cannon et al. (2007) Pain: 129; 76 - 92).
  • the H3 receptor is constitutively active and capable of signaling independently of agonist both in vitro and in vivo (Morisset et al. (2000) Nature: 408, 860 - 864).
  • H3 receptor antagonists like the series in this application could be useful in the treatment of cognitive dysfunctions as well as sleeping and energy homeostasis disorders.
  • antagonist also includes inverse agonists.
  • Neurological disorders include behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol
  • behavioral/cognitive syndromes e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol
  • seizure disorders neurodegenerative disorders e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis
  • sleep disorders e.g. hypersomnia and narcolepsy, excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns
  • neurological disorders also includes psychiatrical disorders within the meaning of the present invention.
  • neurodegenerative disorders also includes neuro- inflammatory disorders within the meaning of the present invention.
  • Pain e.g. neuropathic pain, inflammatory pain, nociception.
  • Pain includes acute and chronic pain within the meaning of the present invention.
  • Cardiovascular disorders e.g. acute myocardial infarction
  • other disorders i.e. gastrointestinal disorders
  • vestibular dysfunction e.g. Morbus Meniere, motion sickness, drug abuse
  • nasal congestion e.g. allergic rhinitis (hay fever), asthma.
  • Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma.
  • schizophrenia Foetal Alcohol Syndrome
  • Mild Cognitive Impairment Mild Cognitive Impairment
  • Age-related Memory Dysfunction disease-related cognitive dysfunctions
  • Lewy body dementia vascular dementia
  • Down Syndrome epilepsy
  • convulsion depression
  • More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma.
  • Alzheimer's disease Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.
  • the compounds of the present invention may be used for fatigue and cognitive impairment/dysfunction associated with Multiple Sclerosis. Accordingly, Multiple Sclerosis is a more preferred disease or disorder for disease related fatigue and cognitive impairment/dysfunction.
  • one aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use as a medicament.
  • Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing diseases and disorders associated with the H3 receptor.
  • Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing neurological disorders, e.g. behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders), seizure disorders, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis), sleep disorders (e.g.
  • behavioral/cognitive syndromes e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders
  • seizure disorders e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis
  • sleep disorders e.g.
  • hypersomnia and narcolepsy excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns), Migraine, Fatigue, Stroke, tremor; disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus; Pain, e.g. neuropathic pain, inflammatory pain, nociception; cardiovascular disorders, e.g. acute myocardial infarction; gastrointestinal disorders; vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse); nasal congestion; allergic rhinitis (hay fever); or asthma.
  • disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus
  • Pain e.g. neuropathic pain, inflammatory pain,
  • Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma.
  • schizophrenia Foetal Alcohol Syndrome
  • Mild Cognitive Impairment Mild Cognitive Impairment
  • Age-related Memory Dysfunction disease-related cognitive dysfunctions
  • Lewy body dementia vascular dementia
  • Down Syndrome epilepsy
  • convulsion depression
  • More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma. Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.
  • Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the H3 receptor.
  • Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of neurological disorders, e.g. behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders), seizure disorders, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis), sleep disorders (e.g.
  • behavioral/cognitive syndromes e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders
  • seizure disorders e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis
  • hypersomnia and narcolepsy excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns), Migraine, Fatigue, Stroke, tremor; disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus; Pain, e.g. neuropathic pain, inflammatory pain, nociception; cardiovascular disorders, e.g. acute myocardial infarction; gastrointestinal disorders; vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse); nasal congestion; allergic rhinitis (hay fever); or asthma.
  • disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus
  • Pain e.g. neuropathic pain, inflammatory pain,
  • Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma.
  • schizophrenia Foetal Alcohol Syndrome
  • Mild Cognitive Impairment Mild Cognitive Impairment
  • Age-related Memory Dysfunction disease-related cognitive dysfunctions
  • Lewy body dementia vascular dementia
  • Down Syndrome epilepsy
  • convulsion depression
  • Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma.
  • Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the H3 receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of neurological disorders, e.g. behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders), seizure disorders, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis), sleep disorders (e.g.
  • neurological disorders e.g. behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders), seizure disorders, neurodegenerative disorders (e.g. Alzheimer'
  • hypersomnia and narcolepsy excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns), Migraine, Fatigue, Stroke, tremor; disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus; Pain, e.g. neuropathic pain, inflammatory pain, nociception; cardiovascular disorders, e.g. acute myocardial infarction; gastrointestinal disorders; vestibular dysfunction (e.g.
  • Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g.
  • Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma.
  • Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.
  • the mammalian patient is a human patient.
  • Yet another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of the present invention together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
  • the one or more bioactive compounds are lipase inhibitors, anorectic agents, selective serotonin uptake inhibitors, neurotransmitter reuptake blocker, agents that stimulate metabolism of body fat, anti-diabetic agents, lipid lowering agents, or histamine Hl receptor antagonists.
  • a combination of one or more histamine H3 receptor antagonists of the present invention and histamine Hl receptor antagonists is preferred, especially for the treatment of allergic rhinitis, allergic congestion or nasal congestion.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other Histamine H3 receptor antagonists.
  • the active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • An exemplary method for the preparation of a compound of the present invention comprises the steps of
  • R 1 , R z , R 3 have the meaning as indicated above;
  • Another aspect of the present invention is a method for the preparation of a compound of the present invention, comprising the steps of (a) activating the hydroxy group of the compound of formula (Ia)
  • R 1 , R 2 , R 3 have the meaning as indicated above;
  • R 5 , R 5a , R 6 , R 6a , R 7 , R 8 have the meaning as indicated above and R 4' , R 4a ,
  • compounds of formula (I), wherein the variables have the above described meanings may be prepared starting from compounds of formula (II) by reacting a compound of formula (II), which can be made following the procedure outlined in US-B 6,875,858
  • a suitable N-atom protecting group such as Boc
  • a compound of formula R 4 O, such as cyclobutanone, in the presence of a reducing agent such as STAB or ii) a compound of formula R 4 -LG where LG is an appropriate leaving group such as halide or sulfonate (i.e. tosylate) followed by cleavage of the Boc protecting group in strong acid (HCl or TFA).
  • a reducing agent such as STAB or ii
  • LG is an appropriate leaving group such as halide or sulfonate (i.e. tosylate) followed by cleavage of the Boc protecting group in strong acid (HCl or TFA).
  • compounds of formula (I), wherein X 1 is CH and X 2 is N can be prepared in a one-pot method starting from a compound of formula (III) above, wherein the method comprises the steps of
  • compounds of formula (I), wherein X 1 is N and X 2 is CH may be prepared starting from a compound of formula R 1 - ⁇ . Accordingly, the method for the preparation of a compound according to the present invention, comprises the steps of
  • compounds of formula (I) may be prepared by conversion of the alcohol group of formula (XI) to a suitable leaving group (such as Cl, Br, OTs) and reacting the resulting compound with a compound of formula (VI) to yield compound of formula (XII)
  • CHO-Kl cell line expressing human H3 receptors were purchased from Euroscreen
  • Human H3 receptor-expressing cell-lines were grown in Ham's F12 [Sigma, Cat. no. N6658], supplemented with 10% FBS [Sigma, Cat. no. F9665], 400 ⁇ g/ml G418 [Sigma, Cat. no.
  • the assay measures the ability of test compounds to inhibit Histamine receptor agonist- induced decrease of intracellular free cAMP (receptor is G 1 coupled).
  • a cAMP quantification assay system from Disco veRx cAMP XS+; Cat. no. 90- 0075 was used.
  • cAMP assay confluent cells were detached from the culture vessels with Ix trypsin- EDTA solution (Sigma), and seeded into 384-well Costar plates (white, clear bottom, Cat. no. 3707) at a density of 10,000 cells per well. Cells were seeded in a volume of 50 ⁇ l in medium without antibiotics and incubated overnight in a humidified atmosphere with 5% CO 2 at 37°C. The cAMP assay was performed according to the protocol provided by DiscoveRx.
  • the cell culture medium was removed and the cells washed once with PBS (50 ⁇ l per well).
  • IBMX and 0.03% BSA were added and incubated for 30min at 37°C.
  • hH3 100 nM histamine, 10 ⁇ M forskolin in PBS (containing ImM IBMX and 0.03% BSA)
  • Test compounds were assayed at 8 concentrations in triplicate. Serial 10-fold dilutions in 100% DMSO were made at a 100-times higher concentration than the final concentration and then diluted with a 2 step protocol in assay buffer to reach the required assay concentrations and 1% DMSO.
  • Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following methods.
  • Example compounds and their intermediates were purified by one of or any combination of the following methods.
  • MeOD dueterated methanol m multiplet min(s) minute(s) mL millilitre ml millilitre mol/M mole/molar
  • the reaction was then cooled to room temperature and acidified to pH3 with 10% aqueous citric acid and extracted with DCM (3 x 100 ml). The organic layers were combined and washed with brine (100 ml) and water (100 ml), dried (MgSO 4 ), filtered and concentrated at reduced pressure to give the title compound (12.9 g, 79%) as colourless oil.
  • the product was used directly in the next step without further purification.
  • reaction mixture was concentrated in vacuo and the resulting residue diluted with DCM (50 ml) and washed with saturated aqueous NaHCOs (20 ml), dried (MgSO 4 ), filtered and concentrated in vacuo. Diethyl ether (15 ml) was added to the residue and the resulting fine precipitate collected by filtration and dried in vacuo to provide the title compound (705 mg, 68% yield) as white solid.
  • Racemeic compound l- ⁇ (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethyl)phenyl]methyl ⁇ -4-cyclobutylpiperazine underwent SFC separation using a Chiralpak AS-H(2 x 15 cm) column to provide the (R) and (S) enantiomers.

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Abstract

The invention relates to compounds of formula (I) wherein R1 to R3 and X0, X1, X2 have the meaning as cited in the description and the claims. Said compounds are useful as Histamine H3 receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.

Description

Evotec Neurosciences GmbH May 17, 2010
EVO66488PC EBU/ust
Piperazine and aminopyrrolidine compounds as Histamine H3 receptor antagonists
The present invention relates to Histamine H3 receptor antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament.
The histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion. The H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al. (1983) Nature: 302; 832 - 837), as well as a heteroreceptor that regulates the release of many other important neurotransmitters (acetylcholine, norepinephrine, dopamine, and serotonin). Structurally divergent H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance. From these studies it is concluded that such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity) (Witkin & Nelson (2004) JPET: 103; 1 - 20; Hancock & Brune (2005) Exp Opin Inves Drugs: 14 (3), 223 - 241).
Accordingly, Histamine H3 receptor antagonists are described in the art for the treatment of the above mentioned diseases and disorders. In WO-A 2007/080140 cyclylhexyl piperazinyl methanone derivatives are disclosed, which are useful as H3 receptor modulators.
In WO-A 2006/136924 cyclo butyl derivatives are disclosed as Histamine-3 receptor antagonists.
WO-A 2006/089076 describes imidazole amides as histamine H3 receptor modulators.
Furthermore histamine H3 receptor modulators are described in international patent applications with application N° PCT/EP2010/051077 and PCT/EP2009/064560 as well as WO-A 2010/026113, WO-A 2009/135842, WO-A 2009/121812 and WO-A 2009/095394.
However there is a continuing need for new compounds useful as Histamine H3 receptor antagonists.
Thus, an object of the present invention is to provide a new class of compounds as Histamine
H3 receptor antagonists which may be effective in the treatment of H3 receptor related diseases and may show improved pharmaceutically relevant properties including activity,
ADMET properties and/or reduced side effects.
Accordingly, the present invention provides compounds of formula (I)
Figure imgf000003_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X0 is
Figure imgf000003_0002
one of X1, X2 is N and the other is CH;
R1 is T; Ci_4 alkyl; C2-4 alkenyl; or C2-4 alkynyl, wherein Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl are optionally substituted with one or more R9, which are the same or different;
R9 is halogen; CN; C(O)OR10; OR10; C(O)R10; C(O)N(R10R10a); S(O)2N(R10R10a); S(O)N(R10R10a); S(O)2R10; S(O)R10; N(R10)S(O)2N(R10aR10b); SR10; N(R10R10a); NO2; OC(O)R10; N(R10)C(O)R10a; N(R10)SO2R10a; N(R10)S(O)R10a; N(R10)C(O)N(R10aR10b); N(R10)C(O)OR10a; OC(O)N(R10R1 Oa); or T;
R10, R1Oa, R10b are independently selected from the group consisting of H; T; Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl, wherein Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl are optionally substituted with one or more R11, which are the same or different;
R11 is halogen; CN; C(O)OR12; OR12; C(O)R12; C(O)N(R12R12a); S(O)2N(R12R12a); S(O)N(R12R12a); S(O)2R12; S(O)R12; N(R12)S(O)2N(R12aR12b); SR12; N(R12R12a); NO2; OC(O)R12; N(R12)C(O)R12a; N(R12)SO2R12a; N(R12)S(O)R12a; N(R12)C(O)N(R12aR12b); N(R12)C(O)OR12a; OC(O)N(R12R12a); or T;
R12, R12a, R12b are independently selected from the group consisting of H; T; Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl, wherein Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T is phenyl; naphthyl; azulenyl; indenyl; indanyl; C3_7 cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T is optionally substituted with one or more R13, which are the same or different;
R13 is halogen; CN; C(O)OR14; OR14; C(O)R14; C(O)N(R14R14a); S(O)2N(R14R14a); S(O)N(R14R14a); S(O)2R14; S(O)R14; N(R14)S(O)2N(R14aR14b); SR14; N(R14R14a); NO2; OC(O)R14; N(R14)C(O)R14a; N(R14)S(O)2R14a; N(R14)S(O)R14a; N(R14)C(0)0R14a; N(R14)C(O)N(R14aR14b); OC(O)N(R14R14a); oxo (=0), where the ring is at least partially saturated; T1; Ci_6 alkyl; C2-6 alkenyl; or C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2- 6 alkynyl are optionally substituted with one or more R15, which are the same or different; R14, R14a, R14b are independently selected from the group consisting of H; T1; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R16, which are the same or different;
R15, R16 are independently selected from the group consisting of halogen; CN; C(O)OR17; OR17; C(O)R17; C(O)N(R17R17a); S(O)2N(R17R17a); S (O)N(R17R17a); S(O)2R17; S(O)R17; N(R17)S(O)2N(R17aR17b); SR17; N(R17R17a); NO2; OC(O)R17; N(R17)C(O)R17a; N(R17)SO2R17a; N(R17)S(O)R17a; N(R17)C(O)N(R17aR17b); N(R17)C(O)OR17a; OC(O)N(R17R17a); and T1;
R17, R17a, R17b are independently selected from the group consisting of H; T1; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T1 is phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T1 is optionally substituted with one or more R18, which are the same or different;
R18 is halogen; CN; C(O)OR19; OR19; C(O)R19; C(O)N(R19R19a); S(O)2N(R19R19a); S(O)N(R19R19a); S(O)2R19; S(O)R19; N(R19)S(O)2N(R19aR19b); SR19; N(R19R19a); NO2; OC(O)R19; N(R19)C(O)R19a; N(R19)S(O)2R19a; N(R19)S(O)R19a; N(R19)C(O)OR19a; N(R19)C(O)N(R19aR19b); OC(O)N(R19R19a); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C2-6 alkenyl; or C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R19, R19a, R19b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R2, R3 are independently selected from the group consisting of H; halogen; Ci_6 alkyl; and A, wherein Ci_6 alkyl is optionally substituted with one or more R20, which are the same or different, provided that at least one of R2, R3 is A;
Optionally R2, R3 are joined together with the carbon atom to which they are attached to form a ring T3; A is T2; Ci_6 alkyl; C2-6 alkenyl; or C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are substituted with at least one R 20a.
R20 is halogen; CN; C(O)OR21; OR21; C(O)R21; C(O)N(R21R21a); S(O)2N(R21R21a); S(O)N(R21R21a); S(O)2R21; S(O)R21; N(R21)S(O)2N(R21aR21b); SR21; N(R21R21a); NO2; OC(O)R21; N(R21)C(O)R21a; N(R2 ^SO2R21'; N(R21)S(O)R21a; N(R21)C(O)N(R21aR21b); N(R21)C(O)OR21a; or OC(O)N(R21R21a);
R21, R21a, R21b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R20a is T2; halogen; CN; C(O)OR20b; OR20b; C(O)R20b; C(O)N(R20bR20c); S(O)2N(R20bR20c); S(O)N(R20bR20c); S(O)2R20b; S(O)R20b; N(R20b)S(O)2N(R20cR20d); SR20b; N(R20bR20c); NO2; OC(O)R20b; N(R20b)C(O)R20c; N(R20b)SO2R20c; N(R20b)S(O)R20c; N(R20b)C(O)N(R20cR20d); N(R20b)C(O)OR20c; or OC(O)N(R20bR20c);
R20b, R20c, R20d are independently selected from the group consisting of H; T2; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T2 is phenyl; naphthyl; azulenyl; indenyl; indanyl; C3_7 cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T2 is optionally substituted with one or more R22, which are the same or different;
T is C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T is optionally substituted with one or more R23, which are the same or different;
R22, R23 are independently selected from the group consisting of halogen; CN; C(O)OR24; OR24; C(O)R24; C(O)N(R24R24a); S(O)2N(R24R24a); S(O)N(R24R24a); S(O)2R24; S(O)R24; N(R24)S(O)2N(R24aR24b); SR24; N(R24R24a); NO2; OC(O)R24; N(R24)C(O)R24a; N(R24)S(O)2R24a; N(R24)S(O)R24a; N(R24)C(O)OR24a; N(R24)C(O)N(R24aR24b); OC(O)N(R24R24a); oxo (=0), where the ring is at least partially saturated; T4; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl; wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R25, which are the same or different;
R24, R24a, R24b are independently selected from the group consisting of H; T4; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R26, which are the same or different;
R25, R26 are independently selected from the group consisting of halogen; CN; C(O)OR27; OR27; C(O)R27; C(O)N(R27R27a); S(O)2N(R27R27a); S(O)N(R27R27a); S(O)2R27; S(O)R27; N(R27)S(O)2N(R27aR27b); SR27; N(R27R27a); NO2; OC(O)R27; N(R27)C(O)R27a; N(R27)SO2R27a; N(R27)S(O)R27a; N(R27)C(O)N(R27aR27b); N(R27)C(O)OR27a; OC(O)N(R27R27a); and T4;
R27, R27a, R27b are independently selected from the group consisting of H; T4; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R28, which are the same or different;
R28 is halogen; CN; C(O)OR29; OR29; C(O)R29; C(O)N(R29R29a); S(O)2N(R29R29a); S(O)N(R29R29a); S(O)2R29; S(O)R29; N(R29)S(O)2N(R29aR29b); SR29; N(R29R29a); NO2; OC(O)R29; N(R29)C(O)R29a; N(R29)SO2R29a; N(R29)S(O)R29a; N(R29)C(O)N(R29aR29b); N(R29)C(O)OR29a; or OC(O)N(R29R29a);
R29, R29a, R29b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T4 is phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T4 is optionally substituted with one or more R30, which are the same or different;
R30 is halogen; CN; C(O)OR31; OR31; C(O)R31; C(O)N(R31R31a); S(O)2N(R31 R3 la); S(O)N(R31R31a); S(O)2R31; S(O)R31; N(R31)S(O)2N(R31aR31b); SR31; N(R31R31a); NO2; OC(O)R31; N(R31)C(O)R31a; N(R3 ^S(O)2R31'; N(R3 ^S(O)R31"; N(R31)C(O)OR31a; N(R31)C(O)N(R31aR31b); OC(O)N(R31R31a); oxo (=0), where the ring is at least partially saturated; T5; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl; wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R32, which are the same or different; R31, R31a, R31b are independently selected from the group consisting of H; T5; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R33, which are the same or different;
R32, R33 are independently selected from the group consisting of halogen; CN; C(O)OR34; OR34; C(O)R34; C(O)N(R34R34a); S(O)2N(R34R34a); S(O)N(R34R34a); S(O)2R34; S(O)R34; N(R34)S(O)2N(R34aR34b); SR34; N(R34R34a); NO2; OC(O)R34; N(R34)C(O)R34a; N(R34)SO2R34a; N(R34)S(O)R34a; N(R34)C(O)N(R34aR34b); N(R34)C(O)OR34a; OC(O)N(R34R34a); and T5;
R34, R34a, R34b are independently selected from the group consisting of H; T5; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R35, which are the same or different;
R35 is halogen; CN; C(O)OR36; OR36; C(O)R36; C(O)N(R36R36a); S(O)2N(R36R36a); S(O)N(R36R36a); S(O)2R36; S(O)R36; N(R36)S(O)2N(R36aR36b); SR36; N(R36R36a); NO2; OC(O)R36; N(R36)C(O)R36a; N(R36)SO2R36a; N(R36)S(O)R36a; N(R36)C(O)N(R36aR36b); N(R36)C(O)OR36a; or OC(O)N(R36R36a);
R36, R36a, R36b are independently selected from the group consisting of H; Ci_6 alkyl; C2-e alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T5 is phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T5 is optionally substituted with one or more R37, which are the same or different;
R37 is halogen; CN; C(O)OR38; OR38; C(O)R38; C(O)N(R38R38a); S(O)2N(R38R38a); S(O)N(R38R38a); S(O)2R38; S(O)R38; N(R38)S(O)2N(R38aR38b); SR38; N(R38R38a); NO2; OC(O)R38; N(R38)C(O)R38a; N(R38) S (O)2R38a; N(R38)S(O)R38a; N(R38)C(O)OR38a; N(R38)C(O)N(R38aR38b); OC(O)N(R38R38a); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl; wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R38, R38a, R38b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R4, R4a, R4b are independently selected from the group consisting of Ci_6 alkyl; C2-6 alkenyl; C2-6 alkynyl; C3-6 cycloalkyl; CH2-cyclopropyl; CHF-cyclopropyl; CF2-cyclopropyl; CH2- cyclobutyl; CHF-cyclobutyl; CF2-cyclobutyl; and 4 to 5 membered saturated heterocyclyl, wherein Ci_6 alkyl; C2-6 alkenyl; C2-6 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; and CN, and wherein C3.5 cycloalkyl; CH2- cyclopropyl; CHF-cyclopropyl; CF2-cyclopropyl; CH2-cyclobutyl; CHF-cyclobutyl; CF2- cyclobutyl; and 4 to 5 membered saturated heterocyclyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; CN; CH3; CH2F; CHF2; and CF3;
Optionally R4a, R4b are joined together with the nitrogen atom to which they are attached to form 3 to 7 membered saturated heterocyclyl, which is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; CN; CH3; CH2F; CHF2; and CF3;
R5, R5a, R6, R6a, R7, R8 are independently selected from the group consisting of H; Ci_5 alkyl; C2-5 alkenyl; and C2-5 alkynyl, wherein Ci .5 alkyl; C2-5 alkenyl; and C2-5 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; and CN;
Optionally one or both pairs R4/R5, R4/R6, R4b/R5, R4a/R6 are joined together with the atoms to which they are attached to form 3 to 7 membered heterocyclyl, wherein 3 to 7 membered heterocyclyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH3; CH2F; CHF2; and CF3;
Optionally one or both pairs R6/R7, R5/R8 are joined together with the carbon atoms to which they are attached to form C3_7 cycloalkyl, wherein C3_7 cycloalkyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH3; CH2F; CHF2; and CF3;
Optionally one or more of the pairs R5/R6, R5/R7, R4/R7, R4a/R7, R4/R8, R6/R8 are joined together with the respective ring X0 to form 8 to 11 membered heterobicyclyl, wherein 8 to 11 membered heterobicyclyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH3; CH2F; CHF2; and CF3;
Provided that the following compounds are excluded:
Figure imgf000010_0001
The three compounds excluded from the scope of formula (I) are described by Y. Deng et al, Organic Letters 4 (2002), 4017-4020.
In case a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
Within the meaning of the present invention the terms are used as follows:
"Alkyl" means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified.
"Alkenyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.
"Alkynyl" means a straight-chain or branched hydrocarbon chain, that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified. "Ci_4 alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. - CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_4 alkyl carbon may be replaced by a substituent as further specified. The term "C2_4 alkyl" is defined accordingly.
"Ci_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, - C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified. The term "Ci_5 alkyl" is defined accordingly.
"C2_6 alkenyl" means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH- CH=CH2, or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C2_6 alkenyl carbon may be replaced by a substituent as further specified. The terms "C2_4 alkenyl" and "C2_5 alkenyl" are defined accordingly.
"C2_6 alkynyl" means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, CH2-C≡C-CH3, or e.g. -C≡C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C2_6 alkynyl carbon may be replaced by a substituent as further specified. The terms "C2_4 alkynyl" and "C2_5 alkynyl" are defined accordingly.
"C3_7 cycloalkyl" or "C3_7 cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified. The term "C3_6 cycloalkyl is defined accordingly.
"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
"3 to 7 membered heterocyclyl" or "3 to 7 membered heterocycle" means a ring with 3, 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom and up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 3 to 7 membered heterocycles are azeridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydro furan, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term "4 to 5 membered heterocyclyl" or "4 to 5 membered heterocycle" is defined accordingly. The term "5 to 6 membered heterocyclyl" or "5 to 6 membered heterocycle" is defined accordingly.
"3 to 7 membered saturated heterocyclyl" or "3 to 7 membered saturated heterocycle" means "3 to 7 membered heterocyclyl" or a "3 to 7 membered heterocycle" which is saturated. The term "4 to 5 membered saturated heterocyclyl" or "4 to 5 membered saturated heterocycle" is defined accordingly.
"8 to 11 membered heterobicyclyl" or "8 to 11 membered heterobicycle" means a heterocyclic system of two rings with 8 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 8 to 11 membered heterobicycles are imidazo[2,l-b][l,3]oxazole, imidazo[2,l-b][l,3]thiazole, indole, indoline, benzo furan, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydro isoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 8 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.
"5 to 6 membered aromatic heterocyclyl" or "5 to 6 membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, - S(O)2-), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole.
Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.
In preferred embodiments of the present invention, the substituents R1 to R3 and X0, X1, X2 of formula (I) independently have the following meaning. Hence, one or more of the substituents R1 to R3 and X0, X1, X2 can have the preferred or more preferred meanings given below.
In one preferred embodiment X0 is
Figure imgf000013_0001
In another preferred embodiment X0 is
Figure imgf000013_0002
Preferably, X2 is N.
Preferably, R1 is Ci_4 alkyl substituted with one or more R9, which are the same or different. In a more preferred embodiment R1 is Ci_4 alkyl substituted with one R9. Even more preferred, R1 is CH2-R9; or CH2CH2R9, even more preferred is CH2-R9.
Preferably, R9 is T.
Preferably, T is phenyl; naphthyl; or 5 to 6 membered aromatic heterocyclyl. Even more preferred is phenyl or a 6 membered heterocycle, even more preferred is phenyl. Preferably, T is unsubstituted or substituted with one or two R13, which are the same or different. More preferred, T is unsubstituted or substituted with one R13.
Preferably, R13 is halogen; Ci-6 alkyl (Ci-4 alkyl more preferred); OH; or 0-Ci-6 alkyl (0-Ci-4 alkyl is more preferred), wherein Ci_6 alkyl (C1-4 alkyl) is optionally substituted with one or more halogen, which are the same or different. More preferred is R13 F; Cl; OCH3; or OCF3.
Preferably, one of R2, R3 is A. More preferred, one of R2, R3 is A and the other is H.
Preferably, A is T2.
Preferably, T2 is phenyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl. More preferred, T2 is phenyl; or 3 to 7 membered heterocyclyl. Even more preferably, T2 is phenyl; or pyridyl, even more preferred phenyl; or 3-pyridyl.
Preferably, T2 is unsubstituted or substituted with one or two R22, which are the same or different.
Preferably, T3 is cyclopentyl; cyclohexyl; tetrahydropyranyl; piperidinyl; pyrrolidinyl; or azetidinyl.
Preferably, T3 is unsubstituted or substituted with one or two R23, which are the same or different.
Preferably, R22, R23 are independently selected from the group consisting of halogen; T4; Ci_6 alkyl; OR24; C(O)N(R24R24a); C(O)OR24; N(R24R24a); S(O)2R24; S(O)2N(R24R24a); oxo (=0), where the ring is at least partially saturated; N(R24)C(O)R24a; C(O)R24, wherein Ci_6 alkyl is optionally substituted with one or more R25, which are the same or different.
Preferably, R24, R24a are independently selected from the group consisting of H; T4; Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different.
Preferably, R25 is halogen; T4; or C(O)N(R27R27a). Preferably, T4 is phenyl; or 5- to 6 membered heterocyclyl.
Preferably, T4 is unsubstituted or substituted with one or two R30, which are the same or different and selected from the group consisting of halogen; OH; O-Ci_6 alkyl; Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different.
Preferably, R4 is cyclobutyl; cyclopentyl; or C2-4 alkyl, optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; and CN. More preferably, R4 is cyclobutyl.
Preferably, R4a, R4b are independently selected from the group consisting of Ci_4 alkyl, optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; and CN.
Preferably, R4a, R4b are together with the nitrogen atom to which they are attached to form a substituted or unsubstituted (more preferably unsubstituted) pyrrolidine ring.
Preferably, R5, R5a, R6, R6a, R7, R8 are H or CH3.
Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.
Preferred specific compounds of the present invention are selected from the group consisting of
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-cyclobutylpiperazine;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-cyclopentylpiperazine; methyl 4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]benzoate; 4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3'<S)- 1 ,3'-bipyrrolidin- 1 '-yl]methyl}benzonitrile;
(3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(difluoromethoxy)phenyl]methyl} -1,3'- bipyrrolidine;
(4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3'5)- 1 ,3'-bipyrrolidin- 1 '-yl]methyl}phenyl)methanol;
(3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(piperidin- 1 -ylmethyl)phenyl]methyl} -1,3'- bipyrrolidine; 4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]benzonitrile;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 ,3'-bipyrrolidine;
1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -yl)phenyl]methyl} - 1 ,3'-bipyrrolidine;
4- {4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]piperazin- 1 -yl} -2-methylbutan- 2-ol;
(2i?)-4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 -cyclobutyl-2- methylpiperazine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N-methylbenzamide;
1.(4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3'5)- 1 ,3'-bipyrrolidin- 1 '-yl]methyl}phenyl)-N,N- dimethylmethanamine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(4-fluoropiperidin- 1 -yl)methyl]phenyl}methyl]-
1 ,3'-bipyrrolidine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(4,4-difluoropiperidin- 1 - yl)methyl]phenyl}methyl]- 1 ,3'-bipyrrolidine; (3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(3,3-difluoropiperidin- 1 - yl)methyl]phenyl}methyl]- 1 ,3'-bipyrrolidine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N- cyclopropylbenzamide;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(3,5-dimethyl- lH-pyrazol- 1 -yl)phenyl]methyl} -A- cyclobutylpiperazine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(4-methylpiperazin- 1 -yl)methyl]phenyl}methyl]- l,3'-bipyrrolidine;
(2i?)-4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 -cyclobutyl-2- methylpiperazine; 4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N-prop-2-yn- 1 - ylbenzamide;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -yl)phenyl]methyl} -A- cyclobutylpiperazine;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(3,5-dimethyl- lH-pyrazol- 1 - yl)methyl]phenyl}methyl]-4-cyclobutylpiperazine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N,N- dimethylbenzamide;
4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3'5)- 1 ,3'-bipyrrolidin- 1 '-yl]methyl}benzonitrile;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-(2-fluoroethyl)piperazine; 1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -yl)phenyl]methyl} -A- cyclopentylpiperazine;
(3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -1,3'- bipyrrolidine; (3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)phenyl]methyl} -
1 ,3'-bipyrrolidine;
1 -cyclobutyl-4- { [4-(4-fluorobenzyl)-4H- 1 ,2,4-triazol-3-yl] [4-( 1 H- 1 ,2,4-triazol- 1 - ylmethyl)phenyl]methyl}piperazine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 ,3'-bipyrrolidine; 1 -cyclobutyl-4- {[4-(4-fluorobenzyl)-4H- 1 ,2,4-triazol-3-yl](4- fluorophenyl)methyl}piperazine;
1 -[(1 -benzyl- IH-1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclopentylpiperazine;
1 - {4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]piperazin- 1 -yl} -2- methylpropan-2-ol; 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -1,3'- bipyrrolidine;
1 -[(1 -benzyl- IH-1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclobutylpiperazine;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-(3-fluoropropyl)piperazine;
(3'R)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -1,3'- bipyrrolidine;
4-[(l -benzyl- 1 H- 1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]- 1 -cyclobutyl-2,6- dimethylpiperazine;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyclobutylpiperazine; 1 - {(7?)-(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyclobutylpiperazine; and
1 - {(5)-(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyclobutylpiperazine.
Prodrugs of the compounds of the invention are also within the scope of the present invention. "Prodrug" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated. These compounds can be produced from compounds of the present invention according to well-known methods.
Metabolites of compounds of formula (I) are also within the scope of the present invention.
Where tautomerism, like e.g. keto-enol tautomerism, of compounds of formula (I) may occur, the individual forms, like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.
Especially, when enantiomeric or diastereomeric forms are given in a compound according to formula (I) each pure form separately and any mixture of at least two of the pure forms in any ratio is comprised by formula (I) and is a subject of the present invention. This applies especially for pure and mixture forms associated with the carbon in the following formula (I*) marked with an asterisk, when R2 and R3 are different.
Figure imgf000018_0001
The same applies for compounds of formula (I) with regard to the carbon marked with an asterisk, wherein X0 is
Figure imgf000018_0002
Iso topic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.
If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials, reagents and/or catalysts.
In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. The present invention provides compounds of general formula (I) as Histamine H3 receptor antagonists.
As described before, the histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion. The H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al. (1983) Nature: 302; 832 - 837), as well as a heteroreceptor that regulates the release of many other important neurotransmitters (acetylcholine, norepinephrine, dopamine, and serotonin). Structurally divergent H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance. From these studies it is concluded that such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity) (Witkin & Nelson (2004) JPET: 103; 1 - 20; Hancock & Brune (2005) Exp Opin Inves Drugs: 14 (3), 223 - 241).
The pharmacology of the H3 receptor seems not only to be determined by its localization but appears also to be regulated by differential splicing. Today more than 20 splice variants (isoforms) have been described but their functions have yet to be elucidated completely (Bongers et al. (2007) Biochem Pharm: 73; 1195 - 1204). The H3 receptor is localized primarily to the central nervous system (CNS), with highest expression, in rodents, in the cerebral cortex, hippocampal formations, striatum, and hypothalamus (Drutel et al. (2001) MoI Pharmacol: 59; 1 - 8). Similarly in human, H3 receptor expression is prominent in the basal ganglia, globus pallidus, hippocampus, and cortex (Martinez-Mir et al. (1990) Brain Res: 526; 322 327). Notably, many of these brain regions are critical for cognition (cortex and hippocampus) and sleep and homeostatic regulation (hypothalamus). The H3 receptor has been shown also to localize to regions which might be involved in pain sensation or transmission and therefore might offer treatment opportunities for different pain states (Cannon et al. (2007) Pain: 129; 76 - 92). In addition to agonist-induced signaling, the H3 receptor is constitutively active and capable of signaling independently of agonist both in vitro and in vivo (Morisset et al. (2000) Nature: 408, 860 - 864).
All these considerations suggest that novel H3 receptor antagonists like the series in this application could be useful in the treatment of cognitive dysfunctions as well as sleeping and energy homeostasis disorders. The term "antagonist" also includes inverse agonists.
Based on the information above and further literature, like WO-A 2007/080140 and WO-A 2006/136924 the following diseases and disorders are preferably affected.
Neurological disorders: Major conditions include behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol
Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down
Syndrome, epilepsy, convulsion, depression, anxiety disorders) seizure disorders neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis) sleep disorders (e.g. hypersomnia and narcolepsy, excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns)
Migraine
Fatigue - Stroke tremor.
The term "neurological disorders" also includes psychiatrical disorders within the meaning of the present invention. The term "neurodegenerative disorders" also includes neuro- inflammatory disorders within the meaning of the present invention.
Disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus. Pain, e.g. neuropathic pain, inflammatory pain, nociception. The term "pain" includes acute and chronic pain within the meaning of the present invention.
Cardiovascular disorders, e.g. acute myocardial infarction, and other disorders, i.e. gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse), nasal congestion, allergic rhinitis (hay fever), asthma.
Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma.
More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma.
Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.
Preferably, the compounds of the present invention may be used for fatigue and cognitive impairment/dysfunction associated with Multiple Sclerosis. Accordingly, Multiple Sclerosis is a more preferred disease or disorder for disease related fatigue and cognitive impairment/dysfunction.
Accordingly, one aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use as a medicament. Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing diseases and disorders associated with the H3 receptor.
Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing neurological disorders, e.g. behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders), seizure disorders, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis), sleep disorders (e.g. hypersomnia and narcolepsy, excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns), Migraine, Fatigue, Stroke, tremor; disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus; Pain, e.g. neuropathic pain, inflammatory pain, nociception; cardiovascular disorders, e.g. acute myocardial infarction; gastrointestinal disorders; vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse); nasal congestion; allergic rhinitis (hay fever); or asthma. Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma. More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma. Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain. Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the H3 receptor.
Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of neurological disorders, e.g. behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders), seizure disorders, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis), sleep disorders (e.g. hypersomnia and narcolepsy, excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns), Migraine, Fatigue, Stroke, tremor; disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus; Pain, e.g. neuropathic pain, inflammatory pain, nociception; cardiovascular disorders, e.g. acute myocardial infarction; gastrointestinal disorders; vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse); nasal congestion; allergic rhinitis (hay fever); or asthma. Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma. More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma. Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain. Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the H3 receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of neurological disorders, e.g. behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders), seizure disorders, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis), sleep disorders (e.g. hypersomnia and narcolepsy, excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns), Migraine, Fatigue, Stroke, tremor; disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus; Pain, e.g. neuropathic pain, inflammatory pain, nociception; cardiovascular disorders, e.g. acute myocardial infarction; gastrointestinal disorders; vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse); nasal congestion; allergic rhinitis (hay fever); and asthma, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, Migraine, Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma. More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma. Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.
Preferably, the mammalian patient is a human patient.
Yet another aspect of the present invention is a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of the present invention together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
Preferably, the one or more bioactive compounds are lipase inhibitors, anorectic agents, selective serotonin uptake inhibitors, neurotransmitter reuptake blocker, agents that stimulate metabolism of body fat, anti-diabetic agents, lipid lowering agents, or histamine Hl receptor antagonists. A combination of one or more histamine H3 receptor antagonists of the present invention and histamine Hl receptor antagonists is preferred, especially for the treatment of allergic rhinitis, allergic congestion or nasal congestion.
"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other Histamine H3 receptor antagonists.
The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions). The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
Starting materials for the synthesis of preferred embodiments of the invention may be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR or can be synthesized using known methods by one skilled in the art.
In general, several methods are applicable to prepare compounds of the present invention. In some cases various strategies can be combined. Sequential or convergent routes may be used. The following routes should be understood as examples. It is clear for a practitioner in the art to combine such routes optionally in combination with standard methods and reagents, like activation of functional groups or protection of functional groups.
For compounds of formula (I) suitable starting materials of formula (Ia) and (VIII) may be used.
An exemplary method for the preparation of a compound of the present invention comprises the steps of
(a) activating the hydroxy group of the compound of formula (Ia)
Figure imgf000029_0001
wherein R1, Rz, R3 have the meaning as indicated above; and
(b) reacting the respective compound with a compound of formula (VIII)
Figure imgf000029_0002
wherein R4a, R4b, R5, R5a, R6, R6a, R7, R8 have the meaning as indicated above and R4' is R4 as indicated above or as suitable N-atom protecting group to yield a compound of formula (I), optionally after removal of the protecting group and reacting the liberated amino group with either i) a compound of formula R4=O, wherein the oxo group is attached to a carbon atom of R4, followed by reduction of the resulting imine or ii) a compound of formula R4-LG where LG is an appropriate leaving group such as halide or sulfonate (such as OMs, OTs or OTf).
Thus, another aspect of the present invention is a method for the preparation of a compound of the present invention, comprising the steps of (a) activating the hydroxy group of the compound of formula (Ia)
Figure imgf000030_0001
wherein R1, R2, R3 have the meaning as indicated above; and
(b) reacting the respective compound with a compound of formula (Ha) or (lib)
Figure imgf000030_0002
(Ha) (Hb)
wherein R5, R5a , R6, R6a, R7, R8 have the meaning as indicated above and R4', R4a ,
R4b represent R4, R4a, R4b as indicated above to yield a compound of formula (I) or R4 represents a suitable N-atom protecting group, then followed by removal of the protecting group and reacting the liberated amino group with either i) a compound of formula R4=O, wherein the oxo group is attached to a carbon atom of R4, followed by reduction of the resulting imine or ii) with a compound of formula R4-LG, wherein LG is an appropriate leaving group to yield a compound of formula (I).
More specifically, compounds of formula (I), wherein the variables have the above described meanings (unless otherwise specifically indicated) may be prepared starting from compounds of formula (II) by reacting a compound of formula (II), which can be made following the procedure outlined in US-B 6,875,858
Me2N^N-N^NMe 2 (")
.2HCI
with a compound of formula R1NH2 under acidic catalysis by reagents such as p-TsOH to yield compounds of formula (III)
Figure imgf000031_0001
and reacting compounds of formula (III) with a strong base such as nBuLi at low temperature (usually < -5O0C) and reacting the resulting compound with (R2R3)C=O to yield a compound of formula (IV)
Figure imgf000031_0002
and converting the alcohol group containing compounds of formula (IV) to a suitable leaving group (such as Br or OTs) via reaction with carbon tetrabromide plus PPh3 or para- toluenesulfonyl chloride, respectively and reacting the resulting compound with a compound of formula (VIII)
Figure imgf000031_0003
wherein R4 can be R4 as defined above or a suitable N-atom protecting group such as Boc to yield a compound of formula (I) optionally after removal of the protecting group and reacting the liberated amino group with either i) a compound of formula R4=O, wherein the oxo group is attached to a carbon atom of R4, followed by reduction of the resulting imine or ii) a compound of formula R4-LG where LG is an appropriate leaving group such as halide or sulfonate (i.e. tosylate).
Compounds of formula (VIII) are either commercially available or can be prepared by the two step process of reacting a compound of formula (VI)
Figure imgf000032_0001
with either i) a compound of formula R4=O, such as cyclobutanone, in the presence of a reducing agent such as STAB or ii) a compound of formula R4-LG where LG is an appropriate leaving group such as halide or sulfonate (i.e. tosylate) followed by cleavage of the Boc protecting group in strong acid (HCl or TFA).
Compounds of formula (VIII) can also be prepared by the three step process of converting an alcohol (which may be enantiomerically enriched from enantioselective reaction, chiral starting materials or chiral separation) of formula (XIII)
Figure imgf000032_0002
to a suitable leaving group (such as Br or OTs) by reaction with/?αra-toluenesulfonyl chloride and reacting the resulting compound with a compound of formula (XIV)
H
R4a/ N \ R4b (XIV)
followed by removal of the benzyl protecting group by hydrogentation with an appropriate catalyst (such as Pd(OH)2 on carbon).
In the case when R > 4' of formula (VIII) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (VII)
Figure imgf000033_0001
requires the additional step of deprotecting a compound of formula (VII) at the nitrogen atom and reacting the resulting compound with either i) R4=0 in the presence of a reducing agent such as STAB or ii) a compound of formula R4-LG where LG is an appropriate leaving group such as halide or sulfonate (i.e. tosylate) to yield a compound of formula (I).
Alternatively, compounds of formula (I), wherein X1 is CH and X2 is N, can be prepared in a one-pot method starting from a compound of formula (III) above, wherein the method comprises the steps of
reacting a compound of formula (III) with a strong base such as nBuLi at low temperature (usually < -5O0C); followed by reacting the resulting intermediate with a compound of formula (R2R3)C=O; followed by converting the resulting intermediate into a leaving group by reaction with a sulfonyl chloride (such as /?αrα-toluenesulfonyl chloride) and then reacting this in situ formed intermediate with a compound of formula (VIII) to yield a compound of formula (I).
In particular, compounds of formula (I), wherein X1 is N and X2 is CH, may be prepared starting from a compound of formula R1-^. Accordingly, the method for the preparation of a compound according to the present invention, comprises the steps of
reacting a compound of formula R^N3 with alkyl(triphenylphosphoranylidene)- pyruvate to yield a compound of formula (IX)
Figure imgf000034_0001
ester group reduction of a compound of formula (IX) and reacting the resulting compound with an oxidising agent such as IBX to yield a compound of formula
(X)
Figure imgf000034_0002
reacting compound of formula R2-halogen with magnesium or BuLi and treating the resulting metallated compound with a compound of formula (X) to yield compound of formula (XI), wherein R is H
Figure imgf000034_0003
- conversion of the alcohol group of formula (XI) to a suitable leaving group (such as Cl, Br, OTs) and reacting the resulting compound with a compound of formula (VIII) to yield compound of formula (I).
Alternatively compounds of formula (I) may be prepared by conversion of the alcohol group of formula (XI) to a suitable leaving group (such as Cl, Br, OTs) and reacting the resulting compound with a compound of formula (VI) to yield compound of formula (XII)
Figure imgf000035_0001
and deprotecting compound formula (XII) and reacting the resulting compound with either i) R4=0 in the presence of a reducing agent such as STAB or ii) a compound of formula R4-LG where LG is an appropriate leaving group such as halide or sulfonate (i.e. tosylate) to yield a compound of formula (I).
It is clear for a practitioner in the art that the preparation routes mentioned herein can be combined and varied optionally by using activation and protection/deprotection techniques.
EXAMPLES
Biological evaluation:
Cell-lines used to characterize invented compounds in vitro
CHO-Kl cell line expressing human H3 receptors were purchased from Euroscreen
(Gosselies, Belgium, Cat. no.: ES-392-C)
Human H3 receptor-expressing cell-lines were grown in Ham's F12 [Sigma, Cat. no. N6658], supplemented with 10% FBS [Sigma, Cat. no. F9665], 400μg/ml G418 [Sigma, Cat. no.
Nl 876] and 250μg/ml Zeocin [Invitrogen, Cat. no. 46-0509]) according to the protocol provided by Euroscreen.
cAMP quantification protocol for human H3 receptor testing
The assay measures the ability of test compounds to inhibit Histamine receptor agonist- induced decrease of intracellular free cAMP (receptor is G1 coupled). Specifically, a cAMP quantification assay system from Disco veRx (cAMP XS+; Cat. no. 90- 0075) was used.
For the cAMP assay, confluent cells were detached from the culture vessels with Ix trypsin- EDTA solution (Sigma), and seeded into 384-well Costar plates (white, clear bottom, Cat. no. 3707) at a density of 10,000 cells per well. Cells were seeded in a volume of 50μl in medium without antibiotics and incubated overnight in a humidified atmosphere with 5% CO2 at 37°C. The cAMP assay was performed according to the protocol provided by DiscoveRx.
The cell culture medium was removed and the cells washed once with PBS (50 μl per well).
The plates were emptied by inversion and 7.5μl/well of compound in PBS (containing ImM
IBMX and 0.03% BSA) were added and incubated for 30min at 37°C.
Subsequent 7.5μl/well specific agonist solution was added and the plates for another 30min incubated at 37°C. The following agonist solution is used for the individual cell- lines: hH3: 100 nM histamine, 10 μM forskolin in PBS (containing ImM IBMX and 0.03% BSA)
After the incubation with the agonist, 5μl/well cAMP XS antibody solution was added followed by 20μl/well Gal/EII/Lysis(l :5:19) +ED (1 :1). The plates were incubated for one hour at room temperature and afterwards 20μl/well EA reagent was added. The luminescence was developed for approximately three hours at room temperature and the plates were read out using a 'BMG Novostar' plate reader.
Assaying of compounds
Test compounds were assayed at 8 concentrations in triplicate. Serial 10-fold dilutions in 100% DMSO were made at a 100-times higher concentration than the final concentration and then diluted with a 2 step protocol in assay buffer to reach the required assay concentrations and 1% DMSO.
The specific compounds exemplified below were categorized by the following potency ranges (IC50 values):
A: < 100 nM; B: > 100 nM to 500 nM; C: > 500 nM to 5000 nM. Synthesis of compounds:
ANALYTICAL METHODS
NMR Spectrometers Used:
Bruker DRX 500 MHz NMR Bruker AVANCE 400 MHz NMR Bruker DPX 250 MHz NMR Bruker DPX 360 MHz NMR
Configuration of the Bruker DRX 500 MHz NMR
High performance digital NMR spectrometer, 2-channel microbay console and Windows XP host workstation running Topspin version 1.3.
Equipped with:
• Oxford instruments magnet 11.74 Tesla (500 MHz proton resonance frequency)
• B-VT 3000 temperature controller • GRASP II gradient spectroscopy accessory for fast acquisition of 2D pulse sequences
• Deuterium lock switch for gradient shimming
• 5mm Broad Band Inverse geometry double resonance probe with automated tuning and matching (BBI ATMA). Allows 1H observation with pulsing/decoupling of nuclei in the frequency range 15N and 31P with 2H lock and shielded z-gradient coils.
Configuration of the Bruker DPX 250MHz NMR
High performance one bay Bruker 250 MHz digital two channel NMR spectrometer console and Windows XP host workstation running XwinNMR version 3.5.
Equipped with: • Oxford instruments magnet 5.87 Tesla (250 MHz proton resonance frequency)
• B-VT 3300 variable temperature controller unit
• Four nucleus (QNP) switchable probe for observation of 1H, 13C, 19F and 31P with 2H lock
Configuration of the Bruker AVANCE 400MHz NMR High performance one bay Bruker AVANCE 400 MHz digital two channel NMR spectrometer console Equipped with:
• Bruker magnet 9.40 Tesla (400MHz proton resonance frequency)
• B-VT 3200 variable temperature controller unit
• GRASP II gradient spectroscopy accessory for the generation of one field gradient of up to 50 Gauss cm"1
• Four nucleus (QNP) switchable probe for observation of 1H, 13C, 19F and 31P with 2H lock with z-gradient coils for gradient spectroscopy.
LCMS methods used
Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following methods.
LCMS Method A (2 min method)
Figure imgf000038_0001
LCMS Method B (3.5 min method)
Figure imgf000039_0001
LCMS Method C (7 min method)
Figure imgf000039_0002
Figure imgf000040_0001
LCMS Method D (10 min method)
Figure imgf000040_0002
LCMS Method E (15 min method)
Column WatersX-terraMSC-18 4.6 x 50 mm, 5 micron
Figure imgf000041_0001
Preparative HPLC Methods Used: Where indicated, Example compounds and their intermediates were purified by one of or any combination of the following methods.
Prep Method 1 (Low pH)
Figure imgf000041_0002
Prep Method 2 (FTE High pH)
Column Phenomenex Gemini Cl 8
Figure imgf000042_0001
Prep Method 3 (Low pH)
Figure imgf000042_0002
Prep Method 4 (FTE prep)
Figure imgf000042_0003
Prep Method 5 (Neutral) Compound Naming
All compounds are named using ACD Labs 10.0 naming software which conforms to IUPAC naming protocols. Some compounds are isolated as TFA salts, which is not reflected by the chemical name. Within the meaning of the present invention the chemical name represents the compound in neutral form as well as its TFA salt or any other salt, especially pharmaceutically acceptable salt, if applicable.
List of Abbreviations
AcOH acetic acid br s broad singlet
Boc te/t-butoxycarbonyl ca. circa cat catalytic
CDCl3 deuterated chloroform
Chloroform-ύf deuterated chloroform
DCE 1 ,2-dichloroethane
DCM dichloromethane
DIPEA JV,jV-diisopropylethylamine
DMF dimethylformamide eq equivalent ee enantiomeric excess
Ether diethyl ether
Et2O diethyl ether
EtOAc ethyl acetate
EtOH ethanol
FCC flash column chromatography h hours
HBTU o-benzotriazol-l-yl-N,N,N\N"-tetramethyluronium tetrafluoroborate
HCl hydrochloric acid
HOBt 1 -hydroxybenzotriazo Ie
HPLC High performance liquid chromatography
LCMS liquid chromatography and mass spectrometry MeCN acetonitrile
MeOH methanol
MeOD dueterated methanol m multiplet min(s) minute(s) mL millilitre ml millilitre mol/M mole/molar
MW molecular weight
/7-BuLi n-Butyllithium
NMR nuclear magnetic resonance
OMs methanesulfonate
OTs /?αra-toluenesulfonate
PBr3 tribromophospine
PMA phosphomolibdic acid
PPh3 triphenylphosphine pTsCl /?αra-toluenesulfonyl chloride
Rt retention time
RT room temperature
SFC supercritical fluid chromatography
STAB sodium triacetoxyborohydride
Ts /?αra-toluenesulfbnyl
TBDMSCl te/t-butyldimethylsilyl chloride
TEA triethylamine
TFA 2,2,2-trifluoroacetic acid
THF tetrahydro furan
TLC thin layer chromatography
TMS trimethylsilyl wt weight Route 1
1. 4M HCI in dioxane / — \ >v
Figure imgf000045_0001
Preparation of tert-buty\ 4-cyclobutylpiperazine-l-carboxylate
Figure imgf000045_0002
To a stirred solution of tert-butyl piperazine-1-carboxylate (13.0 g, 69.8 mmol) in DCE (200 ml) at 20 to 25 0C was added cyclobutanone (5.2 ml, 69.8 mmol) followed by acetic acid (4.2 g, 69.8 mmol) dropwise. The resulting mixture was stirred at 20 to 25 0C for ca. 2 h. Sodium triacetoxyborohydride (22.2 g, 104.7 mmol) was added in several portions, keeping the temperature in the range of 20 to 25 0C. The resulting suspension was stirred at 20 to 25 0C overnight. Saturated aqueous NaHCOs (200 ml) was added in four portions and the biphasic mixture stirred at 20 to 25 0C for ca. 30 mins. The organic layer was separated, washed with water (60 ml) and the aqueous phase back extracted at pH 9 with DCM (60 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (12.0 g, 71.5 % yield) as pale yellow oil. This compound showed a single spot by TLC (uv 215 nm) and was taken through to the next step without further purification.
Preparation of 1-cyclobutylpiperazine
HN N~^>
To a stirred solution of tert-butyl 4-cyclobutylpiperazine-l-carboxylate (12.0 g, 49.9 mmol) in DCM (150 ml) at 20 to 25 0C was added a solution of 4M HCl in dioxane (60 ml, 240 mmol) dropwise. The resulting mixture was stirred at 20 to 25 0C for ca. 2h. MeOH (12 ml) was added and the resulting mixture stirred at 20 to 25 0C for 1 to 2 days. The solvent was removed in vacuo and the resulting gummy residue slurried in ether (200 ml) for 0.5 h. The solvent was evaporated and the residue slurried in ether/MeOH (10:1, 122 ml). The resulting white solid was collected by filtration, suspended in DCM (150 ml) and 2M NaOH was added. The aqueous phase was extracted with DCM until complete transfer of product in the organic layer, as monitored by TLC analysis (eluent, DCM/MeOH/conc.NH3 (90:10:1); stain, PMA) was achieved. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (5.23 g, 74.7 % yield) as white semi- crystalline solid.
LC data: Rt = 2.74 mins (High pH).
1H NMR (500 MHz, CDCl3) δ ppm 5.39 (2 H, br. s.), 3.03 (2 H, t, J=4.8 Hz), 2.63 - 2.82 (1 H, m), 2.10 - 2.62 (6 H, m), 1.96 (2 H, q, J=7.7 Hz), 1.73 - 1.92 (2 H, m), 1.53 - 1.72 (2 H, m).
Route 2
Figure imgf000046_0001
Preparation of (31S)-I '-benzyl- 1,3 '-bipyrrolidine
Figure imgf000046_0002
To a stirred solution of (3i?)-pyrrolidin-3-ol (2.79 g, 15.7 mmol) in THF (50 ml) at -78 0C was added nBuLi (11.2 ml of a 1.4M solution in hexanes, 15.7 mmol) giving a deep pink solution. After 5 mins, /?αra-toluenesulfonyl chloride (3.00 g, 15.7 mmol) in THF (10 ml) was added dropwise and the reaction was then raised to room temperature. The reaction was quenched with saturated aqueous NH4Cl (5 ml) and the reaction was concentrated. The residue was then dissolved in DCM (100 ml) and washed with saturated NH4CI (3 x 50 ml), dried (MgSO4), filtered and concentrated giving brown oil. This was dissolved in EtOH (25 ml) and pyrrolidine (3.95 ml, 47.0 mmol) was added. The mixture was heated in a sealed tube at 90 0C for 12 hours and then concentrated to remove excess solvent, re-dissolved in DCM (100 ml), washed with saturated aqueous NH4Cl (3 x 50 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The crude material was purified on silica gel chromatography (using a gradient of eluents, 98:2:1 to 80:20:1 DCM/MeOH/NH3) to give the title compound (2.35 g, 65%) as brown oil. LCMS data: Calculated MH+ (231); Found 91% (MH+) m/z 231, Rt 4.57 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.19 - 7.37 (5 H, m), 3.54 - 3.72 (2 H, m), 2.84 - 2.98 (2 H, m), 2.72 - 2.83 (1 H, m), 2.54 (5 H, s), 2.26 - 2.41 (1 H, m), 1.96 - 2.14 (1 H, m), 1.80 (5 H, m).
Preparation of (3'S)-l,3'-bipyrrolidine
Figure imgf000047_0001
(3 'S)-I '-Benzyl- U'-bipyrrolidine (2.35 g, 10.1 mmol) and Pd(OH)2 on carbon (500 mg) were stirred in MeOH (100 ml) under a hydrogen atmosphere for 3 days. The mixture was then filtered over celite and concentrated at reduced pressure to give the title product (1.27 g, 89%) as light brown oil.
The product did not ionize by LCMS
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 3.05 (2 H, m), 2.82 - 2.95 (1 H, m), 2.65 - 2.81 (2 H, m), 2.47 - 2.65 (4 H, m), 1.93 - 2.07 (1 H, m), 1.82 (4H, m), 1.62 - 1.76 (1 H, m).
Determination of enantiomeric excess of (31S)- 1 ,3 '-bipyrrolidine
To determine the enatiomeric excess of (3'5)-l,3'-bipyrrolidine, the derivative (3 'S)-I '-{[4- (lH-pyrazol-l-ylmethyl)phenyl]carbonyl}-l,3'-bipyrrolidine was synthesised and analysed using chiral ΗPLC. It is assumed that enantiomeric purity of (3'5)-l,3'-bipyrrolidine is unaffected by any synthetic steps in which it is used.
Figure imgf000047_0002
To a stirred solution of 4-(lH-pyrazol-l-ylmethyl)benzoic acid (53 mg, 0.26 mmol) in DCM (5 ml) was added HOBt (39 mg, 0.29 mmol) followed by HBTU (110 mg, 0.29 mmol) at room temperature. After 5 minutes, (3'5)-l,3'-bipyrrolidine (37 mg, 0.26 mmol) was added and the resulting mixture was stirred for 16 hours. DIPEA (50 μl, 0.29 mmol) was then added and after a further 4 hours the reaction was diluted with DCM (20 ml) and washed with saturated aq. NaHCO3 (10 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (using a gradient of eluent 98:2:1 to 90:10:1 DCM/MeOH/2M NH3 in MeOH) followed by preparative HPLC to give the title compound (99 mg, 87%, TFA salt) as pink oil.
LCMS data: Calculated MH+ (325); Found 93% (MH+) m/z 325, Rt 2.21 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.76 (1 H, s), 7.47 - 7.60 (3 H, m), 7.25 - 7.35
(2 H, m), 6.34 - 6.40 (1 H, m), 5.42 (2 H, s), 3.36 - 4.08 (7 H, m), 2.95 - 3.29 (2 H, m), 2.36 -
2.56 (1 H, m), 1.86 - 2.31 (5 H, m).
Chiral HPLC data: Using a Chiralpak AD-H column, Mobile phase: Heptane / Ethanol 85:15
+0.1% TEA, uv at 254 nm wavelength; Found: Rt 7.36 mins, 91% (uv); Rt 11.61, 9% (uv);
82% ee.
Route 3
Figure imgf000048_0001
MSO
Preparation of 4-({[ført-butyl(dimethyl)silyl]oxy}methyl)benzoic acid
Figure imgf000048_0002
To a solution of TBDMSCl (9.29 g, 61.7 mmol) in DCM (100 ml) was added imidazole (4.20 g, 61.7) followed by 4-(hydroxymethyl)benzoic acid (5.0 g, 32.9 mmol). The reaction was heated at 40 0C for 8 h then cooled to room temperature. Excess solvent was removed and EtOAc (100 ml) was added giving a white slurry. This was filtered and the solvent concentrated. The residue was dissolved in 1 :1 THF/water (200 ml), basified by addition of K2CO3 (4.5 g, 32.5 mmol) and heated at 50 0C for 2 h. The reaction was then cooled to room temperature and acidified to pH3 with 10% aqueous citric acid and extracted with DCM (3 x 100 ml). The organic layers were combined and washed with brine (100 ml) and water (100 ml), dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (12.9 g, 79%) as colourless oil. The product was used directly in the next step without further purification.
LCMS data: Calculated MH+ (266); Found 94% (MH+) m/z 266, Rt 2.38 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.08 (2 H, d, J=8.3 Hz), 7.43 (2 H, d, J=8.6 Hz), 4.82 (2 H, s), 0.94 - 0.98 (9 H, m), 0.12 - 0.13 (6 H, m).
Preparation of [4-({[ført-butyl(dimethyl)silyl]oxy}methyl)phenyl] methanol
Figure imgf000049_0001
To a solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)benzoic acid (8.75 g, 32.9 mmol) in THF (100 ml) at 0 0C was added BH3THF (65.8 ml of a IM solution in THF). This was warmed to room temperature and after 6 h quenched with MeOH (20 ml) and concentrated at reduced pressure. The residue was purified directly by silica FCC (using a gradient of eluents 8:2 Heptane/EtOAc to 100% MeOH) to give the title compound as (8.3 g, quantitative yield) colourless oil.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.34 (4 H, m), 4.75 (2 H, s), 4.69 (2 H, d, J=5.9 Hz), 0.95 (9 H, s), 0.11 (6 H, s).
Preparation of 4-({[før*-butyl(dimethyl)silyl]oxy}methyl)benzaldehyde
Figure imgf000049_0002
To a stirred solution of [4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]methanol (8.30 g, 32.9 mmol) in acetonitrile (100 ml) was added MnO2 (18 g, 131 mmol) and the reaction was stirred at room temperature for 6 h. The reaction was then filtered over celite to give the title compound (5.52 g, 67%) as colourless oil.
LCMS data: Calculated MH+ (250); Found 93% (MH+) m/z 250, Rt 1.72 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ 10.00 (1 H, s), 7.86 (2 H, d, J=8.1 Hz), 7.50 (2 H, d, J=8.1 Hz), 4.82 (2 H, s), 0.94 - 0.99 (9 H, m), 0.11- 0.15 (6 H, m). Route 4
General Procedure A
Figure imgf000050_0001
General Procedure A: Preparation of (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- yl)phenyl] methanol
Figure imgf000050_0002
To a stirred solution of 4-benzyl-4H-l,2,4-triazole (500 mg, 3.14 mmol) in dry TΗF (20 ml) at -78 0C was added dropwise, over 30 minutes, n-BuLi (2.2 ml of a 1.6M solution in hexanes, 3.14 mmol). After 1 hour at -78 0C, 4-pyrazol-l-yl-benzaldehyde (649 mg, 3.77 mmol) in TΗF (3 ml) was added dropwise over 10 mins. The reaction was stirred for a further 1 hour then warmed to room temperature and quenched with saturated aqueous NaΗCθ3 (1 ml). The reaction mixture was concentrated in vacuo and the resulting residue diluted with DCM (50 ml) and washed with saturated aqueous NaHCOs (20 ml), dried (MgSO4), filtered and concentrated in vacuo. Diethyl ether (15 ml) was added to the residue and the resulting fine precipitate collected by filtration and dried in vacuo to provide the title compound (705 mg, 68% yield) as white solid.
LCMS data: Calculated MH+ (332); Found 97% (MH+) m/z 332, Rt 1.58 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.42 (1 H, s), 8.17 - 8.21 (1 H, m), 7.70 - 7.73 (1 H, m), 7.67 (2 H, d, J=8 Hz), 7.46 (2 H, d, J=8 Hz), 7.20 - 7.27 (3 H, m), 6.99 - 7.07 (2 H, m), 6.50 - 6.55 (1 H, m), 6.18 (1 H, s), 5.32 (1 H, d, J=15 Hz), 5.25 (1 H, d, J=15 Hz).
Preparation of (4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methanol
Figure imgf000051_0001
In a similar fashion (Route 4, GP A), 4-benzyl-4H-l,2,4-triazole (1.0 g, 6.3 mmol) and A- fluorobenzaldehyde (0.81 ml, 6.9 mmol) gave the title compound (1.4 g, 79% yield) as a white solid.
LCMS data: Calculated MH+ (284); Found 99% (MH+) m/z 284, Rt 1.59 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.40 (1 H, s), 7.31 - 7.40 (2 H, m), 7.23 - 7.30
(3 H, m), 6.97 - 7.07 (4 H, m), 6.11 (1 H, s), 5.30 (1 H, d, J=16 Hz), 5.23 (1 H, d, J=16 Hz).
Preparation of methyl 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(hydroxy)methyl]benzoate
Figure imgf000051_0002
In a similar fashion (Route 4, GP A), methyl-4-formylbenzoate (619 mg, 3.14 mmol) gave the title compound (655 mg, 64% yield) as white solid.
LCMS data: Calculated MH+ (324); Found 100% (MH+) m/z 324, Rt 1.77 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.42 (1 H, s), 7.94 (2 H, d, J=8.6 Hz), 7.45 (2
H, d, J=8.1 Hz), 7.21 - 7.28 (3 H, m), 6.98 - 7.05 (2 H, m), 6.20 (1 H, s), 5.30 (1 H, d, J=15.4
Hz), 5.23 (1 H, d, J= 15.4 Hz), 3.90 (3 H, s).
Preparation of 4- [(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(hydr oxy)methyl] benzonitrile
Figure imgf000051_0003
In a similar fashion (Route 4, GP A), 4-cyanobenzaldehyde (198 mg, 1.51 mmol) gave the title compound (137 mg, 37% yield) as white solid.
LCMS data: Calculated MH+ (291); Found 100% (MH+) m/z 291, Rt 1.48 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.47 (1 H, s), 7.62 (2 H, d, J=8.0 Hz), 7.49 (2
H, d, J=8.1 Hz), 7.22 - 7.29 (3 H, m), 6.97 - 7.03 (2 H, m), 6.18 (1 H, s), 5.24 - 5.36 (2 H, m). Preparation of (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(difluoromethoxy)phenyl] methanol
Figure imgf000052_0001
In a similar fashion (Route 4, GP A), 4-(difluoromethoxy)benzaldehyde (0.20 ml, 1.50 mmol) gave the title compound (193 mg, 53% yield) as white solid.
LCMS data: Calculated MH+ (332); Found 100% (MH+) m/z 332, Rt 1.67 mins.
NMR data: 1H NMR (360 MHz, MeOD) δ ppm 8.41 (1 H, s), 7.37 (2 H, d, J=9 Hz), 7.22 -
7.31 (3 H, m), 7.07 (2 H, d, J=9 Hz), 6.95 - 7.03 (2 H, m), 6.68 (1 H, t, J=84 Hz), 6.13 (1 H, s), 5.21 - 5.35 (2 H, m).
Preparation of (4-benzyl-4H-l,2,4-triazol-3-yl)[4-({[førf- butyl(dimethyl)silyl]oxy}methyl)phenyl] methanol
Figure imgf000052_0002
TBDMS
In a similar fashion (Route 4, GP A), 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)benzaldehyde
(820 mg, 5.16 mmol) gave the title compound (800 mg, 38% yield) as white solid.
LCMS data: Calculated MH+ (410); Found 98% (MH+) m/z 410, Rt 2.33 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.35 (1 H, s), 7.20 - 7.36 (7 H, m), 6.95 - 7.03
(2 H, m), 6.14 (1 H, s), 5.25 (1 H, d, J=12 Hz), 5.16 (1 H, d, J=12 Hz), 4.72 (2 H, s), 0.94 (9
H, s), 0.07 - 0.12 (6 H, m).
Preparation of (4-benzyl-4H- 1 ,2,4-triazol-3-yl) [4-(piperidin- l-ylmethyl)phenyl] methanol
Figure imgf000052_0003
In a similar fashion (Route 4, GP A), 4-(piperidin-l-ylmethyl)benzaldehyde (211 mg, 1.04 mmol) gave the title compound (153 mg, 49% yield) as white solid. LCMS data: Calculated MH+ (363); Found 100% (MH+) m/z 363, Rt 0.88 mins.
NMR data: 1H NMR (250 MHz, MeOD) δ ppm 8.36 (1 H, s), 7.16 - 7.39 (7 H, m), 6.88 - 7.04
(2 H, m), 6.15 (1 H, s), 5.24 (2 H, s), 3.48 (2 H, s), 2.29 - 2.51 (4 H, m), 1.37 - 1.68 (6 H, m).
Route 5
Figure imgf000053_0001
General Procedure B: Example 1 - Preparation of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4- cyclobutylpiperazine. Potency Range A.
Figure imgf000053_0002
To a stirred room temperature suspension of (4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methanol (80 mg, 0.28 mmol) in MeCN (4 mL) was added PBr3 (29 μL, 0.31 mmol) and the resulting mixture was stirred for 2 h. Evaporation of the solvent in vacuo gave a white solid. This material was suspended in dry MeCN (2 ml) at room temperature, 1- cyclobutyl-piperazine (44 mg, 0.31 mmol) and potassium carbonate (97 mg, 0.71 mmol) were added. The stirred reaction mixture was heated at reflux (ca. 80 0C) overnight then cooled to room temperature. EtOAc (20 mL) was added and the resulting mixture washed with water (2 x 20 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated at reduced pressure to give a yellow solid. The crude material was purified by silica gel chromatography (eluting with DCM/MeOH 90:10; stain PMA) followed by preparative
HPLC to give the title compound (39 mg, 38%; TFA salt) as white solid. LCMS data: Calculated MH+ (406); Found 98% (MH+) m/z 406, Rt 1.27 mins. NMR data: 1U NMR (400 MHz, MeOD) δ ppm 8.92 (1 H, s), 7.26 - 7.39 (5 H, m), 7.00 - 7.13 (4 H, m), 5.27 - 5.45 (2 H, m), 5.10 (1 H, s), 3.54 - 3.68 (1 H, m), 3.22 - 3.47 (2 H, m), 2.72 - 3.09 (4 H, m), 2.50 - 2.65 (1 H, m), 2.34 - 2.46 (1 H, m), 2.10 - 2.33 (4 H, m), 1.76 - 1.92 (2 H, m).
Example 2 - Preparation of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4- cyclopentylpiperazine. Potency range A
Figure imgf000054_0001
In a similar fashion (Route 5, GP B), (4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methanol (100 mg, 0.35 mmol) and 1-cyclopentyl-piperazine (60 mg, 0.39 mmol) gave the title compound (48 mg, 33%; TFA salt).
LCMS data: Calculated MH+ (420); Found 98% (MH+) m/z 420, Rt 1.31 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.98 (1 H, s), 7.26 - 7.44 (5 H, m), 6.95 - 7.15
(4 H, m), 5.30 - 5.49 (2 H, m), 5.12 (1 H, s), 3.38 - 3.60 (3 H, m), 2.82 - 3.19 (4 H, m), 2.51 - 2.70 (1 H, m), 2.33 - 2.50 (1 H, m), 2.01 - 2.20 (2 H, m), 1.56 - 1.91 (6 H, m).
Route 6
General
CK -N N
Figure imgf000054_0002
General Procedure C: Example 3 - Preparation of methyl 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4- cyclobutylpiperazin-l-yl)methyl]benzoate.
Figure imgf000054_0003
To a stirred solution of methyl 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(hydroxy)methyl]benzoate (150 mg, 0.46 mmol) in TΗF (5 ml) at -78 0C was added dropwise /?-BuLi (0.35 ml of a 1.4M solution in hexanes, 0.48 mmol) over 10 mins. The reaction was warmed to room temperature and /?αra-toluenesulfonyl chloride (97 mg, 0.51 mmol) was added as a solid in one single portion. After a further 1 hour, 1-cyclobutyl-piperazine (145 mg, 1.02 mmol) and DIPEA (170 μl, 1.02 mmol) in TΗF (1 ml) were added and the reaction was heated at 60 0C for 12 hours. Excess TΗF was removed in vacuo and the residue was diluted with dichloromethane (30 ml) and washed with saturated aqueous NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated in vacuo. Purfϊcation by silica flash column chromatography (using a gradient of eluents; 95:5:1 to 85:15:1 DCM/MeOH/NHs) followed by preparative HPLC gave the title compound (20 mg, 8% yield; TFA salt) as light brown oil. LCMS data: Calculated MH+ (446); Found 97% (MH+) m/z 446, Rt 2.96 mins. NMR data : 1H NMR (400 MHz, MeOD) δ ppm 8.37 (1 H, s), 7.35 (2 H, d, J=8.3 Hz), 6.84 (2 H, d, J=8.3 Hz), 6.67 - 6.76 (3 H, m), 6.44 - 6.52 (2 H, m), 4.72 - 4.85 (2 H, m), 4.62 (1 H, s), 2.95 - 3.10 (1 H, m), 2.69 - 2.85 (5 H, m), 2.13 - 2.47 (4 H, m), 1.76 - 2.08 (2 H, m), 1.51 - 1.73 (4 H, m), 1.18 - 1.32 (2 H, m).
Example 4 - Preparation of 4-{(4-benzyl-4H-l,2,4-triazol-3-yl)[(3'S)-l,3'-bipyrrolidin-l'- yl]methyl}benzonitrile. Potency range A
Figure imgf000055_0001
In a similar fashion (Route 6, GP C), 4-[(4-benzyl-4H-l,2,4-triazol-3- yl)(hydroxy)methyl]benzonitrile (100 mg, 0.34 mmol) and (3'5)-l,3'-bipyrrolidine (58 mg, 0.41 mmol) gave the title compound (98 mg, 52% yield, TFA salt) as pink oil. LCMS data: Calculated MH+ (413); Found 86% (MH+) m/z 413, Rt 2.81 mins. NMR data - 1 :1 mixture of diastereoisomers observed: 1H NMR (360 MHz, MeOD) δ ppm 8.94 (s), 8.87 (s), 7.54 - 7.63 (m), 7.41 - 7.52 (m), 7.18 - 7.33 (m), 6.88 - 7.00 (m), 5.34 - 5.47 (m), 5.20 (s), 5.17 (s), 3.77 - 3.93 (m), 3.34 - 3.77 (m), 2.92 - 3.28 (m), 2.71 - 2.89 (m), 2.42 - 2.61 (m), 2.26 - 2.40 (m), 1.93 - 2.20 (m). Example 5 - Preparation of (3'S)-l'-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4- (difluoromethoxy)phenyl]methyl}-l,3'-bipyrrolidine. Potency range A
Figure imgf000056_0001
In a similar fashion (Route 6, GP C), (4-benzyl-4H-l,2,4-triazol-3-yl)[4- (difluoromethoxy)phenyl]methanol (70 mg, 0.21 mmol) and (3'5)-l,3'-bipyrrolidine (36 mg, 0.25 mmol) gave the title compound (32 mg, 26% yield, TFA salt) as pink oil. LCMS data: Calculated MH+ (454); Found 97% (MH+) m/z 454, Rt 3.11 mins. NMR data - 1 :1 mixture of diastereoisomers observed: 1H NMR (360 MHz, MeOD) δ ppm 8.88 (br. s.), 8.81 (br. s.), 7.40-7.30 (m), 7.17 - 7.30 (m), 6.99 - 7.11 (m), 6.94 (m), 6.82 (t, J=73.6 Hz), 5.22 - 5.38 (m), 5.16 (m), 3.77 - 3.95 (m), 3.01 - 3.77 (m), 2.76 - 3.01 (m), 2.22 - 2.57 (m), 1.92 - 2.22 (m).
Example 6 - Preparation of (4-{(4-benzyl-4H-l,2,4-triazol-3-yl)[(3'S)-l,3'-bipyrrolidin- l'-yl]methyl}phenyl)methanol. Potency range B
Figure imgf000056_0002
In a similar fashion (Route 6, GP C), (4-benzyl-4H-l,2,4-triazol-3-yl)[4-({[tert- butyl(dimethyl)silyl]oxy}methyl)phenyl]methanol (815 mg, 2.0 mmol) and (3 'S)- 1,3'- bipyrrolidine (307 mg, 2.19 mmol) gave the title compound (634 mg, 60% yield) as pink oil. LCMS data: Calculated MH+ (418); Found 100% (MH+) m/z 418, Rt 2.59 mins. NMR data - 1 :1 mixture of diastereoisomers observed: 1H NMR (360 MHz, MeOD) δ ppm 8.40 (s), 7.21 - 7.44 (m), 6.90 - 7.03 (m), 5.20 - 5.44 (m), 4.74 (s), 4.56 (s), 2.70 - 2.97 (m), 2.37 - 2.61 (m), 2.20 - 2.36 (m), 1.95 - 2.11 (m), 1.65 - 1.85 (m).
Example 7 - Preparation of (3'5)-l'-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(piperidin-l- ylmethyl)phenyl]methyl}-l,3'-bipyrrolidine. Potency range A
Figure imgf000057_0001
In a similar fashion (Route 6, GP C), (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(piperidin-l- ylmethyl)phenyl]methanol (149 mg, 0.44 mmol) and (3'5)-l,3'-bipyrrolidine (73 mg, 0.52 mmol) gave the title compound (13 mg, 5%, TFA salt) as brown oil.
LCMS data: Calculated MH+ (485); Found 100% (MH+) m/z 485, Rt 2.59 mins. NMR data - 1 :1 mixture of diastereoisomers observed: 1H NMR (250 MHz, MeOD) δ 8.44 (d, J=3.0 Hz), 7.31 - 7.41 (m), 7.19 - 7.31 (m), 6.87 - 6.99 (m), 5.21 - 5.42 (m), 4.78 (m), 3.50 (m), 3.16 (m), 2.57 - 2.89 (m), 2.44 (m), 1.98 - 2.22 (m), 1.69 - 1.96 (m), 1.38 - 1.69 (m).
Example 8 - Preparation of 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-cyclobutylpiperazin-l- yl)methyl]benzonitrile. Potency range A
Figure imgf000057_0002
In a similar fashion (Route 6, GP C), 4-[(4-benzyl-4H-l,2,4-triazol-3- yl)(hydroxy)methyl]benzonitrile (48 mg, 0.17 mmol) and 1-cyclobutyl-piperazine (31 mg,
0.18 mmol) gave the title compound (16 mg, 23%) as brown oil.
LCMS data: Calculated MH+ (413); Found 94% (MH+) m/z 413, Rt 2.90 mins.
1H NMR (400 MHz, MeOD) δ ppm 8.55 (1 H, s), 7.61 (2 H, d, J=8.6Hz), 7.51 (2 H, d, J=8.6Hz), 7.25 - 7.37 (3 H, m), 6.97 - 7.08 (2 H, m), 5.50 (1 H, s), 5.42 (2 H, s), 2.69 - 2.82 (1
H, m), 2.17 - 2.56 (8 H, m), 1.93 - 2.06 (2 H, m), 1.76 - 1.93 (2 H, m), 1.64 - 1.76 (2 H, m).
Example 9 - Preparation of (3'S)-l'-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methyl]-l,3'-bipyrrolidine. Potency range B
Figure imgf000058_0001
In a similar fashion (Route 6, GP C), (4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methanol (100 mg, 0.29 mmol) and (3'5)-l,3'-bipyrrolidine (44 mg, 0.32 mmol) gave the title compound (8 mg, 7%).
LCMS data: Calculated MH+ (406); Found 88% (MH+) m/z 406, Rt 2.84 mins.
1H NMR - 1 :1 mixture of diastereoisomers observed: (360 MHz, MeOD) δ ppm 8.72 - 8.77
(m), 8.69 (), 7.18 - 7.40 (m), 6.88 - 7.10 (m), 5.16 - 5.37 (m), 4.95 - 5.03 (m), 3.81 - 3.92 (m),
3.70 - 3.80 (m), 3.06 - 3.63 (m), 2.59 - 2.87 (m), 2.44 - 2.59 (m), 2.32 (m), 1.91 - 2.20 (m).
Preparation of tert-buty\ 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methyl]piperazine-l-carboxylate
Figure imgf000058_0002
In a similar fashion (Route 6, GP C), (4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methanol (600 mg, 2.12 mmol) and tert-butyi piperazine-1-carboxylate (866 mg, 4.66 mmol) gave the title compound (782 mg, 82%). LCMS data: Calculated MH+ (452); Found 97% (MH+) m/z 452, Rt 1.39 mins. 1H NMR (360 MHz, MeOD) δ ppm 8.51 (1 H, s), 7.27 - 7.42 (5 H, m), 6.95 - 7.10 (4 H, m), 5.29 - 5.45 (2 H, m), 4.79 (1 H, s), 3.31 - 3.41 (4 H, m), 2.20 - 2.40 (4 H, m), 1.43 (9 H, s).
Preparation of (3R)- 1- [(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl] -3- methylpiperazine
Figure imgf000058_0003
In a similar fashion (Route 6, GP C), (4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methanol (200 mg, 0.69 mmol) and (i?)-2-methylpiperazine (280 mg, 1.52 mmol) gave the compound (63 mg, 25%).
LCMS data: Calculated MH+ (366); Found 86% (MH+) m/z 366, Rt 1.02 mins.
1H NMR - 1 :1 mixture of diastereoisomers observed: (400 MHz, MeOD) δ ppm 8.52 (m),
7.27 - 7.45 (m), 6.94 - 7.13 (m), 5.25 - 5.48 (m), 4.79 (m), 2.90 (m), 2.65 (m), 1.91 - 2.18 (m),
1.61 - 1.85 (m), 0.97 (m).
Route 7
Figure imgf000059_0001
Example 10 - Preparation of l'-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- yl)phenyl]methyl}-l,3'-bipyrrolidine. Potency range A
Figure imgf000059_0002
(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l-yl)phenyl]methanol (71 mg, 0.22 mmol) and carbon tetrabromide (100 mg, 0.30 mmol) were stirred in dichloromethane (2 ml) at 0 0C giving a white suspension. Triphenylphosphine (159 mg, 0.60 mmol) was then added as a solid and after 20 mins, l,3'-bipyrrolidine hydrochloride (55 mg, 0.26 mmol) and DIPEA (85 μl, 0.52 mmol) in DCM (1 ml) were added. After stirring for 48 hours the reaction was diluted with dichloromethane (30 ml) and washed with IM NaOH (10 ml), dried (MgSO4), filtered and concentrated in vacuo. Purification by silica flash column chromatography (using a gradient of eluents; 98:2:1 to 85:15:1 DCM/MeOΗ/NΗ3) gave the title compound (19 mg, 20% yield) as yellow oil. LCMS data: Calculated MH+ (454); Found 100% (MH+) m/z 454, Rt 2.82 mins. NMR data - 1 :1 mixture of diastereoisomers observed: 1H NMR (400 MHz, MeOD) δ ppm
8.48 (d, J=3.2 Hz), 8.18 (d, J=2.7 Hz), 7.71 (d, J=1.7 Hz), 7.58 - 7.68 (m), 7.43 - 7.55 (m), 7.19 - 7.35 (m), 6.92 - 7.06 (m), 6.48 - 6.56 (m), 5.29 - 5.46 (m), 2.98 - 3.18 (m), 2.58 - 2.83 (m), 2.40 - 2.58 (m), 1.99 - 2.17 (m), 1.73 - 1.93 (m).
Route 8 pTsCI OTs
Figure imgf000060_0001
Pyridine HO
Preparation of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate
Figure imgf000060_0002
To a solution of 3-methylbutane-l,3-diol (213 μl, 2 mmol) in pyridine (2 ml) at 0 0C was added /?αra-toluenesulfonyl chloride (836 mg, 4.4 mmol). After 4 hours, the reaction was quenched with water (4 ml) and raised to room temperature. EtOAc (30 ml) was added and the organic layer was washed with IM aq. HCl (20 ml), saturated aq. NaHCO3 (20 ml) and brine (20 ml), dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (340 mg, 66%) as colourless oil.
NMR data: 1H NMR (400 MHz, CDCl3) δ 7.33 - 7.47 (4 H, m), 4.37 (3 H, s), 4.24 (2 H, t, J=6.9 Hz), 1.84 (2 H, t, J=6.9 Hz), 1.21 (6 H, s).
Route 9
Figure imgf000060_0003
Preparation of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]piperazine
Figure imgf000060_0004
To a stirred solution of tert-butyl 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methyl]piperazine-l-carboxylate (782 mg, 1.73 mmol) in DCM (50 ml) at room temperature was added HCl (3.02 ml of a 4M solution in dioxane, 12.1 mmol). The reaction was stirred for 16 hours and then concentrated at reduced pressure. The residue was dissolved in DCM (20 ml), Ambersep 900-OH resin (1.2 g) added and the mixture stirred for 2 hours, filtered and finally concentrated to give the title compound (354 mg, 58%). LCMS data: Calculated MH+ (352); Found 80% (MH+) m/z 352, Rt 1.00 mins. 1H NMR (250 MHz, MeOD) δ ppm 8.56 (1 H, s), 7.25 - 7.40 (5 H, m), 6.95 - 7.10 (4 H, m), 5.13 - 5.43 (2 H, m), 4.84 - 4.89 (1 H, m), 3.00 - 3.15 (4 H, m), 2.49 - 2.67 (4 H, m).
Example 11 - Preparation of 4-{4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methyl]piperazin-l-yl}-2-methylbutan-2-ol. Potency range A
Figure imgf000061_0001
A mixture of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]piperazine (94 mg,
0.27 mmol), 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (49 mg, 0.19 mmol) and
DIPEA (69 mg, 0.53 mmol) were heated at 80 0C in DMF (3 ml) for 48 hours. The reaction was then concentrated at reduced pressure and purified by preparative HPLC followed by silica flash column chromatography (90:10:1 DCM/MeOH/NHs) to give the title compound
(26 mg, 22% yield).
LCMS data: Calculated MH+ (438); Found 94% (MH+) m/z 438, Rt 2.90 mins.
1H NMR (360 MHz, MeOD) δ ppm 8.50 (1 H, s), 7.24 - 7.45 (5 H, m), 6.92 - 7.10 (4 H, m),
5.26 - 5.46 (2 H, m), 4.75 (1 H, s), 2.19 - 2.72 (10 H, m), 1.62 (2 H, t, J=7.5 Hz), 1.18 (6 H, s).
Route 10
Figure imgf000061_0002
Example 12 - Preparation of (2R)-4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4- fluorophenyl)methyl]-l-cyclobutyl-2-methylpiperazine. Potency range A
Figure imgf000062_0001
To a stirred solution of (3i?)-l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-3- methylpiperazine (63 mg, 0.17 mmol) in DCE (5 ml) at room temperature was added cyclobutanone (18 mg, 0.26 mmol) followed by acetic acid (16 mg, 0.26 mmol) dropwise. The resulting mixture was stirred for 1 hour then sodium triacetoxyborohydride (220 mg, 1.04 mmol) was added and the resulting suspension stirred for 16 hours. The reaction was diluted with DCM (30 ml), washed with saturated aqueous NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated in vacuo. Purification by silica flash column chromatography (using a gradient of eluents; 95:5:1 to 85:15:1 DCM/MeOH/NH3) gave the title compound (63 mg, 88% yield) as yellow oil. LCMS data: Calculated MH+ (420); Found 90% (MH+) m/z 420, Rt 2.98 mins. 1H NMR - 1 :1 mixture of diastereoisomers observed: (250 MHz, MeOD) δ ppm 8.46 - 8.58 (m), 7.24 - 7.48 (m), 6.91 - 7.14 (m), 5.26 - 5.48 (m), 4.66 - 4.82 (m), 2.93 - 3.21 (m), 2.66 - 2.85 (m), 2.39 - 2.65 (m), 1.77 - 2.37 (m), 1.56 - 1.75 (m), 0.90 - 1.11 (m).
Route 11
Figure imgf000062_0002
Example 13 - Preparation of 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-cyclobutylpiperazin-l- yl)methyl]-N-methylbenzamide. Potency range A
Figure imgf000063_0001
To methyl 4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]benzoate (280 mg, 0.50 mmol) in THF (6 ml) was added LiOH (63 mg, 1.50 mmol) dissolved in water (1 ml). The mixture was stirred for 16 hours then concentrated at reduced pressure and re- dissolved in DMF (2 ml). To this was added HOBt (35 mg, 0.26 mmol), HBTU (98 mg, 0.26 mmol) and methylamine (0.13 ml of a 2.0M solution in THF, 0.26 mmol). After stirring for 16 hours, DMF was removed in vacuo and the residue purified by silica flash column chromatography (using a gradient of eluents; 95:5:1 to 90:10:1 DCM/MeOH/NHs) to give the title compound (16 mg, 30% yield) as colourless oil.
LCMS data: Calculated MH+ (445); Found 97% (MH+) m/z 445, Rt 2.56 mins. 1H NMR (400 MHz, MeOD) δ ppm 8.54 (1 H, s), 7.72 (2 H, d, J=8.3 Hz), 7.43 (2 H, d, J=8.3 Hz), 7.22 - 7.35 (3 H, m), 6.99 - 7.08 (2 H, m), 5.27 - 5.42 (2 H, m), 4.97 (1 H, s), 3.18 (1 H, d, J=4.9 Hz), 2.90 (3 H, s), 2.41 - 2.83 (8 H, m), 2.06 - 2.21 (2 H, m), 1.87 - 2.06 (2 H, m), 1.67 - 1.84 (2 H, m).
The following example compounds have been prepared following the methods disclosed herein:
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
(3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol- 3-yl)[4-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl]methyl} - 1 ,3'-bipyrrolidine
1 -cyclobutyl-4- { [4-(4-fluorobenzyl)- 4H-l,2,4-triazol-3-yl][4-(lH-l,2,4- triazol-1- ylmethyl)phenyl]methyl}piperazine
Figure imgf000067_0001
(3'5)-r-[(4-benzyl-4H-l,2,4-triazol- 3-yl)(4-fluorophenyl)methyl]- 1 ,3'- bipyrrolidine
1 -cyclobutyl-4- { [4-(4-fluorobenzyl)- 4H-l,2,4-triazol-3-yl](4- fluorophenyl)methyl} piperazine
l-[(l-benzyl-lH-l,2,3-triazol-5- yl)(4-fluorophenyl)methyl] -4- cyclopentylpiperazine
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000069_0001
^ Racemeic compound l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethyl)phenyl]methyl}-4-cyclobutylpiperazine underwent SFC separation using a Chiralpak AS-H(2 x 15 cm) column to provide the (R) and (S) enantiomers.

Claims

Patent Claims
1. A compound of formula (I)
Figure imgf000070_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X0 is
Figure imgf000070_0002
one of X , X is N and the other is CH;
R1 is T; Ci_4 alkyl; C2-4 alkenyl; or C2-4 alkynyl, wherein Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl are optionally substituted with one or more R9, which are the same or different;
R9 is halogen; CN; C(O)OR10; OR10; C(O)R10; C(O)N(R10R10a); S (O)2N(R10R1 Oa); S(O)N(R10R10a); S(O)2R10; S(O)R10; N(R10)S(O)2N(R10aR10b); SR10; N(R10R10a); NO2; OC(O)R10; N(R10)C(O)R10a; N(R10)SO2R10a; N(R10)S(O)R10a; N(R10)C(O)N(R10aR10b);
N(R10)C(O)OR10a; OC(O)N(R10R1 Oa); or T;
R10, R1Oa, R10b are independently selected from the group consisting of H; T; Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl, wherein Ci_4 alkyl; C2-4 alkenyl; and C2-4 alkynyl are optionally substituted with one or more R11, which are the same or different; R11 is halogen; CN; C(O)OR12; OR12; C(O)R12; C(O)N(R12R12a); S(O)2N(R12R12a); S(O)N(R12R12a); S(O)2R12; S(O)R12; N(R12)S(O)2N(R12aR12b); SR12; N(R12R12a); NO2; OC(O)R12; N(R12)C(O)R12a; N(R12)SO2R12a; N(R12)S(O)R12a; N(R12)C(O)N(R12aR12b); N(R12)C(O)OR12a; OC(O)N(R12R12a); or T;
R12, R12a, R12b are independently selected from the group consisting of H; T; Ci_4 alkyl; C2_4 alkenyl; and C2_4 alkynyl, wherein Ci_4 alkyl; C2_4 alkenyl; and C2_4 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T is phenyl; naphthyl; azulenyl; indenyl; indanyl; C3-7 cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T is optionally substituted with one or more R13, which are the same or different;
R13 is halogen; CN; C(O)OR14; OR14; C(O)R14; C(O)N(R14R14a); S(O)2N(R14R14a); S(O)N(R14R14a); S(O)2R14; S(O)R14; N(R14)S(O)2N(R14aR14b); SR14; N(R14R14a); NO2;
OC(O)R14; N(R14)C(O)R14a; N(R14)S(O)2R14a; N(R14)S(O)R14a; N(R14)C(O)OR14a; N(R14)C(O)N(R14aR14b); OC(O)N(R14R14a); oxo (=0), where the ring is at least partially saturated; T1; Ci_6 alkyl; C2_6 alkenyl; or C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more R15, which are the same or different;
R14, R14a, R14b are independently selected from the group consisting of H; T1; Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more R16, which are the same or different;
R15, R16 are independently selected from the group consisting of halogen; CN;
C(O)OR17; OR17; C(O)R17; C(O)N(R17R17a); S(O)2N(R17R17a); S (O)N(R17R17a);
S(O)2R17; S(O)R17; N(R17)S(O)2N(R17aR17b); SR17; N(R17R17a); NO2; OC(O)R17;
N(R17)C(O)R17a; N(R17)SO2R17a; N(R17)S(O)R17a; N(R17)C(O)N(R17aR17b); N(R17)C(O)OR17a; OC(O)N(R17R17a); and T1;
R17, R17a, R17b are independently selected from the group consisting of H; T1; Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more halogen, which are the same or different; T1 is phenyl; C3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T1 is optionally substituted with one or more R18, which are the same or different;
R18 is halogen; CN; C(O)OR19; OR19; C(O)R19; C(O)N(R19R19a); S(O)2N(R19R19a);
S(O)N(R19R19a); S(O)2R19; S(O)R19; N(R19)S(O)2N(R19aR19b); SR19; N(R19R19a); NO2; OC(O)R19; N(R19)C(O)R19a; N(R19)S(O)2R19a; N(R19)S(O)R19a; N(R19)C(O)OR19a; N(R19)C(O)N(R19aR19b); OC(O)N(R19R19a); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C2_6 alkenyl; or C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R19, R19a, R19b are independently selected from the group consisting of H; Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R2, R3 are independently selected from the group consisting of H; halogen; Ci_6 alkyl; and A, wherein Ci_6 alkyl is optionally substituted with one or more R20, which are the same or different, provided that at least one of R2, R3 is A;
Optionally R2, R3 are joined together with the carbon atom to which they are attached to form a ring T3;
A is T2; Ci_6 alkyl; C2_6 alkenyl; or C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are substituted with at least one R20a;
R20 is halogen; CN; C(O)OR21; OR21; C(O)R21; C(O)N(R21R21a); S(O)2N(R21R21a); S(O)N(R21R21a); S(O)2R21; S(O)R21; N(R21)S(O)2N(R21aR21b); SR21; N(R21R21a); NO2; OC(O)R21; N(R21)C(O)R21a; N(R2 ^SO2R21'; N(R2 ^S(O)R21"; N(R21)C(O)N(R21aR21b); N(R21)C(O)OR21a; or OC(O)N(R21R21a);
R21, R21a, R21b are independently selected from the group consisting of H; Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R20a is T2; halogen; CN; C(O)OR20b; OR20b; C(O)R20b; C(O)N(R20bR20c);
S(O)2N(R20bR20c); S(O)N(R20bR20c); S(O)2R20b; S(O)R20b; N(R20b)S(O)2N(R20cR20d); SR20b; N(R20bR20c); NO2; OC(O)R20b; N(R20b)C(O)R20c; N(R20b)SO2R20c; N(R20b)S(O)R20c; N(R20b)C(O)N(R20cR20d); N(R20b)C(O)OR20c; or OC(O)N(R20bR20c);
R20b, R20c, R20d are independently selected from the group consisting of H; T2; Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T2 is phenyl; naphthyl; azulenyl; indenyl; indanyl; C3-7 cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl, wherein T2 is optionally substituted with one or more R22, which are the same or different;
T3 is C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T3 is optionally substituted with one or more R23, which are the same or different;
R22, R23 are independently selected from the group consisting of halogen; CN;
C(O)OR24; OR24; C(O)R24; C(O)N(R24R24a); S(O)2N(R24R24a); S(O)N(R24R24a); S(O)2R24; S(O)R24; N(R24)S(O)2N(R24aR24b); SR24; N(R24R24a); NO2; OC(O)R24;
N(R24)C(O)R24a; N(R24)S(O)2R24a; N(R24)S(O)R24a; N(R24)C(O)OR24a;
N(R24)C(O)N(R24aR24b); OC(O)N(R24R24a); oxo (=0), where the ring is at least partially saturated; T4; Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl; wherein Ci_6 alkyl; C2.
6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more R25, which are the same or different;
R24, R24a, R24b are independently selected from the group consisting of H; T4; Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl, wherein Ci_6 alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more R26, which are the same or different;
R25, R26 are independently selected from the group consisting of halogen; CN; C(O)OR27; OR27; C(O)R27; C(O)N(R27R27a); S(O)2N(R27R27a); S(O)N(R27R27a); S(O)2R27; S(O)R27; N(R27)S(O)2N(R27aR27b); SR27; N(R27R27a); NO2; OC(O)R27; N(R27)C(O)R27a; N(R27)SO2R27a; N(R27)S(O)R27a; N(R27)C(O)N(R27aR27b); N(R27)C(O)OR27a; OC(O)N(R27R27a); and T4;
R27, R27a, R27b are independently selected from the group consisting of H; T4; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R28, which are the same or different;
R28 is halogen; CN; C(O)OR29; OR29; C(O)R29; C(O)N(R29R29a); S(O)2N(R29R29a); S(O)N(R29R29a); S(O)2R29; S(O)R29; N(R29)S(O)2N(R29aR29b); SR29; N(R29R29a); NO2; OC(O)R29; N(R29)C(O)R29a; N(R29)SO2R29a; N(R29)S(O)R29a; N(R29)C(O)N(R29aR29b);
N(R29)C(O)OR29a; or OC(O)N(R29R29a);
R29, R29a, R29b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T4 is phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T4 is optionally substituted with one or more R30, which are the same or different;
R30 is halogen; CN; C(O)OR31; OR31; C(O)R31; C(O)N(R31 R3 la); S(O)2N(R31R31a);
S(O)N(R31R31a); S(O)2R31; S(O)R31; N(R3 ^S(O)2N(R3 laR31b); SR31; N(R31R31a); NO2;
OC(O)R31; N(R31)C(O)R31a; N(R31)S(O)2R31a; N(R31)S(O)R31a; N(R3 ^C(O)OR31";
N(R31)C(O)N(R31aR31b); OC(O)N(R31 R3 la); oxo (=0), where the ring is at least partially saturated; T5; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl; wherein Ci_6 alkyl; C2- 6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R32, which are the same or different;
R31, R31a, R31b are independently selected from the group consisting of H; T5; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R33, which are the same or different;
R32, R33 are independently selected from the group consisting of halogen; CN; C(O)OR34; OR34; C(O)R34; C(O)N(R34R34a); S(O)2N(R34R34a); S(O)N(R34R34a); S(O)2R34; S(O)R34; N(R34)S(O)2N(R34aR34b); SR34; N(R34R34a); NO2; OC(O)R34; N(R34)C(O)R34a; N(R34)SO2R34a; N(R34)S(O)R34a; N(R34)C(O)N(R34aR34b); N(R34)C(O)OR34a; OC(O)N(R34R34a); and T5;
R34, R34a, R34b are independently selected from the group consisting of H; T5; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R35, which are the same or different;
R35 is halogen; CN; C(O)OR36; OR36; C(O)R36; C(O)N(R36R36a); S(O)2N(R36R36a); S(O)N(R36R36a); S(O)2R36; S(O)R36; N(R36)S(O)2N(R36aR36b); SR36; N(R36R36a); NO2; OC(O)R36; N(R36)C(O)R36a; N(R36)SO2R36a; N(R36)S(O)R36a; N(R36)C(O)N(R36aR36b);
N(R36)C(O)OR36a; or OC(O)N(R36R36a);
R36, R36a, R36b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T5 is phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T5 is optionally substituted with one or more R37, which are the same or different;
R37 is halogen; CN; C(O)OR38; OR38; C(O)R38; C(O)N(R38R38a); S(O)2N(R38R38a);
S(O)N(R38R38a); S(O)2R38; S(O)R38; N(R38)S(O)2N(R38aR38b); SR38; N(R38R38a); NO2;
OC(O)R38; N(R38)C(O)R38a; N(R38)S(O)2R38a; N(R38)S(O)R38a; N(R38)C(O)OR38a;
N(R38)C(O)N(R38aR38b); OC(O)N(R38R38a); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C2-6 alkenyl; and C2-β alkynyl; wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R38, R38a, R38b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R4, R4a, R4b are independently selected from the group consisting of Ci_6 alkyl; C2-6 alkenyl; C2-6 alkynyl; C3-6 cycloalkyl; CH2-cyclopropyl; CHF-cyclopropyl; CF2- cyclopropyl; CH2-cyclobutyl; CHF-cyclobutyl; CF2-cyclobutyl; and 4 to 5 membered saturated heterocyclyl, wherein Ci_6 alkyl; C2-6 alkenyl; C2-6 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; and CN, and wherein C3-5 cycloalkyl; CH2-cyclopropyl; CHF-cyclopropyl; CF2-cyclopropyl; CH2-cyclobutyl; CHF-cyclobutyl; CF2-cyclobutyl; and 4 to 5 membered saturated heterocyclyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; CN; CH3; CH2F; CHF2; and CF3;
Optionally R4a, R4b are joined together with the nitrogen atom to which they are attached to form 3 to 7 membered saturated heterocyclyl, which is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; CN; CH3; CH2F; CHF2; and CF3;
R5, R5a, R6, R6a, R7, R8 are independently selected from the group consisting of H; Ci_5 alkyl; C2-5 alkenyl; and C2-5 alkynyl, wherein Ci .5 alkyl; C2-5 alkenyl; and C2-5 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; and CN;
Optionally one or both pairs R4/R5, R4/R6, R4b/R5, R4a/R6 are joined together with the atoms to which they are attached to form 3 to 7 membered heterocyclyl, wherein 3 to 7 membered heterocyclyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH3; CH2F; CHF2; and CF3;
Optionally one or both pairs R6/R7, R5/R8 are joined together with the carbon atoms to which they are attached to form C3_7 cycloalkyl, wherein C3_7 cycloalkyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH3; CH2F; CHF2; and CF3;
Optionally one or more of the pairs R5/R6, R5/R7, R4/R7, R4a/R7, R4/R8, R6/R8 are joined together with the respective ring X0 to form 8 to 11 membered heterobicyclyl, wherein 8 to 11 membered heterobicyclyl is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; CN; CH3; CH2F; CHF2; and CF3;
Provided that the following compounds are excluded:
Figure imgf000077_0001
2. A compound of claim 1, wherein X O is
Figure imgf000077_0002
3. A compound of claim 1, wherein X0 is
Figure imgf000077_0003
4. A compound of any of claims 1 to 3, wherein X2 is N.
5. A compound of any of claims 1 to 4, wherein R is Ci_4 alkyl substituted with one or more R9, which are the same or different.
6. A compound of any of claims 1 to 5, wherein T is phenyl; naphthyl; or 5 to 6 membered aromatic heterocyclyl.
7. A compound of any of claims 1 to 6, wherein A is T2.
8. A compound of any of claims 1 to 7, wherein T2 is phenyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl.
9. A compound of any of claims 1 to 8, wherein T2 is unsubstituted or substituted with one or two R22, which are the same or different.
10. A compound of any of claims 1 to 9, wherein T3 is cyclopentyl; cyclohexyl; tetrahydropyranyl; piperidinyl; pyrrolidinyl; or azetidinyl.
11. A compound of any of claims 1 to 10, wherein T3 is unsubstituted or substituted with one or two R23, which are the same or different.
12. A compound of any of claims 1 to 11, wherein R22, R23 are independently selected from the group consisting of halogen; T4; Ci-6 alkyl; OR24; C(O)N(R24R24a); C(O)OR24; N(R24R24a); S(O)2R24; S(O)2N(R24R24a); oxo (=0), where the ring is at least partially saturated; N(R24)C(O)R24a; C(O)R24, wherein Ci-6 alkyl is optionally substituted with one or more R25, which are the same or different.
13. A compound of any of claims 1 to 12, wherein R24, R24a are independently selected from the group consisting of H; T4; Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different.
14. A compound of any of claims 1 to 13, wherein R25 is halogen; T4; or C(O)N(R27R27a).
15. A compound of any of claims 1 to 14, wherein T4 is phenyl; or 5- to 6 membered heterocyclyl.
16. A compound of any of claims 1 to 15, wherein T4 is unsubstituted or substituted with one or two R30, which are the same or different and selected from the group consisting of halogen; OH; O-Ci_6 alkyl; Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different.
17. A compound of any of claims 1 to 16, wherein R4 is cyclo butyl; cyclopentyl; or C2-4 alkyl, optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; and CN.
18. A compound of any of claims 1 to 17, wherein R4a, R4b are independently selected from the group consisting of Ci_4 alkyl, optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH3; OCH2F; OCHF2; OCF3; and CN.
19. A compound of any of claims 1 to 18, wherein R4a, R4b are together with the nitrogen atom to which they are attached to form a substituted or unsubstituted pyrrolidine ring.
20. A compound of any of claims 1 to 19, wherein R5, R5a, R6, R6a, R7, R8 are H or CH3.
21. A compound of claim 1 selected from the group consisting of
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-cyclobutylpiperazine;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-cyclopentylpiperazine; methyl 4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 - yl)methyl]benzoate;
4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3\S)- 1 ,3'-bipyrrolidin- 1 '-yl]methyl}benzonitrile;
(3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(difluoromethoxy)phenyl]methyl} -1,3'- bipyrrolidine;
(4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3\S)- 1 ,3'-bipyrrolidin- 1 '- yl]methyl}phenyl)methanol;
(3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(piperidin- 1 -ylmethyl)phenyl]methyl} - l,3'-bipyrrolidine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]benzonitrile;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 ,3'-bipyrrolidine; 1 •- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -yl)phenyl]methyl} -1,3'- bipyrrolidine;
4- {4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]piperazin- 1 -yl} -2- methylbutan-2-ol; (2i?)-4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 -cyclobutyl-2- methylpiperazine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N- methylbenzamide; 1.(4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3'5)- 1 ,3'-bipyrrolidin- 1 '-yl]methyl}phenyl)-
N,N-dimethylmethanamine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(4-fluoropiperidin- 1 - yl)methyl]phenyl}methyl]- 1 ,3'-bipyrrolidine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(4,4-difluoropiperidin- 1 - yl)methyl]phenyl}methyl]- 1 ,3'-bipyrrolidine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(3,3-difluoropiperidin- 1 - yl)methyl]phenyl}methyl]- 1 ,3'-bipyrrolidine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N- cyclopropylbenzamide; 1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(3,5-dimethyl- lH-pyrazol- 1 -yl)phenyl]methyl} -
4-cyclobutylpiperazine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(4-methylpiperazin- 1 - yl)methyl]phenyl}methyl]- 1 ,3'-bipyrrolidine;
(2i?)-4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 -cyclobutyl-2- methylpiperazine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N-prop-2-yn-
1-ylbenzamide;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -yl)phenyl]methyl} -A- cyclobutylpiperazine; 1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl) {4-[(3,5-dimethyl- lH-pyrazol- 1 - yl)methyl]phenyl}methyl]-4-cyclobutylpiperazine;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutylpiperazin- 1 -yl)methyl]-N,N- dimethylbenzamide;
4- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[(3'5)- 1 ,3'-bipyrrolidin- 1 '-yl]methyl}benzonitrile; 1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-(2- fluoroethyl)piperazine;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -yl)phenyl]methyl} -A- cyclopentylpiperazine; (3 'S)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} - l,3'-bipyrrolidine;
(3'5)-r-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl]methyl} - 1 ,3'-bipyrrolidine; 1 -cyclobutyl-4- { [4-(4-fluorobenzyl)-4H- 1 ,2,4-triazol-3-yl] [4-( 1 H- 1 ,2,4-triazol- 1 - ylmethyl)phenyl]methyl}piperazine;
(3 'S)- 1 '-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1 ,3'-bipyrrolidine;
1 -cyclobutyl-4- {[4-(4-fluorobenzyl)-4H- 1 ,2,4-triazol-3-yl](4- fluorophenyl)methyl}piperazine; 1 -[(1 -benzyl- IH-1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclopentylpiperazine;
1 - {4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]piperazin- 1 -yl} -2- methylpropan-2-ol;
1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -1,3'- bipyrrolidine; 1 -[(1 -benzyl- IH-1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclobutylpiperazine;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-(3- fluoropropyl)piperazine;
(3'R)- 1 '- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} - l,3'-bipyrrolidine; 4-[(l -benzyl- 1 H- 1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]- 1 -cyclobutyl-2,6- dimethylpiperazine;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyclobutylpiperazine;
1 - {(i?)-(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyclobutylpiperazine; and
1 - {(5)-(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyclobutylpiperazine.
22. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 21 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
23. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 21 for use as a medicament.
24. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 21 for use in a method of treating or preventing diseases and disorders associated with the H3 receptor.
25. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 21 for use in a method of treating or preventing neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; vestibular dysfunction; drug abuse; nasal congestion; allergic rhinitis; or asthma.
26. A method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the H3 receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of any of claims 1 to 21 or a pharmaceutically acceptable salt thereof.
27. A method for the preparation of a compound of any of claims 1 to 21, comprising the steps of
(a) activating the hydroxy group of the compound of formula (Ia)
Figure imgf000082_0001
wherein R , R , R have the meaning as indicated in any of claims 1 to 21; and
(b) reacting the respective compound with a compound of formula (Ha) or (lib)
Figure imgf000083_0001
(Ha) (lib)
wherein R5, R5a R6, R6a, R7, R8 have the meaning as indicated in any of claims
1 to 21 and R4', R4a', R4b' represent R4, R4a, R4b as indicated in any of claims 1 to 21 to yield a compound of formula (I) or R4 represents a suitable N-atom protecting group, then followed by removal of the protecting group and reacting the liberated amino group with either i) a compound of formula R4=O, wherein the oxo group is attached to a carbon atom of R4, followed by reduction of the resulting imine or ii) with a compound of formula R4-LG, wherein LG is an appropriate leaving group to yield a compound of formula
(I)-
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WO2015073310A1 (en) * 2013-11-12 2015-05-21 Merck Sharp & Dohme Corp. Piperidine or piperazine linked imidazole and triazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug
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