WO2009095394A1 - Diazepanes as histamine h3 receptor antagonists - Google Patents

Diazepanes as histamine h3 receptor antagonists Download PDF

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WO2009095394A1
WO2009095394A1 PCT/EP2009/050920 EP2009050920W WO2009095394A1 WO 2009095394 A1 WO2009095394 A1 WO 2009095394A1 EP 2009050920 W EP2009050920 W EP 2009050920W WO 2009095394 A1 WO2009095394 A1 WO 2009095394A1
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benzyl
methyl
tetrazol
diazepane
cyclobutyl
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PCT/EP2009/050920
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French (fr)
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Adam James Davenport
David James Hallett
Christopher Charles Stimson
Massimo Corsi
Mark Gemkow
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Evotec Neurosciences Gmbh
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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
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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.
  • 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.
  • X 1 , X 2 are independently selected from the group consisting of N; and CH;
  • R 1 is T; Ci -4 alkyl; alkenyl; or C2-4 alkynyl, wherein C 1-4 alkyl; C2-4 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 1 Oa ); 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; C 1-4 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 );
  • R 12 , R 12a , R 12b are independently selected from the group consisting of H; T; C 1-4 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 14 , R 14a , R 14b are independently selected from the group consisting of H; T 1 ; C 1 ⁇ alkyl; C 2 _6 alkenyl; and C 2 _ ⁇ alkynyl, wherein C 1 ⁇ alkyl; C 2 _ ⁇ 5 alkenyl; and C 2 _ ⁇ alkynyl are optionally substituted with one or more R 16 , 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 ; C 1 ⁇ alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C 1 ⁇ alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • T 1 is phenyl; C ⁇ ,. ⁇ 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;
  • 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 ;
  • 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 21 )SO 2 R 21a ; N(R 21 )S(O)R 21a ; N
  • 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 );
  • R 20b , R 20c , R 20d are independently selected from the group consisting of H; T 2 ; C 1 ⁇ 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; C3-7 cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 1 1 membered heterobicyclyl, wherein T 2 is optionally substituted with one or more R 22 , which are the same or different;
  • T 3 is C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 3 is optionally substituted with one or more R 23 , which are the same or different;
  • R 22 , R 23 are independently selected from the group consisting of halogen; CN;
  • N(R 24 )C(O)R 24a ; N(R 24 )S(O) 2 R 24a ; N(R 24 )S(O)R 24a ; N(R 24 )C(O)OR 24a ; N(R 24 )C(O)N(R 24a R 24b ); OC(O)N(R 24 R 24a ); oxo ( 0), where the ring is at least partially saturated; T 4 ; Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl; wherein C 1 ⁇ alkyl; C 2 .
  • 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;
  • 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 _ ⁇ 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 );
  • R 29 , R 29a , R 29b are independently selected from the group consisting of H; Ci_6 alkyl;
  • 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; C3_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 31 , R 31a , R 31b 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 33 , 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 _ ⁇ 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 );
  • R 36 , R 36a , R 36b are independently selected from the group consisting of H; Ci_ 6 alkyl;
  • 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; C3_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 is Ci_5 alkyl; C 2 - 5 alkenyl; C 2 - 5 alkynyl; C3-5 cycloalkyl; CHz-cyclopropyl; CHF- cyclopropyl; CF 2 -cyclopropyl; CH 2 -cyclobutyl; CHF-cyclobutyl; CF 2 -cyclobutyl; or 4 to 5 membered saturated heterocyclyl, wherein Ci .5 alkyl; C 2 -5 alkenyl; C 2 _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; OCH 3 ; OCH 2 F; OCHF 2 ; OCF3; and CN, and wherein C3-5 cycloalkyl; CH 2 -cyclopropyl; CHF-cyclopropyl; CHF-cyclopropyl;
  • CF 2 -cyclopropyl; CH 2 -cyclobutyl; CHF-cyclobutyl; CF 2 -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; OCH 3 ; OCH 2 F; OCHF 2 ; OCF 3 ; CN; CH 3 ; CH 2 F; CHF 2 ; and CF 3 ;
  • R 5 , R 6 , R 7 , R 8 are independently selected from the group consisting of H; C1-5 alkyl; C 2 _ 5 alkenyl; and C 2 _ 5 alkynyl, wherein C 1 - 5 alkyl; C 2 _ 5 alkenyl; and C 2 _s 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 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 7 /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 5 /R 8 , R 4 /R 7 , R 4 /R 8 , R 6 /R 8 are joined together with the seven membered ring 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. - CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -C(CH 3 ) 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.
  • Ci_ 6 alkyl means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: C 1-4 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.
  • 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, -CH 2 -C ⁇ CH, CH 2 -CH 2 -C ⁇ CH, CH 2 -OC-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 "C2-5 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.
  • 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, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine
  • Examples for 8 to 11 membered heterobicycles are imidazo[2,l-b][l,3]oxazole, imidazo[2,l-b][l,3]thiazole, indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydro isoquinoline, dihydro isoquinoline, 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 8 and X 1 , X 2 of formula (I) independently have the following meaning.
  • one or more of the substituents R 1 to R 8 and X 1 , X 2 can have the preferred or more preferred meanings given below.
  • At least one of X 1 , X 2 is N, i.e. X 1 is N and X 2 is CH; X 1 is CH and X 2 is N, or X 1 and X 2 are N. Furthermore, it is preferred that X 1 is CH. Furthermore, it is preferred that X 2 is N. In a more preferred embodiment X 1 is CH and X 2 is N.
  • R 1 is C 1-4 alkyl substituted with one or more R 9 , which are the same or different. In a more preferred embodiment R 1 is C 1-4 alkyl substituted with one R 9 . Even more preferred, R 1 is CH 2 -R 9 ; or CH 2 CH 2 R 9 , even more preferred is CH 2 -R 9 .
  • R 9 i • s 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; C 1 ⁇ alkyl (C 1-4 alkyl more preferred); OH; or O-Ci_6 alkyl (O-C1-4 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; OCH3; or OCF3.
  • 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 .
  • 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 cyclopropyl; cyclobutyl; cyclopentyl; isopropyl; methyl; or ethyl. More preferred is cyclobutyl.
  • R 5 , R 6 , R 7 , R 8 are H.
  • Preferred specific compounds of the present invention are selected from the group consisting of
  • 1,4-diazepane 1 - ⁇ (1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl ⁇ -4-cyclobutyl- 1 ,A- diazepane;
  • 1,4-diazepane methyl [4-( 1 -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)piperidin- 1 - yl] acetate; l-[4-(l-benzyl-lH-tetrazol-5-yl)-l-(lH-imidazol-4-ylacetyl)piperidin-4-yl]-4-cyclobutyl-l,4- diazepane;
  • 1,4-diazepane l- ⁇ 4-(l-benzyl-lH-tetrazol-5-yl)-l-[(5-chloropyridin-2-yl)carbonyl]piperidin-4-yl ⁇ -4- cyclobutyl- 1 ,4-diazepane; 1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -pyrimidm-2-ylpiperidm-4-yl] -4-cyclo butyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(4-ethoxyphenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; l-[4-(l-benzyl-l ⁇ -tetrazol-5-yl)-l-(l,2,3-thiadiazol-4-ylcarbonyl)pipe
  • 1,4-diazepane l-[(l-benzyl-lH-tetrazol-5-yl)(3-methoxyphenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(2-chlorophenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane;
  • 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.
  • 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.
  • Isotopic 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) (Witkin & Nelson (2004) JPET:103; 1 - 20; Hancock & Brune (2005) Exp Opin Inves Drugs: 14 (3), 223 - 241).
  • 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
  • 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. Today more than 20 splice variants
  • 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
  • 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
  • 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. 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 include behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, and others).
  • 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, and
  • gastrointestinal disorders e.g. heartburn
  • vestibular dysfunction e.g. Morbus Meniere, motion sickness, drug abuse
  • nasal congestion e.g. allergic rhinitis (hay fever), asthma.
  • 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, 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 (e.g. heartburn); 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,
  • neurological disorders and pain are preferred.
  • neurological disorders the following is preferred: neurodegenerative disorders, sleep disorders, behavioral/cognitive syndromes.
  • behavioral/cognitive syndromes the following is preferred: hyperactivity disorder, schizophrenia, Mild Cognitive Impairment.
  • 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, 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 (e.g. heartburn); 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,
  • neurological disorders and pain are preferred.
  • neurological disorders the following is preferred: neurodegenerative disorders, sleep disorders, behavioral/cognitive syndromes.
  • behavioral/cognitive syndromes the following is preferred: hyperactivity disorder, schizophrenia, Mild Cognitive Impairment.
  • 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, 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 (e.g. heartburn); vestibular dysfunction (e.g.
  • neurological disorders and pain are preferred.
  • behavioral/cognitive syndromes the following is preferred: hyperactivity disorder, schizophrenia, Mild Cognitive Impairment.
  • 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, dopamine replacement agents, agents that stimulate metabolism of body fat, anti-diabetic agents, lipid lowering agents, anti-stroke 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.
  • 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.
  • another aspect of the present invention is a method for the preparation of a compound of the present invention, wherein one of X 1 , X 2 is CH and the other is N, or alternatively both X 1 , X 2 are CH, comprising the steps of
  • R 1 , R 2 , R 3 have the meaning as indicated above;
  • the amino group may be reacted with an alkyl halide of formula R 4 -halide.
  • another aspect of the present invention is a method for the preparation of a compound of the present invention, wherein X 1 is N and X 2 is N, comprising the step of
  • compounds of formula (I), wherein X 1 is CH and X 2 is N and 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
  • R 4 ' can be R 4 as defined above or a suitable N-atom protecting group such as Boc to yield a compound of formula (I) when R 4 is defined as above.
  • a compound of formula R 4 O, like cyclobutanone, in the presence of an acid such as acetic acid and a reducing agent such as STAB.
  • an acid such as acetic acid
  • a reducing agent such as STAB.
  • the amino group may be reacted with an alkyl halide of formula R 4 -halide 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
  • the method for the preparation of a compound according to the present invention comprises the step of
  • a compound of formula (I), wherein X 1 is N and X 2 is N can be prepared starting from compounds of formula R'-N ⁇ C using a one-pot multi component Ugi-reaction [Ugi, I; Angew. Chem.; 1959, 71, 386] and a compound of formula (VI) 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
  • R 4 O in the presence of an acid such as acetic acid and a reducing agent such as STAB.
  • an acid such as acetic acid
  • a reducing agent such as STAB.
  • the amino group may be reacted with an alkyl halide of formula R 4 -halide to yield compound of formula (I).
  • compounds of formula (I), wherein X 1 is CH and X 2 is CH may be prepared starting from methyl 4-imidazolecarboxylate. Accordingly, the method for the preparation of a compound according to the present invention, comprises the steps of
  • 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], 400 ⁇ g/ml G418 [Sigma, Cat. no. Nl 876] and 250 ⁇ g/ml Zeocin [Invitrogen, Cat. no. 46-0509]) according to the protocol provided by Euroscreen.
  • the assay measures the ability of test compounds to inhibit Histamine receptor agonist- induced decrease of intracellular free cAMP (receptor is G 1 coupled).
  • cAMP quantification assay system from DiscoveRx (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).
  • the plates were emptied by inversion and 7.5 ⁇ l/well of compound in PBS (containing ImM 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.
  • A ⁇ 100 nM
  • B > 100 nM to 500 nM
  • C > 500 nM to 1000 nM
  • D >1000 nM to 2000 nM.
  • Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following instrumentation: Shimadzu, Waters or Micromass ZMD, ZQ or LCT mass spectrometers with an Agilent, Waters or Polymer Labs UV and ELS detector.
  • the HPLC conditions are tabulated below.
  • Micromass MassLynxTM Operating Software with OpenLynxTM Browser were used for data acquisition, processing and reporting.
  • AU 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.
  • reaction mixture was concentrated in vacuo and the resulting residue diluted with dichloromethane (50 ml) and washed with saturated aqueous NaHCCb (20 ml), dried (MgS ⁇ 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 as white solid (705 mg, 68% yield).
  • reaction was stirred for a further 10 minutes then warmed to room temperature and /? ⁇ ra-toluenesulfonyl chloride (119 mg, 0.62 mmol) added in T ⁇ F (2ml).
  • the reaction was stirred at room temperature for a further 10 minutes, after which 1 -eye Io butyl- 1 ,4-diazepane (131 mg, 0.93 mmol) in T ⁇ F (2ml) was added and the reaction mixture stirred for 6Oh.
  • the reaction mixture was concentrated in vacuo and purified by preparative ⁇ PLC to provide the title compound as pale oil (5.5 mg, 2% yield, TFA salt).
  • Example 65 Preparation of: l-[(l-benzyl-lH-[l,2,3,4]tetrazol-5-yl)-[4-(5-methyl- [ 1 ,2,4] oxadiazol)phenyl] methyl-4-cyclobutyl- [ 1 ,4] diazepane. Potency range A

Abstract

The invention relates to compounds of formula (I) wherein R1 to R8 and 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

Diazepanes 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.
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.
Accordingly, the present invention provides compounds of formula (I)
Figure imgf000003_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X1, X2 are independently selected from the group consisting of N; and CH;
R1 is T; Ci-4 alkyl;
Figure imgf000003_0002
alkenyl; or C2-4 alkynyl, wherein C 1-4 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; C1-4 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; C1-4 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(R14R143); 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; C1^ alkyl; C2_6 alkenyl; or C2_6 alkynyl, wherein C1^ 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; C1^ alkyl; C2_6 alkenyl; and C2_β alkynyl, wherein C1^ alkyl; C2_<5 alkenyl; and C2_β 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; C1^ alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1^ 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; Cτ,.η 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(R19R193); 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 C1^ alkyl; C2-6 alkenyl; and C2-β 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 T ;
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(R21)SO2R21a; 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; C1^ 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 1 1 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 C1^ 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 _β 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(R29R293); 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_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;
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(R31R313); S(O)2R31; S(O)R31; N(R31)S(O)2N(R3l3R31b); SR31; N(R31R313); NO2; OC(O)R31; N(R31)C(O)R31a; N(R31)S(O)2R31a; N(R31)S(O)R31a; 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 _β 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(R36R363); 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_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;
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(R38R383); 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 C1^ alkyl; C2_6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R4 is Ci_5 alkyl; C2-5 alkenyl; C2-5 alkynyl; C3-5 cycloalkyl; CHz-cyclopropyl; CHF- cyclopropyl; CF2-cyclopropyl; CH2-cyclobutyl; CHF-cyclobutyl; CF2-cyclobutyl; or 4 to 5 membered saturated heterocyclyl, wherein Ci .5 alkyl; C2 -5 alkenyl; 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; 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;
R5, R6, R7, R8 are independently selected from the group consisting of H; C1-5 alkyl; C2_5 alkenyl; and C2_5 alkynyl, wherein C1-5 alkyl; C2_5 alkenyl; and C2_s 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 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, R7/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, R5/R8, R4/R7, R4/R8, R6/R8 are joined together with the seven membered ring 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.
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.
"Ci_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: C1-4 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-OC-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.
"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(0)-) 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, tetrahydrofuran, 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.
"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, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydro isoquinoline, dihydro isoquinoline, 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 R8 and X1, X2 of formula (I) independently have the following meaning. Hence, one or more of the substituents R1 to R8 and X1 , X2 can have the preferred or more preferred meanings given below.
Preferably, at least one of X1, X2 is N, i.e. X1 is N and X2 is CH; X1 is CH and X2 is N, or X1 and X2 are N. Furthermore, it is preferred that X1 is CH. Furthermore, it is preferred that X2 is N. In a more preferred embodiment X1 is CH and X2 is N.
Preferably, R1 is C1-4 alkyl substituted with one or more R9, which are the same or different. In a more preferred embodiment R1 is C1-4 alkyl substituted with one R9. Even more preferred, R1 is CH2-R9; or CH2CH2R9, even more preferred is CH2-R9.
Preferably, R 9 i •s 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; C1^ alkyl (C1-4 alkyl more preferred); OH; or O-Ci_6 alkyl (O-C1-4 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 T .
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(R24R24"); 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 cyclopropyl; cyclobutyl; cyclopentyl; isopropyl; methyl; or ethyl. More preferred is cyclobutyl.
Preferably, R5, R6, R7, R8 are H.
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-(lH-pyrazol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
1- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -yl)phenyl]methyl} -4-cyclopentyl- 1 ,4- diazepane; l-{(4-benzyl-4Η-l,2,4-triazol-3-yl)[4-(lΗ-l,2,4-triazol-l-yl)phenyl]methyl}-4-cyclobutyl- 1,4-diazepane; l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-bromophenyl)methyl]-4-cyclobutyl-l,4-diazepane;
1 -cyclobutyl-4- { [4-(3-fluorobenzyl)-4H- 1 ,2,4-triazol-3-yl] [4-( 1 H-pyrazol- 1 - ylmethyl)phenyl]methyl} - 1 ,4-diazepane;
1 -cyclobutyl-4- { [4-(3-fluorobenzyl)-4H- 1 ,2,4-triazol-3-yl] [4-( 1 H- 1 ,2,4-triazol- 1 - ylmethyl)phenyl]methyl} - 1 ,4-diazepane; l-cyclobutyl-4- {(4-fluorophenyl)[4-(2-phenylethyl)-4H- 1 ,2,4-triazol-3-yl]methyl} - 1 ,4- diazepane; l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-ethoxyphenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(2-methyl-l,3-thiazol-4-yl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane; l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-cyclopentyl-l,4 diazepane;
1- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl] methyl} -4-cyclobutyl-
1,4-diazepane;
1- {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(lH-pyrazol- 1 -ylmethyl)phenyl]methyl} -4-cyclopentyl- 1,4-diazepane;
4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-cyclobutyl-l ,4-diazepan-l-yl)methyl]-N- methylbenzamide;
1 -[( 1 -benzyl- IH-1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclobutyl- 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H- 1 ,2,3 -triazol-5 -yl) [4-( 1 H-pyrazo 1- 1 -ylmethyl)phenyl]methyl} -4-cyclobutyl- 1,4-diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-morpholin-4-ylphenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(lH-pyrazol-3-yl)methyl]-4-cyclo butyl- 1,4-diazepane;
1 - {(1 -benzyl- 1 Η-tetrazol-5-yl)[4-( 1 H-pyrazo 1- 1 -yl)phenyl]methyl} -4-cyclopentyl- 1 ,4- diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl} -4-cyclopentyl- 1 ,4- diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(morpholin-4-ylmethyl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(4-methylpiperazin- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
4-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl] -N ,N- dimethylbenzenesulfonamide;
1 -cyclobutyl-4- {[ 1 -(3 -fluorobenzyl)- 1 H-tetrazol-5 -yl] [4-( 1 H-pyrazo 1- 1 - ylmethyl)phenyl]methyl} - 1 ,4-diazepane; l-cyclobutyl-4-{[l-(3-fluorobenzyl)-lH-tetrazol-5-yl][4-(lH-l,2,4-triazol-l- ylmethyl)phenyl]methyl} - 1 ,4-diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)phenyl]methyl} -4-cyclobutyl-
1,4-diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,A- diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5-yl)(4-bromophenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 -morpholin-4-ylphenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane; 1 -[( 1 -butyl- 1 H-tetrazol-5-yl)(4-fluorophenyl)methyl]-4-cyc Io butyl- 1 ,4-diazepane; 5-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl] - 1 -methyl- 1 H- benzotriazole;
1 - {4- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)methyl]phenyl}pyrrolidin- 2-one; 2-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cy clobutyl- 1 ,4-diazepan- 1 -yl)methyl]imidazo [1,2- ajpyridine;
6-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]imidazo[l ,2- a]pyridine; 2-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]thieno[2,3-b]pyridine; 5-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl] - 1 -methyl- 1 H-indo Ie; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-piperidin- 1 -ylpyridin-2-yl)methyl] -4-cyclobutyl- 1 ,4- diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 - {( 1 -benzyl- 1 H-tetrazol-5-yl) [3 -(difluoromethoxy)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H-pyrazol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(5 -methylisoxazo 1-3 -yl)methyl] -4-cyclobutyl- 1 ,4-diazepane; l-{(l-benzyl-lH-tetrazol-5-yl)[3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl]methyl}-4- cyclobutyl- 1 ,4-diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[3-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H-pyrazol- 1 -ylmethyl)phenyl]methyl} -4-cyclobutyl- 1 ,A- diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[3-( 1 H-pyrazol- 1 -ylmethyl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 2-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]quino line; 3-[( 1 -benzyl- 1 H-tetrazol-5-yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]quinoline; 1 -
[( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-tert-butoxypyridin-3 -yl)methyl] -4-cyclobutyl- 1 ,4-diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5-yl)(2,3-dihydro- 1 ,4-benzodioxin-6-yl)methyl]-4-cyclo butyl- 1 ,4- diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5-yl)(l -methyl- lH-imidazol-2-yl)methyl]-4-cyclobutyl- 1 ,4- diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(methylsulfonyl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[3-( 1 H-pyrrol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-2,l,3-benzoxadiazole; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-pyrrolidin- 1 -ylpyridin-3-yl)methyl] -4-cyclobutyl- 1 ,4- diazepane; 1 - {(1 -benzyl- lH-tetrazol-5-yl)[4-(pyrimidin-2-yloxy)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
5-[(l-benzyl-lΗ-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-2,l,3- benzothiadiazole;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 ,2,3-thiadiazol-4-yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 6-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]imidazo[2, 1 - b][l,3]tbiazole;
1 -[( 1 -benzyl- 1 H-tetrazol-5-yl)(2,3-dihydro- 1 -benzofuran-5-yl)methyl]-4-cyclo butyl- 1 ,4- diazepane; 6-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]- 1 H-indole; 5-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]pyridin-2-o 1; 7-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]pyrazo Io [ 1 ,5 - a]pyridine;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(difluoromethoxy)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-methylpyridin-2-yl)methyl] -4-cyclobutyl- 1 ,4-diazepane; 1 -[( 1 -benzyl- lH-[ 1 ,2,3 ,4]tetrazol-5-yl)-[4-(5-methyl-[ 1 ,2,4]oxadiazol)phenyl]methyl-4- cyclobutyl- [1,4] diazep ane;
1 - {(1 -benzyl- 1 Η-tetrazol-5-yl)[4-(2-methyl- 1 H-imidazol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1,4-diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl) {4- [(4-methylpiperazin- 1 -yl)methyl]phenyl} methyl] -A- cyclobutyl- 1 ,4-diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(pyridin-2-yloxy)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H-pyrazol- 1 -ylmethyl)phenyl]methyl} -4-cyclopentyl- 1 ,4- diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)phenyl]methyl} -4-cyclopentyl- 1,4-diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(methylsulfonyl)phenyl]methyl} -4-cyclopentyl- 1 ,A- diazepane;
1 - {4- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclopentyl- 1 ,4-diazepan- 1 -yl)methyl]phenyl}pyrrolidin-
2-one;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-fluorophenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(6-phenoxypyridm-3-yl)methyl]-4-cyclo butyl- 1 ,4-diazepane; 1 -[( 1 -benzyl- 1 Η-tetrazol-5 -yl)(l -methyl- 1 Η-pyrazol-4-yl)methyl] -4-cyclobutyl- 1 ,4- diazepane; l-[l-benzofuran-5-yl(l-benzyl-lH-tetrazol-5-yl)methyl]-4-cyclo butyl- 1 ,4-diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(pyridin-3 -yl)methyl] -4-cyclobutyl- 1 ,4-diazepane; l-cyclobutyl-4-[(4-fluorophenyl){l-[4-(trifluoromethoxy)benzyl]-lH-tetrazol-5-yl}methyl]- 1,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(2,2-difluoro-l,3-benzodioxol-5-yl)methyl]-4-cyclobutyl-l,4- diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(l -oxidopyridin-4-yl)methyl] -4-cyclobutyl- 1 ,4-diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -(6-fluoropyridin-2-yl)piperidin-4-yl] -4-cyclobutyl- 1 ,4- diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(6-morpholin-4-ylpyridm-3-yl)methyl]-4-cyclo butyl- 1,4- diazepane;
1 -[( 1 -benzyl- lH-tetrazol-5-yl)(2 -methyl- IH- imidazol-4-yl)methyl]-4-cyclo butyl- 1 ,4- diazepane; 1 - {(1 -benzyl- 1 Η-tetrazol-5-yl)[4-( 1 H-pyrrol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
1 - {(1 -benzyl- lH-tetrazol-5-yl)[4-(trifluoromethoxy)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(2-methyl- 1 ,3-thiazol-4-yl)phenyl]methyl} -4-cyclobutyl-
1,4-diazepane;
1 -cyclobutyl-4- [(4-fluorophenyl) { 1 -[( 1 S)- 1 -phenylethyl] - 1 H-tetrazol-5-yl}methyl] -1,4- diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(6-thiomorpholin-4-ylpyridin-3-yl)methyl]-4-cyclo butyl- 1,4- diazepane;
5-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl] -N,N-diethylpyridin-2- amine;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 -fluorophenyl)methyl] -4-cyclo butyl- 1 ,4-diazepane; 1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(phenyl)methyl] -4-cyclo butyl- 1 ,4-diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 ,4-dichlorophenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane;
1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(trifluoromethyl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
5-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]- 1 H-indole; 6-[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]quino line;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 ,5-dimethylphenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-chloro-3 -fluorophenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(6-chloropyridm-3-yl)methyl]-4-cyclo butyl- 1 ,4-diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(5 -bromopyridin-3 -yl)methyl] -4-cyclobutyl- 1 ,4-diazepane; l-[4-(l -benzyl- 1 H-tetrazol-5 -yl)tetrahydro-2H-pyran-4-yl] -4-cyclobutyl- 1 ,4-diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl]-4-cyclopentyl- 1 ,4-diazepane; l-[l-acetyl-4-(l-benzyl-lH-tetrazol-5-yl)piperidin-4-yl]-4-cyclo butyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(4-fluorophenyl)metriyl]-4-metliyl-l,4-diazepane;
1 -[( 1 -benzyl- lH-tetrazol-5-yl)(4-methoxyphenyl)methyl]-4-methyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(4-fluorophenyl)metriyl]-4-etriyl-l,4-diazepane;
1 -[( 1 -benzyl- lH-tetrazol-5-yl)(4-methoxyphenyl)methyl]-4-ethyl- 1 ,4-diazepane;
1 -ethyl-4- {(4-fluorophenyl) [ 1 -(4-methoxybenzyl)- lH-tetrazol-5-yl]methyl} - 1 ,4-diazepane;
1 -ethyl-4- { [ 1 -(3-fluorobenzyl)- lH-tetrazol-5 -yl] (4-fluorophenyl)methyl} - 1 ,4-diazepane;
1 - {[ 1 -(3-fluorobenzyl)- lH-tetrazol-5-yl](4-fluorophenyl)methyl} -4-methyl- 1 ,4-diazepane; l-{[l-(4-chlorobenzyl)-lH-tetrazol-5-yl](4-fluorophenyl)methyl}-4-ethyl-l,4-diazepane;
1 -ethyl-4- [(4-fluorophenyl) { 1 -[4-(trifluoromethoxy)benzyl]- lH-tetrazol-5-yl}methyl]- 1 ,4- diazepane;
1 -cyclobutyl-4- { [ 1 -(3-fluorobenzyl)- lH-tetrazol-5 -yl](4-fluorophenyl)methyl} - 1 ,4-diazepane; 1 -cyclopentyl-4- { [ 1 -(3 -fluorobenzyl)- lH-tetrazol-5 -yl](4-fluorophenyl)methyl} -1,4- diazepane;
1 -[ 1 -( 1 -benzyl- lH-tetrazol-5-yl)cyclohexyl]-4-ethyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(4-fluorophenyl)methyl]-4-cyclopentyl-l,4-diazepane; 1 -[ 1 -( 1 -benzyl- lH-tetrazol-5-yl)cyclohexyl]-4-cyclopentyl- 1 ,4-diazepane; l-[4-(l-benzyl-lH-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl]-4-ethyl-l,4-diazepane;
1 -[ 1 -( 1 -benzyl- lH-tetrazol-5 -yl)cyclopentyl] -4-ethyl- 1 ,4-diazepane;
1. {3.( 1 -benzyl- 1 Η-tetrazol-5-yl)- 1 - [( 1 -methyl- 1 H-imidazol-2-yl)methyl]azetidin-3-yl} -A- cyclobutyl- 1 ,4-diazepane; l-{3-(l-benzyl-lH-tetrazol-5-yl)-l-[(l-methyl-lH-imidazol-2-yl)methyl]piperidin-3-yl}-4- cyclobutyl- 1 ,4-diazepane;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -[( 1 -methyl- 1 H-pyrazo 1-5 -yl)sulfonyl]piperidin-4-yl} -4- cyclobutyl- 1 ,4-diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -(methylsulfonyl)piperidin-4-yl] -4-cyclobutyl- 1,4- diazepane;
4-( 1 -benzyl- 1 H-tetrazo 1-5 -yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)-N,N-dimethylpiperidine- 1 - sulfonamide;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - [( 1 -methyl- 1 H-pyrazo l-4-yl)methyl]piperidin-4-yl} -A- cyclobutyl- 1 ,4-diazepane; l-{4-(l-benzyl-lH-tetrazol-5-yl)-l-[(l-methyl-lH-pyrazol-5-yl)methyl]piperidin-4-yl}-4- cyclobutyl- 1 ,4-diazepane;
1 - {3 -( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - [( 1 -methyl- 1 H-imidazol-2-yl)methyl]pyrrolidin-3 -yl} -A- cyclobutyl- 1 ,4-diazepane;
1 -[3-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -ylacetyl)pyrrolidin-3 -yl] -4-cyclobutyl- 1,4-diazepane;
4-(l -benzyl- 1 H-tetrazol-5 -yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)-N-ethylpiperidine- 1 - carboxamide;
4-(l -benzyl- 1 H-tetrazol-5 -yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)-N-phenylpiperidine- 1 - carboxamide; l-[3-(l-benzyl-lH-tetrazol-5-yl)-l-(lH-l,2,4-triazol-l-ylacetyl)azetidin-3-yl]-4-cyclobutyl-
1,4-diazepane;
1 -cyclobutyl-4- { [ 1 -(4-fluorobenzyl)- 1 H-tetrazol-5 -yl](4-fluorophenyl)methyl} - 1 ,4-diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-pyridin-2-ylphenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane; 1 - {(1 -benzyl- 1 H-tetrazol-5-yl)[4-(4-methyl- 1 ,2,5-oxadiazol-3-yl)phenyl]methyl} -A- cyclobutyl- 1 ,4-diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -(1 ,3-tbiazol-2-ylmethyl)piperidin-4-yl]-4-cyc Io butyl- 1 ,4- diazepane; l-[4-(l-benzyl-lH-tetrazol-5-yl)-l-(lH-imidazol-2-ylmethyl)piperidin-4-yl]-4-cyclobutyl-l,4- diazepane; tert-butyl 4-(l -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)piperidine- 1 - carboxylate;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5-yl)piperidin-4-yl]-4-cyc Io butyl- 1 ,4-diazepane; 1 - {4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - [( 1 -methyl- 1 H-imidazol-2-yl)methyl]piperidin-4-yl} -A- cyclobutyl- 1 ,4-diazepane;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - [(2-methyl- 1 H-imidazol-4-yl)methyl]piperidin-4-yl} -A- cyclobutyl- 1 ,4-diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -( 1 H-pyrazo 1-3 -ylmethyl)piperidin-4-yl] -4-cyclobutyl- 1 ,4- diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -(1 ,3-thiazol-5-ylmethyl)piperidm-4-yl]-4-cyc Io butyl- 1 ,4- diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -(1 ,2,3-thiadiazol-4-ylmethyl)piperidin-4-yl]-4-cyclobutyl-
1,4-diazepane; l-[4-(l-benzyl-lH-tetrazol-5-yl)-l-(lH-pyrazol-4-ylcarbonyl)piperidin-4-yl]-4-cyclobutyl-
1,4-diazepane; methyl [4-( 1 -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)piperidin- 1 - yl] acetate; l-[4-(l-benzyl-lH-tetrazol-5-yl)-l-(lH-imidazol-4-ylacetyl)piperidin-4-yl]-4-cyclobutyl-l,4- diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -(phenylcarbonyl)piperidin-4-yl]-4-cyclobutyl- 1 ,4- diazepane; methyl 3-[4-(l -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)piperidin- 1 - yl]propanoate; 2-[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)-4-(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)piperidin- 1 -yl] -N- methylacetamide; l-[3-(l-benzyl-lH-tetrazol-5-yl)piperidin-3-yl]-4-cyclo butyl- 1 ,4-diazepane;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - [( 1 -methyl- 1 H-imidazol-2-yl)carbonyl]piperidin-4-yl} -A- cyclobutyl- 1 ,4-diazepane; 1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -( 1 H-imidazol-2-ylcarbonyl)piperidin-4-yl] -4-cyclobutyl-
1,4-diazepane; l-{4-(l-benzyl-lH-tetrazol-5-yl)-l-[(5-chloropyridin-2-yl)carbonyl]piperidin-4-yl}-4- cyclobutyl- 1 ,4-diazepane; 1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -pyrimidm-2-ylpiperidm-4-yl] -4-cyclo butyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(4-ethoxyphenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; l-[4-(l-benzyl-lΗ-tetrazol-5-yl)-l-(l,2,3-thiadiazol-4-ylcarbonyl)piperidin-4-yl]-4- cyclobutyl- 1 ,4-diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -(phenylsulfonyl)piperidin-4-yl] -4-cyclobutyl- 1 ,4- diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -ylacetyl)piperidin-4-yl] -4-cyclobutyl-
1,4-diazepane;
1 -[4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -( 1 H-imidazol-4-ylcarbonyl)piperidin-4-yl] -4-cyclobutyl-
1,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(3-methoxyphenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(2-chlorophenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane;
1 - {3 -( 1 -benzyl- 1 Η-tetrazol-5-yl)- 1 - [( 1 -methyl- 1 H-imidazol-2-yl)carbonyl]piperidin-3-yl} -4- cyclobutyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(pyridin-4-yl)methyl]-4-cyclobutyl-l,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(3-chlorophenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane;
1 - {(1 -benzyl- lH-tetrazol-5-yl)[4-( 1 -methylethyl)phenyl]methyl} -4-cyclobutyl- 1 ,4-diazepane;
1 -[( 1 -benzyl- 1 Η-tetrazol-5 -yl)(4-chlorophenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane;
4-[( 1 -benzyl- 1 Η-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl] -N-phenylbenzamide;
4-[( 1 -benzyl- 1 Η-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl] -N-methylbenzamide; 4-[( 1 -benzyl- 1 Η-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]benzamide;
N- {5 - [( 1 -benzyl- 1 Η-tetrazol-5 -yl)(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)methyl]pyridin-2- yljacetamide;
N- {5 -[( 1 -benzyl- 1 Η-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]pyridin-2-yl} -2- methylpropanamide; l-[l-(l-benzyl-lΗ-tetrazol-5-yl)-4-(lΗ-pyrazol-l-yl)butyl]-4-cyclobutyl-l,4-diazepane.
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 imgf000023_0001
Isotopic 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
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, and
other disorders, i.e. gastrointestinal disorders (e.g. heartburn), vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse), nasal congestion, allergic rhinitis (hay fever), asthma.
With regard to the abovementioned diseases and disorders neurological disorders and pain are preferred. For neurological disorders the following is preferred: neurodegenerative disorders, sleep disorders, behavioral/cognitive syndromes. For behavioral/cognitive syndromes the following is preferred: hyperactivity disorder, schizophrenia, Mild Cognitive Impairment. 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, 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 (e.g. heartburn); vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse); nasal congestion; allergic rhinitis (hay fever); or asthma. With regard to the abovementioned diseases and disorders neurological disorders and pain are preferred. For neurological disorders the following is preferred: neurodegenerative disorders, sleep disorders, behavioral/cognitive syndromes. For behavioral/cognitive syndromes the following is preferred: hyperactivity disorder, schizophrenia, Mild Cognitive Impairment.
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, 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 (e.g. heartburn); vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse); nasal congestion; allergic rhinitis (hay fever); or asthma. With regard to the abovementioned diseases and disorders neurological disorders and pain are preferred. For neurological disorders the following is preferred: neurodegenerative disorders, sleep disorders, behavioral/cognitive syndromes. For behavioral/cognitive syndromes the following is preferred: hyperactivity disorder, schizophrenia, Mild Cognitive Impairment.
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, 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 (e.g. heartburn); 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. With regard to the abovementioned diseases and disorders neurological disorders and pain are preferred. For neurological disorders the following is preferred: neurodegenerative disorders, sleep disorders, behavioral/cognitive syndromes. For behavioral/cognitive syndromes the following is preferred: hyperactivity disorder, schizophrenia, Mild Cognitive Impairment.
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, dopamine replacement agents, agents that stimulate metabolism of body fat, anti-diabetic agents, lipid lowering agents, anti-stroke 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.
For compounds of formula (I), wherein one of X1, X2 is CH and the other is N, suitable starting materials of formula (Ia) and (V) may be used.
Accordingly, another aspect of the present invention is a method for the preparation of a compound of the present invention, wherein one of X1, X2 is CH and the other is N, or alternatively both X1 , X2 are CH, comprising the steps of
(a) activating the hydroxy group of the compound of formula (Ia)
Figure imgf000032_0001
wherein R1, R2, R3 have the meaning as indicated above; and
(b) reacting the respective compound with a compound of formula (V)
Figure imgf000032_0002
wherein R5, R6, R7, R8 have the meaning as indicated above and R4 is R4 as indicated in above or a 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 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. Alternatively, the amino group may be reacted with an alkyl halide of formula R4 -halide.
In case X1 and X2 are N a one pot reaction may be used with R^N+Nr, (R2R3)C=O, TMSN3 and a compound of formula (V) as starting materials. Accordingly, another aspect of the present invention is a method for the preparation of a compound of the present invention, wherein X1 is N and X2 is N, comprising the step of
• reacting a compound of formula R'-N ≡C, a compound of formula (R2R3)C=O, wherein R1, R2, R3 have the meaning as indicated above, with a compound of formula
(V) as indicated above in the presence of trimethylsilyl azide in a one pot reaction to yield a compound of formula (I), optionally after removal of the protecting group and reacting the liberated amino group with 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. Alternatively, the amino group may be reacted with an alkyl halide of formula
R4-halide.
More specifically, compounds of formula (I), wherein X1 is CH and X2 is N and 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 R1NE^ under acidic catalysis by reagents such as p-TsOH to yield compounds of formula (III)
Figure imgf000033_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 imgf000033_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 PPI13 or para- toluenesulfonyl chloride, respectively and reacting the resulting compound with a compound of formula (V)
Figure imgf000034_0001
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) when R4 is defined as above.
Compounds of formula (V) are either commercially available or can be prepared by the two step process of reacting a compound of formula (VI)
Figure imgf000034_0002
with a compound of formula R4=O, like cyclobutanone, in the presence of an acid such as acetic acid and a reducing agent such as STAB. Alternatively the amino group may be reacted with an alkyl halide of formula R4-halide followed by cleavage of the Boc protecting group in strong acid (HCl or TFA).
In the case when R4' of formula (V) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (VII)
Figure imgf000034_0003
requires the additional step of deprotecting the compound of formula (VII) at the nitrogen atom and then the resulting unprotected compound may be reacted with R4=O in the presence of an acid such as acetc acid and a reducing agent such as STAB. Alternatively the amino group may be reacted with an alkyl halide of formula R4-halide 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 reacting the resulting intermediate withparα-toluenesulfonyl chloride and then reacting this in situ formed intermediate with a compound of formula (V) to yield a compound of formula (I).
In general, compounds of formula (I), wherein X1 is N and X2 is N and wherein the variables have the above described meanings (unless otherwise specifically indicated) may be prepared starting from compounds of formula R'-N ≡C" using a one-pot multi component Ugi-reaction [Ugi, I; Angew. Chem.; 1959, 71, 386]
Accordingly, the method for the preparation of a compound according to the present invention, comprises the step of
reacting a compound of formula R^N+=C", TMS-azide, a compound of formula
(R > 2r R>3 )C=O and a compound of formula (V) to yield a compound of formula (I).
Alternatively, a compound of formula (I), wherein X1 is N and X2 is N can be prepared starting from compounds of formula R'-N ≡C using a one-pot multi component Ugi-reaction [Ugi, I; Angew. Chem.; 1959, 71, 386] and a compound of formula (VI) above, wherein the method comprises the steps of
- reacting a compound of formula R'-N ≡C", TMS-azide, a compound of formula
(R2R3)C=O and a compound of formula (VI) to yield a compound of formula (VIII)
Figure imgf000036_0001
deprotecting compound of formula (VIII) at the nitrogen atom and reacting the resulting compound with R4=O in the presence of an acid such as acetic acid and a reducing agent such as STAB. Alternatively the amino group may be reacted with an alkyl halide of formula R4-halide 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 imgf000036_0002
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 imgf000036_0003
reacting magnesium with a compound of formula R2R3-halogen and treating the resulting Grignard compound with a compound of formula (X) to yield compound of formula (XI)
Figure imgf000037_0001
conversion of the alcohol group of formula (XI) to a suitable leaving group (Cl, Br, OTs etc) and reacting the resulting compound with a compound of formula (V) to yield compound of formula (I).
Alternatively compounds of formula (I), wherein X1 is N and X2 is CH, may be prepared by conversion of the alcohol group of formula (XI) to a suitable leaving group (Cl, Br, OTs etc) and reacting the resulting compound with a compound of formula (VI) to yield compound of formula (XII)
Figure imgf000037_0002
and deprotecting compound formula (XII) and reacting the resulting compound with
R4=O in the presence of an acid such as acetic acid and a reducing agent such as STAB. Alternatively the amino group may be reacted with an alkyl halide of formula R4-halide to yield compound of formula (I).
In particular, compounds of formula (I), wherein X1 is CH and X2 is CH, may be prepared starting from methyl 4-imidazolecarboxylate. Accordingly, the method for the preparation of a compound according to the present invention, comprises the steps of
- reacting methyl 4-imidazolecarboxylate with R!-halogen under basic conditions such as 33% NaOH aqueous to yield a compound of formula (XIII)
Figure imgf000038_0001
ester group reduction of a compound of formula (XIII) and reacting the resulting compound with an oxidising agent such as IBX to yield a compound of formula (XIV)
Figure imgf000038_0002
- reacting magnesium with a compound of formula R2R3-halogen and treating the resulting Grignard compound with a compound of formula (XIV) to yield compound of formula (XV)
Figure imgf000038_0003
- conversion of the alcohol group of formula (XV) to a suitable leaving group (Cl,
Br, OTs etc) and reacting the resulting compound with a compound of formula (V) to yield compound of formula (I).
Alternatively compounds of formula (I), wherein X1 is CH and X2 is CH, may be prepared by conversion of the alcohol group of formula (XV) to a suitable leaving group (Cl, Br, OTs etc) and reacting the resulting compound with a compound of formula (VI) to yield compound of formula (XVI)
Figure imgf000039_0001
and deprotecting compound formula (XVI) and reacting the resulting compound with R4=0 in the presence of an acid such as acetic acid and a reducing agent such as STAB. Alternatively the amino group may be reacted with an alkyl halide of formula R4-halide to yield compound of formula (I).
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 DiscoveRx (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 (IC5O values):
A: < 100 nM; B: > 100 nM to 500 nM; C: > 500 nM to 1000 nM; D: >1000 nM to 2000 nM.
Synthesis of compounds:
ANALYTICAL METHODS
NMR Spectrometers Used: Bruker AVANCE 400 MHz NMR Bruker DPX 250 MHz NMR Bruker DPX 360 MHz NMR
LCMS methods used
Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following instrumentation: Shimadzu, Waters or Micromass ZMD, ZQ or LCT mass spectrometers with an Agilent, Waters or Polymer Labs UV and ELS detector. The HPLC conditions are tabulated below. Micromass MassLynx™ Operating Software with OpenLynx™ Browser were used for data acquisition, processing and reporting.
LCMS Method A LCMS Method B
Column Waters Atlantis dC18 Waters Atlantis dC18
2.1 x 50mm, 5μm 100 x 2.1 mm, 3 μm
Mobile phase A = Formic Acid (aq) A = Formic Acid (aq)
0.1% 0.1%
B = Formic Acid B = Formic Acid
(acetonitrile) 0.1% (acetonitrile) 0.1%
Preparative HPLC Methods Used: Prep Method 1
Waters SunFire Prep C18 Column
OBD 5um 19 x 100mm
A, TFA (aq) 0.1 % Mobile Phase
B, TFA (CH3CN) 0.1%
Prep Method 2
Phenomenex Gemini C18 Column
AXIA 5u 100 x 21.2mm
A, 2mM amm. bicarbonate, buffered to pH10 Mobile Phase
B, Acetonitrile:2mM amm. bicarbonate 95:5 Prep Method 3
Waters SunFire Prep C18
Column
OOBBDD 55uumm 1199 xx 11000( mm
A, TFA (aq) 0 1 % Mobile Phase
B, TFA (CH3CN) 0.1%
Compound Naming
AU 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 tert-butoxycarbonyl cat catalytic
CDI 1 , 1 '-carbonyldiimidazole
Chloroform-ύ? deuterated chloroform
CDCl3 deuterated chloroform
DCE 1 ,2-dichloroethane
DCM dichloromethane
DIPEA N,N-diisopropylethylamine
DMAP N,N-4-dimethylaminopyridine eq equivalent
Ether diethyl ether
Et2O diethyl ether
EtOAc ethyl acetate
EtOH ethanol
FCC flash column chromatography h hours
HCl hydrochloric acid HOBt 1 -hydroxybenzotriazo Ie
HBTU o-benzotriazo 1- 1 -yl-N,N,N" ,NΛ -tetramethyluronium tetrafluoroborate
IBX 1 -hydroxy-1 ,2-benziodoxol-3(lh)-one 1 -oxide
LAH lithium aluminium hydride
LCMS liquid chromatography and mass spectrometry
MeCN acetonitrile
MeOH methanol
MeOD dueterated methanol m multiplet min(s) minute(s) mL millilitre mol/M mole/molar
MW molecular weight
NMR nuclear magnetic resonance
PBr3 tribromophospine
PMA phosphomolibdic acid
PPh3 triphenylphosphine
PS-DIPEA polymer-supported N,N-diisopropylethylamine
Rt retention time
RT room temperature
STAB sodium triacetoxyborohydride
TBAF tetra-rø-butylammonium fluoride
TBAI tetra-n-butylammonium iodide
TBDMSCl tert-butyldimethylsilyl chloride
TEA triethylamine
TFA 2,2,2-trifluoroacetic acid
TFE 2,2,2-trifluoroethanol
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
Route 1 General procedure A General procedure B
2. 4M HCI in dioxane 1. DCE, Ketone/aldehyde DCM ; Me0H j V AcOH, STAB, RT / y r, Amherςpn rpςin / \ b0C ^N NH *■ b0C ^N N 'R4 HN N ' R4
Scheme 1: Describes a general route to the products R4 = CH2CH3, CH(CH3)2, cyclobutyl, cyclopentyl
General procedure A: Preparation of 4-{cyclo}alkyl-[l,4]diazepane-l-carboxylic acid tert-butyl esters
4-cyclobutyl-l,4-diazepane-l-carboxylate
Figure imgf000044_0001
To a stirred solution of [l,4]diazepane-l-carboxylic acid ter^-butyl ester (5 g, 24.97 mmol) in DCE (70 ml) at 20 to 25 0C was added cyclobutanone (1.75 g, 24.97 mmol) followed by acetic acid (1.5 g, 24.97 mmol) dropwise. The resulting mixture was stirred at 20 to 25 0C for ca. 2 h. Sodium triacetoxyborohydride (7.94 g, 37.46 mmol) was added in 9 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 NaHCO3 (80 mL) was added in four portions and the biphasic mixture stirred at 20 to 25 0C for ca. 1A h. The organic layer was separated, washed with water (20 mL) and the aqueous phase back extracted at pH 9 with DCM (20 mL). The combined organic phases were dried (Na2SC^), filtered and concentrated in vacuo to provide the title compound as yellow oil (6.1 g, 96%).
LCMS data: Calculated MH+ (255); Found 100% [2(M-Boc)]H+ m/z (307), Rt = 1.4 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 3.38 - 3.52 (4 H, m), 2.86 - 2.98 (1 H, m), 2.40 - 2.54 (4 H, m), 2.02 - 2.12 (2 H, m), 1.77 - 1.92 (4 H, m), 1.61 - 1.75 (2 H, m), 1.46 (9 H, s).
General procedure B; Preparation of l-{cyclo}alkyl-[l,4]diazepanes
Preparation of l-cyclobutyl-l,4-diazepane HN -O
To a stirred solution of tert-butyl 4-cyclo butyl- 1 ,4-diazepane- 1 -carboxylate (6.1 g, 23.98 mmol) in DCM (70 ml) at 20 to 25 0C was added a solution of 4M HCl in dioxane (30 mL, 120 mmol) dropwise. The resulting mixture was stirred at 20 to 25 0C for ca. 2h. MeOH (6 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 (100 mL) for 0.5 h. The solvent was evaporated and the residue slurried in ether/MeOH (10: 1, 66 mL). The resulting white solid was collected by filtration, suspended in DCM (150 mL) and treated with 2M NaOH. 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 as orange oil (2.67 g, 73%). LCMS data: Calculated MH+ (155); Found 100% (MH+) m/z 155, Rt = 0.44 min. NMR data: 1H NMR (400 MHz, Chloroform-J) δ ppm 2.85 - 2.97 (5 H, m), 2.43 - 2.53 (4 H, m), 1.97 - 2.08 (2 H, m), 1.52 - 1.91 (7 H, m).
The following intermediate was prepared as described in Route 1, General Procedure A above.
Preparation of tert-butyl 4-cyclopentyl-l,4-diazepane-l-carboxylate
Figure imgf000045_0001
In a similar fashion (Rl, GP A), cyclopentanone (1.36 mL, 15 mmol), gave the title compound (3.68g, 91% yield) as clear pale yellow oil. LCMS data: Calculated MH+ (269); Found 98% [(M-Boc)]H+ m/z (213), Rt = 1.4 mins.
NMR data: 1H NMR (400 MHz, Chloroform- d) δ ppm 1.24 - 1.35 (2 H, m), 1.37 (9 H, s), 1.42 - 1.49 (2 H, m), 1.53 - 1.66 (4 H, m), 1.97 - 2.08 (2 H, m), 1.69 - 1.84 (4 H, m), 2.55 - 2.67 (4 H, m), 2.73 - 2.85 (1 H, m), 3.33- 3.47 (4 H, m).
The following intermediate was prepared as described in Route 1, General Procedure B above. Preparation of l-cyclopentyl-l,4-diazepane
HN -O
In a similar fashion (Rl, GP B), tert-butyl 4-cyclopentyl-l,4-diazepane-l-carboxylate (3.68g, 13.7 mmol), gave the title compound (1.96 g, 85% yield) as pale yellow semi-solid. LCMS data: Calculated MH+ (169); Found 100% (MH+) m/z 169, Rt = 0.25 min.
NMR data: 1H NMR (400 MHz, Chloroform-J) δ ppm 2.73 - 2.84 (5 H, m), 2.53 - 2.62 (4 H, m), 1.56 - 1.76 (4 H, m), 1.16 - 1.56 (6 H, m).
Route 2
°
Figure imgf000046_0001
General proceudure E
Figure imgf000046_0002
Scheme 2: Preparation of l-[(4-(alkyl-aryl-4H-[l,2,4]triazol-3-yl)-(aryl)-methyl]-4- (cyclo)alkyl-[ 1 ,4]diazepanes
Preparation of Λ^-[(l£)-(dimethylamino)methylidene] -TV^V- dimethylhydrazonoformamide bis hydrochloride
,NMe,
Me2N
.2HCI
To a stirred solution of 1 ,2-diformylhydrazine (12 g, 136.27 mmol) in DMF (270 ml) was added thionyl chloride (24.6 mL, 338 mmol) dropwise, keeping the temperature of the mixture between 10 and 15 0C. The resulting mixture was stirred at 10 0C until gas emission ceased and then it was allowed to warm to 20 to 25 0C under stirring. [NB: reaction is exothermic and gas emission quenched with a IM NaOH solution placed in scrubber container]. Precipitation of a white solid occurred and the resulting fine slurry was stirred at 20 to 25 0C for 2 days. The slurry was filtered under suction and the solid was washed with ether (5 x 100 mL) and dried in vacuo to provide the title compound as white solid (28.3 g,
96.6 % yield).
LCMS data: Calculated MH+ (143); Found, 100% (MH+) m/z 143, Rt 0.27 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.63 (2 H, s), 3.40 (6 H, br. s.), 3.24 (6 H, br.s).
General procedure C; Preparation of 4-substituted-4H-[l,2,4]triazoles
Preparation of 4-benzyl-4H-l,2,4-triazole
Figure imgf000047_0001
To a stirred suspension of jV-[(l£)-(dimethylamino)methylidene]-N,N- dimethylhydrazonoformamide bis hydrochloride (3.1 g, 14.41 mmol) in toluene (31 ml) was added dropwise benzyl amine (1.62 g, 15.13 mmol) followed by 4-methylbenzenesulfonic acid (0.15 g, 0.81 mmol) in one portion. The mixture was stirred for ca. 10 mins at 20 to 25 0C, and then heated to reflux (105 to 110 0C) for 12 h. The solvent was then evaporated and the residue partitioned between DCM (70 mL) and brine (30 mL). The organic phase was collected, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (2.2 g, 96% yield) as pale yellow solid.
LCMS data: Calculated MΗ+ (160); Found 100% (MH+) m/z 160.3, Rt 1.12 - 1.15 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.57 (2 H, s), 7.29 - 7.45 (5 H, m), 5.32 (2 H, s).
The following intermediates were prepared as described in Route 2, General Procedure C above.
Preparation of 4-(2-phenylethyl)-4H-l,2,4-triazole r
CJ NN^ΛN In a similar fashion (R2, GP C) N<-[(lJ£)-(dimethylamino)methylidene]-N,N- dimethylhydrazonoformamide bis hydrochloride (8.50 g, 39.72 mmol) and 2-phenylethyl amine (4.81 g, 39.72 mmol) gave the title compound (1.51 g, 22% yield) as off-white solid. LCMS data: Calculated MH+ (174); Found 100% (MH+) m/z 174, Rt 1.14 mins. ΝMR data: 1H ΝMR (400 MHz, MeOD) δ ppm 8.15 (1 H, s), 7.40 (2 H, dd, J=8.3, 5.4 Hz), 7.19 - 7.29 (3 H, m), 7.08 - 7.16 (2 H, m), 6.99 - 7.05 (2 H, m), 6.02 (IH, s), 4.16 - 4.33 (2 H, m), 2.83 (2 H, t, J=7.3 Hz)
The following intermediates were prepared as described in Route 2, General Procedure C above.
Preparation of 4-(3-fluorobenzyl)-4H-l,2,4-triazole
Figure imgf000048_0001
In a similar fashion (R2, GP C), N'-[(lJ£)-(dimethylamino)methylidene]-N,N- dimethylhydrazonoformamide bis hydrochloride (7.0 g, 32.5 mmol) and l-(3- fiuorophenyl)methanamine (3.9 ml, 34.2 mmol) gave the title compound (3.4 g, 61%) as pale yellow solid. LCMS data: Calculated MH+ (178); Found 100% (MH+) m/z 178, Rt 1.19 mins. ΝMR data: 1H ΝMR (400 MHz, MeOD) δ ppm 8.61 (2 H, s), 7.39 - 7.48 (1 H, m), 7.07 - 7.17 (3 H, m), 5.35 (2 H, s).
General procedure D; Preparation of (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- yl)phenyl] methanol
Figure imgf000048_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 one hour at -78 0C, 4-pyrazol-l-yl-benzaldehyde (649 mg, 3.77 mmol) in THF (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 NaHCCb (1 ml). The reaction mixture was concentrated in vacuo and the resulting residue diluted with dichloromethane (50 ml) and washed with saturated aqueous NaHCCb (20 ml), dried (MgSθ4), 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 as white solid (705 mg, 68% yield).
LCMS data: Calculated MH+ (332); Found (MH+) m/z 332, Rt 1.58 mins. Purity (UV): 97%. 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).
The following compounds were prepared as described in Route 2, General procedure D above.
Preparation of (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-l,2,4-triazol-l-yl)phenyl] methanol
Figure imgf000049_0001
In a similar fashion (R2, GP D) 4-benzyl-4H-l,2,4-triazole (63 mg, 0.37 mmol), gave the title compound (69 mg, 63% yield) as yellow solid.
LCMS data: Calculated MH+ (333); Found (MH+) m/z 333, Rt 1.40 mins. Purity (UV):
100%.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 9.01 (1 H, s), 8.40 (1 H, s), 8.11 (1 H, s), 7.68
(2 H, d, J=8.3 Hz), 7.46 (2 H, d, J=8.3 Hz), 7.14 - 7.23 (3 H, m), 6.95 - 7.02 (2H, m), 6.16 (1 H, s), 5.30 (1 H, d, J=15.4 Hz), 5.24 (1 H, d, J=ISA Hz).
(4-Benzyl-4H- [ 1 ,2,4] triazol-3-yl)- [4-(lH-pyrazol- l-ylmethyl)phenyl] methanol
Figure imgf000050_0001
In a similar fashion (R2, GP D), 4-benzyl-4H-l,2,4-triazole (620 mg, 3.89 mmol) and 4-[(lΗ- pyrazol-l-yl)methyl]benzaldehyde (870 mg, 4.67 mmol) gave the title compound (990 mg,
74% yield) as white solid.
LCMS data: Calculated MH+ (346); Found 100% (MH+) m/z 346.18, Rt 1.56 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.36 (1 H, s), 7.67 (1 H, d, J=2.0 Hz), 7.52 (1
H, d, J=I .2 Hz), 7.32 (2 H, d, J=8.1 Hz), 7.14 - 7.27 (5 H, m), 6.95 (2 H, dd, J=7.8, 1.7 Hz),
6.33 (1 H, t, J=2.2 Hz), 6.12 (1 H, s), 5.32 (2 H, s), 5.14 - 5.27 (2 H, m).
Preparation of (4-benzyl-4H-l,2,4-triazol-3-yl)(4-bromophenyl)methanol
Figure imgf000050_0002
In a similar fashion (R2, GP D), 4-bromo-benzaldehyde (698 mg, 3.77 mmol) gave the title compound (908 mg, 84% yield) as white solid.
LCMS data: Calculated MH+ (344); Found 100% (MH+) m/z 344, Rt 1.77 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.42 (1 H, s), 7.43 (2 H, d, J=8 Hz), 7.21 -
7.30 (5 H, m), 6.97 - 7.03 (2 H, m), 6.09 (1 H, s), 5.29 (1 H, d, J=15 Hz), 5.23 (1 H, d, J=15
Hz).
Preparation of methyl 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(hydroxy)methyl]benzoate
Figure imgf000050_0003
In a similar fashion (R2, GP D), 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-(3-fluorobenzyl)-4H-l,2,4-triazol-3-yl] [4-(lH-pyrazol-l- ylmethy])phenyl] methanol
Figure imgf000051_0001
In a similar fashion (R2, GP D), 4-(3-fluoro-benzyl)-4Η-[l,2,4]triazole (78 mg, 0.44 mmol) and 4-pyrazol- 1 -yl-benzaldehyde (98 mg, 0.53 mmol) gave the title compound (83 mg, 52% yield) as white solid.
LCMS data: Calculated MH+ (364); Found 100% (MH+) m/z 364, Rt 3.19 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.44 (1 H, s), 7.66 (1 H, d, J=I .7 Hz), 7.52 (1
H, d, J=1.5 Hz), 7.31 (2 H, d, J=7.8 Hz), 7.17 - 7.24 (1 H, m), 7.15 (2H, d, J=8.3 Hz), 6.93 - 6.99 (1 H, m), 6.74 (1 H, d, J=7.8 Hz), 6.64 - 6.69 (1 H, m), 6.32 - 6.35 (1 H, m), 6.15 (1 H, s), 5.31 (2 H, s), 5.25 (2 H, s).
Preparation of [4-(3-fluorobenzyl)-4H-l,2,4-triazol-3-yl] [4-(lH-l,2,4-triazol-l- ylmethy])phenyl] methanol
Figure imgf000051_0002
In a similar fashion (R2, GP D) 4-(3-fluoro-benzyl)-4Η-[l,2,4]triazole (78 mg, 0.44 mmol) and 4-[l,2,4]triazol-l-yl-benzaldehyde (99 mg, 0.53 mmol), gave the title compound (82 mg, 52% yield) as white solid. LCMS data: Calculated MH+ (365); Found 100% (MH+) m/z 365, Rt 2.91 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.53 (1 H, s), 8.45 (1 H, s), 8.00 (1 H, s), 7.34 (2 H, d, J=8.3 Hz), 7.26 (2 H, d, J=8.3 Hz), 7.15 - 7.22 (1 H, m), 6.89 - 6.96 (1 H, m), 6.72 (1 H, d, J=7.6 Hz), 6.61 - 6.67 (1 H, m), 6.15 (1 H, s), 5.39 (2 H, s), 5.27 (2 H, s).
Preparation of (4-fluorophenyl)[4-(2-phenylethyl)-4H- 1,2,4- triazol-3-yl] methanol
Figure imgf000052_0001
In a similar fashion (R2, GP D), 4-(2-phenyl)ethyl-4H-[l,2,4]triazole (150 mg, 0.87 mmol) and 4-fluorobenzaldehyde (140 mg, 1.13 mmol) gave the title compound (180 mg, 70% yield) as pale yellow oil.
LCMS data: Calculated MH+ (298); Found 100% (MH+) m/z 298, Rt 1.62 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.15 (1 H, s), 7.40 (2 H, dd, J=8.3, 5.4 Hz), 7.19 - 7.29 (3 H, m), 7.08 - 7.16 (2 H, m), 6.99 - 7.05 (2 H, m), 6.02 (1 H, s), 4.16 - 4.33 (2 H, m), 2.83 (2 H, t, J=7.3 Hz).
General procedure E
Example 1 - l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l-yl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range B
Figure imgf000052_0002
The alcohol (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l-yl)phenyl]methanol (23 mg, 70 μmol) and carbon tetrabromide (32 mg, 97 μmol) were stirred in dichloromethane (1 ml) at O0C giving a white suspension. Triphenylphosphine (51 mg, 194 μmol) was then added as a solid and the reaction turned a clear brown colour. After 20 minutes, 1-cyclobutyl- [l,4]diazepane (22 mg, 139 μmol) was added giving a cloudy yellow solution. After a further 6 hours the reaction was diluted with dichloromethane (30 ml) and washed with IM NaOH (10 ml), dried (MgSO/i), filtered and concentrated in vacuo. Purification by silica flash column chromatography (using a gradient of eluents; 98:2:1 to 80:20:5 DCM/MeOH/NH3) gave the title compound as yellow oil (18 mg, 56% yield).
LCMS data: Calculated MH+ (468); Found 100% MH+ m/z (468), Rt = 3.01 mins NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.58 (1 H, s), 8.20 (1 H, d, J=2.4 Hz), 7.72 (1 H, m), 7.66 (2 H, d, J=8.6 Hz), 7.39 (2 H, d, J=8.8 Hz), 7.24 - 7.32 (3H, m), 7.03 - 7.10 (2 H, m), 6.51 - 6.54 (1 H, m), 5.37 (1 H, d, J=15.9 Hz), 5.26 (1 H, d, J=15.9 Hz), 5.18 (1 H, s), 2.62 - 2.99 (9 H, m), 1.63 - 2.22 (8 H, m).
The following compounds were prepared as described in Route 2, General Procedure E above.
Example 2 - l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l-yl)phenyl]methyl}-4- cyclopentyl-l,4-diazepane . Potency range A
Figure imgf000053_0001
In a similar fashion (R2, GP E), (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- yl)phenyl]methanol (92 mg, 0.28 mmol) gave the title compound (55 mg, 41% yield) as yellow oil.
LCMS data: MH+ (483); Found 100%, MH+ m/z (483), Rt = 3.05 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.57 (1 H, s), 8.17 (1 H, d, J=2.2 Hz), 7.68 (1 H, s), 7.63 (2 H, d, J=8.8 Hz), 7.34 (2 H, d, J=8.6 Hz), 7.19 - 7.27 (3H, m), 6.97 - 7.04 (2 H, m), 6.96 - 7.04 (2 H, m), 6.49 (1 H, s), 5.30 (1 H, d, J=15.6 Hz), 5.20 (1 H, s), 5.18 (1 H, d, J=15.6 Hz), 3.51 - 3.61 (1 H, m), 3.25 - 3.29 (2 H, m), 2.93 - 3.18 (3 H, m), 2.63 - 2.90 (3 H, m), 2.00 - 2.13 (2 H, m), 1.84 - 1.97 (2 H, m), 1.72 - 1.82 (2 H, m), 1.55 - 1.70 (4 H, m).
Example 3 - l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-l,2,4-triazol-l-yl)phenyl]methyl}- 4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000054_0001
In a similar fashion (R2, GP E) (4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-l,2,4-triazol-l- yl)phenyl]methanol (21 mg, 0.10 mmol), gave the title compound (25 mg, 53% yield) as orange oil. LCMS data: MH+ (469); Found 100% MH+ m/z (469), Rt = 2.76 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 9.08 (1 H, s), 8.60 (1 H, s), 8.16 (1 H, s), 7.74 (2 H, d, J=8.6 Hz), 7.45 (2 H, d, J=8.6 Hz), 7.22 - 7.33 (3 H, m), 7.03 - 7.10 (2H, m), 5.39 (1 H, d, J=15.9 Hz), 5.31 (1 H, d, J=15.9 Hz), 5.23 (1 H, s), 2.61 - 2.98 (9 H, m), 2.10 - 2.21 (2 H, m), 1.95 - 2.07 (2 H, m), 1.64 - 1.91 (4 H, m).
General procedure F
Example 4 - Preparation of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-bromophenyl)methyl]-
4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000054_0002
To a stirred solution of the (4-benzyl-4H-l,2,4-triazol-3-yl)(4-bromophenyl)methanol (107 mg, 0.31 mmol) in TΗF (10 ml) at -78 0C was added dropwise n-BuLi (0.22 ml of a 1.4M solution in hexanes, 0.31 mmol) over 10 minutes. The reaction was warmed to room temperature and /?αra-toluenesulfonyl chloride (65 mg, 0.34 mmol) was added as a solid in one single portion. After a further 1 hour, l-cyclobutyl-[l,4]diazepane (53 mg, 0.34 mmol) and diisopropylethylamme (112 μl, 0.68 mmol) in TΗF (1 ml) were added and the reaction was heated at 75 0C for 12 hours in a sealed tube. Excess TΗF was removed in vacuo and the residue was diluted with dichloromethane (30 ml) and washed with saturated NaHCO3 (15 ml), dried (MgSO/i) and concentrated in vacuo. Purfication by silica flash column chromatography (using a gradient of eluents; 98:2:1 to 80:20: 1 DCM/MeOH/NH3) gave the title compound as colourless oil (83 mg, 56% yield). LCMS data: Calculated MH+ (482); Found 98% MH+ m/z (482), Rt = 3.23 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.54 (1 H, s), 7.37 - 7.44 (2 H, d, J=8.6 Hz), 7.27 - 7.35 (3 H, m), 7.17 - 7.25 (2 H, d, J=8.6 Hz), 7.02 - 7.10 (2 H, m), 5.40 (1 H, d, 15.9 Hz), 5.32 (1 H, d, 15.9 Hz), 5.08 (1 H, s), 2.89 - 3.00 (1 H, m), 2.62 - 2.82 (4 H, m), 2.50 - 2.60 (2 H, m), 2.37 - 2.48 (2 H, m), 1.96 - 2.09 (2 H, m), 1.77 - 1.91 (2 H, m), 1.56 - 1.75 (4 H, m).
The following compounds were prepared as described by Route 2, General Procedure F above.
Example 5 - l-cyclobutyl-4-{[4-(3-fluorobenzyl)-4H-l,2,4-triazol-3-yl] [4-(lH-pyrazol-l- ylmethy])pheny]]methyl}-l,4-diazepane. Potency range A
Figure imgf000055_0001
In a similar fashion (R2, GP F), using [4-(3-fiuorobenzyl)-4H-l,2,4-triazol-3-yl][4-(lH- pyrazol-l-ylmethyl)phenyl]methanol (79 mg, 0.22 mmol) with purification by preparative
ΗPLC gave the title compound as colourless oil (62 mg, 55% yield, TFA salt).
LCMS data: MH+ (500); Found 94% MH+ m/z (500), Rt = 3.03 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ 9.14 (1 H, s), 7.72 (1 H, d, J=2.0 Hz), 7.55 (1 H, d, J=1.5 Hz), 7.16 - 7.25 (3 H, m), 7.14 (2 H, d, J=8.3 Hz), 6.93 - 7.00 (1 H, m), 6.77 (1 H, d, J=7.8 Hz), 6.72 (1 H, d, J=9.5 Hz), 6.34 - 6.38 (1 H, m), 5.41 (1 H, s), 5.32 (2 H, s), 5.29 (2
H, s), 3.67 - 3.79 (1 H, m), 3.07 - 3.42 (4 H, m), 2.77 - 3.05 (4 H, m), 2.15 - 2.35 (4 H, m),
1.96 - 2.07 (2 H, m), 1.70 - 1.92 (2 H, m).
Example 6 - l-cyclobutyl-4-{[4-(3-fluorobenzyl)-4H-l,2,4-triazol-3-yl] [4-(lH-l,2,4- triazol-l-ylmethyl)phenyl]methyl}-l,4-diazepane. Potency range A
Figure imgf000056_0001
In a similar fashion (R2, GP F), using [4-(3-fluorobenzyl)-4H-l,2,4-triazol-3-yl][4-(lH-l,2,4- triazol-l-ylmethyl)phenyl]methanol (57 mg, 0.16 mmol) gave the title compound as colourless oil (45 mg, 56% yield).
LCMS data: MH+ (501); Found 98% MH+ m/z (501), Rt = 2.77 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ 8.55 (2 H, s), 8.00 (1 H, s), 7.30 (2 H, d, J=8.1
Hz), 7.19 - 7.27 (3 H, m), 6.93 - 7.00 (1 H, m), 6.78 (1 H, d, J=7.8 Hz), 6.71 (IH, d, J=9.5
Hz), 5.35 - 5.40 (4 H, m), 5.12 (1 H, s), 2.92 - 3.04 (1 H, m), 2.63 - 2.86 (4 H, m), 2.53 - 2.63
(2 H, m), 2.39 - 2.53 (2 H, m), 1.96 - 2.10 (2 H, m), 1.78 - 1.91 (2 H, m), 1.56 - 1.77 (4 H, m).
Example 7 - l-cyclobutyl-4-{(4-fluorophenyl)[4-(2-phenylethyl)-4H-l,2,4-triazol-3- yl]methyl}-l,4-diazepane. Potency range B
Figure imgf000056_0002
In a similar fashion (R2, GP F), using [4-(2-phenyl)ethyl]-4H-[l,2,4]triazol-3-yl]-(4- fluorophenyl)methanol (50 mg, 0.168 mmol) and 4-cyclobutyl-[l,4]diazepane (34 mg, 0.218 mmol) gave the title compound as colourless oil after purification by flash column chromatography (33 mg, 45%). LCMS data: Calculated MH+ (434); Found 100% (MH+) m/z 434.38, Rt 3.07 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.33 (1 H, s), 7.20 - 7.37 (5 H, m), 7.01 - 7.12 (4 H, m), 4.83 (1 H, s), 4.25 - 4.48 (2 H, m), 2.88 - 3.02 (3 H, m), 2.60 - 2.76 (4 H, m), 2.52 - 2.59 (2 H, m), 2.40 - 2.49 (2 H, m), 1.97 - 2.07 (2 H, m), 1.57 - 1.89 (6 H, m).
Route 3
Figure imgf000057_0001
Scheme 3: One-pot Preparation of l-[(4-(alkyl-aryl-4H-[l,2,4]triazol-3-yl)-(aryl)-methyl]-4- (cyclo)alkyl-[ 1 ,4]diazepanes
General procedure G
Example 8 - Preparation of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-ethoxyphenyl)methyl]-
4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000057_0002
ft-BuLi (0.22 ml of a 1.6M solution in hexanes, 0.31 mmol) was added dropwise over 30 minutes to a solution of 4-benzyl-4H-[l,2,4]triazole (50 mg, 0.34 mmol) in dry THF (5 ml) at -78 0C. After one hour at -78 0C, 4-ethoxy-benzaldehyde (32 μl, 0.34 mmol) was added dropwise over 10 mins and the mixture was stirred for a further 1 hour. The reaction mixture was warmed to room temperature and /?αrα-toluenesulfonyl chloride (66 mg, 0.34 mmol) added giving a clear brown solution. After stirring for 15 minutes at room temperature, 1- cyclobutyl-[l,4]diazepane (97 mg, 0.63 mmol) was added in THF (1 ml) and the mixture stirred for a further 12 hours. The reaction was diluted with dichloromethane (20 ml), washed with saturated aqueous NaHCCh (10 ml), dried (MgSO/t), filtered and concentrated in vacuo. Silica flash column chromatography (using a gradient of eluents; 98:2 to 85:15:1 DCM/MeOH/NH3) followed by preparative HPLC purification gave the TFA salt title compound as yellow oil (9 mg, 7% yield).
LCMS data: Calculated MH+ (446); Found 100% (MH+) m/z 446, Rt 3.18 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.81 (1 H, s), 7.24 - 7.34 (3 H, m), 7.14 (2 H, d, J=8.8 Hz), 6.95 - 7.05 (2 H, m), 6.85 (2 H, d, J=8.8 Hz), 5.27 (1 H, d, J=15.7 Hz), 5.16 (1 H, s), 5.05 (1 H, d, J=15.7 Hz), 4.00 (2 H, q, J=7.1 Hz), 3.67 - 3.80 (1 H, m), 2.99 - 3.34 (4 H, m), 2.65 - 2.99 (4 H, m), 2.13 - 2.40 (4 H, m), 1.70 - 2.06 (4 H, m), 1.35 (3 H, t, J=7.1 Hz). The following compounds were prepared as described in Route 3, General procedure G above.
Example 9 - l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(2-methyl-l,3-thiazol-4- yl)phenyl]methyl}-4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000058_0001
ft-BuLi (0.31 ml of a 1.4M solution in hexanes, 0.49 mmol) was added dropwise over 30 minutes to a solution of 4-benzyl-4H-[l,2,4]triazole (71 mg, 0.45 mmol) in dry THF (5 ml) at -78 0C. After one hour at -78 0C, 4-(2-Methyl-thiazol-4-yl)-benzaldehyde (100 mg, 0.49 mmol) in THF (1 ml) was added dropwise over 10 mins and the mixture was stirred for a further 1 hour and then warmed to room temperature. pαra-Toluenesulfonyl chloride (66 mg, 0.34 mmol) was added giving a clear brown solution and after stirring for 15 minutes at room temperature, l-cyclobutyl-[l,4]diazepane (200 mg, 1.00 mmol) was added in THF (1 ml). After stirring for 12 hours, the reaction was diluted with dichloromethane (20 ml) and washed with saturated aqueous NaHCC>3 (10 ml), dried (MgSC>4) and concentrated in vacuo. Purification by silica flash column chromatography (using a gradient of eluents; 98:2 to 85:15:1 DCM/MeOH/NH3) followed by preparative HPLC gave the TFA salt title compound as yellow oil. This was then returned to the free base by dissolving the product in DCM (20 ml) and rapidly stirring with IM NaOH (10ml) for 30 mins, The organics were separated, washed with brine (20 ml), dried (MgSθ4) and concentrated giving the product as a clear yellow oil (22mg, 10% yield).
LCMS data: Calculated MH+ (498); Found 100% (MH+) m/z 498, Rt 3.16 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.50 (1 H, s), 7.80 (2 H, d, J=8.3 Hz), 7.61 (1 H, s), 7.36 (2 H, d, J=8.3 Hz), 7.25 - 7.33 (3 H, m), 7.04 - 7.11 (2 H, m), 5.40 (1 H, d, J=16.0 Hz), 5.29 (1 H, d, J=16.0 Hz), 5.11 (1 H, s), 2.89 - 2.99 (1 H, m), 2.67 - 2.85 (7 H, m), 2.52 - 2.60 (2 H, m), 2.41 - 2.48 (2 H, m), 1.96 - 2.07 (2 H, m), 1.57 - 1.89 (6 H, m).
Route 4 General proceudure D
Figure imgf000059_0001
Figure imgf000059_0002
General proceudure I
General proceudure J
Figure imgf000059_0004
Figure imgf000059_0003
Scheme 4: Preparation of l-[(4-(alkyl-aryl-4H-[l,2,4]triazol-3-yl)-(aryl)-methyl]-4- (cyclo)alkyl-[ 1 ,4]diazepanes
General procedure H:
Preparation of l-(4-benzyl-4H-[ 1,2,4] triazol-3-yl)-l-(4-tertbutoxycarbonyl-
[1,4] diazepan-l-yl)methyl-4-substituted benzenes.
Preparation of
Figure imgf000059_0005
4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-l,4- diazepane-1-carboxylate
Figure imgf000059_0006
To a stirred room temperature suspension of (4-benzyl-4H-[l,2,4]triazol-3-yl)-(4- fluorophenyl)-methanol (75 mg, 0.265 mmol) in DCM (4 ml) was added PBr3 (27.3 μL, 0.291 mmol) and the resulting mixture stirred overnight. Evaporation of the solvent in vacuo gave a white solid. This material was suspended in dry acetonitrile (4 mL) at room temperature, [l,4]diazepane-l-carboxylic acid terz-butyl ester (58.3 mg, 0.291 mmol) added, followed by potassium carbonate (91.5 mg, 0.662 mmol). The stirred reaction mixture was heated at reflux (ca. 80 0C) overnight, and 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 (Na2SU4), filtered and concentrated to give a yellow oil. The crude material was purified on silica gel chromatography (e luting with DCM/MeOH 95:5; stain PMA) to give the title compound as white solid (86 mg, 70%).
LCMS data: Calculated MH+ (466); Found 100% (MH+) m/z 466.05, Rt 1.79 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.52 (1 H, d), 7.25 - 7.37 (5 H, m), 6.94 - 7.13 (4 H, m), 5.20 - 5.42 (2 H, m), 5.09 (1 H, s), 3.30 - 3.43 (10 H, m), 2.52 - 2.75 (4 H, m), 1.58 - 1.71 (2 H, m), 1.43 (9 H, d).
The following compounds were prepared as described in Route 4, General Procedure H above.
Preparation of tert-butγ\ 4-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethy])phenyl] methyl}- 1 ,4-diazepane- 1-carboxylate
Figure imgf000060_0001
In a similar fashion (R4, GP Η), (4-benzyl-4H-[l,2,4]triazol-3-yl)-[4-(lH-pyrazol-l- ylmethyl)phenyl]methanol (100 mg, 0.29 mmol) PBr3 (86 mg, 0.32 mmol) and [l,4]diazepane-l-carboxylic acid tert-butyl ester (64 mg, 0.318 mmol) gave the title compound (36 mg, 24%) as white solid after silica flash column chromatography. LCMS data: Calculated MH+ (528); Found 100% (MH+) m/z 528.2, Rt 1.66 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.51 (1 H, s), 8.48 (1 H, s), 7.49 - 7.60 (4 H, m), 7.22 - 7.32 (10 H, m), 7.09 - 7.18 (4 H, m), 6.97 - 7.06 (4 H, m), 6.33 (2 H, t, J=2.1 Hz), 5.19 - 5.39 (8 H, m), 5.07 (2 H, s), 3.32 - 3.43 (8 H, m), 2.52 - 2.73 (8 H, m), 1.58 - 1.68 (4 H, m), 1.44 (9 H, s), 1.41 (9 H, s).
General procedure I; Preparation of l-(4-benzyl-4H-[l,2,4]triazol-3-yl)-l-(4H- [1,4] diazepan-l-yl)methyl-4-substituted benzenes
Preparation of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-l,4-diazepane
Figure imgf000061_0001
To a stirred solution of tert-butyl 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1,4-diazepane-l-carboxylate (77 mg, 0.165 mmol) in DCM (3 ml) was added a solution of 4M ΗCl/dioxane (410 μL, 1.65 mmol) at room temperature. The reaction mixture was stirred for 2.5h and then the solvent evaporated in vacuo to give a white solid. This material was dissolved in DCM/MeOΗ, 1 :1 (3 mL) and the resulting solution treated with Ambersep® resin (150 mg) until complete neutralization of the hydrochloride salt had occurred, as monitored by TLC analysis (eluting with DCM/MeOΗ, 90:10). The resin was removed by filtration, washing with DCM / MeOH (1 :1, 3 x 20ml), and the filtrate concentrated in vacuo to provide the title compound as yellow oil (62 mgs, 93%).
LCMS data: Calculated MH+ (366); Found 100% (MH+) m/z 365.95, Rt = 1.29 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.52 (1 H, s), 7.27 - 7.35 (5 H, m), 7.03 - 7.09 (2 H, m), 6.96 - 7.03 (2 H, m), 5.24 - 5.41 (2 H, m), 5.10 (1 H, s), 2.91 (2 H, dd, J=6.5, 5.3 Hz), 2.60 - 2.80 (7 H, m), 1.64 - 1.74 (2 H, m).
The following compounds were prepared as described in Route 4, General Procedure I above.
Preparation of l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethy])phenyl] methyl}- 1 ,4-diazepane
Figure imgf000061_0002
In a similar fashion (R4, GP I), tert-butyl 4-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol- l-ylmethyl)phenyl]methyl}-l,4-diazepane-l-carboxylate (36 mg, 0.07 mmol) and 4M ΗCl/dioxane (85 μL, 0.34 mmol) gave the title compound (27 mg, 98%) as a colorless oil (27 mg, 98%).
General procedure J: Example 10 - l-(4-benzyl-4H-[l,2,4]triazol-3-yl)-4-fluorophenyl)methyl]-4-cycloalkyl- [ 1 ,4] diazepanes. Potency range A
Figure imgf000062_0001
To a stirred solution of l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-l,4- diazepane (22.5 mg, 0.075 mmol) in DCE (2 ml) was added cyclobutanone (5.6 μL, 0.075 mmol) followed by AcOH (4.3 μL, 0.075 mmol). The resulting mixture stirred at room temperature for 2 h, then sodium triacetoxyborohydride (24 mg, 0.113 mmol) was added and the suspension stirred at room temperature overnight. A solution of 3.5% w/w NaΗCC>3 (3 mL) was added and the mixture was stirred for V2 h. The organic layer was separated, dried (Na2SC^), filtered and concentrated in vacuo to a yellow oil. Purification by preparative HPLC provided the title compound as colorless oil (28 mg, 70%, TFA salt). LCMS data: Calculated MH+ (420); Found 96% (MH+) m/z 420.2, Rt 2.97 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.73 (1 H, s), 7.21 - 7.36 (5 H, m), 6.97 - 7.08 (4 H, m), 5.10 - 5.32 (3 H, m), 3.68 - 3.79 (1 H, m), 2.55 - 3.43 (8 H, m), 2.15 - 2.40 (4 H, m), 1.72 - 2.03 (4 H, m).
The following compounds were prepared as described in Route 4, General procure J above.
Example 11 - l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-cyclopentyl- 1,4-diazepane. Potency range B
Figure imgf000062_0002
In a similar fashion (R4, GP J), l-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-fluorophenyl)methyl]- 1,4-diazepane (22.5 mg, 0.075 mmol) and cyclopentanone (6.7 μL, 0.075 mmol) gave the title compound as colourless oil after preparative ΗPLC purification (28 mg, 68%, TFA salt). LCMS data: Calculated MH+ (434); Found 95% (MH+) m/z 434.2, Rt 3.08 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.65 - 8.73 (1 H, m), 7.21 - 7.35 (5 H, m), 6.97 - 7.07 (4 H, m), 5.09 - 5.32 (3 H, m), 3.67 (1 H, q, J=7.8 Hz), 3.32 - 3.56 (2 H, m), 2.53 - 3.29 (6 H, m), 2.05 - 2.21 (2 H, m), 1.90 - 2.04 (2 H, m), 1.61 - 1.87 (6 H, m). Example 12 - l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethy])pheny]]methyl}-4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000063_0001
In a similar fashion (R4, GP J), l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethyl)phenyl]methyl}-l,4-diazepane (29 mg, 0.068 mmol) and cyclobutanone (5.1 μL, 0.068 mmol) gave the title compound as colourless oil after silica flash column chromatography (20 mg, 61%).
LCMS data: Calculated MH+ (482); Found 100% (MH+) m/z 482.52, Rt 2.89 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.49 (1 H, s), 7.68 (1 H, d, J=2.4 Hz), 7.52 (1 H, d, J=2.0 Hz), 7.24 - 7.31 (5 H, m), 7.12 (2 H, d, J=8.1 Hz), 6.99 - 7.05 (2 H, m), 6.33 (1 H, t, J=2.1 Hz), 5.33 - 5.39 (1 H, m), 5.31 (2 H, s), 5.22 - 5.29 (1 H, m), 5.07 (1 H, s), 2.89 - 2.99 (1 H, m), 2.61 - 2.81 (4 H, m), 2.37 - 2.60 (4 H, m), 1.96 - 2.06 (2 H, m), 1.76 - 1.89 (2 H, m), 1.57 - 1.75 (4 H, m).
Example 13 - l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethyl)phenyl]methyl}-4-cyclopentyl-l,4-diazepane. Potency range A
Figure imgf000063_0002
In a similar fashion (R4, GP J), l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-pyrazol-l- ylmethyl)phenyl]methyl}-l,4-diazepane (35 mg, 0.082 mmol) and cyclopentanone (7.9 μL,
0.089 mmol) gave the title compound as colourless oil after silica flash column chromatography (30 mg, 75%).
LCMS data: Calculated MH+ (496); Found (MH+) m/z 496.47, Rt 2.98 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.48 (1 H, s), 7.68 (1 H, d, J=2.0 Hz), 7.52 (1 H, d, J=1.5 Hz), 7.23 - 7.32 (5 H, m), 7.13 (2 H, d, J=8.3 Hz), 7.01 (2H, dd, J=5.4, 3.9 Hz),
6.33 (2 H, t, J=2.1 Hz), 5.36 (1 H, d), 5.31 (2 H, s), 5.26 (1 H, d), 5.07 (2 H, s), 2.90 - 3.01 (1
H, m), 2.61 - 2.84 (8 H, m), 1.80 - 1.90 (2 H, m), 1.49 - 1.78 (6 H, m), 1.32 - 1.45 (2 H, m). Route 5
Figure imgf000064_0001
Preparation of methyl 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] benzoate
Figure imgf000064_0002
In a similar fashion (R2, GP F), using methyl 4-[(4-benzyl-4H-l,2,4-triazol-3- yl)(hydroxy)methyl]benzoate (100 mg, 0.31 mmol) with purification using preparative ΗPLC gave the title compound as colourless oil (105 mg, 74% yield, TFA salt). LCMS data: Calculated MH+ (460); Found MH+ m/z (460), Rt = 1.07 mins. NMR data: 1H NMR (400 MHz, MeOD) δ 8.94 (1 H, s), 7.96 (2 H, d, J=8.6 Hz), 7.24 - 7.42 (5 H, m), 7.01 - 7.13 (2 H, m), 5.16 - 5.41 (3 H, m), 3.93 (3 H, s), 3.70 - 3.84 (1 H, m), 3.02 - 3.47 (4 H, m), 2.64 - 3.00 (4 H, m), 2.13 - 2.45 (4 H, m), 1.75 - 2.10 (4 H, m).
General procedure K:
Example 14 - 4-[(4-benzyl-4H-l,2,4-triazol-3-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-
N-methylbenzamide. Potency range A
Figure imgf000064_0003
LiOH (10 mg, 0.23 mmol) in water (0.2 ml) was added to methyl 4-[(4-benzyl-4H- 1,2,4- triazol-3-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]benzoate (75 mg, 0.16 mmol) in TΗF (2 ml) and the reaction was stirred overnight at room temperature giving complete hydrolysis of the ester, as shown by LCMS. The solvent was evaporated and the residue dissolved in DMF (4ml). To this stirred room temperature solution was added ΗBTU (93 mg, 0.25 mmol), ΗOBt (33 mg, 0.25 mmol) and methylamine (0.13 ml of a 2M solution in THF, 0.25 mmol) and the reaction stirred for 6 hours. Excess DMF was removed and the residue was dissolved in DCM (30 ml) and washed with NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated in vacuo. Purification by silica flash column chromatography (eluting with 90:10:1 DCM/MeOH/NHs) gave the title compound as pale yellow oil (26 mg, 36%). LCMS data: Calculated MH+ (459); Found 100% MH+ m/z (459), Rt = 2.71 mins. NMR data: 1H NMR (400 MHz, MeOD) δ 8.49 (1 H, s), 7.61 (2 H, d, J=8.3 Hz), 7.23 (2 H, d, J=8.3 Hz), 7.11 - 7.19 (3 H, m), 6.87 - 6.96 (2 H, m), 5.12 - 5.22 (2 H, m), 5.07 (1 H, d, J=15.6 Hz), 3.57 - 3.71 (1 H, m), 2.54 - 3.19 (11 H, m), 2.03 - 2.28 (4 H, m), 1.63 - 1.90 (4 H, m).
Route 6
Figure imgf000065_0001
Preparation of l-[(l-benzyl-lH-l,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclobutyl- 1,4-diazepane.
Preparation of ethyl l-benzyl-lH-l,2,3-triazole-5-carboxylate
Figure imgf000065_0002
To a stirred solution of ethyl(triphenylphosphoranylidene)pyruvate (10.15g, 26.99 mmol) in xylene (30 ml) was added benzyl azide (3.Og, 22.56 mmol). The reaction mixture was heated to 1380C for 16 h in a sealed tube then cooled to RT and the solvent evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (50 ml), washed with water (2 x 20 ml), brine (I x 20 ml), dried (Na2SO4), filtered and the evaporated at reduced pressure. Purification by silica flash column chromatography [eluting with 94:6 Petroleum ether / EtOAc] provided the title compound (1.8g, 35% yield) as pale yellow oil.
LCMS data: Calculated MH+ (232); Found 99% (MH+) m/z 232, Rt 4.43 mins.
NMR data: 1H NMR (300 MHz, CDCl3) δ ppm 8.17 (1 H, s), 7.29 - 7.35 (5 H, m), 5.99 (2 H, s),
4.40 (2 H, q), 1.21 (3H, t).
Preparation of (l-benzyl-lH-l,2,3-triazol-5-yl)methanol
Figure imgf000066_0001
To a stirred mixture of LAH in THF (60 ml) at -100C was added a solution of ethyl 1-benzyl- lH-l,2,3-triazole-5-carboxylate (8.0g, 34.63 mmol) in TΗF (20 ml) over a period of 15min. The reaction mixture was warmed to RT, stirred for lh.45 mins before cooling to O0C and quenching by addition of saturated Na2SC>4 solution. The resulting white insoluble inorganic material was removed by filtration, washed with EtOAc (2 x 20 ml) and the filtrate evaporated to obtain brown residue. The residue was dissolved in EtOAc (50 ml), washed with water (20 ml), brine (20 ml) and the organic layer dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (4.Og, 61% yield) as a brown oil. This material was used without further purification.
LCMS data: Calculated MH+ (190); Found (MH+) m/z 190, Rt 2.03 mins. NMR data: 1H NMR (300 MHz, CDCl3) consistent with title compound.
Preparation of l-benzyl-l//-l,2,3-triazole-5-carbaldehyde
Figure imgf000066_0002
To a O0C stirred solution of IBX (10.47g, 39.66 mmol) in DMSO (50 ml) was added a premixed solution of compound (l-benzyl-lH-l,2,3-triazol-5-yl)methanol (5.Og, 26.46 mmol) in DCM (100 ml) over a period of lOmin. After stirring at RT for 4h the reaction mixture was filtered and the organic solution washed with water (2 x 30 ml), brine (30 ml), dried (Na2SC>4), filtered and concentrated in vacuo give the title compound (0.5g, 61% yield) as a brown liquid. This material was used without further purification. LCMS data: Calculated MH+ (188); Found (MH+) m/z 188, Rt 3.42 mins. NMR data: 1H NMR (300 MHz, CDCl3) consistent with title compound.
General Procedure L - Preparation of (l-benzyl-lH-l,2,3-triazol-5-yl)(4- fluorophenyl)methanol
Figure imgf000067_0001
A stirred mixture of Mg (0.499g, 20.79 mmol) and 4-bromofluorobenzene (2.8g, 16.04 mmol) in THF (20 ml) was heated to reflux (65°C) for 1 h under N2 atmosphere. The reaction mixture was cooled to 100C and a premixed solution of l-benzyl-lH-l,2,3-triazole-5-carbaldehyde (3.0g, 16.04 mmol) in TΗF (20 ml) was added drop wise over a period of 10 mins. After stirring the reaction mixture for 6h at RT the reaction mixture was quenched with 2N HCl (5 ml), basifϊed to pΗ 8 with NaHCO3 solution and extracted with EtOAc (2 x 40 ml). The combined organic layer was washed with water (2 x 20 ml), brine (20 ml), dried (Na2SO4), filtered and evaporated in vacuo. The crude material was purified by silica flash column chromatography [eluting with 78:22 Petroleum ether / EtOAc] to provide the title compound (1.8g, 40% yield) as white solid. LCMS data: Calculated MH+ (284); Found 100% (MH+) m/z 284, Rt 2.98 mins. NMR data: 1H NMR (300 MHz, CDCl3) consistent with title compound.
The following compound was prepared as described in Route 4, General Procedure H above.
Preparation of tert-buty\ 4-[(l-benzyl-lH-l,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-l,4- diazepane-1-carboxylate
Figure imgf000068_0001
In a similar fashion (Route 4, GP H), (l-benzyl-lH-l,2,3-triazol-5-yl)(4- fluorophenyl)methanol (3.27 g, 11.54 mmol), PBr3 (1.19 mL, 12.67 mmol) and
[l,4]diazepane-l-carboxylic acid tert-butyl ester (3.0 g, 15.0 mmol) gave the title compound
(2.4 g, 42% yield) as pale yellow semi-solid after silica flash column chromatography [eluting
97:3 Chloroform / MeOH].
LCMS data: Calculated MH+ (466); Found, 66% (MH+) m/z 466, Rt 4.47 mins.
NMR data: 1H NMR (300 MHz, CDCl3) consistent with title compound.
Preparation of l-[(l-benzyl-lH-l,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-l,4-diazepane
Figure imgf000068_0002
To a stirred RT solution of tert-butyl 4-[(l-benzyl-lH-l,2,3-triazol-5-yl)(4-fiuorophenyl)methyl]-
1 ,4-diazepane- 1 -carboxylate (3.3 g, 3.33 mmol) in DCM was added TFA (7.2 mL) drop wise.
After stirring for 4h at RT the solvent was evaporated in vacuo, diluted with ethyl acetate (50 mL), and washed with saturated NaHCO3 (2 x 20 mL). The organic layer was washed with water
(2 x 10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated at reduced pressure.
Purification by flash column chromatography [neutral alumina, eluting 97:3 Chloroform / MeOH] gave the title compound (0.6g, 31.6 %) as a brown viscous liquid.
LCMS data: Calculated MH+ (366); Found, 87% (MH+) m/z 366, Rt 2.06 mins.
NMR data: 1H NMR (300 MHz, CDCl3) δ ppm 7.61 (1 H, s), 7.31 (3 H, m), 7.02 - 7.10 (4 H, m), 6.94 - 6.99 (2 H, m), 5.75 (IH, d), 5.40 (IH, d), 4.70 (IH, s), 2.90 - 2.95 (2 H, m), 2.75 -
2.82 (2 H, m), 2.52 - 2.59 (4 H, m), 1.72 - 1.82 (2 H, m).
The following compound was prepared as described in Route 4, General Procedure J above. Example 15 - l-[(l-benzyl-lH-l,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclobutyl- 1,4-diazepane. Potency range A
Figure imgf000069_0001
In a similar fashion (Route 4, GP J), l-[(l-benzyl-lH-l,2,3-triazol-5-yl)(4- fluorophenyl)methyl]-l,4-diazepane (22.5 mg, 0.075 mmol) and cyclobutanone (6.7 μL,
0.075 mmol) gave the title compound as colourless oil after preparative ΗPLC purification
(28 mg, 68%, TFA salt).
LCMS data: Calculated MH+ (434); Found 95% (MH+) m/z 434.20, Rt 3.08 mins.
IH NMR (400 MHz, MeOD) d ppm 7.79 - 7.95 (1 H, m), 7.14 - 7.36 (5 H, m), 6.95 - 7.13 (4
H, m), 5.63 - 5.75 (1 H, m), 5.46 - 5.62 (1 H, m), 5.05 (1 H, s), 3.62 - 3.80 (1 H, m), 2.99 -
3.43 (3 H, m), 2.49 - 2.94 (5 H, m), 1.60 - 2.42 (8 H, m).
Route 7
1 ) nBuϋ, THF
Figure imgf000069_0002
Preparation of l-{(l-benzyl-lH-l,2,3-triazol-5-yl)[4-(lH-pyrazol-l- ylmethy])pheny]]methyl}-4-cyclobutyl-l,4-diazepane
Preparation of l-benzyl-lH-l,2,3-triazole
N=N
To a solution of lH-l,2,3-triazole (5.0 g, 72.3 mmol) and K2CO3 (9.1 g, 65.8 mmol) in acetone at 560C was added benzyl bromide (7.8 ml, 65.8 mmol) drop wise over 90 minutes. The reaction mixture was heated at reflux for a further Ih, cooled to room temperature and quenched with distilled water (4 ml). Acetone was evaporated in vacuo and the remaining aqueous phase back extracted with DCM (3 x 20 ml). The combined organic layers were dried (MgSθ4), filtered and concentrated in vacuo to provide the title compound (9.8 g, 94% yield) as off-white solid. LCMS data: Calculated MH+ (160); Found 97% MH+ m/z (160), Rt = 1.44 mins.
Example 16 - l-{(l-benzyl-lH-l,2,3-triazol-5-yl)[4-(lH-pyrazol-l- ylmethy])pheny]]methyl}-4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000070_0001
To a stirred solution of 1 -benzyl- IH- 1,2,3-triazo Ie (90 mg, 0.565 mmol) in THF (2 ml) at -78 0C was added n-BuLi (0.48ml of a 1.3M solution in hexanes, 0.622 mmol) drop wise over 30 minutes. After one hour at -78 0C, 4-(lH-pyrazol-l-ylmethyl)benzaldehyde (116 mg, 0.622 mmol) in TΗF (3 ml) was added drop wise over 10 mins. The reaction was stirred for a further 10 minutes then warmed to room temperature and /?αra-toluenesulfonyl chloride (119 mg, 0.62 mmol) added in TΗF (2ml). The reaction was stirred at room temperature for a further 10 minutes, after which 1 -eye Io butyl- 1 ,4-diazepane (131 mg, 0.93 mmol) in TΗF (2ml) was added and the reaction mixture stirred for 6Oh. The reaction mixture was concentrated in vacuo and purified by preparative ΗPLC to provide the title compound as pale oil (5.5 mg, 2% yield, TFA salt).
LCMS data: Calculated MH+ (482); Found 100% MH+ m/z (482), Rt = 2.57mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.82 (1 H, s), 7.70 (1 H, d, J=I .9 Hz), 7.49 - 7.54 (1 H, m), 7.21 - 7.29 (3 H, m), 7.10 - 7.19 (4 H, m), 6.99 - 7.07 (2 H, m), 6.34 (1 H, t, J=2.1 Hz), 5.66 (1 H, d), 5.53 (1 H, d), 5.31 (2 H, s), 4.99 (1 H, s), 3.54 - 3.68 (1 H, m), 3.04 - 3.20 (2 H, m), 2.67 - 3.02 (4 H, m), 2.53 - 2.67 (2 H, m), 2.18 - 2.31 (2 H, m), 2.04 - 2.17 (2 H, m), 1.68 - 1.93 (4 H, m)
Route 8
Figure imgf000071_0001
General Procedure M
Example 17 - l-[(l-benzyl-lH-tetrazol-5-yl)(4-morpholin-4-y]phenyl)methyl]-4- cyclobutyl-l^-diazepane. Potency range C
Figure imgf000071_0002
4-Morpholinobenzaldehyde (50 mg, 0.26 mmol) and l-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol) were stirred in methanol (2.0 ml) at room temperature for 2 hours before benzylisocyanide (32 μl, 0.26 mmol) was added in one portion. After a further 2 hours, trimethylsilylazide (34 μl, 0.26 mmol) was added in one portion and the resulting mixture stirred for 16 hours. The reaction was quenched with 2M HCl (2 ml) and stirred for 2 hours before basifying with 2M NaOH (2.5 ml). The mixture was extracted with DCM (3 x 15 ml), dried (MgSO4), filtered and concentrated in vacuo. Purification by silica flash column chromatography (using a gradient of eluents; 98:2:1 to 80:20:1 DCM/MeOH/NH3) followed by preparative HPLC purification gave the title compound as light blue oil (60 mg, 47% yield, TFA salt).
LCMS data: Calculated MH+ (488); Found 100% MH+ m/z (488), Rt = 3.26 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.34 (2 H, d, J=8.3 Hz), 7.18 - 7.29 (5 H, m), 7.03 - 7.09 (2 H, m), 6.24 (1 H, s), 5.66 (2 H, s), 3.90 - 3.96 (4 H, m), 3.78 - 3.89 (1 H, m), 3.51 - 3.69 (4 H, m), 3.42 - 3.47 (2 H, m), 3.34 - 3.40 (4 H, m), 3.28 - 3.34 (2 H, m), 2.23 - 2.38 (6 H, m), 1.72 - 1.92 (2 H, m).
The following compounds were made as described in R8, General Procedure M above. The compounds were purified by silica flash column chromatography, unless otherwise stated.
Example 18 - l-[(l-benzyl-lH-tetrazol-5-yl)(lH-pyrazol-3-yl)methyl]-4-cyclobutyl-l,4- diazepane. Potency range B
Figure imgf000072_0001
In a similar fashion (R8, GP M), lH-pyrazole-5-carbaldehyde (28 mg, 0.29 mmol) and 1- cyclobutyl-[l,4]diazepane (49 mg, 0.29 mmol) gave the title compound as colourless oil after purification by preparative HPLC (55 mg, 37% yield, TFA salt). LCMS data: MH+ (393); Found 98% MH+ m/z (393.2), Rt = 2.77 mins.
NMR data: 1H NMR (360 MHz, MeOH) δ ppm 7.61 - 7.67 (1 H, m), 7.23 - 7.37 (3 H, m), 7.04 - 7.21 (2 H, m), 6.26 - 6.34 (1 H, m), 5.65 (1 H, d, J=15.9 Hz), 5.52 (1 H, s), 5.43 (1 H, d, J=15.4 Hz), 3.62 - 3.76 (1 H, m), 2.63 - 3.40 (8 H, m), 2.10 - 2.36 (4 H, m), 1.71 - 2.04 (4 H, m).
Example 19 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-pyrazol-l-yl)phenyl]methyl}-4- cyclopentyl-l,4-diazepane. Potency range A
Figure imgf000072_0002
In a similar fashion (R8, GP M), 4-pyrazol-l-yl-benzaldehyde (50 mg, 0.29 mmol) and 1- cyclopentyl-[l,4]diazepane (49 mg, 0.29 mmol) gave the title compound as colourless oil after purification by preparative HPLC (46 mg, 46% yield, TFA salt). LCMS data: MH+ (483); Found 100% MH+ m/z (483), Rt = 3.28 mins. NMR data: 1H NMR (400 MHz, MeOD) δ 8.20 (1 H, d, J=2.4 Hz), 7.73 (1 H, d, J=I .5 Hz), 7.65 (2 H, d, J=8.8 Hz), 7.25 - 7.32 (2 H, m), 7.16 - 7.25 (3 H, m), 7.00 - 7.10 (2 H, m), 6.51 - 6.55 (1 H, m), 5.54 - 5.68 (2 H, m), 5.48 - 5.54 (1 H, m), 3.61 - 3.73 (1 H, m), 3.44 - 3.55 (1 H, m), 3.27 - 3.43 (2 H, m), 3.08 - 3.19 (1 H, m), 2.61 - 3.03 (4 H, m), 1.90 - 2.19 (4 H, m), 1.58 - 1.88 (6 H, m).
Example 20 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-l,2,4-triazol-l-yl)phenyl]methyl}-4- cyclopentyl-l,4-diazepane. Potency range A
Figure imgf000073_0001
In a similar fashion (R8, GP M), 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (50 mg, 0.29 mmol) and l-cyclopentyl-[l,4]diazepane (49 mg, 0.29 mmol) gave the product as colourless oil after purification by preparative HPLC (77 mg, 45% yield, TFA salt). LCMS data: MH+ (484); Found 97% MH+ m/z (484), Rt = 2.50 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ 9.09 (1 H, s), 8.17 (1 H, s), 7.72 (2 H, d, J=8.6 Hz), 7.28 - 7.39 (2 H, m), 7.14 - 7.27 (3 H, m), 6.98 - 7.11 (2 H, m), 5.60 - 5.68 (2 H, m), 5.53 - 5.60 (1 H, m), 3.60 - 3.72 (1 H, m), 3.23 - 3.56 (4 H, m), 2.63 - 3.20 (4 H, m), 1.90 - 2.20 (4 H, m), 1.57 - 1.87 (6 H, m).
Example 21 - l-{(l-benzy]-lH-tetrazol-5-yl)[4-(morpholin-4-ylmethyl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000073_0002
In a similar fashion (R8, GP M), 4-(morpholine-4-ylmethyl)benzaldehyde (53 mg, 0.26 mmol) and l-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol) gave the title compound as colourless oil after purification by preparative HPLC (30 mg, 19% yield, TFA salt). LCMS data: MH+ (502); Found 100% MH+ m/z (502), Rt = 2.38 mins. NMR data: 1H NMR (400 MHz, MeOD) δ 7.38 - 7.48 (2 H, m), 7.19 - 7.37 (5 H, m), 7.04 - 7.15 (2 H, m), 5.58 - 5.72 (2 H, m), 5.54 (1 H, s), 4.32 (2 H, s), 3.92 - 4.11 (2 H, m), 3.66 - 3.84 (3 H, m), 3.01 - 3.38 (8 H, m), 2.63 - 2.97 (4 H, m), 2.12 - 2.38 (4 H, m), 1.71 - 2.06 (4 H, m).
Example 22 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(4-methylpiperazin-l-yl)phenyl]methyl}- 4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000074_0001
In a similar fashion (R8, GP M), 4-(4-methylpiperazineo)benzaldehyde (53 mg, 0.26 mmol) and l-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol) gave the product as colourless oil (25 mg, 19% yield). LCMS data: MH+ (501); Found 98% MH+ m/z (501), Rt = 2.45 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ 7.21 - 7.31 (3 H, m), 6.98 - 7.11 (4 H, m), 6.86 (2 H, d, J=8.8 Hz), 5.62 (1 H, d, J=15.4 Hz), 5.48 (1 H, d, J=15.4 Hz), 5.28 (1 H, s), 3.34 - 3.44 (1 H, m), 3.14 - 3.25 (4 H, m), 2.88 - 3.05 (3 H, m), 2.56 - 2.86 (9 H, m), 2.36 (3 H, s), 1.98 - 2.24 (4 H, m), 1.64 - 1.91 (4 H, m). .
Example 23 - 4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-N,N- dimethylbenzenesulfonamide. Potency range A
Figure imgf000074_0002
In a similar fashion (R8, GP M), 4-Formyl-N,N-dimethyl-benzenesulfonamide (43 mg, 0.20 mmol) and l-cyclobutyl-[l,4]diazepane (31 mg, 0.20 mmol) gave the product as colourless oil as the TFA salt (31 mg, 31% yield).
LCMS data: MH+ (510); Found 98% MH+ m/z (510), Rt = 3.16 mins.
NMR data: 1H NMR (360 MHz, MeOD) δ ppm 7.58 - 7.69 (2 H, m), 7.32 - 7.45 (2 H, m), 7.16 - 7.28 (3 H, m), 7.02 - 7.12 (2 H, m), 5.58 - 5.74 (3 H, m), 3.64 - 3.78 (1 H, m), 3.22 - 3.40 (2 H, m), 3.00 - 3.20 (2 H, m), 2.79 - 2.99 (2 H, m), 2.59 - 2.78 (8 H, m), 2.11 - 2.39 (4 H, m), 1.70 - 2.08 (4 H, m).
Example 24 - l-cyclobutyl-4-{[l-(3-fluorobenzyl)-lH-tetrazol-5-yl] [4-(lH-pyrazol-l- ylmethyl)phenyl]methyl}-l,4-diazepane. Potency range A
Figure imgf000075_0001
In a similar fashion (R8, GP M), 4-Pyrazol-l-ylmethyl-benzaldehyde (53 mg, 0.29 mmol), 1- cyclobutyl-[l,4]diazepane (44 mg, 0.29 mmol) and 4-(3-Fluoro-benzyl)-4H-[l,2,4]triazole (40 μl, 0.29 mmol) gave the product as colourless oil (31 mg, 21% yield) as the TFA salt.
LCMS data: MH+ (501); Found 100 % MH+ m/z (501), Rt = 3.23 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.69 (1 H, d, J=2.2 Hz), 7.53 (1 H, d, J=I .5 Hz), 7.05 - 7.19 (5 H, m), 6.93 (1 H, t, J=8.0 Hz), 6.74 (1 H, d, J=7.6 Hz), 6.69 (IH, d, J=7.6 H), 6.35 (1 H, t, J=2.1 Hz), 5.59 (1 H, d, J=15.9 Hz), 5.53 (1 H, d, J=15.9 Hz), 5.50 (1 H, s), 5.30 (2H, s), 3.67 - 3.81 (1 H, m), 3.04 - 3.41 (4 H, m), 2.64 - 3.00 (4 H, m), 2.12 - 2.39 (4 H,m), 1.69 - 2.10 (4 H, m).
Example 25 - l-cyclobutyl-4-{[l-(3-fluorobenzyl)-lH-tetrazol-5-yl] [4-(lH-l,2,4-triazol-l- ylmethy])pheny]]methyl}-l,4-diazepane. Potency range A
Figure imgf000075_0002
In a similar fashion (R8, GP M), 4-(lH-l,2,4-triazol-l-yl)methyl-benzaldehyde (53 mg, 0.29 mmol), l-cyclobutyl-[l,4]diazepane (44 mg, 0.29 mmol) and 4-(3-Fluoro-benzyl)-4H- [l,2,4]triazole (40 μl, 0.29 mmol) gave the product as colourless oil (45 mg, 31% yield) as the TFA salt.
LCMS data: MH+ (502); Found 100% MH+ m/z (502), Rt = 2.77 mins.
NMR data: 1H NMR (360 MHz, MeOH) δ ppm 8.82 (1 H, s), 8.19 (1 H, s), 7.20 - 7.28 (2 H, d, J=8.1 Hz), 7.08 - 7.08 (3 H, m), 6.85 - 6.95 (1 H, t, J=8.6 Hz), 6.73 - 6.80 (1 H, d, J=7.7 Hz), 6.61 - 6.70 (1 H, d, J=7.7 Hz), 5.50 - 5.66 (3 H, m), 5.42 (2 H, s), 3.67 - 3.81 (1 H, m), 3.06 - 3.40 (4 H, m), 2.82 - 3.01 (2 H, m), 2.68 - 2.80 (2 H, m), 2.12 - 2.37 (4 H, m), 1.71 - 2.08 (4 H, m). Example 26 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-l,2,4-triazol-l- ylmethy])pheny]]methyl}-4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000076_0001
In a similar fashion (R8, GP M), 4-(lH-l,2,4-triazol-l-yl)methyl-benzaldehyde (359 mg, 1.92 mmol) and l-cyclobutyl-[l,4]diazepane (296 mg, 1.92 mmol) gave the product as a white solid (100 mg, 11% yield).
LCMS data: MH+ (484); Found 100% MH+ m/z (484), Rt = 1.03 mins.
NMR data: 1H NMR (360 MHz, MeOH) δ IH NMR (400 MHz, MeOD) d ppm 8.55 (1 H, s), 8.01 (1 H, s), 7.17 - 7.27 (7 H, m), 7.03 - 7.09 (2 H, m), 5.68 (1 H, d, J=15.7 Hz), 5.62 (1 H, d, J=15.7 Hz), 5.39 (2 H, s), 5.33 (1 H, s), 2.85 - 2.97 (1 H, m), 2.69 - 2.83 (2 H, m), 2.57 - 2.69 (2 H, m), 2.30 - 2.56 (4 H, m), 1.94 - 2.06 (2 H, m), 1.74 - 1.87 (2 H, m), 1.58 - 1.72 (4 H, m).
Example 27 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-l,2,4-triazol-l-yl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000076_0002
In a similar fashion (R8, GP M), 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (225 mg, 1.30 mmol) and l-cyclobutyl-[l,4]diazepane (200 mg, 1.30 mmol) gave the product as a white solid (180 mg, 30% yield).
LCMS data: MH+ (470); Found 100% MH+ m/z (470), Rt = 1.06 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.96 (1 H, s), 8.05 (1 H, s), 7.62 (2 H, d, J=8.8 Hz), 7.30 (2 H, d, J=8.8 Hz), 7.12 - 7.21 (3 H, m), 7.00 - 7.07 (2 H, m), 5.56 - 5.67 (2 H, m), 5.29 - 5.33 (1 H, m), 2.75 - 2.85 (1 H, m), 2.51 - 2.74 (4 H, m), 2.22 - 2.46 (4 H, m), 1.84 - 1.95 (2 H, m), 1.47 - 1.76 (6 H, m). Example 28 - l-[(l-benzyl-lH-tetrazol-5-yl)(4-bromophenyl)methyl]-4-cyclobutyl-l,4- diazepane. Potency range B
Figure imgf000077_0001
In a similar fashion (R8, GP M), 4-bromobenzaldehyde (120 mg, 0.64 mmol) and 1- cyclobutyl-[l,4]diazepane (100 mg, 0.64 mmol) gave the product as a clear oil (192 mg, 64% yield).
LCMS data: MH+ (482); Found 100% MH+ m/z (482), Rt = 3.51 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.55 (2 H, d, J=8.6 Hz), 7.38 - 7.46 (3 H, m), 7.21 - 7.30 (4 H, m), 5.76 - 5.87 (2 H, m), 5.46 (1 H, s), 3.03 - 3.14 (1 H, m), 2.72 - 2.97 (4 H, m), 2.47 - 2.71 (4 H, m), 2.11 - 2.20 (2 H, m), 1.91 - 2.02 (2 H, m), 1.71 - 1.88 (4 H, m).
Example 29 - l-[(l-benzyl-lH-tetrazol-5-yl)(3-morpholin-4-ylphenyl)methyl]-4- cyclobutyl-l,4-diazepane. Potency range B
Figure imgf000077_0002
In a similar fashion (R8, GP M), 3-N-morpholinebenzaldehyde (49.6 mg, 0.26) and 1- cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol) gave the product as pale yellow oil (40 mg,
31%, free base).
LCMS data: Calculated MH+ (487); Found 100% (MH+) m/z 487.31, Rt 3.07 mins.
ΝMR data: 1H ΝMR (400 MHz, MeOD) δ ppm 7.21 - 7.30 (3 H, m), 7.15 - 7.20 (1 H, m), 6.99 - 7.04 (2 H, m), 6.89 (1 H, dd, J=8.3, 2.0 Hz), 6.68 - 6.76 (2 H, m), 5.50 - 5.66 (2 H, m),
5.34 (1 H, s), 3.74 - 3.81 (4 H, m), 3.47 - 3.56 (1 H, m), 2.89 - 3.08 (8 H, m), 2.64 - 2.87 (4 H, m), 2.03 - 2.28 (4 H, m), 1.67 - 1.94 (4 H, m).
Example 30 - l-[(l-butyl-lH-tetrazol-5-yl)(4-fluorophenyl)methyl]-4-cyclobutyl-l,4- diazepane. Potency range C
Figure imgf000078_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (50 mg, 0.32 mmol), 4- fluorobenzaldehyde (40.2 mg, 0.32 mmol), rc-butyl isocyanide (27 mg, 0.32 mmol) and trimethylsilyl azide (37.3 mg, 0.32 mmol) gave the title compound after purification by preparative HPLC (74 mg, 44%, TFA salt).
LCMS data: Calculated MH+ (387); Found 100% (MH+) m/z 387.39, Rt 3.04 mins. NMR data: IH NMR (400 MHz, MeOD) δ ppm 7.34 - 7.42 (2 H, m), 7.11 - 7.19 (2 H, m), 5.57 (1 H, s), 4.22 - 4.34 (2 H, m), 3.79 (1 H, d, J=5.1 Hz), 2.68 - 3.46 (8 H, m), 1.93 - 2.41 (6 H, m), 1.52 - 1.92 (4 H, m), 1.12 - 1.30 (2 H, m), 0.83 (3 H, t, J=7.3 Hz).
Example 31 - 5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-l- methyl-lH-benzotriazole. Potency range A
Figure imgf000078_0002
In a similar fashion (R 8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 1-methyl- lH-l,2,3-benzotriazole-5-carbaldehyde (42 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound (65 mg, 55%). LCMS data: Calculated MH+ (457); Found 95% (MH+) m/z 457.27, Rt 2.86 mins. NMR data: 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (1 H, s), 7.64 (1 H, dd, J=8.7, 1.3 Hz), 7.46 (1 H, d, J=8.6 Hz), 7.28 - 7.34 (3 H, m), 7.07 - 7.14 (2 H, m), 5.52 - 5.76 (2 H, m), 5.18 (1 H, s), 4.29 (3 H, s), 2.81 - 2.90 (1 H, m), 2.62 - 2.80 (4 H, m), 2.48 (2 H, t, J=5.7 Hz), 2.31 - 2.43 (2 H, m), 1.93 - 2.03 (2 H, m), 1.53 - 1.83 (6 H, m).
Example 32 - l-{4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] phenyl} pyrrolidin-2-one. Potency range A
Figure imgf000079_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-(2-oxo- l-pyrrolidinyl)benzaldehyde (49 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (31 mg, 25%, free base).
LCMS data: Calculated MH+ (486); Found 100% (MH+) m/z 486.41, Rt 2.94 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.51 - 7.57 (2 H, m), 7.17 - 7.30 (5 H, m), 7.01 - 7.10 (2 H, m), 5.51 - 5.67 (2 H, m), 5.39 (1 H, s), 3.83 - 3.92 (2 H, m), 3.41 - 3.53 (1 H, m), 2.95 - 3.06 (2 H, m), 2.64 - 2.92 (5 H, m), 2.54 - 2.62 (2 H, m), 2.01 - 2.26 (6 H, m), 1.67 - 1.92 (4 H, m).
Example 33 - 2-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]imidazo[l,2-a]pyridine. Potency range C
Figure imgf000079_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), imidazo(l,2-a)pyridine-2-carbaldehyde (38 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification by preparative HPLC (61 mg, 42%, TFA salt). LCMS data: Calculated MH+ (443); Found 100% (MH+) m/z 443.38, Rt 2.74 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.59 (1 H, br. s.), 7.76 - 8.04 (3 H, m), 7.45 (1 H, t, J=6.4 Hz), 7.10 - 7.34 (5 H, m), 6.05 (1 H, br. s.), 5.71 - 5.94 (2 H, m), 3.62 (1 H, br. s.), 2.58 - 3.40 (8 H, m), 2.10 - 2.38 (4 H, m), 1.67 - 2.08 (4 H, m).
Example 34 - 6-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]imidazo[l,2-a] pyridine. Potency range B
Figure imgf000080_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), imidazo(l,2-a)pyridine-6-carbaldehyde (38 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification by preparative HPLC (46 mg, 32%, TFA salt).
LCMS data: Calculated MH+ (443); Found 97% (MH+) m/z 443.38, Rt 2.07 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.15 (1 H, d, J=50.6 Hz), 7.94 - 8.06 (3 H, m), 7.85 (1 H, d, J=9.3 Hz), 6.97 - 7.17 (5 H, m), 5.87 (1 H, d, ./=15.7 Hz), 5.81 (1 H, d, J=10.3 Hz), 5.60 - 5.69 (1 H, m), 3.64 - 3.77 (1 H, m), 2.63 - 3.41 (8 H, m), 2.14 - 2.39 (4 H, m), 1.70 - 2.12 (4 H, m).
Example 35 - 2-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] thieno [2,3-b] pyridine. Potency range A
Figure imgf000080_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), thieno[2,3- b]pyridine-2-carbaldehyde (42 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (6 mg, 5%, free base). LCMS data: Calculated MH+ (460); Found 99% (MH+) m/z 460.4, Rt 3.04 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.48 (1 H, dd, J=4.8, 1.6 Hz), 8.00 (1 H, dd, J=8.1, 1.7 Hz), 7.37 (1 H, dd, J=8.1, 4.6 Hz), 7.17 - 7.28 (5 H, m), 6.69 (1 H, d, J=1.2 Hz), 5.86 (1 H, d, J=1.2 Hz), 5.72 - 5.83 (2 H, m), 3.20 (1 H, d, J=18.3 Hz), 2.89 - 3.05 (3 H, m), 2.58 - 2.82 (5 H, m), 2.05 - 2.18 (2 H, m), 1.60 - 2.00 (6 H, m). Example 36 - 5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-l- methyl-lH-indole. Potency range A
Figure imgf000081_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 1-methyl- lH-indole-5-carbaldehyde (41.3 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification by preparative ΗPLC (29 mg, 20%, TFA salt).
LCMS data: Calculated MH+ (456); Found 95% (MH+) m/z 456.48, Rt 3.27 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.34 (1 H, d, J=8.6 Hz), 7.28 (1 H, s), 7.11 -
7.22 (4 H, m), 7.08 (1 H, dd, J=8.6, 1.7 Hz), 6.93 (2 H, d, J=6.6 Hz), 6.37 (1 H, d, J=2.4 Hz),
5.56 (1 H, d, J=15.6 Hz), 5.44 - 5.51 (1 H, m), 5.32 (1 H, d, J=15.7 Hz), 3.69 - 3.82 (4 H, m),
2.66 - 3.29 (8 H, m), 2.12 - 2.38 (4 H, m), 1.71 - 2.05 (4 H, m).
Example 37 - l-[(l-benzyl-lH-tetrazol-5-yl)(6-piperidin-l-ylpyridin-2-yl)methyl]-4- cyclobutyl-l,4-diazepane. Potency range B
Figure imgf000081_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 6- piperidmopyridine-2-carbaldehyde (49.3 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification by preparative HPLC (63 mg, 40%, TFA salt).
LCMS data: Calculated MH+ (487); Found 95% (MH+) m/z 487.48, Rt 3.43 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.54 (1 H, dd, J=8.7, 7.2 Hz), 7.21 - 7.30 (3
H, m), 7.02 - 7.10 (2 H, m), 6.80 (1 H, d, J=8.8 Hz), 6.64 (1 H, d, J=6.8 Hz), 5.42 - 5.62 (3 H, m), 3.68 - 3.78 (1 H, m), 2.66 - 3.57 (12 H, m), 1.91 - 2.38 (6 H, m), 1.71 - 1.90 (2 H, m),
1.44 - 1.69 (6 H, m). Example 38 - l-{(l-benzyl-lH-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000082_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 3-
(trifluormethoxy)benzaldehyde (49.3 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (53 mg, 34%, TFA salt).
LCMS data: Calculated MH+ (487); Found 97% (MH+) m/z 487.47, Rt 3.46 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.33 (1 H, t, J=7.8 Hz), 7.13 - 7.28 (5 H, m),
7.00 - 7.12 (3 H, m), 5.59 - 5.72 (2 H, m), 5.57 (1 H, s), 3.68 - 3.79 (1 H, m), 3.01 - 3.40 (4 H, m), 2.62 - 2.99 (4 H, m), 2.11 - 2.39 (4 H, m), 1.70 - 2.09 (4 H, m).
Example 39 - l-{(l-benzyl-lH-tetrazol-5-yl)[3-(difluoromethoxy)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000082_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 3- (difluoromethoxy)benzaldehyde (44.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (65 mg, 43%, TFA salt).
LCMS data: Calculated MH+ (469); Found, 100% (MH+) m/z 469.45, Rt 3.34 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.17 - 7.32 (4 H, m), 6.94 - 7.10 (5 H, m), 6.74 (1 H, t, J=73.7 Hz), 5.62 (2 H, br. s.), 5.51 (1 H, s), 3.67 - 3.78 (1 H, m), 3.02 - 3.40 (4 H, m), 2.63 - 2.99 (4 H, m), 2.12 - 2.38 (4 H, m), 1.70 - 2.09 (4 H, m). Example 40 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-pyrazol-l-yl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000083_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-(1H- pyrazol-l-yl)benzaldehyde (44.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative ΗPLC purification (67 mg, 44%, TFA salt).
LCMS data: Calculated MH+ (469); Found 100% (MH+) m/z 469.51, Rt 3.17 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.19 (1 H, d, J=2.4 Hz), 7.72 (1 H, d, ./=1.5 Hz), 7.65 (2 H, d, J=8.6 Hz), 7.17 - 7.33 (5 H, m), 7.06 (2 H, br. s.), 6.53 (1 H, t, J=2.2 Hz), 5.56 - 5.67 (2 H, m), 5.53 (1 H, s), 3.68 - 3.78 (1 H, m), 3.05 - 3.42 (4 H, m), 2.63 - 3.04 (4 H, m), 2.12 - 2.37 (4 H, m), 1.69 - 2.11 (4 H, m).
Example 41 - l-[(l-benzyl-lH-tetrazol-5-yl)(5-methylisoxazol-3-yl)methyl]-4-cyclobutyl- 1,4-diazepane. Potency range B
Figure imgf000083_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 5-methyl- 3-isoxazolecarbaldehyde (29 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (31 mg, 23%, TFA salt).
LCMS data: Calculated MH+ (408); Found 93% (MH+) m/z 408.42, Rt 2.98 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.21 - 7.33 (3 H, m), 7.06 - 7.19 (2 H, m), 6.16 (1 H, d, J=5.9 Hz), 5.45 - 5.70 (3 H, m), 3.41 - 3.63 (1 H, m), 2.63 - 3.27 (7 H, m), 1.60 - 2.48 (12 H, m). Example 42 - l-{(l-benzyl-lH-tetrazol-5-yl)[3-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl]methyl}-4-cyclobutyl-l,4-diazepane. Potency range B
Figure imgf000084_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 3-(5- methyl-[l,2,4]oxadiazol-3-yl)benzaldehyde (48.8 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (67 mg, 43%, TFA salt).
LCMS data: Calculated MH+ (485); Found 100% (MH+) m/z 485.56, Rt 3.20 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.92 (1 H, d, J=7.8 Hz), 7.79 (1 H, d, J=13.0 Hz), 7.32 - 7.46 (2 H, m), 7.00 - 7.21 (5 H, m), 5.56 - 5.71 (3 H, m), 3.66 - 3.81 (1 H, m), 3.04 - 3.42 (4 H, m), 2.60 - 3.04 (7 H, m), 2.13 - 2.40 (4 H, m), 1.70 - 2.11 (4 H, m).
Example 43 - l-{(l-benzyl-lH-tetrazol-5-yl)[3-(lH-l,2,4-triazol-l-yl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range B
Figure imgf000084_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 3-(1H- l,2,4-triazol-l-yl)benzaldehyde (45 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (43 mg, 35%, free base).
LCMS data: Calculated MH+ (470); Found 100% (MH+) m/z 470.39, Rt 2.83 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.99 (1 H, s), 8.15 (1 H, s), 7.72 (1 H, dd, J=8.1, 1.2 Hz), 7.62 (1 H, t, J=I.8 Hz), 7.44 (1 H, t, J=7.9 Hz), 7.26 (1 H, d, J=7.8 Hz), 7.12 - 7.21 (3 H, m), 7.03 - 7.10 (2 H, m), 5.63 - 5.77 (2 H, m), 5.54 (1 H, s), 3.33 - 3.44 (1 H, m), 2.67 - 3.07 (8 H, m), 2.11 - 2.22 (2 H, m), 1.97 - 2.09 (2 H, m), 1.64 - 1.93 (4 H, m). Example 44 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-pyrazol-l-ylmethyl)phenyl]methyl}- 4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000085_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-(1H- pyrazol-l-yl)methylbenzaldehyde (48.3 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative ΗPLC purification (77 mg, 50%, TFA salt).
LCMS data: Calculated MH+ (483); Found 97% (MH+) m/z 483.50, Rt 3.10 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.70 (1 H, d, J=2.0 Hz), 7.53 (1 H, d, J=I .5 Hz), 7.08 - 7.24 (7 H, m), 6.98 (2 H, d, J=7.1 Hz), 6.35 (1 H, t, J=2.2 Hz), 5.48 - 5.61 (2 H, m), 5.45 (1 H, s), 3.66 - 3.78 (1 H, m), 2.57 - 3.40 (8 H, m), 2.11 - 2.39 (4 H, m), 1.70 - 2.10 (4 H, m).
Example 45 - l-{(l-benzyl-lH-tetrazol-5-yl)[3-(lH-pyrazol-l-ylmethyl)phenyl]methyl}- 4-cyclobutyl-l,4-diazepane. Potency range B
Figure imgf000085_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 3-(1H- pyrazol-l-ylmethyl)benzaldehyde (48.3 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative ΗPLC purification (79 mg, 51%, TFA salt).
LCMS data: Calculated MH+ (483); Found 97% (MH+) m/z 483.50, Rt 3.11 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.66 (1 H, d, J=2.0 Hz), 7.52 (1 H, d, J=I .5
Hz), 7.18 - 7.28 (4 H, m), 7.13 - 7.18 (1 H, m), 6.95 - 7.10 (4 H, m), 6.33 (1 H, t, J=2.1 Hz), 5.44 - 5.61 (2 H, m), 5.43 (1 H, s), 3.66 - 3.79 (1 H, m), 3.00 - 3.39 (4 H, m), 2.55 - 2.94 (4 H, m), 2.13 - 2.39 (4 H, m), 1.71 - 2.08 (4 H, m). Example 46 2-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] qu inoline. Potency range B
Figure imgf000086_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 2- quinolinecarbaldehyde (40.8 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (3.5 mg,
3%, free base).
LCMS data: Calculated MH+ (455); Found 100% (MH+) m/z 455.37, Rt 3.27 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.31 (1 H, d, J=8.6 Hz), 7.89 (1 H, d, J=7.8
Hz), 7.73 - 7.79 (2 H, m), 7.66 - 7.72 (1 H, m), 7.56 - 7.61 (1 H, m), 7.12 - 7.19 (3 H, m), 7.03
- 7.10 (2 H, m), 5.67 - 5.74 (2 H, m), 5.54 - 5.60 (1 H, m), 3.03 - 3.27 (2 H, m), 2.47 - 3.01 (7
H, m), 2.04 - 2.17 (2 H, m), 1.63 - 2.01 (6 H, m).
Example 47 3-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] qu inoline. Potency range b
Figure imgf000086_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 3- quinolinecarbaldehyde (40.8 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (9 mg, 7%, free base).
LCMS data: Calculated MH+ (454); Found 99% (MH+) m/z 454.36, Rt 2.99 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.89 (1 H, d, J=2.4 Hz), 7.99 (1 H, d, J=8.6 Hz), 7.71 - 7.81 (3 H, m), 7.56 - 7.61 (1 H, m), 7.00 - 7.13 (5 H, m), 5.77 - 5.83 (1 H, m), 5.75 (1 H, s), 5.64 - 5.71 (1 H, m), 3.23 - 3.35 (1 H, m), 2.55 - 3.07 (8 H, m), 2.06 - 2.19 (2 H, m), 1.64 - 2.03 (6 H, m). Example 48 - l-[(l-benzyl-lH-tetrazol-5-yl)(6-tert-butoxypyridin-3-yl)methyl]-4- cyclobutyl-l,4-diazepane. Potency range B
Figure imgf000087_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 6- methoxy-3-pyridinecarbaldehyde (35.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (14 mg, 12%, free base).
LCMS data: Calculated MH+ (434); Found 100% (MH+) m/z 434.39, Rt 2.96 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.86 (1 H, d, J=2.7 Hz), 7.63 (1 H, dd, J=8.7, 2.6 Hz), 7.26 - 7.31 (3 H, m), 7.09 - 7.15 (2 H, m), 6.71 (1 H, d, J=8.8 Hz), 5.66 - 5.75 (2 H, m), 5.37 (1 H, s), 3.86 (3 H, s), 3.12 - 3.23 (1 H, m), 2.52 - 2.92 (8 H, m), 2.05 - 2.15 (2 H, m), 1.86 - 1.99 (2 H, m), 1.62 - 1.82 (4 H, m).
Example 49 - l-[(l-benzyl-lH-tetrazol-5-yl)(2,3-dihydro-l,4-benzodioxin-6-yl)methyl]-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000087_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 1,4- benzodioxan-6-carbaldehyde (42.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative
HPLC purification (75 mg, 50%, TFA salt).
LCMS data: Calculated MH+ (461); Found 100% (MH+) m/z 461.30, Rt 3.09 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.20 - 7.30 (3 H, m), 6.98 - 7.03 (2 H, m),
6.69 - 6.74 (1 H, m), 6.58 - 6.65 (2 H, m), 5.47 - 5.61 (2 H, m), 5.33 (1 H, s), 4.13 - 4.22 (4 H, m), 3.69 - 3.79 (1 H, m), 2.65 - 3.47 (8 H, m), 2.14 - 2.39 (4 H, m), 2.14 - 2.39 (4 H, m), 1.71
- 2.14 (4 H, m), 1.71 - 2.14 (4 H, m). Example 50 - l-[(l-benzyl-lH-tetrazol-5-yl)(l-methyl-lH-imidazol-2-yl)methyl]-4- cyclobutyl-l,4-diazepane. Potency range C
Figure imgf000088_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 1-methyl- 2-imidazolecarbaldehyde (28.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (42 mg, 31%, TFA salt).
LCMS data: Calculated MH+ (407); Found 100% (MH+) m/z 407.27, Rt 2.26 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.58 (1 H, d, J=I.7 Hz), 7.18 - 7.42 (6 H, m), 6.09 - 6.24 (1 H, m), 5.70 - 5.92 (2 H, m), 3.97 (3 H, s), 3.55 - 3.73 (1 H, m), 2.53 - 3.43 (8 H, m), 2.20 (4 H, dd, J=19.9, 9.7 Hz), 1.68 - 2.08 (4 H, m).
Example 51 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(methylsulfbnyl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000088_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4- methylsulphonyl benzaldehyde (47.7 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (50 mg, 32%, free base).
LCMS data: Calculated MH+ (481); Found 98% (MH+) m/z 481.31, Rt 2.81 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.80 (2 H, d, J=8.3 Hz), 7.42 (2 H, d, J=8.3 Hz), 7.20 - 7.28 (3 H, m), 7.04 - 7.12 (2 H, m), 5.63 - 5.77 (2 H, m), 5.57 (1 H, s), 3.24 - 3.35 (1 H, m), 3.09 (3 H, s), 2.60 - 2.99 (8 H, m), 2.07 - 2.20 (2 H, m), 1.93 - 2.05 (2 H, m), 1.62 - 1.89 (4 H, m). Example 52 - l-{(l-benzyl-lH-tetrazol-5-yl)[3-(lH-pyrrol-l-yl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000089_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 3-(1H- pyrrol- l-yl)benzaldehyde (44.3 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative ΗPLC purification (47 mg, 32%, TFA salt).
LCMS data: Calculated MH+ (468); Found 99% (MH+) m/z 468.34, Rt 3.36 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.36 - 7.41 (1 H, m), 7.32 (1 H, t, J=7.8 Hz), 7.11 - 7.28 (4 H, m), 6.98 - 7.09 (5 H, m), 6.26 (2 H, t, J=2.2 Hz), 5.59 - 5.69 (2 H, m), 5.54 (1 H, s), 3.67 - 3.77 (1 H, m), 2.65 - 3.43 (8 H, m), 2.11 - 2.37 (4 H, m), 1.69 - 2.10 (4 H, m).
Example 53 - 5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]- 2,1,3-benzoxadiazole. Potency range B
Figure imgf000089_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 2,1,3- benzoxadiazole-5-carbaldehyde (38.4 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (38 mg, 26%, TFA salt).
LCMS data: Calculated MH+ (445); Found 100% (MH+) m/z 445.30, Rt 3.05 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.85 (1 H, d, J=9.3 Hz), 7.65 (1 H, d, J=9.3 Hz), 7.00 - 7.17 (6 H, m), 5.76 - 5.84 (1 H, m), 5.60 - 5.70 (2 H, m), 3.68 - 3.81 (1 H, m), 2.62 - 3.43 (8 H, m), 1.70 - 2.39 (8 H, m).
Example 54 - l-[(l-benzyl-lH-tetrazol-5-yl)(6-pyrrolidin-l-ylpyridin-3-yl)methyl]-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000090_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 2- pyrrolidinopyridine-5-carbaldehyde (45.7 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (71 mg, 47%, TFA salt).
LCMS data: Calculated MH+ (473); Found 99% (MH+) m/z 473.34, Rt 2.24 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.95 (1 H, d, J=9.3 Hz), 7.44 (1 H, d, J=46.2 Hz), 7.25 - 7.35 (3 H, m), 7.08 - 7.20 (2 H, m), 7.01 (1 H, d, J=9.5 Hz), 5.79 - 5.87 (1 H, m), 5.63 - 5.75 (1 H, m), 5.52 - 5.59 (1 H, m), 3.43 - 3.77 (5 H, m), 3.20 - 3.40 (2 H, m), 2.63 - 3.15 (6 H, m), 2.09 - 2.37 (8 H, m), 1.70 - 2.06 (4 H, m).
Example 55 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(pyrimidin-2-yloxy)phenyl]niethyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000090_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4- (pyrimidin-2-yloxy)benzaldehyde (51.9 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative ΗPLC purification (92 mg, 49%, TFA salt). LCMS data: Calculated MH+ (497); Found 95% (MH+) m/z 497.4, Rt 3.09 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.60 (2 H, d), 8.51 - 8.71 (2 H, m), 7.37 - 7.60 (1 H, m), 6.91 - 7.36 (10 H, m), 5.38 - 5.77 (3 H, m), 3.67 - 3.87 (1 H, m), 3.51 - 3.64 (1 H, m), 2.59 - 3.24 (6 H, m), 1.68 - 2.47 (8 H, m). Example 56 - 5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]- 2,1,3-benzothiadiazole. Potency range B
Figure imgf000091_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 2,1,3- benzothiadiazole-5-carbaldehyde (42.5 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (45 mg, 30%, TFA salt).
LCMS data: Calculated MH+ (461); Found 100% (MH+) m/z 461.39, Rt 3.06 mins. NMR data: IH NMR (400 MHz, MeOD) δ ppm 7.94 (1 H, d, J=9.0 Hz), 7.74 (1 H, d, J=9.3 Hz), 7.22 - 7.36 (1 H, m), 6.91 - 7.05 (5 H, m), 5.69 - 5.79 (2 H, m), 5.57 - 5.66 (1 H, m), 3.66 - 3.82 (1 H, m), 3.33 - 3.43 (1 H, m), 2.66 - 3.29 (7 H, m), 1.71 - 2.40 (8 H, m).
Example 57 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(l,2,3-thiadiazol-4-yl)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000091_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-(l,2,3- thiadiazol-4-yl)benzaldehyde (49.3 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (54 mg, 43%, free base).
LCMS data: Calculated MH+ (487); Found 92% (MH+) m/z 487.42, Rt 3.14 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 9.25 (1 H, s), 7.96 - 8.03 (2 H, m), 7.39 (2 H, d, J=8.1 Hz), 7.23 - 7.32 (3 H, m), 7.14 (2 H, dd, J=6.7, 2.8 Hz), 5.66 - 5.79 (2 H, m), 5.42 (1 H, s), 2.65 - 2.98 (5 H, m), 2.35 - 2.60 (4 H, m), 1.96 - 2.07 (2 H, m), 1.58 - 1.87 (6 H, m). Example 58 - 6-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]imidazo[2,l-b][l,3]thiazole. Potency range B
Figure imgf000092_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), imidazo[2,l-b]thiazole-6-carbaldehyde (39.5 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (58 mg, 40%, TFA salt).
LCMS data: Calculated MH+ (449); Found 95% (MH+) m/z 449.37, Rt 2.80 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.74 (1 H, d, J=4.4 Hz), 7.39 - 7.59 (1 H, m), 7.31 - 7.35 (1 H, m), 7.18 - 7.27 (3 H, m), 7.09 - 7.15 (2 H, m), 5.63 - 5.77 (3 H, m), 3.61 - 3.73 (1 H, m), 2.67 - 3.41 (8 H, m), 2.13 - 2.36 (4 H, m), 1.72 - 2.06 (4 H, m).
Example 59 - l-[(l-benzyl-lH-tetrazol-5-yl)(2,3-dihydro-l-benzofuran-5-yl)methyl]-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000092_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 2,3- dihydrobenzo[b]furan-5-carboxaldehyde (38.4 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (42 mg, 29%, TFA salt).
LCMS data: Calculated MH+ (445); Found 95% (MH+) m/z 445.37, Rt 3.12 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.20 - 7.29 (3 H, m), 6.98 (2 H, dd, J=7.8, 1.5 Hz), 6.85 - 6.96 (2 H, m), 6.62 (1 H, d, J=8.1 Hz), 5.46 - 5.59 (2 H, m), 5.35 (1 H, s), 4.50 (2 H, t, J=8.9 Hz), 3.70 - 3.80 (1 H, m), 2.61 - 3.46 (10 H, m), 2.13 - 2.39 (4 H, m), 1.71 - 2.07 (4 H, m). Example 60 - 6-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-lH- indole. Potency range A
Figure imgf000093_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), lH-indole-
6-carbaldehyde (37.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative ΗPLC purification (16 mg, 11%, TFA salt).
LCMS data: Calculated MH+ (442); Found 98% (MH+) m/z 442.36, Rt 3.20 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.55 (1 H, d, J=8.3 Hz), 7.25 - 7.29 (1 H, m),
7.09 - 7.19 (3 H, m), 6.97 - 7.04 (2 H, m), 6.89 - 6.94 (2 H, m), 6.44 (1 H, d, J=2.9 Hz), 5.55
(1 H, d, J=15.4 Hz), 5.47 (1 H, s), 5.34 (1 H, d, J=15.4 Hz), 3.75 (1 H, d, J=8.3 Hz), 2.58 -
3.42 (8 H, m), 2.11 - 2.39 (4 H, m), 1.72 - 2.05 (4 H, m).
Example 61 5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] pyridin-2-ol. Potency range A
Figure imgf000093_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 2- hydroxypyridine-5-carbaldeyde (32 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative
HPLC purification (22 mg, 16%, TFA salt).
LCMS data: Calculated MH+ (420); Found 94% (MH+) m/z 420.31, Rt 2.49 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.62 (1 H, dd, J=9.5, 2.4 Hz), 7.24 - 7.33 (3
H, m), 7.06 - 7.16 (2 H, m), 6.81 (1 H, d, J=48.7 Hz), 6.46 (1 H, d, J=9.3 Hz), 5.74 - 5.81 (1
H, m), 5.57 - 5.67 (1 H, m), 5.34 (1 H, s), 3.66 - 3.78 (1 H, m), 2.59 - 3.39 (8 H, m), 1.71 -
2.39 (8 H, m). Example 62 - 7-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]pyrazolo[l,5-a]pyridine. Potency range C
Figure imgf000094_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), pyrazolo[l,5-a]pyridine-7-carbaldehyde (32 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (3 mg, 2%, TFA salt).
LCMS data: Calculated MH+ (443); Found 96% (MH+) m/z 443.36, Rt 2.93 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.04 (2 H, dd, J=25.6, 2.1 Hz), 7.60 (2 H, dd, J=8.8, 5.1 Hz), 6.89 - 7.20 (12 H, m), 6.70 (2 H, dd, J=13.3, 2.3 Hz), 6.55 (1 H, d, J=6.8 Hz), 6.34 - 6.44 (3 H, m), 5.55 - 5.80 (4 H, m), 3.63 (2 H, dd, J=21.9, 8.7 Hz), 2.64 - 3.43 (15 H, m), 2.45 - 2.54 (1 H, m), 1.67 - 2.34 (16 H, m).
Example 63 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(difluoromethoxy)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000094_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4- (difluoromethoxy)benzaldehyde (44.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (57 mg, 38%, TFA salt).
LCMS data: Calculated MH+ (469); Found 100% (MH+) m/z 469.36, Rt 3.22 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.16 - 7.32 (5 H, m), 7.03 - 7.10 (4 H, m), 6.83 (1 H, t, J=73.7 Hz), 5.62 (2 H, dd), 5.51 (1 H, s), 2.65 - 3.44 (8 H, m), 1.73 - 2.41 (8 H, m). Example 64 - l-[(l-benzyl-lH-tetrazol-5-yl)(6-methylpyridin-2-yl)methyl]-4-cyclobutyl- 1,4-diazepane. Potency range B
Figure imgf000095_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 6-methyl- pyridine-2-carbaldehyde (47.5 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after purification (30 mg, 24%, free base).
LCMS data: Calculated MH+ (418); Found 95% (MH+) m/z 418.40, Rt 3.00 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.60 (1 H, d, J=4.4 Hz), 7.79 - 7.92 (4 H, m), 7.37 (3 H, d, J=8.3 Hz), 7.23 - 7.31 (3 H, m), 7.10 - 7.17 (2 H, m), 5.62 - 5.77 (2 H, m), 5.40 (1 H, s), 2.62 - 2.96 (5 H, m), 2.33 - 2.58 (4 H, m), 1.93 - 2.05 (2 H, m), 1.56 - 1.87 (6 H, m).
Example 65 - Preparation of: l-[(l-benzyl-lH-[l,2,3,4]tetrazol-5-yl)-[4-(5-methyl- [ 1 ,2,4] oxadiazol)phenyl] methyl-4-cyclobutyl- [ 1 ,4] diazepane. Potency range A
Figure imgf000095_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-(5- methyl-l,2,4-oxadiazol-3-yl)benzaldehyde (48.7 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative ΗPLC purification (56 mg, 36%, TFA salt).
LCMS data: Calculated MH+ (485); Found 100% (MH+) m/z 485.40, Rt 3.17 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.91 (2 H, d, J=8.1 Hz), 7.24 - 7.34 (2 H, m), 7.20 (3 H, br. s.), 7.06 (2 H, br. s.), 5.63 (2 H, br. s.), 5.57 (1 H, s), 3.67 - 3.79 (1 H, m), 2.81 - 3.41 (6 H, m), 2.73 (2 H, d, J=10.3 Hz), 2.64 (3 H, s), 2.12 - 2.37 (4 H, m), 1.69 - 2.12 (4 H, m). Example 66 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(2-methyl-lH-imidazol-l- yl)phenyl]methyl}-4-cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000096_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-(2- methyl-imidazol-l-yl)-benzaldehyde (48.2 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (40 mg, 26%, TFA salt).
LCMS data: Calculated MH+ (485); Found 99% (MH+) m/z 485.34, Rt 2.25 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.61 (2 H, s), 7.40 - 7.50 (4 H, m), 7.26 (3 H, br. s.), 7.12 (2 H, br. s.), 5.69 - 5.79 (2 H, m), 5.67 (1 H, s), 3.65 - 3.80 (1 H, m), 3.33 - 3.43 (1 H, m), 2.68 - 3.29 (7 H, m), 2.55 (3 H, s), 2.13 - 2.39 (4 H, m), 1.70 - 2.11 (4 H, m).
Example 67 - l-[(l-benzyl-lH-tetrazol-5-yl){4-[(4-methylpiperazin-l- y^methyllphenyljmethyl^-cyclobutyl-l^-diazepane. Potency range A
Figure imgf000096_0002
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-[(4- methylpiperazin-l-yl)methyl]benzaldehyde (56.5 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (56 mg, 34%, TFA salt).
LCMS data: Calculated MH+ (514); Found 94% (MH+) m/z 514.44, Rt 2.30 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.39 (2 H, d, J=8.1 Hz), 7.19 - 7.31 (5 H, m), 7.08 (2 H, br. s.), 5.55 - 5.69 (2 H, m), 5.49 (1 H, s), 4.11 (2 H, s), 3.67 - 3.78 (1 H, m), 3.53 (4 H, br. s.), 3.02 - 3.38 (8 H, m), 2.95 (3 H, s), 2.62 - 2.92 (4 H, m), 2.21 (4 H, d, J=9.3 Hz), 1.72 - 2.07 (4 H, m). Example 68 - l-{(l-benzy]-lH-tetrazol-5-yl)[4-(pyridin-2-yloxy)phenyl]methyl}-4- cyclobutyl-l,4-diazepane. Potency range A
Figure imgf000097_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (40 mg, 0.26 mmol), 4-(pyrid-2- yloxy)benzaldehyde (51.6 mg, 0.26 mmol), benzyl isocyanide (30.4 mg, 0.26 mmol) and trimethylsilyl azide (29.8 mg, 0.26 mmol) gave the title compound after preparative HPLC purification (61 mg, 38%, TFA salt).
LCMS data: Calculated MH+ (496); Found 99% (MH+) m/z 496.41, Rt 3.22 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1 H, dd, J=5.0, 1.3 Hz), 7.82 - 7.89 (1 H, m), 7.19 - 7.32 (5 H, m), 7.12 - 7.17 (1 H, m), 7.05 - 7.12 (2 H, m), 7.00 - 7.05 (2 H, m), 6.96 (1 H, d, J=8.3 Hz), 5.51 - 5.70 (2 H, m), 5.48 (1 H, s), 3.68 - 3.79 (1 H, m), 2.64 - 3.42 (8 H, m), 2.14 - 2.39 (4 H, m), 1.71 - 2.12 (4 H, m).
Example 69 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-pyrazol-l-ylmethyl)phenyl]methyl}- 4-cyclopentyl-l,4-diazepane. Potency range A
Figure imgf000097_0002
In a similar fashion (R8, GP M), 4-cyclopentyll-[l,4]diazepane (40.7 mg, 0.242 mmol), 4-
(lH-pyrazol-l-yl)methylbenzaldehyde (45 mg, 0.242 mmol), benzyl isocyanide (28.4 mg, 0.242 mmol) and trimethylsilyl azide (28 mg, 0.242 mmol) gave the title compound after purification (55 mg, 46%, free base).
LCMS data: Calculated MH+ (497); Found 99% (MH+) m/z 497.42, Rt 3.17 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.68 (1 H, d, J=2.4 Hz), 7.52 (1 H, d, J=I .2
Hz), 7.18 - 7.28 (5 H, m), 7.03 - 7.14 (4 H, m), 6.33 (1 H, t, J=2.1 Hz), 5.58 - 5.72 (2 H, m), 5.31 (3 H, s), 2.56 - 2.92 (9 H, m), 1.75 - 1.87 (2 H, m), 1.46 - 1.72 (6 H, m), 1.27 - 1.40 (2 H, m). Example 70 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(lH-l,2,4-triazol-l- ylmethy])pheny]]methyl}-4-cyclopentyl-l,4-diazepane. Potency range A
Figure imgf000098_0001
In a similar fashion (R8, GP M), 4-cyclopentyl-[l,4]diazepane (40.4 mg, 0.24 mmol), 4-(1H- l,2,4-triazol-l-ylmethyl)benzaldehyde (45 mg, 0.24 mmol), benzyl isocyanide (28 mg, 0.24 mmol) and trimethylsilyl azide (27.7 mg, 0.24 mmol) gave the title compound after preparative ΗPLC purification (10 mg, 7%, TFA salt).
LCMS data: Calculated MH+ (498); Found 90% (MH+) m/z 498.43, Rt 2.35 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.62 (1 H, s), 8.06 (1 H, s), 7.10 - 7.27 (7 H, m), 6.97 (2 H, t, J=7.8 Hz), 5.48 - 5.61 (2 H, m), 5.45 (1 H, d, J=7.8 Hz), 3.60 - 3.72 (1 H, m), 3.05 - 3.53 (4 H, m), 2.58 - 3.00 (4 H, m), 1.88 - 2.20 (4 H, m), 1.58 - 1.87 (6 H, m).
Example 71 - l-{(l-benzyl-lH-tetrazol-5-yl)[4-(methylsulfonyl)phenyl]methyl}-4- cyclopentyl-l,4-diazepane. Potency range A
Figure imgf000098_0002
In a similar fashion (R8, GP M), 4-cyclopentyl-[l,4]diazepane (41.1 mg, 0.244 mmol), 4- methylsulphonyl benzaldehyde (45 mg, 0.244 mmol), benzyl isocyanide (28.6 mg, 0.244 mmol) and trimethylsilyl azide (28.1 mg, 0.244 mmol) gave the title compound after purification (27 mg, 26.5%, free base).
LCMS data: Calculated MH+ (495); Found 99% (MH+) m/z 495.29, Rt 3.00 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.78 - 7.83 (2 H, m), 7.40 (2 H, d, J=8.3 Hz), 7.18 - 7.27 (3 H, m), 7.03 - 7.08 (2 H, m), 5.60 - 5.76 (3 H, m), 3.44 - 3.54 (1 H, m), 3.25 (2 H, t, J=5.4 Hz), 2.98 - 3.18 (6 H, m), 2.80 - 2.90 (2 H, m), 2.65 - 2.73 (1 H, m), 1.85 - 2.11 (4 H, m), 1.54 - 1.83 (6 H, m). Example 72 - l-{4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclopentyl-l,4-diazepan-l- yl)methyl] phenyl} pyrrolidin-2-one. Potency range A
Figure imgf000099_0001
In a similar fashion (R8, GP M), 4-cyclopentyl-[l,4]diazepane (40.1 mg, 0.238 mmol), 4-(2- oxo-l-pyrrolidinyl)benzaldehyde (45 mg, 0.238 mmol), benzyl isocyanide (27.9 mg, 0.238 mmol) and trimethylsilyl azide (27.4 mg, 0.238 mmol) gave the title compound after preparative HPLC purification (60 mg, 41%, TFA salt).
LCMS data: Calculated MH+ (500); Found 97% (MH+) m/z 500.44, Rt 2.57 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.51 - 7.56 (2 H, m), 7.15 - 7.28 (5 H, m),
7.02 (2 H, d, J=5.6 Hz), 5.41 - 5.64 (3 H, m), 3.87 (2 H, t, J=I Λ Hz), 3.61 - 3.73 (1 H, m),
2.63 - 3.57 (8 H, m), 2.53 - 2.62 (2 H, m), 1.89 - 2.22 (6 H, m), 1.58 - 1.87 (6 H, m).
The following compounds in Table 1 were synthesised according to R8 General Procedure M, above.
Table 1
Mass
Example Expected Rt Potency
Name Found; Number MH+ (mins) range Purity
Figure imgf000099_0002
l-[(l-benzyl-lH-tetrazol-5-yl)(4- fluorophenyl)methyl]-4- cyclo butyl- 1 ,4-diazepane
Figure imgf000100_0001
1 - [( 1 -benzyl- lH-tetrazol-5 -yl)(6- phenoxypyridin-3 -yl)methyl] -A- cyclo butyl- 1 ,4-diazepane
Figure imgf000100_0002
l-[(l-benzyl-lΗ-tetrazol-5-yl)(l- methyl- 1 H-pyrazol-4-yl)methyl]-4- cyclo butyl- 1 ,4-diazepane
Figure imgf000100_0003
1 - [ 1 -benzo furan-5 -yl( 1 -benzyl- 1 H- tetrazol-5-yl)methyl]-4-cyclobutyl- 1 ,4-diazepane
Figure imgf000100_0004
1 - [( 1 -benzyl- 1 H-tetrazol-5 - yl)(pyridin-3 -yl)methyl] -A- cyclo butyl- 1 ,4-diazepane
Figure imgf000100_0005
l-cyclobutyl-4-[(4- fluorophenyl) { 1 - [4- (trifluoromethoxy)benzyl] - 1 H- tetrazol-5-yl}methyl]-l,4- diazepane
Figure imgf000101_0001
1- [(I -benzyl- 1 H-tetrazol-5 -yl)(2,2- difluoro- 1 ,3-benzodioxol-5- yl)methyl]-4-cyclo butyl- 1 ,4- diazepane
Figure imgf000101_0002
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(l - oxidopyridin-4-yl)methyl]-4- cyclo butyl- 1 ,4-diazepane
Figure imgf000101_0003
1 -[4-(I -benzyl- 1 H-tetrazol-5 -yl)-l- (6-fluoropyridin-2-yl)piperidin-4- yl]-4-cyc Io butyl- 1 ,4-diazepane
Figure imgf000101_0004
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(6- morpholin-4-ylpyridin-3- yl)methyl]-4-cyclo butyl- 1 ,4- diazepane
Figure imgf000101_0005
1 - [( 1 -benzyl- lH-tetrazol-5 -yl)(2- methyl- 1 H-imidazo l-4-yl)methyl] - 4-cyclobutyl- 1 ,4-diazepane
Figure imgf000102_0001
l-{(l-benzyl-lH-tetrazol-5-yl)[4- ( 1 H-pyrro 1- 1 -yl)phenyl]methyl} -A- cyclo butyl- 1 ,4-diazepane
Figure imgf000102_0002
1 - {(l-benzyl- lH-tetrazol-5-yl)[4- (trifluoromethoxy)phenyl]methyl} - 4-cyclobutyl- 1 ,4-diazepane
Figure imgf000102_0003
l-{(l-benzyl-lΗ-tetrazol-5-yl)[4- (2-methyl- 1 ,3 -thiazo 1-4- yl)phenyl]methyl} -4-cyclobutyl- 1 ,4-diazepane
Figure imgf000102_0004
l-cyclobutyl-4-[(4- fluorophenyl) {1-[(1 S)-I- phenylethyl]- 1 H-tetrazol-5 - yl} methyl]- 1 ,4-diazepane
Figure imgf000103_0001
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(6- thiomorpholin-4-ylpyridin-3- yl)methyl]-4-cyclo butyl- 1 ,4- diazepane
Figure imgf000103_0002
5- [(I -benzyl- 1 H-tetrazol-5 -yl)(4- cyclo butyl- 1 ,4-diazepan- 1 - yl)methyl]-N,N-diethylpyridin-2- amme
Figure imgf000103_0003
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(3- fluorophenyl)methyl]-4-cyclobutyl- 1 ,4-diazepane
Figure imgf000103_0004
1 -[(1 -benzyl- 1 H-tetrazol-5- yl)(phenyl)methyl]-4-cyclobutyl- 1 ,4-diazepane
Figure imgf000103_0005
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(3,4- dichlorophenyl)methyl]-4- eye Io butyl- 1 ,4-diazepane
Figure imgf000104_0001
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4- (trifluoromethyl)phenyl]methyl}-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000104_0002
5-[(l -benzyl- 1 H-tetrazol-5-yl)(4- cyc Io butyl- 1 ,4-diazepan- 1 - yl)methyl]-lH-indole
Figure imgf000104_0003
6-[(l -benzyl- 1 H-tetrazol-5-yl)(4- cyc Io butyl- 1 ,4-diazepan- 1 - yl)methyl] quino line
Figure imgf000104_0004
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(3,5- dimethylphenyl)methyl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000104_0005
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(4- chloro-3-fluorophenyl)methyl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000105_0001
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(6- chloropyridin-3-yl)methyl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000105_0002
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(5- bromopyridin-3-yl)methyl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000105_0003
1 - [4-( 1 -benzyl- 1 H-tetrazol-5- yl)tetrahydro-2H-pyran-4-yl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000105_0004
1 - [4-( 1 -benzyl- 1 H-tetrazol-5- yl)tetrahydro-2H-pyran-4-yl]-4- cyclopentyl- 1 ,4-diazepane
Figure imgf000105_0005
1 -[I -acetyl-4-(l -benzyl- IH- tetrazol-5-yl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000106_0001
1 -[(1 -benzyl- lH-tetrazol-5-yl)(4- fluorophenyl)methyl] -4-methyl- 1 ,4-diazepane
Figure imgf000106_0002
1 -[(1 -benzyl- lH-tetrazol-5-yl)(4- methoxyphenyl)methyl] -4-methyl- 1 ,4-diazepane
Figure imgf000106_0003
1 -[(1 -benzyl- lH-tetrazol-5-yl)(4- fluorophenyl)methyl]-4-ethyl- 1 ,4- diazepane
Figure imgf000106_0004
1 -[(1 -benzyl- lH-tetrazol-5-yl)(4- methoxyphenyl)methyl] -4-ethyl- 1 ,4-diazepane
Figure imgf000106_0005
l-ethyl-4-{(4-fluorophenyl)[l-(4- methoxybenzyl)- lH-tetrazol-5- yljmethyl} - 1 ,4-diazepane
Figure imgf000107_0001
1 -ethyl-4- { [ 1 -(3 -fluorobenzyl)- IH- tetrazol-5-yl](4- fluorophenyl)methyl} -1,4- diazepane
Figure imgf000107_0002
1 - { [ 1 -(3-fluorobenzyl)- lH-tetrazol- 5-yl](4-fluorophenyl)methyl} -4- methyl- 1 ,4-diazepane
Figure imgf000107_0003
1 - { [ 1 -(4-chlorobenzyl)- lH-tetrazol- 5-yl](4-fluorophenyl)methyl} -4- ethyl- 1 ,4-diazepane
Figure imgf000107_0004
1 -ethyl-4- [(4-fluorophenyl) { 1 -[4- (trifluoromethoxy)benzyl]- IH- tetrazol-5-yl}methyl]- 1 ,4- diazepane
Figure imgf000108_0001
l-cyclobutyl-4-{[l-(3- fluorobenzyl)-lH-tetrazol-5-yl](4- fluorophenyl)methyl} -1,4- diazepane
Figure imgf000108_0002
1 -cyclopentyl-4- { [ 1 -(3- fluorobenzyl)-lH-tetrazol-5-yl](4- fluorophenyl)methyl} -1,4- diazepane
Figure imgf000108_0003
1 -[ 1 -( 1 -benzyl- lH-tetrazol-5- yl)cyclohexyl]-4-ethyl- 1 ,4- diazepane
Figure imgf000108_0004
1 -[(1 -benzyl- lH-tetrazol-5-yl)(4- fluorophenyl)methyl] -A- cyclopentyl- 1 ,4-diazepane
Figure imgf000109_0001
1 -[ 1 -( 1 -benzyl- lH-tetrazol-5- yl)cyclohexyl]-4-cyclopentyl- 1 ,4- diazepane
Figure imgf000109_0002
1 -[4-( 1 -benzyl- lH-tetrazol-5- yl)tetrahydro-2H-pyran-4-yl]-4- ethyl- 1 ,4-diazepane
Figure imgf000109_0003
1 -[ 1 -( 1 -benzyl- lH-tetrazol-5- yl)cyclopentyl]-4-ethyl- 1 ,4- diazepane
Figure imgf000109_0004
1 - {3 -( 1 -benzyl- 1 Η-tetrazol-5 -yl)- 1 - [(I -methyl- 1 H-imidazo 1-2- yl)methyl]azetidin-3-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000109_0005
l-{3-(l-benzyl-lH-tetrazol-5-yl)-l- [(I -methyl- 1 H-imidazo 1-2- yl)methyl]piperidin-3 -yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000110_0001
1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 - [(I -methyl- 1 H-pyrazo 1-5 - yl)sulfonyl]piperidin-4-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000110_0002
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - (methylsulfonyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000110_0003
4-(l -benzyl- 1 H-tetrazol-5 -yl)-4-(4- cyc Io butyl- 1 ,4-diazepan- 1 -yl)-N,N- dimethylpiperidine- 1 -sulfonamide
Figure imgf000110_0004
1 - {4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - [(I -methyl- 1 H-pyrazo 1-4- yl)methyl]piperidin-4-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000111_0001
1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 - [(I -methyl- 1 H-pyrazo 1-5 - yl)methyl]piperidin-4-yl} -4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000111_0002
1 - {3 -( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 - [(I -methyl- 1 H-imidazo 1-2- yl)methyl]pyrrolidin-3 -yl} -4- cyc Io butyl- 1 ,4-diazepane
127 4 49Q11. ή6 4 1 9 0 L 0% 2;' 29.6 (,i7 A
Figure imgf000111_0003
- d[3-(l-benzyl-lH-tetrazol-5-yl)-l- (lH-l,2,4-triazol-l- ylacetyl)pyrrolidin-3-yl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000111_0004
4-(l -benzyl- 1 H-tetrazol-5 -yl)-4-(4- cyc Io butyl- 1 ,4-diazepan- 1 -yl)-N- ethylpiperidine- 1 -carboxamide
Figure imgf000112_0001
4-(l -benzyl- lH-tetrazol-5 -yl)-4-(4- cyc Io butyl- 1 ,4-diazepan- 1 -yl)-N- phenylpiperidine- 1 -carboxamide
Figure imgf000112_0002
l-[3-(l-benzyl-lH-tetrazol-5-yl)-l- (lH-l,2,4-triazol-l- ylacetyl)azetidin-3-yl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000112_0003
l-cyclobutyl-4-{[l-(4- fluorobenzyl)-lH-tetrazol-5-yl](4- fluorophenyl)methyl} - 1 ,4- diazepane
Figure imgf000112_0004
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(4- pyridin-2-ylphenyl)methyl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000112_0005
l-{(l-benzyl-lH-tetrazol-5-yl)[4- (4-methyl-l,2,5-oxadiazol-3- yl)phenyl]methyl} -4-cyclobutyl- 1 ,4-diazepane
Figure imgf000113_0001
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 ■ ( 1 ,3 -thiazo l-2-ylmethyl)piperidin- 4-yl]-4-cyclo butyl- 1 ,4-diazepane
Figure imgf000113_0002
1. [4_( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - ( 1 H-imidazol-2-ylmethyl)piperidin- 4-yl]-4-cyclo butyl- 1 ,4-diazepane
Figure imgf000113_0003
tert-butyl 4-( 1 -benzyl- 1 H-tetrazol- 5-yl)-4-(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)piperidine- 1 -carboxylate
Figure imgf000113_0004
. [4_(' 1 -benzyl- 1 H-tetrazol-5- yl)piperidin-4-yl]-4-cyclobutyl-l,4- diazepane
Figure imgf000113_0005
- {4r-( 1 -benzyl- 1 H-te1t-razol-5-yl)- 1 - [(I -methyl- 1 H-imidazo 1-2- yl)methyl]piperidin-4-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000114_0001
1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 - [(2-methyl- 1 H-imidazo 1-4- yl)methyl]piperidin-4-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000114_0002
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - ( 1 H-pyrazo 1-3 -ylmethyl)piperidin- 4-yl]-4-cyclo butyl- 1 ,4-diazepane
Figure imgf000114_0003
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - (l,3-thiazol-5-ylmethyl)piperidin- 4-yl]-4-cyclo butyl- 1 ,4-diazepane
Figure imgf000114_0004
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - (l,2,3-thiadiazol-4- ylmethyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000115_0001
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 ■ (lH-pyrazol-4- ylcarbonyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000115_0002
methyl [4-( 1 -benzyl- 1 H-tetrazol-5 - yl)-4-(4-cyclo butyl- 1 ,4-diazepan- 1 - yl)pip eridin- 1 -yl] acetate
Figure imgf000115_0003
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 ■ ( 1 H-imidazol-4-ylacetyl)piperidin- 4-yl]-4-cyclo butyl- 1 ,4-diazepane
Figure imgf000115_0004
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 ■ (phenylcarbonyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000115_0005
methyl 3- [4-( 1 -benzyl- 1 H-tetrazol- 5-yl)-4-(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)piperidin- 1 -yljpropanoate
Figure imgf000116_0001
2- [4-( 1 -benzyl- 1 H-tetrazol-5-yl)-4- (4-cyclo butyl- 1 ,4-diazepan- 1 - yl)pip eridin- 1 -yl] -N- methylacetamide
Figure imgf000116_0002
l-[3-(l-benzyl-lH-tetrazol-5- yl)piperidin-3-yl]-4-cyclobutyl-l,4- diazepane
Figure imgf000116_0003
l-{4-(l -benzyl- 1 H-tetrazol-5 -yl)- 1 - [(I -methyl- 1 H-imidazo 1-2- yl)carbonyl]piperidin-4-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000116_0004
1. [4_( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - (1 H-imidazo 1-2- ylcarbonyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000116_0005
1 - {4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - [(5 -chloropyridin-2- yl)carbonyl]piperidin-4-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000117_0001
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 - pyrimidin-2-ylpiperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000117_0002
1 -[(1 -benzyl- lH-tetrazol-5-yl)(4- ethoxyphenyl)methyl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000117_0003
1 - [4-( 1 -benzyl- 1 Η-tetrazol-5-yl)- 1 ■ (l,2,3-thiadiazol-4- ylcarbonyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000117_0004
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 ■ (phenylsulfbnyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000117_0005
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 ■ (lH-l,2,4-triazol-l- ylacetyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000118_0001
1 _[4_( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 ■ (lH-imidazol-4- ylcarbonyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000118_0002
1 -[(1 -benzyl- lH-tetrazol-5-yl)(3- methoxyphenyl)methyl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000118_0003
1 -[(1 -benzyl- lH-tetrazol-5-yl)(2- chlorophenyl)methyl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000118_0004
1 - {3 -( 1 -benzyl- 1 Η-tetrazol-5 -yl)- 1 - [(I -methyl- 1 H-imidazo 1-2- yl)carbonyl]piperidin-3-yl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000118_0005
1 -[(1 -benzyl- lH-tetrazol-5- yl)(pyridin-4-yl)methyl] -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000119_0001
1 -[(1 -benzyl- lH-tetrazol-5-yl)(3- chlorophenyl)methyl]-4- cyc Io butyl- 1 ,4-diazepane
Figure imgf000119_0002
1 - {( 1 -benzyl- lH-tetrazol-5 -yl)[4- ( 1 -methylethyl)phenyl]methyl} -A- cyc Io butyl- 1 ,4-diazepane
Figure imgf000119_0003
1 -[(1 -benzyl- 1 Η-tetrazol-5-yl)(4- chlorophenyl)methyl]-4- cyc Io butyl- 1 ,4-diazepane
Route 9
Figure imgf000119_0004
Route 9: Describes a general route to the products R = H, Me, Ph
Preparation of methyl 4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]benzoate
Figure imgf000120_0001
In a similar fashion (R8, GP M), 4-cyclopentyl-[l,4]diazepane (250 mg, 1.621 mmol), methyl 4-formylbenzoate (266 mg, 1.621 mmol), benzyl isocyanide (190 mg, 1.621 mmol) and trimethylsilyl azide (187 mg, 1.621 mmol) gave the title compound after Flash column chromatography on silica gel eluting with a solution of MeOH/MVDCM (1/0.5/98.5) to yield the title compound as pale oil (361 mg, 48%). LCMS data: Calculated MH+ (461); Found 96% (MH+) m/z 461.36, Rt 3.05 mins.
General Procedure N
Example 166 - Preparation of 4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan- l-yl)methyl]-N-phenylbenzamide. Potency range A
Figure imgf000120_0002
To a solution of methyl 4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]benzoate (171 mg; 0.371 mmol) in TΗF (ImI) was added LiOFLH2O in distilled water (ImI). The reaction was stirred at room temperature over night, then solvent was removed in vacuo (MH+ for acid observed in LCMS).
To a portion of this crude, lithium 4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan- l-yl)methyl]benzoate, (49 mg; 0.108 mmol) in DMF (ImI) was added; ΗBTU (82 mg; 0.217mmol), ΗOBt (29 mg; 0.217 mmol), aniline (l lμL; 0.119 mmol) and the resulting reaction mixture stirred overnight at room temperature. Solvent was evaporated in vacuo and the crude material purified by preparative ΗPLC to yield the title compound as pale oil
(7.0mg, 3%, TFA salt).
LCMS data: Calculated MH+ (522); Found 97% MH+ m/z (522.41), Rt = 2.80 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.85 (2 H, d, J=I .1 Hz), 7.67 (2 H, d, J=7.7 Hz), 7.04 - 7.41 (10 H, m), 5.52 - 5.69 (3 H, m), 2.59 - 3.44 (8 H, m), 1.75 - 2.42 (8 H, m)
The following compounds were prepared as described in Route 9, General procure N, above.
Example 167 - 4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l-yl)methyl]-N- methylbenzamide. Potency range A
Figure imgf000121_0001
In a similar fashion (Route 9, GP N), intermediate lithium 4-[(l-benzyl-lH-tetrazol-5-yl)(4- cyclobutyl-l,4-diazepan-l-yl)methyl]benzoate (38 mg; 0.0841 mmol) was treated with ΗBTU
(63 mg; 0.168 mmol), ΗOBt (23 mg; 0.168 mmol) and methylamine (46μL, 2M solution in
MeOH; 0.0925 mmol) to give the title compound as pale oil after purification by preparative
ΗPLC (4.2mg, 11%, TFA salt).
LCMS data: Calculated MH+ (460); Found 97% MH+ m/z (460.41), Rt = 2.81 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.62 - 7.74 (2 H, m), 7.14 - 7.31 (5 H, m),
6.99 - 7.10 (2 H, m), 5.60 (2 H, s), 5.54 (1 H, s), 3.64 - 3.81 (1 H, m), 2.99 - 3.29 (4 H, m),
2.63 - 2.98 (4 H, m), 2.23 - 2.39 (2 H, m), 2.08 - 2.23 (2 H, m), 1.71 - 2.05 (4 H, m)
Example 168 4-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] benzamide. Potency range A
Figure imgf000121_0002
In a similar fashion (Route 9, GP N), the intermediate lithium 4-[(l-benzyl-lH-tetrazol-5- yl)(4-cyclo butyl- 1 ,4-diazepan- 1 -yl)methyl]benzoate (38 mg; 0.0841 mmol) was treated with ΗBTU (63 mg; 0.168 mmol), ΗOBt (23 mg; 0.168 mmol) and ammonia (0.1 mL, concentrated aqueous solution, 1.68 mmol) to give the title compound as pale oil after purification by preparative HPLC (2.4 mg, 6%) as the TFA salt.
LCMS data: Calculated MH+ (446); Found 99% MH+ m/z (446.37), Rt = 2.77 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.73 - 7.82 (2 H, m), 7.16 - 7.34 (5 H, m),
6.98 - 7.10 (2 H, m), 5.48 - 5.65 (3 H, m), 3.66 - 3.81 (1 H, m), 3.02 - 3.41 (4 H, m), 2.61 -
3.01 (4 H, m), 1.72 - 2.39 (8 H, m)
Route 10
Figure imgf000122_0001
Route 10: Describes a general route to the products R = Me, /-Pr
Preparation of 5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl] pyridin-2-amine
Figure imgf000122_0002
In a similar fashion (R8, GP M), tert-butyl (4-formylphenyl)carbamate (190 mg, 0.856 mmol) and l-cyclobutyl-[l,4]diazepane (132 mg, 0.856 mmol), benzyl isocyanide (104 μl, 0.856 mmol) and trimethylsilyl azide (112 μl, 0.856 mmol) gave the title compound as pale solid
(200 mg, 51% yield, HCl salt) after purification by silica flash column chromatography
(eluents; 100:0 to 90:10 DCM/MeOΗ).
LCMS data: Calculated MH+ (418); Found 100% MH+ m/z (419.37), Rt = 0.87 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.64 (1 H, d), 7.42 - 7.47 (2 H, m), 7.28 - 7.33
(3 H, m), 7.12 - 7.17 (2 H, m), 6.49 (1 H, d, J=8.7 Hz), 5.64 - 5.75 (2
H, m), 5.17 (1 H, s), 2.95 (1 H, q), 2.59 - 2.82 (4 H, m), 2.38 - 2.57 (4 H, m), 1.96 - 2.07 (2 H, m), 1.76 - 1.90 (2 H, m), 1.57 - 1.74 (4 H, m) General Procedure O:
Example 169 - Preparation of N-{5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4- diazepan-l-yl)methyl]pyridin-2-yl}acetamide. Potency range B
Figure imgf000123_0001
To a solution of 5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]pyridin-2-amine (80 mg, 0.191 mmol) in DCM was added TEA (80 μl , 0.573 mmol) followed by acetyl chloride (34 μl, 0.478 mmol). The reaction mixture was stirred at room temperature for 6Oh. Approximately half the crude material was purified by preparative ΗPLC followed by further purification with silica flash column chromatography (using a gradient of eluents; 100:0 to 95:5 DCM/MeOΗ). This gave the title compound as yellow oil (6.6 mg, 15% yield, TFA salt).
LCMS data: Calculated MH+ (461); Found 89% MH+ m/z (461.37), Rt = 2.83 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 8.11 (1 H, d, J=2.3 Hz), 7.90 - 8.04 (1 H, m), 7.62 - 7.73 (1 H, m), 7.22 - 7.36 (3 H, m), 7.08 - 7.21 (2 H, m), 5.74 (2H, s), 5.36 (1 H, s), 2.84 - 3.00 (1 H, m), 2.58 - 2.84 (4 H, m), 2.30 - 2.58 (4 H, m), 2.16 (3 H, s), 1.90 - 2.09 (2 H, m), 1.55 - 1.90 (6 H, m)
The following compound was prepared as described in Route 10, General procedure O, above.
Example 170 - N-{5-[(l-benzyl-lH-tetrazol-5-yl)(4-cyclobutyl-l,4-diazepan-l- yl)methyl]pyridin-2-yl}-2-methylpropanamide. Potency range A
Figure imgf000123_0002
In a similar fashion (Route 10, GP O), 5- [(I -benzyl- lH-tetrazol-5-yl)(4-cyclo butyl- 1,4- diazepan-l-yl)methyl]pyridin-2-amine (40 mg, 0.0956 mmol), TEA (34 μl , 0.239 mmol) and 2-methylpropanoyl chloride (11 μL, 0.100 mmol) gave the title compound as yellow oil (2.2 mg, 10% yield).
LCMS data: Calculated MH+ (489); Found 92% MH+ m/z (489.43), Rt = 3.08 mins.
NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.88 - 8.06 (1 H, m), 7.51 - 7.67 (1 H, m),
6.98 - 7.30 (6 H, m), 5.59 - 5.69 (1 H, m), 5.41 - 5.54 (2 H, m), 3.61 - 3.76 (1 H, m), 2.57 -
3.28 (8 H, m), 1.68 - 2.41 (8 H, m), 1.19 (6 H, d).
Route 11
TBSCl DMSO
Imidazole Oxalyl chloride
DMAP NEt,
OTBS
DCM
DCM
Figure imgf000124_0001
4-[(terM)utylsilyl)oxy]butan-l-ol
To a solution of 1,4-butandiol (9.Og, 100 mmol), imidazole (2.27g, 33 mmol) and DMAP (203 mg, 1.7 mmol) in DCM (100 ml) at 0 0C was added TBSCl (5.Og, 33 mmol) in DCM (20 ml) over 30 minutes. The reaction mixture was then stirred at room temperature for 4 hours.
The organics were washed with water (3 x 50 ml), dried (MgSO/i) and concentrated in vacuo.
The residue was purified by flash column chromatography (eluting with 4: 1 Pentane/Et2O) to give the title compound as clear oil (5.15g, 76%). LCMS data: The compound did not ionise.
NMR data: 1H NMR (400 MHz, CDCl3) δ ppm 3.62 - 3.72 (4 H, m), 1.60 - 1.71 (4 H, m),
0.91 (9 H, s), 0.08 (6 H, s).
Prearation of 4-[(tert-butylsilyl)oxy]butanal 0<5-"~v-/^0TBS
DMSO (1.30 ml, 18.3 mmol) was added to oxalyl chloride (0.78 ml, 9.17 mmol) in DCM (100 ml) at -78 0C over 10 minutes. After 30 minutes, a -780C solution of 4-[(tert- butylsilyl)oxy]butan-l-ol (1.70 g, 8.32 mmol) in DCM (5 ml) was added over 10 minutes resulting in a thick white precipitate. The slurry was stirred for a further 30 minutes then NEt3 (6.9 ml, 50 mmol) was added dropwise and the reaction mixture stirred for 15 minutes, before warming to room temperature and quenched with sat. NaHCO3. The organic layer was separated and the aqueous layer washed with DCM (3 x 50 ml). The combined organic layers were dried (MgSO/ι), filtered and concentrated in vacuo. Flash column chromatography (eluting with 95:5 Hexane/Et2θ) gave the title compound as colourless oil (1.06g, 62%). LCMS data: The compound did not ionise.
NMR data: IH NMR (400 MHz, CDCl3) δ ppm 9.79 (1 H, t, J=I .7 Hz), 3.66 (2 H, t, J=5.9 Hz), 2.50 (2 H, td, J=7.09Hz & 1.7Hz), 1.81 - 1.92 (2 H, m), 0.89 (9 H, s), 0.05 (6 H, s).
Prearation of 4-(l-benzyl-lH-tetrazol-5-yl)-4-(4-cyclobutyl-l,4-diazepan-l-yl)butan-l-ol
Figure imgf000125_0001
In a similar fashion (R8, GP M), 4-cyclobutyl-[l,4]diazepane (76 mg, 0.49 mmol), 4-[(tert- butylsilyl)oxy]butanal (100 mg, 0.49 mmol), benzyl isocyanide (60 μl, 0.49 mmol) and trimethylsilyl azide (65 μl, 0.49 mmol) gave the title compound after flash column chromatography purification as colourless oil (120 mg, 64%). LCMS data: Calculated MH+ (385); Found 85% (MH+) m/z 385, Rt 1.78 mins. NMR data: 1H NMR (400 MHz, MeOD) δ ppm 7.32 - 7.42 (3 H, m), 7.23 - 7.30 (2 H, m), 5.79 (1 H, d, J=15.4 Hz), 5.72 (1 H, d, J=15.4 Hz), 4.09 (1 H, t, J=7.1 Hz), 3.42 - 3.53 (2 H, m), 2.66 - 2.91 (5 H, m), 2.35 - 2.48 (3 H, m), 2.22 - 2.31 (1 H, m), 1.93 - 2.08 (4 H, m), 1.52 - 1.88 (6 H, m), 1.27 - 1.48 (2 H, m).
Example 171 - l-[l-(l-benzyl-lH-tetrazol-5-yl)-4-(lH-pyrazol-l-yl)butyl]-4-cyclobutyl- 1,4-diazepane. Potency range C
Figure imgf000125_0002
Thionyl chloride (20 μl, 0.27 mmol) was added to 4-(l-benzyl-lH-tetrazol-5-yl)-4-(4- cyclobutyl-l,4-diazepan-l-yl)butan-l-ol (26 mg, 68 μmol) and stirred for 16 hours prior to evaporation of excess thionyl chloride at reduced pressure. In a separate flask, pyrazole (41 mg, 0.20 mmol), KO1Bu (68 mg, 0.20 mmol) and 18-crown-6 (161 mg, 0.20 mmol) were stirred for 15 minutes in TΗF (5 ml) and then added to the chloride intermediate. The reaction mixture was heated to 60 0C in a sealed tube for 12 hours and then cooled to room temperature, diluted with diethyl ether (25 ml) and washed with brine (15 ml), dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (eluting with 90:10:1 DCM/MeOΗ/NΗ3) gave the title compound as colourless oil (6 mg, 20%). LCMS data: Calculated MH+ (436); Found 93% (MH+) m/z 436, Rt 3.03 mins.

Claims

Patent Claims
A compound of formula (I)
Figure imgf000127_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
A V2
X , X are independently selected from the group consisting of N; and CH;
R1 is T; Ci-4 alkyl; C2^t 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, R10 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 R1 1, which are the same or different;
R1 1 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; C1-4 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(R14R143); 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; C1^ alkyl; C2_6 alkenyl; or C2_6 alkynyl, wherein C1^ 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; C1^ alkyl; C2_β alkenyl; and C2_β alkynyl, wherein C1^ alkyl; C2_β alkenyl; and C2-β 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; C1^ 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; C1-6 alkyl; C2_6 alkenyl; or C2_6 alkynyl, wherein Ci_6 alkyl; C2_β alkenyl; and C2_β 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_β 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 T ;
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(R21)SO2R21a; 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_β alkynyl, wherein C1^ 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 _β 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; C^ cycloalkyl; 3 to 7 membered heterocyclyl; or 8 to 1 1 membered heterobicyclyl, wherein T2 is optionally substituted with one or more R22, which are the same or different;
T3 is Ci-η 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_γ 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(R31)S(O)2N(R31aR31b); SR31; N(R31R31a); NO2; OC(O)R31; N(R31)C(O)R31a; N(R31)S(O)2R31a; N(R31)S(O)R31a; 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_β alkenyl; and C2_β 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 _β alkyl; C2_6 alkenyl; and C2_6 alkynyl are optionally substituted with one or more R 33 , which are the same or different;
R , R 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_γ 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_β alkenyl; and C2_β alkynyl; wherein Ci_6 alkyl; C2 _β 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_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;
R4 is Ci_5 alkyl; C2_5 alkenyl; C2_5 alkynyl; C3-5 cycloalkyl; CH2-cyclopropyl; CHF- cyclopropyl; CF2-cyclopropyl; CH2-cyclobutyl; CHF-cyclo butyl; CF2-cyc Io butyl; or 4 to 5 membered saturated heterocyclyl, wherein Ci .5 alkyl; C2 -5 alkenyl; 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; 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;
R5, R6, R7, R8 are independently selected from the group consisting of H; C1-S alkyl; C2_5 alkenyl; and C2_5 alkynyl, wherein C1-S alkyl; C2_5 alkenyl; and C2_s 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 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, R7/R8 are joined together with the carbon atoms to which they are attached to form C3_7 cycloalkyl, wherein C3_γ 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, R5/R8, R4/R7, R4/R8, R6/R8 are joined together with the seven membered ring 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.
2. A compound of claim 1, wherein at least one of X1, X2 is N.
3. A compound of claim 1 or 2, wherein X1 is CH.
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 R1 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 R1 is Ci_4 alkyl substituted with one R9.
7. A compound of any of claims 1 to 6, wherein R1 is CH2-R9; or CH2CH2R9.
8. A compound of any of claims 1 to 7, wherein R9 is T.
9. A compound of any of claims 1 to 8, wherein T is phenyl; naphthyl; or 5 to 6 membered aromatic heterocyclyl.
10. A compound of any of claims 1 to 9, wherein T is unsubstituted or substituted with one or two R13, which are the same or different.
11. A compound of any of claims 1 to 10, wherein R13 is halogen; Ci_6 alkyl; OH; or 0-C1- 6 alkyl, wherein Ci _6 alkyl is optionally substituted with one or more halogen, which are the same or different.
12. A compound of any of claims 1 to 11 , wherein R13 is F; Cl; OCH3; or OCF3.
13. A compound of any of claims 1 to 12, wherein one of R2, R3 is A.
14. A compound of any of claims 1 to 13, wherein A is T2.
15. A compound of any of claims 1 to 14, wherein T2 is phenyl; 3 to 7 membered heterocyclyl; or 8 to 11 membered heterobicyclyl.
16. A compound of any of claims 1 to 15, wherein T is unsubstituted or substituted with one or two R22, which are the same or different.
17. A compound of any of claims 1 to 16, wherein T3 is cyclopentyl; cyclohexyl; tetrahydropyranyl; piperidinyl; pyrrolidinyl; or azetidinyl.
18. A compound of any of claims 1 to 17, wherein T3 is unsubstituted or substituted with one or two R23, which are the same or different.
19. A compound of any of claims 1 to 18, wherein R22, R23 are independently selected from the group consisting of halogen; T4; C1-6 alkyl; OR24; C(O)N(R24R24a);
C(O)OR24; N(R24R24a); S(O)2R24; S(O)2N(R24R24"); 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.
20. A compound of any of claims 1 to 19, 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.
21. A compound of any of claims 1 to 20, wherein R25 is halogen; T4; or C(O)N(R27R27a).
22. A compound of any of claims 1 to 21, wherein T4 is phenyl; or 5- to 6 membered heterocyclyl.
23. A compound of any of claims 1 to 22, 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_<5 alkyl; Ci_β alkyl, wherein C1^ alkyl is optionally substituted with one or more halogen, which are the same or different.
24. A compound of any of claims 1 to 23, wherein R4 cyclobutyl; cyclopentyl; methyl; or ethyl.
25. A compound of any of claims 1 to 24, wherein R5, R6, R7, R8 are H.
26. A compound of claim 1 selected from the group consisting of
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-( lH-pyrazol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4-diazepane;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-( lH-pyrazol- 1 -yl)phenyl]methyl} -4- cyclopentyl- 1 ,4-diazepane; l-{(4-benzyl-4H-l,2,4-triazol-3-yl)[4-(lH-l,2,4-triazol-l-yl)phenyl]methyl}-4- cyc Io butyl- 1 ,4-diazepane;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-bromophenyl)methyl]-4-cyclo butyl- 1 ,4- diazepane; l-cyclobutyl-4-{[4-(3-fluorobenzyl)-4H-l,2,4-triazol-3-yl][4-(lH-pyrazol-l- ylmethyl)phenyl]methyl} - 1 ,4-diazepane;
1 -cyclobutyl-4- {[4-(3-fluorobenzyl)-4H-l ,2,4-triazol-3-yl][4-(lH- 1 ,2,4-triazol- 1 - ylmethyl)phenyl]methyl} - 1 ,4-diazepane; l-cyclobutyl-4-{(4-fluorophenyl)[4-(2-phenylethyl)-4H-l,2,4-triazol-3-yl]methyl}- 1 ,4-diazepane;
1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-ethoxyphenyl)methyl]-4-cyclo butyl- 1 ,4- diazepane.;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-(2-methyl- 1 ,3-thiazol-4-yl)phenyl]methyl} -A- cyc Io butyl- 1 ,4-diazepane; 1 -[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-fluorophenyl)methyl]-4-cyclopentyl-l ,4- diazepane;
1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-( 1 H-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyc Io butyl- 1 ,4-diazepane; 1 - {(4-benzyl-4H- 1 ,2,4-triazol-3-yl)[4-( 1 H-pyrazol- 1 -ylmethyl)phenyl]methyl} -A- cyclopentyl-l,4-diazepane;
4-[(4-benzyl-4H- 1 ,2,4-triazol-3-yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]-N- methylbenzamide;
1 -[(1-benzyl- 1 H- 1 ,2,3-triazol-5-yl)(4-fluorophenyl)methyl]-4-cyclobutyl-l ,4- diazepane; l-{(l-benzyl-lH-l,2,3-triazol-5-yl)[4-(lH-pyrazol-l-ylmethyl)phenyl]methyl}-4- cyc Io butyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-morpho lin-4-ylphenyl)methyl]-4-cyclo butyl- 1 ,4- diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)( lH-pyrazo 1-3 -yl)methyl] -4-cyc Io butyl- 1 ,4-diazepane; 1 - {( 1 -benzyl- 1 Η-tetrazol-5 -yl)[4-( 1 Η-pyrazo 1- 1 -yl)phenyl]methyl} -4-cyclopentyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- lΗ-tetrazol-5-yl)[4-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl} -A- cyclopentyl- 1 ,4-diazepane; l-{(l-benzyl-lH-tetrazol-5-yl)[4-(morpholin-4-ylmethyl)phenyl]methyl}-4- eye Io butyl- 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-(4-methylpiperazin- 1 -yl)phenyl]methyl} -4- cyc Io butyl- 1 ,4-diazepane; 4- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]-N,N- dimethylbenzenesulfonamide;
1 -cyclobutyl-4- {[ 1 -(3 -fluorobenzyl)- 1 H-tetrazol-5 -yl] [4-( 1 H-pyrazo 1- 1 - ylmethyl)phenyl]methyl} - 1 ,4-diazepane;
1 -cyclobutyl-4- {[l-(3-fluorobenzyl)-l H-tetrazol-5 -yl] [4-(1H-1, 2,4-triazol-l- ylmethyl)phenyl]methyl} - 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)phenyl]methyl} -4- cyc Io butyl- 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl} -4-cyclobutyl-
1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-bromophenyl)methyl] -4-cyclo butyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 -morpho lin-4-ylphenyl)methyl]-4-cyclo butyl- 1 ,4- diazepane;
1 - [( 1 -butyl- 1 H-tetrazol-5 -yl)(4-fluorophenyl)methyl] -4-cyclo butyl- 1 ,4-diazepane;
5 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cy clobutyl- 1 ,4-diazepan- 1 -yl)methyl]- 1 -methyl- 1 H- benzotriazole;
1 - {4- [( 1 -benzyl- 1 H-tetrazol-5-yl)(4-cyclobutyl- 1 ,4-diazepan- 1 - yl)methyl]phenyl}pyrrolidin-2-one;
2- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cy clobutyl- 1 ,4-diazepan- 1 -yl)methyl]imidazo [ 1 ,2- a]pyridine; 6- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cy clobutyl- 1 ,4-diazepan- 1 -yl)methyl]imidazo [ 1 ,2- ajpyridine;
2- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cy clobutyl- 1 ,4-diazepan- 1 -yl)methyl]thieno [2,3 - b]pyridine;
5 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cy clobutyl- 1 ,4-diazepan- 1 -yl)methyl]- 1 -methyl- 1 H- indole;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-piperidin- 1 -ylpyridin-2-yl)methyl]-4-cyclo butyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- lH-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methyl} -4-cyclo butyl- 1 ,4- diazepane; l-{(l-benzyl-lH-tetrazol-5-yl)[3-(difluoromethoxy)phenyl]methyl}-4-cyclo butyl- 1,4- diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-( 1 H-pyrazo 1- 1 -yl)phenyl]methyl} -4-cyclo butyl- 1,4- diazepane; 1 -[(1-benzyl- 1 H-tetrazol-5-yl)(5-methylisoxazol-3-yl)methyl]-4-cyclo butyl- 1 ,A- diazepane; l-{(l-benzyl-lH-tetrazol-5-yl)[3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl]methyl}-4- cyc Io butyl- 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[3 -( 1 H- 1 ,2,4-triazol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-( 1 H-pyrazo 1- 1 -ylmethyl)phenyl]methyl} -A- cyc Io butyl- 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[3-( 1 H-pyrazo 1- 1 -ylmethyl)phenyl]methyl} -A- cyc Io butyl- 1 ,4-diazepane; 2- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]quino line;
3 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]quino line; 1 -
[(1-benzyl- lH-tetrazol-5-yl)(6-tert-butoxypyridin-3-yl)methyl]-4-cyclo butyl- 1,4- diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(2,3 -dihydro- 1 ,4-benzodioxin-6-yl)methyl] -A- eye Io butyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)( 1 -methyl- 1 H-imidazol-2-yl)methyl] -4-cyclobutyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- lH-tetrazol-5-yl)[4-(methylsulfonyl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[3 -( 1 H-pyrrol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
5-[(l-benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl-l ,4-diazepan- 1 -yl)methyl]-2, 1 ,3- benzoxadiazole;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-pyrrolidin- 1 -ylpyridin-3 -yl)methyl]-4-cyc Io butyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- lH-tetrazol-5-yl)[4-(pyrimidin-2-yloxy)phenyl]methyl} -4-cyclobutyl-
1 ,4-diazepane;
5-[(l-benzyl- 1 Η-tetrazol-5-yl)(4-cyclobutyl-l ,4-diazepan- 1 -yl)methyl]-2, 1 ,3- benzothiadiazole; l-{(l-benzyl-lH-tetrazol-5-yl)[4-(l,2,3-thiadiazol-4-yl)phenyl]methyl}-4-cyclobutyl- 1 ,4-diazepane;
6- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]imidazo [2,1- b][l,3]thiazole; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(2,3 -dihydro- 1 -benzofuran-5 -yl)methyl] -4-cyclobutyl-
1 ,4-diazepane;
6- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]- 1 H-indo Ie; 5 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]pyridin-2-o 1;
7- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]pyrazolo [1,5- a]pyridine; l-{(l-benzyl-lH-tetrazol-5-yl)[4-(difluoromethoxy)phenyl]methyl}-4-cyclo butyl- 1 ,4- diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-methylpyridin-2-yl)methyl]-4-cyclo butyl- 1 ,4- diazepane; 1 - [(I -benzyl- IH- [ 1 ,2,3,4]tetrazol-5-yl)-[4-(5-methyl-[ 1 ,2,4]oxadiazol)phenyl]methyl-
4-cyc Io butyl- [ 1 ,4]diazepane;
1 - {( 1 -benzyl- 1 Η-tetrazol-5 -yl)[4-(2-methyl- 1 Η-imidazo 1- 1 -yl)phenyl] methyl} -A- cyc Io butyl- 1 ,4-diazepane; 1 -[(1-benzyl- 1 Η-tetrazol-5-yl) {4-[(4-methylpiperazin- 1 -yl)methyl]phenyl}methyl]-4- eye Io butyl- 1 ,4-diazepane; l-{(l-benzyl-lH-tetrazol-5-yl)[4-(pyridm-2-yloxy)phenyl]methyl}-4-cyclo butyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-( 1 H-pyrazo 1- 1 -ylmethyl)phenyl]methyl} -A- cyclopentyl- 1 ,4-diazepane; 1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)phenyl]methyl} -A- cyclopentyl- 1 ,4-diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-(methylsulfonyl)phenyl]methyl} -4-cyclopentyl- 1 ,4- diazepane; 1 - {4-[( 1 -benzyl- 1 H-tetrazol-5-yl)(4-cyclopentyl- 1 ,4-diazepan- 1 - yl)methyl]phenyl}pyrrolidin-2-one;
1 -[(1-benzyl- 1 H-tetrazol-5-yl)(4-fluorophenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-phenoxypyridin-3 -yl)methyl] -4-cyclobutyl- 1 ,4- diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)( 1 -methyl- 1 H-pyrazol-4-yl)methyl]-4-cyclobutyl- 1,4- diazepane; l-[l-benzofuran-5-yl(l-benzyl-lH-tetrazol-5-yl)methyl]-4-cyclobutyl-l,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(pyridin-3 -yl)methyl]-4-cyclo butyl- 1 ,4-diazepane; 1 -cyclobutyl-4- [(4-fluorophenyl) { 1 - [4-(trifluoromethoxy)benzyl] - 1 H-tetrazol-5 - yl}methyl]- 1 ,4-diazepane;
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(2,2-difluoro- 1 ,3-benzodioxol-5-yl)methyl]-4- cyc Io butyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)( 1 -oxidopyridin-4-yl)methyl] -4-cyclobutyl- 1 ,4- diazepane;
1 -[4-(I -benzyl- lH-tetrazol-5-yl)- 1 -(6-fluoropyridm-2-yl)piperidin-4-yl]-4-cyclobutyl-
1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-morpho lin-4-ylpyridm-3-yl)methyl] -4-cyclobutyl-
1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(2-methyl- lH-imidazol-4-yl)methyl] -4-cyclobutyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- 1 Η-tetrazol-5 -yl)[4-( 1 Η-pyrrol- 1 -yl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- lH-tetrazol-5-yl)[4-(trifluoromethoxy)phenyl]methyl} -4-cyclobutyl- 1 ,A- diazepane; l-{(l-benzyl-lΗ-tetrazol-5-yl)[4-(2-methyl-l,3-thiazol-4-yl)phenyl]methyl}-4- cyc Io butyl- 1 ,4-diazepane;
1 -cyclobutyl-4- [(4-fluorophenyl) { 1 - [( 1 S)- 1 -phenylethyl]- 1 H-tetrazol-5 -yl} methyl]-
1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-thiomorpholin-4-ylpyridin-3 -yl)methyl] -A- cyc Io butyl- 1 ,4-diazepane;
5 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cy clobutyl- 1 ,4-diazepan- 1 -yl)methyl]-N,N- diethylpyridin-2-amine;
1 -[(1 -benzyl- 1 H-tetrazol-5-yl)(3-fluorophenyl)methyl]-4-cyclo butyl- 1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(phenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 ,4-dichlorophenyl)methyl]-4-cyclo butyl- 1 ,4- diazepane;
1 - {( 1 -benzyl- 1 H-tetrazol-5 -yl)[4-(trifluoromethyl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane; 5 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]- 1 H-indo Ie; 6- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]quino line; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 ,5 -dimethylphenyl)methyl] -4-cyclo butyl- 1 ,4- diazepane; 1 -[(1-benzyl- 1 H-tetrazol-5-yl)(4-chloro-3-fluorophenyl)methyl]-4-cyclo butyl- 1 ,4- diazepane;
1 -[( 1 -benzyl- 1 H-tetrazol-5 -yl)(6-chloropyridin-3-yl)methyl] -4-cyclo butyl- 1 ,4- diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(5 -bromopyridin-3-yl)methyl] -4-cyclo butyl- 1 ,4- diazepane; l-[4-(l-benzyl-lH-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl]-4-cyclobutyl-l,4- diazepane; l-[4-(l-benzyl-lH-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl]-4-cyclopentyl-l,4- diazepane; l-[l-acetyl-4-(l-benzyl-lH-tetrazol-5-yl)piperidin-4-yl]-4-cyclo butyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-fluorophenyl)methyl]-4-methyl- 1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-methoxyphenyl)methyl] -4-methyl- 1 ,4-diazepane; 1 -[(1-benzyl- lH-tetrazol-5-yl)(4-fluorophenyl)methyl]-4-ethyl- 1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-methoxyphenyl)methyl] -4-ethyl- 1 ,4-diazepane; 1 -ethyl-4- {(4-fluorophenyl)[l -(4-methoxybenzyl)- lH-tetrazol-5-yl]methyl} - 1 ,4- diazepane;
1 -ethyl-4- { [ 1 -(3-fluorobenzyl)- lH-tetrazol-5-yl](4-fluorophenyl)methyl} - 1 ,4- diazepane; 1 - { [ 1 -(3-fluorobenzyl)- lH-tetrazol-5-yl](4-fluorophenyl)methyl} -4-methyl- 1 ,4- diazepane;
1 - { [ 1 -(4-chlorobenzyl)- lH-tetrazol-5-yl](4-fluorophenyl)methyl} -4-ethyl- 1 ,4- diazepane; l-ethyl-4-[(4-fluorophenyl){l-[4-(trifluoromethoxy)benzyl]-lH-tetrazol-5-yl}methyl]- 1 ,4-diazepane; 1 -cyclobutyl-4- { [ 1 -(3-fluorobenzyl)- lH-tetrazol-5 -yl](4-fluorophenyl)methyl} - 1 ,4- diazepane;
1 -cyclopentyl-4- {[ 1 -(3-fluorobenzyl)- lH-tetrazol-5-yl](4-fluorophenyl)methyl} - 1 ,4- diazepane; 1 -[ 1 -( 1 -benzyl- lH-tetrazol-5-yl)cyclohexyl] -4-ethyl- 1 ,4-diazepane; l-[(l-benzyl-lH-tetrazol-5-yl)(4-fluorophenyl)methyl]-4-cyclopentyl-l,4-diazepane;
1 -[ 1 -( 1 -benzyl- lH-tetrazol-5-yl)cyclohexyl] -4-cyclopentyl- 1 ,4-diazepane;
1 -[4-(I -benzyl- lH-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl]-4-ethyl- 1 ,4-diazepane; l-[l-(l-benzyl-lH-tetrazol-5-yl)cyclopentyl]-4-ethyl-l,4-diazepane; 1 - {3 -( 1 -benzyl- 1 Η-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-imidazo l-2-yl)methyl] azetidin-3 - yl} -4-cyclobutyl- 1 ,4-diazepane;
1 - {3 -( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-imidazo l-2-yl)methyl]piperidin-3 - yl} -4-cyclobutyl- 1 ,4-diazepane;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-pyrazol-5 -yl)sulfonyl]piperidin-4- yl} -4-cyclobutyl- 1 ,4-diazepane;
1 -[4-(I -benzyl- lH-tetrazol-5-yl)- 1 -(methylsulfonyl)piperidin-4-yl]-4-cyclobutyl- 1 ,4- diazepane;
4-(l -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)-N,N- dimethylpiperidine- 1 -sulfonamide; 1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-pyrazol-4-yl)methyl]piperidin-4- yl} -4-cyclobutyl- 1 ,4-diazepane;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-pyrazol-5 -yl)methyl]piperidin-4- yl} -4-cyclobutyl- 1 ,4-diazepane;
1 - {3 -( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-imidazo l-2-yl)methyl]pyrrolidin-3 - yl} -4-cyclobutyl- 1 ,4-diazepane;
1 -[3 -(I -benzyl- lH-tetrazol-5-yl)- 1 -(1H- 1 ,2,4-triazol- 1 -ylacetyl)pyrrolidin-3-yl]-4- cyc Io butyl- 1 ,4-diazepane;
4-(l -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyclo butyl- 1 ,4-diazepan- 1 -yl)-N-ethylpiperidine- 1 - carboxamide; 4-(l -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyclo butyl- 1 ,4-diazepan- 1 -yl)-N-phenylpiperidine-
1 -carboxamide;
1 -[3 -(I -benzyl- lH-tetrazol-5-yl)- 1 -(1H- 1 ,2,4-triazol- 1 -ylacetyl)azetidin-3-yl]-4- cyc Io butyl- 1 ,4-diazepane;
1 -cyclobutyl-4- { [ 1 -(4-fluorobenzyl)- 1 H-tetrazol-5 -yl](4-fluorophenyl)methyl} - 1 ,4- diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-pyridin-2-ylphenyl)methyl] -4-cyclobutyl- 1 ,4- diazepane; l-{(l-benzyl-lH-tetrazol-5-yl)[4-(4-methyl-l,2,5-oxadiazol-3-yl)phenyl]methyl}-4- cyc Io butyl- 1 ,4-diazepane; 1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -( 1 ,3 -thiazo l-2-ylmethyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane;
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -( 1 H-imidazo l-2-ylmethyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane; tert-butyl 4-( 1 -benzyl- 1 H-tetrazol-5 -yl)-4-(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)piperidine-
1 -carboxylate; l-[4-(l-benzyl-lH-tetrazol-5-yl)piperidin-4-yl]-4-cyclo butyl- 1 ,4-diazepane;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-imidazo l-2-yl)methyl]piperidin-4- yl} -4-cyclobutyl- 1 ,4-diazepane; 1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[(2-methyl- 1 H-imidazo l-4-yl)methyl]piperidin-4- yl} -4-cyclobutyl- 1 ,4-diazepane; l-[4-(l-benzyl-lH-tetrazol-5-yl)-l-(lH-pyrazol-3-ylmethyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane;
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -( 1 ,3 -thiazo l-5-ylmethyl)piperidin-4-yl] -A- eye Io butyl- 1 ,4-diazepane; l-[4-(l-benzyl-lH-tetrazol-5-yl)-l-(l,2,3-thiadiazol-4-ylmethyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane;
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -( 1 H-pyrazol-4-ylcarbonyl)piperidin-4-yl] -A- cyc Io butyl- 1 ,4-diazepane; methyl [4-( 1 -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)piperidin- 1 - yl] acetate; l-[4-(l-benzyl-lH-tetrazol-5-yl)-l-(lH-imidazol-4-ylacetyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane;
1 -[4-(I -benzyl- 1 H-tetrazol-5-yl)- 1 -(phenylcarbonyl)piperidin-4-yl] -4-cyclobutyl- 1 ,4- diazepane; methyl 3 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)-4-(4-cyclo butyl- 1 ,4-diazepan- 1 -yl)piperidin- l-yl]propanoate;
2- [4-(l -benzyl- lH-tetrazol-5-yl)-4-(4-cyclobutyl-l ,4-diazepan- 1 -yl)piperidin- 1 -yl]-N- methylacetamide; l-[3-(l-benzyl-lH-tetrazol-5-yl)piperidin-3-yl]-4-cyclo butyl- 1 ,4-diazepane;
1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 H-imidazo l-2-yl)carbonyl]piperidin-4- yl} -4-cyclobutyl- 1 ,4-diazepane;
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -( 1 H-imidazo l-2-ylcarbonyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane; 1 - {4-( 1 -benzyl- 1 H-tetrazol-5 -yl)- 1 -[(5 -chloropyridin-2-yl)carbonyl]piperidin-4-yl} -4- cyc Io butyl- 1 ,4-diazepane;
1 -[4-(I -benzyl- lH-tetrazol-5-yl)- 1 -pyrimidin-2-ylpiperidin-4-yl]-4-cyclo butyl- 1 ,4- diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-ethoxyphenyl)methyl] -4-cyclo butyl- 1 ,4-diazepane; l-[4-(l-benzyl-lΗ-tetrazol-5-yl)-l-(l,2,3-thiadiazol-4-ylcarbonyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane;
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -(phenylsulfonyl)piperidin-4-yl] -4-cyclobutyl- 1 ,4- diazepane; 1 -[4-(I -benzyl- 1 H-tetrazol-5-yl)- 1 -(1H- 1 ,2,4-triazol- 1 -ylacetyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane;
1 - [4-( 1 -benzyl- 1 H-tetrazol-5-yl)- 1 -( 1 H-imidazo l-4-ylcarbonyl)piperidin-4-yl]-4- cyc Io butyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 -methoxyphenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane; 1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(2-chlorophenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane;
1 - {3 -( 1 -benzyl- 1 Η-tetrazol-5 -yl)- 1 -[( 1 -methyl- 1 Η-imidazo l-2-yl)carbonyl]piperidin-3 - yl} -4-cyclobutyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(pyridin-4-yl)methyl]-4-cyclo butyl- 1 ,4-diazepane;
1 - [( 1 -benzyl- 1 H-tetrazol-5 -yl)(3 -chlorophenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane; 1 - {( 1 -benzyl- lH-tetrazol-5-yl)[4-( 1 -methylethyl)phenyl]methyl} -4-cyclobutyl- 1 ,4- diazepane;
1 - [(I -benzyl- 1 Η-tetrazol-5-yl)(4-chlorophenyl)methyl] -4-cyclobutyl- 1 ,4-diazepane;
4- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]-N- phenylbenzamide; 4- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]-N- methylbenzamide;
4- [( 1 -benzyl- 1 H-tetrazol-5 -yl)(4-cyclobutyl- 1 ,4-diazepan- 1 -yl)methyl]benzamide;
N- {5-[(l-benzyl- 1 H-tetrazol-5 -yl)(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)methyl]pyridin-2- yljacetamide; N- {5-[(l-benzyl- 1 H-tetrazol-5 -yl)(4-cyc Io butyl- 1 ,4-diazepan- 1 -yl)methyl]pyridin-2- yl} -2-methylpropanamide;
1.[ l .( l -benzyl- 1 H-tetrazol-5-yl)-4-( 1 H-pyrazol- 1 -yl)butyl] -4-cyclobutyl- 1 ,4- diazepane.
27. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 26 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
28. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 26 for use as a medicament.
29. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 26 for use in a method of treating or preventing diseases and disorders associated with the H3 receptor.
30. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 26 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; nasal congestion; allergic rhinitis; or asthma.
31. Use of a compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 26 for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the H3 receptor.
32. Use of a compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 26 for the manufacture of a medicament for the treatment or prophylaxis of neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; vestibular dysfunction; nasal congestion; allergic rhinitis; or asthma.
33. 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 26 or a pharmaceutically acceptable salt thereof.
34. 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; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; vestibular dysfunction; nasal congestion; allergic rhinitis; and asthma, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of any of claims 1 to 26 or a pharmaceutically acceptable salt thereof.
35. A method for the preparation of a compound of any of claims 1 to 26, wherein one of X1 , X2 is CH and the other is N, or alternatively both X1 , X2 are CH, comprising the steps of
(a) activating the hydroxy group of the compound of formula (Ia)
Figure imgf000146_0001
wherein R1, R2, R3 have the meaning as indicated in claim 1 ; and
(b) reacting the respective compound with a compound of formula (V)
Figure imgf000146_0002
wherein R5, R6, R7, R8 have the meaning as indicated in claim 1 and R4 is R4 as indicated in claim 1 or a 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 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.
36. A method for the preparation of a compound of any of claims 1 to 26, wherein X1 is N and X2 is N, comprising the step of
• reacting a compound of formula R^-N+=C", a compound of formula (R2R3)C=O, wherein R1, R2, R3 have the meaning as indicated in claim 1, with a compound of formula (V) as indicated in claim 35 in the presence of trimethylsilyl azide in a one pot reaction to yield a compound of formula (I), optionally after removal of the protecting group and reacting the liberated amino group with 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.
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Cited By (8)

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Publication number Priority date Publication date Assignee Title
US8912176B2 (en) 2009-02-02 2014-12-16 Evotec Ag Azetidines as histamine H3 receptor antagonists
WO2010133544A1 (en) * 2009-05-22 2010-11-25 Evotec Ag Piperazine and aminopyrrolidine compounds as histamine h3 receptor antagonists
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WO2013151982A1 (en) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Methods and compounds useful in treating pruritus, and methods for identifying such compounds
US10189864B2 (en) 2016-02-19 2019-01-29 Lawrence Livermore National Security, Llc Metal complexes based on a bis(2-pyridylmethyl)amine-based scaffold and methods of making the same
US10112912B2 (en) * 2016-03-02 2018-10-30 Lawrence Livermore National Security, Llc Homopiperazine-based catalysts for neutralization of organophosphorus-based compounds
CN110372616A (en) * 2019-07-09 2019-10-25 上海应用技术大学 A kind of synthetic method of the 1,2,3- triazole derivative of N1 substitution
CN113527220A (en) * 2021-07-26 2021-10-22 京博农化科技有限公司 Synthetic method of desulfurization prothioconazole isomer

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