WO2006067385A1 - Chemical compounds - Google Patents

Chemical compounds Download PDF

Info

Publication number
WO2006067385A1
WO2006067385A1 PCT/GB2005/004841 GB2005004841W WO2006067385A1 WO 2006067385 A1 WO2006067385 A1 WO 2006067385A1 GB 2005004841 W GB2005004841 W GB 2005004841W WO 2006067385 A1 WO2006067385 A1 WO 2006067385A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
piperidin
compound
phenyl
optionally substituted
Prior art date
Application number
PCT/GB2005/004841
Other languages
French (fr)
Inventor
Howard Tucker
John Oldfield
Dearg Brown
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to EP05818258A priority Critical patent/EP1833792A1/en
Priority to JP2007546181A priority patent/JP2008524188A/en
Priority to US11/793,436 priority patent/US20080200460A1/en
Publication of WO2006067385A1 publication Critical patent/WO2006067385A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system.
  • Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or ⁇ ) and Cys-Cys (C- C, or ⁇ ) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating peptide 2
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP- 1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MIP- l ⁇ and MIP-I ⁇ ).
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO, CXCRl, CXCR2, CXCR3 and CXCR4.
  • CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types.
  • chemokines principally "regulated on activation normal T-cell expressed and secreted” (RANTES), macrophage inflammatory proteins (MIP) MIP- l ⁇ and MIP-I ⁇ and monocyte chemoattractant protein-2 (MCP-2).
  • RANTES normal T-cell expressed and secreted
  • MIP macrophage inflammatory proteins
  • MIP-I monocyte chemoattractant protein-2
  • CCR5 is also a co-receptor for HIV-I and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection.
  • the present invention provides a compound of formula (I):
  • R 1 is C 1-8 alkyl, C(O)NR 10 R 11 , C(O) 2 R 12 , NR 13 C(O)R 14 , NR 15 C(O)NR 16 R 17 , NR 18 C(O) 2 R 19 , heterocyclyl, aryl or heteroaryl;
  • R 10 , R 13 , R 15 , R 16 and R 18 are hydrogen or C 1-6 alkyl
  • R 11 , R 12 , R 14 , R 17 and R 19 are Ci -8 alkyl (optionally substituted by halo, hydroxy, Ci -6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl (optionally substituted by halo), C 5-6 cycloalkenyl,
  • R 11 , R 12 , R 14 and R 17 can also be hydrogen; or R 10 and R 11 , and/or R 16 and R 17 may join to form a A-, 5- or 6-membered ring which optionally includes a nitrogen, oxygen or sulphur atom, said ring being optionally substituted by Ci -6 alkyl, Ci -6 haloalkyl, S(O)i(Ci -6 alkyl) or C(O)(Ci -6 alkyl);
  • R 2 is C i-6 alkyl, phenyl, heteroaryl or C 3-7 cycloalkyl; when X is NR 5 , Y is absent or is CH 2 ; when X is CH 2 , Y is absent, CH 2 , NR 6 , O, S, S(O) or S(O) 2 ; Z is a 5- or 6-membered heterocyclyl ring; R 3 , R 5 and R 6 are, independently, hydrogen or Ci -6 alkyl; R 4 is hydrogen, C 1-4 alkyl, C 3-4 alkenyl, C 3-4 alkynyl or C 3-6 cycloalkyl; aryl, phenyl and heteroaryl moieties are independently optionally substituted by: halo, cyano, nitro, hydroxy, OC(O)NR 20 R 21 , NR 22 R 23 , NR 24 C(O)R 25 , NR 26 C(O)NR 27 R 28 , S(O) 2 NR 29 R 30
  • R 52 , R 53 , R 55 , R 56 and R 57 are, independently, C 1-6 alkyl (optionally substituted by halo, hydroxy, Ci -6 alkoxy, Ci -6 haloalkoxy, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, S(Ci -4 alkyl),
  • R 21 , R 23 , R 25 , R 28 , R 30 , R 34 , R 35 , R 36 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 52 , R 53 , R 55 and R 57 may additionally be hydrogen; alternatively, R 20 and R 21 , and/or R 22 and R 23 , and/or R 27 and R 28 , and/or R 29 and R 30 , and/or R 33 and R 34 , and/or R 51 and R 52 and/or R 54 and R 55 , and/or R 40 and R 41 may join to form a 5- or 6-membered ring which is optionally substituted with halo, Ci -4 alkyl or phenyl (wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy,
  • Ci -4 alkoxy S(O) 1n Ci -4 alkyl, S(O) 2 NH 2 , S(O) 2 NH(Ci -4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , NHS(O) 2 (Ci -4 alkyl), NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2s NHC(O)NH 2 , C(O)NH 2 , C(O)NH(Ci -4 alkyl), NHC(O)(C 1-4 alkyl), CO 2 H, CO 2 (Ci -4 alkyl), C(O)(Ci -4 alkyl), CF 3 ,
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers).
  • the present invention covers all such isomers and mixtures thereof in all proportions.
  • Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate, succinate or ⁇ >-toluenesulphonate.
  • the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl. Methyl is sometimes abbreviated to Me hereinbelow.
  • Haloalkyl comprises, for example, one to six, such as one to three, halogen (such as fluorine) atoms, and is, for example, CF 3 or CH 2 CF 3 .
  • Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
  • Phenyl(C 1-4 alkyl) is, for example, benzyl, l-(phenyl)eth-l-yl or l-(phenyl)eth-2-yl.
  • Heteroaryl(C 1-4 alkyl) is, for example, pyridinylmethyl, pyrimidinylmethyl or 1- (pyridinyl)eth-2-yl.
  • Phenyl(C 1-4 alkoxy) is, for example, benzyloxy or l-(phenyl)eth-l-yloxy.
  • Aryloxy is, for example, phenoxy.
  • Heteroaryloxy is, for example, pyridinyloxy or pyrimidinyloxy.
  • Heteroaryl(C 1-4 alkoxy) is, for example, pyridinylmethoxy, pyrimidinylmethoxy or 1 -(pyridinyl)eth-2-oxy .
  • Heteroaryl is an aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [l,2,4]-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzo.[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2a]pyridinyl), thieno[3,2-b]pyridin
  • Suitable 5- or 6-membered heterocyclyl rings include rings having one or two nitrogen atoms and, optionally, one oxygen or sulphur atom.
  • Suitable rings are, for example, piperidine, piperazine, morpholine, thiomorpholine or pyrrolidine.
  • Z is piperidine, piperazine or pyrrolidine (such as piperidine or piperazine).
  • the present invention provides a compound of formula (I) wherein, unless specified otherwise, aryl, phenyl and heteroaryl moieties are independently optionally substituted by one or more of halo, hydroxy, nitro, S(C 1-6 alkyl), S(O)(Ci -6 alkyl), S(O) 2 (C 1-6 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 alkyl), S(O) 2 N(C 1-6 alkyl) 2 , cyano, C 1-6 alkyl, C 1-6 alkoxy, CH 2 S(O) 2 (C 1-6 alkyl), OS(O) 2 (C 1-6 alkyl), OCH 2 heteroaryl (such as OCH 2 tetrazolyl), OCH 2 CO 2 H, OCH 2 CO 2 (C 1-6 alkyl), OCH 2 C(O)NH 2 , OCH 2 C(O)NH(C 1-6 alkyl), OCH 2
  • the present invention provides a compound of formula (I) wherein, unless specified otherwise, aryl, phenyl and heteroaryl moieties are independently optionally substituted by one or more of halo, hydroxy, nitro, S(Ci -4 alkyl), S(O)(Ci -4 alkyl), S(O) 2 (Ci -4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (Ci -4 alkyl), NHC(O)(Ci -4 alkyl), NHS(O) 2 (C 1-4 alkyl), CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 or OCF 3 .
  • R 10 , R 13 , R 15 , R 16 and R 18 are hydrogen or Ci -4 alkyl (for example methyl). In yet another aspect R 10 , R 13 , R 15 , R 16 and R 18 are hydrogen. In a further aspect of the invention R 11 , R 12 , R 14 , R 17 , R 18 and R 19 are Ci -8 alkyl
  • R 11 , R 12 , R 14 , R 17 and R 19 are Ci -8 alkyl (optionally substituted by halo (such as fluoro)), phenyl (optionally substituted as recited above), C 3-6 cycloalkyl (optionally substituted by halo (such as fluoro)) or C-lmked nitrogen containing heterocyclyl (optionally substituted on the ring nitrogen).
  • R 1 is NHC(O)R 14 , phenyl or heterocyclyl, wherein R 14 is as defined above, and phenyl and heterocyclyl are optionally substituted as described above.
  • R 1 is NR 13 C(O)R 14 , wherein R 13 and R 14 are as defined above.
  • R 13 is hydrogen.
  • R 14 is Ci -8 alkyl (optionally substituted by halo (such as fluoro, for example to form CF 3 CH 2 )), phenyl (optionally substituted as recited above), C 3-6 cycloalkyl (optionally substituted by halo (such as fluoro, for example to form l,l-difluorocyclohex-4-yl)) or C-linked nitrogen containing heterocyclyl (such as tetrahydropyran or piperidine, optionally substituted on the ring nitrogen).
  • halo such as fluoro, for example to form CF 3 CH 2
  • phenyl optionally substituted as recited above
  • C 3-6 cycloalkyl optionally substituted by halo (such as fluoro, for example to form l,l-difluorocyclohex-4-yl)) or C-linked nitrogen containing heterocyclyl (such as tetrahydropyran or piperidine, optionally substituted
  • the present invention provides a compound of the invention wherein R 14 is Ci -8 alkyl (optionally substituted by halo (such as fluoro, for example to form CF 3 CH 2 )), phenyl (optionally substituted by halo) or C 5-6 cycloalkyl (optionally substituted by halo (such as fluoro, for example to form l,l-difluorocyclohex-4-yl)).
  • halo such as fluoro, for example to form CF 3 CH 2
  • phenyl optionally substituted by halo
  • C 5-6 cycloalkyl optionally substituted by halo (such as fluoro, for example to form l,l-difluorocyclohex-4-yl)
  • heterocyclyl of R 1 is optionally substituted (such as singly substituted for example on a ring nitrogen atom when present) by Ci -6 alkyl [optionally substituted by phenyl ⁇ which itself optionally substituted by halo, Ci -4 alkyl, Ci -4 alkoxy, cyano, nitro, CF 3 , OCF 3 , (Ci -4 alkyl)C(O)NH, S(O) 2 NH 2 , Ci -4 alkylthio or S(O) 2 (Ci -4 alkyl) ⁇ or heteroaryl ⁇ which itself optionally substituted by halo, C 1 .
  • R 1 is optionally substituted aryl (such as optionally substituted phenyl) or optionally substituted heteroaryl, wherein the optional substituents are as recited above.
  • R 1 when R 1 is heterocyclyl it is, for example, tetrahydropyran, tetrahydrothiopyran, tetrahydrodioxythiopyran, piperidine, piperazine, pyrrolidine or azetidine. In another aspect when R 1 is heterocyclyl it is, for example, piperidine, piperazine, pyrrolidine or azetidine.
  • R 1 is optionally substituted heterocyclyl, such as optionally substituted: piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, azetidin-1-yl or azetidin-3-yl.
  • the heterocyclyl of R 1 is mono-substituted by C 1-6 alkyl, C 3-7 cycloalkyl, phenyl ⁇ optionally substituted by halo (for example fluoro), C L4 alkyl (for example methyl), C 1-4 alkoxy (for example methoxy), CF 3 or OCF 3 ), S(O) 2 (C 1-4 alkyl) (for example S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 or S(O) 2 CH(CH 3 ) 2 ), S(O) 2 (C 1-4 fluoroalkyl) (for example S(O) 2 CF 3 or S(O) 2 CH 2 CF 3 ), S(O) 2 phenyl ⁇ optionally substituted (such as mono-substituted) by halo (for example chloro), cyano, C 1-4 alkyl, C 1-4 alkoxy, CF 3 , OCF 3 , S(O)
  • Said heterocyclyl can also be mono-substituted by S(O) 2 N(Ci -4 alkyl) 2 .
  • said heterocyclyl is a 4-substituted piperidin-1-yl, a 1 -substituted piperidin-4-yl, a 4-substituted piperazin-1-yl, a 3-substituted pyrrolidin-1-yl, a 1 -substituted pyrrolidin-3-yl, a 3-substituted azetidin-1-yl or a 1-substituted azetidin-3-yl (for example where said substituent is as recited earlier in this paragraph).
  • heterocyclyl is a 1-substituted piperidin-4-yl or a 4- substituted piperazin-1-yl, wherein the substituent is S(O) 2 (C 1-4 alkyl), S(O) 2 (Ci -4 haloalkyl), S(O) 2 (phenyl), S(O) 2 N(C 1-4 alkyl) 2 or phenyl.
  • R 1 is piperidinyl or piperazinyl (such as piperidin-4-yl or piperazin-1-yl), either of which is N-substituted by phenyl, S(O) 2 R 39 (wherein R 39 is Ci -4 alkyl (such as methyl or ethyl), phenyl or CF 3 ) or S(O) 2 NR 29 R 30 (wherein R 29 and R 30 are, independently, Ci -4 alkyl (such as methyl)).
  • R 1 is NHC(O)R 14 wherein R 14 is Ci -4 haloalkyl (for example Ci -4 fluoroalkyl, such as CH 2 CF 3 or CH 2 CH 2 CF 3 ), phenyl (optionally substituted by halo) or C 3-6 cycloalkyl (substituted by one or two fluoros).
  • R 1 is phenyl optionally substituted by S(O) 2 R 39
  • R 39 is Ci -4 alkyl (such as methyl)
  • R 1 is heteroaryl (such as pyridinyl) optionally substituted by CF 3 .
  • R 1 is heterocyclyl (such as tetrahydropyran or tetr ahy drothiopyran) .
  • R 2 is phenyl or heteroaryl, either of which is optionally substituted by halo, Ci -4 alkyl, Ci -4 alkoxy, S(O) n (C 1-4 alkyl), nitro, cyano or CF 3 ; wherein n is O, 1 or 2, for example O or 2.
  • R 2 is heteroaryl it is, for example, an optionally substituted thiophenyl (that is, thienyl).
  • R 2 is phenyl or thienyl, either of which is optionally substituted by halo (such as chloro or fluoro) or CF 3 .
  • R 2 is phenyl optionally substituted by halo (such as fluoro) or CF 3 .
  • R 2 is phenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-CF 3 -phenyl, 3,5- dichlorophenyl or 3,5-difluorophenyl.
  • R 2 is phenyl, 3 -fluorophenyl or 3,5-difluorophenyl.
  • R 3 is hydrogen or methyl.
  • R 3 is Ci -4 alkyl (such as methyl) the carbon to which R 3 is attached has the R absolute configuration.
  • R 3 is hydrogen.
  • R 4 is hydrogen, methyl, ethyl, n-propyl, allyl or cyclopropyl. In another aspect R 4 is ethyl.
  • X is CH 2 and Y is absent.
  • X is NH and Y is CH 2 .
  • Z is heterocyclyl (such as piperidinyl or piperazinyl) optionally substituted (such as on a ring nitrogen) by C(O)(Ci -6 alkyl), C(O)(Ci -6 alkoxy) or S(O) 2 (C 1 . 4 alkyl).
  • R 2a is one or 2 halogens (for example two fluoros);
  • R 4 is Ci -4 alkyl (for example ethyl or n- propyl);
  • Z 1 is CH or N; and
  • Z 2 is C(O)(Ci -6 alkyl) (such as acetyl), C(O)(Ci -6 alkoxy) (such as fert-butoxycarbonyl) or S(O) 2 (Ci -4 alkyl) (such as S(O) 2 CH 3 ).
  • R 2a and Z 2 are as defined above.
  • the present invention provides a compound of formula (Ic): wherein R 2a and Z 1 are as defined above; and Z 3 is oxygen or N-S(O) 2 (C 1-4 alkyl) (such as N-S(O) 2 CH 3 ).
  • R 2a and Z 2 are as defined above.
  • R >2a a , R D 4 , and Z are as defined above.
  • the present invention provides a compound of formula (If): wherein ⁇ R>4 and Z r?2 are as defined above.
  • Table I comprises compounds of formula (Ia).
  • Table II comprises compounds of formula (Ib).
  • Table III comprises compounds of formula (Ic).
  • Table IV comprises compounds of formula (Id).
  • the invention provides each individual compound listed in the tables above.
  • the compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If) can be prepared as shown below.
  • the compounds of the invention can be prepared by reacting a compound of formula (II):
  • a suitable solvent such as an aliphatic alcohol such as methanol
  • a suitable organic acid such as an aliphatic acid, for example acetic acid
  • a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • a compound of the invention can be prepared by reacting a compound of formula (IV):
  • R 1 R 3 2 JkJk 1 wherein the leaving group LG 1 is, for example, tosylate, mesylate, triflate or halogen; with a compound of formula (III), under standard literature conditions.
  • a compound of the invention can be prepared by reacting (V): with: when X is CH 2 , a compound of formula (VI):
  • LG 2 is, for example, halogen, an active ester or OH (thus forming a carboxylic acid), activated with a carbodiimide coupling agent such as HATU or the activated product of the reaction of an acid with carbonyldiimidazole; the reaction being carried out in an inert solvent (such as dichloromethane) in the presence of a base (such as triethylamine); OR when X is NH, a compound of formula (VII):
  • LG 3 is halogen or an active ester; the reaction being carried out in an inert solvent (such as dichloromethane) in the presence of a base (such as triethylamine).
  • an inert solvent such as dichloromethane
  • a base such as triethylamine
  • a compound of formula (V) can be prepared by deprotecting (IX): wherein the protecting group PG is, for example, benzyl, Cbz (benzyloxycarbonyl) or tert- butoxycarbonyl, and can be removed by hydrogenation or by treatment with acid (such as trifluoroacetic acid).
  • a compound of formula (IX) can be prepared by reacting (X):
  • a compound of the invention wherein Y is absent, X is CH 2 and Z is a N containing heterocycle can be prepared by reacting a compound of formula (XI):
  • LG 3 is halogen (such as bromine), tosylate or mesylate), with an N-containing heterocycle in an inert solvent (such as dichloromethane, dioxane or tetrahydrofuran) in presence of base (such as triethylamine or diisopropylethylamine) at a temperature in the range from ambient to the boiling point of the solvent).
  • an inert solvent such as dichloromethane, dioxane or tetrahydrofuran
  • base such as triethylamine or diisopropylethylamine
  • a compound of formula (XI) can be prepared by reaction of a compound of formula (V) with a halo acetic acid, using an acid coupling reagent known in the art, or with a haloacetyl halide.
  • the invention provides processes for preparing the compounds of formulae (I), (Ia), (Ib), (Ic) (Id), (Ie) and (If). Many of the intermediates in the processes are novel and these are provided as further features of the invention.
  • the compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
  • modulators such as agonists, partial agonists, inverse agonists or antagonists
  • CCR5 chemokine receptor
  • the compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS).
  • viruses such as human immunodeficiency virus (HIV)
  • HIV human immunodeficiency virus
  • a method for modulating chemokine receptor activity in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (for example rheumatoid arthritis).
  • Respiratory disease is, for example, COPD, asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ or rhinitis ⁇ acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis ⁇ ; and is particularly asthma or rhinitis].
  • COPD chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇
  • the present invention provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) (Id) 3 (Ie) or (If) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
  • chemokine receptor activity especially CCR5 receptor activity (especially rheumatoid arthritis)
  • the invention also provides a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis.
  • the present invention provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
  • chemokine receptor activity especially CCR5 receptor activity (especially rheumatoid arthritis)
  • the invention further provides the use of a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
  • obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis;
  • COPD chronic
  • arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
  • arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis
  • psoriasis atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosin
  • (5) Allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man.
  • AIDS Acquired Immunodeficiency Syndrome
  • Lupus disorders such as lupus erythemat
  • the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof.
  • a chemokine mediated disease state especially a CCR5 mediated disease state
  • a warm blooded animal such as man
  • a compound of the invention or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity
  • said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or I(f) or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • the pharmaceutical composition will comprise, for example, from 0.05 to 99 %w (per cent by weight), such as from 0.05 to 80 %w, for example from 0.10 to 70 %w (such as from 0.10 to 50 %w), of active ingredient, all percentages by weight being based on total composition.
  • the pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • aerosols dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.
  • composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 of the compound, preferably in the range of O.lmgkg "1 to 20mgkg “1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • the invention further relates to combination therapies or compositions wherein a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states.
  • a compound of the invention can be combined with a TNF- ⁇ inhibitor (such as an anti-TNF monoclonal antibodie (such as Remicade, CDP-870 and D.sub2.E.sub7.), or a TNF receptor immunoglobulin molecule (such as Enbrel.reg.)), a non-selective COX-I / COX-2 inhibitor (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid, indomethacin, sulindac or apazone; a pyrazolone such as phenylbutazone; or a salicylate such as aspirin
  • the present invention still further relates to the combination of a compound of the invention together with:
  • a leukotriene biosynthesis inhibitor such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, an N-(5-substituted)-thiophene- 2-alkylsulfonamide, a 2,6-di-tert-butylphenol hydrazones, a methoxytetrahydropyran such as Zeneca ZD-2138, SB-210661, a pyridinyl- substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or quinoline compound such as MK-591,
  • a receptor antagonist for a leukotriene LTB.sub4., LTC.sub4., LTD.sub4. or LTE.sub4. selected from the group consisting of a phenothiazin-3-one such as L- 651,392; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BIIL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) or BAY x 7195;
  • a phenothiazin-3-one such as L- 651,392
  • an amidino compound such as CGS-25019c
  • a benzoxalamine such as ontazolast
  • a PDE4 inhibitor including an inhibitor of the isoform PDE4D
  • an antihistaminic H.subl . receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine;
  • vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride or ethylnorepinephrine hydrochloride;
  • an anticholinergic agent such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
  • a ⁇ .subl.- to ⁇ .sub4.-adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate or pirbuterol, or a methylxanthanine including theophylline and aminophylline; sodium cromoglycate; or a muscarinic receptor (Ml, M2, and M3) antagonist;
  • Ml, M2, and M3 muscarinic receptor
  • IGF-I insulin-like growth factor type I
  • IGF-I insulin-like growth factor type I
  • an inhaled glucocorticoid with reduced systemic side effects such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate or mometasone furoate;
  • MMP matrix metalloprotease
  • a matrix metalloprotease such as a stromelysin, a collagenase, or a gelatinase or aggrecanase
  • MMP-I collagenase-1
  • MMP-8 collagenase-2
  • MMP- 13 collagenase-3
  • MMP-3 stromelysin- 1
  • MMP-IO stromelysin-2
  • MMP-Il stromelysin-3
  • a modulator of chemokine receptor function such as CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-
  • an osteoporosis agent such as raloxifene, droloxifene, lasofoxifene or fosomax;
  • an immunosuppressant agent such as FK-506, rapamycin, cyclosporine, azathioprine or methotrexate
  • an existing therapeutic agent for the treatment of osteoarthritis for example a nonsteroidal anti-inflammatory agent (hereinafter NSAID's) such as piroxicam or diclofenac, a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen, a fenamate such as mefenamic acid, indomethacin, sulindac or apazone, a pyrazolone such as phenylbutazone, a salicylate such as aspirin, a COX- 2 inhibitor such as celecoxib, valdecoxib, rofecoxib or etoricoxib, an analgesic or intra-articular therapy such as a corticosteroid or a hyaluronic acid such as
  • the present invention still further relates to the combination of a compound of the invention together with: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor including a VLA-4 antagonist; (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kinin-B.subl. - and B.sub2.
  • PAF platelet activating factor
  • ICE interleukin converting enzyme
  • IMPDH interleukin converting enzyme
  • adhesion molecule inhibitor including a VLA-4 antagonist
  • a cathepsin (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix)
  • a -receptor antagonist comprising: (x) an anti-gout agent, e.g., colchicine; (xi) a xanthine oxidase inhibitor, e.g., allopurinol; (xii) an uricosuric agent, e.g., probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGF ⁇ ); (xv) a platelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) a granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) a capsaicin cream; (xix) a Tachykinin NK.
  • an anti-gout agent e.g., colchicine
  • NKP-608C sub 1. and NK.sub3. receptor antagonist selected from the group consisting of NKP-608C; SB-233412 (talnetant); andD-4418; (xx) an elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; (xxi) a TNF ⁇ converting enzyme inhibitor (TACE); (xxii) an induced nitric oxide synthase inhibitor (iNOS); or
  • IsoluteTM SCX column a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK.
  • ArgonautTM PS-tra-amine scavenger resin this means a £r ⁇ -(2-aminoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA.
  • the LC comprised water symmetry 4.6x50 column Cl 8 with 5 micron particle size.
  • the eluents were: A, water with 0.05% formic acid and B, acetonitrile with 0.05% formic acid.
  • the eluent gradient went from 95% A to 95% B in 6 minutes.
  • ionisation was effected by electrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H) + and (xi) the following abbreviations are used:
  • HATU O-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafiuorophosphate
  • HBTU O-(7-Benzotriazol- 1 -yl)-N,N,N;N'-tetramethyluronium hexafiuorophosphate
  • EXAMPLE 1 This Example illustrates the preparation of tert-butyl 4- ⁇ 2-[(l- ⁇ (3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)(ethyl)amino]- 2-oxoethyl ⁇ piperazine-l-carboxylate (Compound 1 Table I).
  • Methanesulphonyl chloride (55 ⁇ l) was added to a solution of N-(l- ⁇ (3i?)-3-(3,5- difluorophenyi)-3 - [ 1 -(methylsulfony l)piperidin-4-yl]propyl ⁇ piperidin-4-y l)-N-ethyl-2- piperazin-1-ylacetamide (200 mg) and triethylamine (143 ⁇ l) in dichloromethane (3.5 ml) at 0 0 C under argon. The reaction mixture was allowed to warm to room temperature and stirring was continued for 3 hours.
  • reaction mixture was diluted with dichloromethane (15 ml) and washed with water (2x20 ml), saturated aqueous sodium bicarbonate solution (2x20 ml), brine (10 ml) and dried.
  • the solvent was evaporated and the residue purified on a silica column eluting with a solvent gradient of ethyl acetate - 20% methanol/ethyl acetate, yield 184 mg, M+H 640.
  • Acetic anhydride (66 ⁇ l) was added to a stirred solution of N-(I- ⁇ (3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulphonyl)piperidm-4-yl]propyl ⁇ piperidin-4-yl)-N-ethyl-2- piperazin-1-ylacetamide (200 mg) [Example 3, part 2] and triethylamine (143 ⁇ l) in dichloromethane (3.5 ml) at 0 0 C under an argon atmosphere.
  • Step 1 Preparation of 2-bromo-N-(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[4- (methylsulphonyl)phenyl]propyl ⁇ piperidin-4-yl)-N-ethylacetamide
  • Step 1 Preparation of t ⁇ t-butyl 4- ⁇ 2-[[l-((3i?)-3-(3,5-difluoroplienyl)-3- ⁇ l- [(trifluoromethyl)sulfonyl]piperidin-4-yl ⁇ propyl)piperidin-4-yl](ethyl)amino]-2- oxoethyl ⁇ piperidine- 1 -carboxylate
  • Step 1 Preparation of tert-butyl (2-S)-2- ⁇ 2-[(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)(ethyl)amino]-2- oxoethyl ⁇ pyrrolidine- 1 -carboxylate
  • Step 2 Preparation of N-(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl ⁇ piperidin-4-yl)-N-ethyl-2-[(25)-pyrrolidin-2-yl]acetamide
  • Step 1 Preparation of (2£)-N-(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-N-ethyl-3 - [ 1 - (methylsulfonyl)piperidin-4-yl]acrylamide
  • Step 2 Preparation of (4i?,55)-l,5-dimethyl-3- ⁇ (2 J E)-3-[l-(methylsulfonyl)piperidin-4- yl]prop-2-enoyl ⁇ ⁇ -phenylimidazolidin ⁇ -one.
  • Lithium bis(trimethylsilyl)amide (8 ml of a IM solution in THF) was added dropwise to a suspension of (4R,5S)-l,5-dimethyl-4-phenyl-2-imidazolidinone (1.52g) in THF (20 ml) under argon at -10 0 C.
  • the reaction mixture was stirred at -10 0 C for 10 minutes, allowed to warm to 0 0 C and maintained at this temperature for 10 minutes then cooled again to -10°C.
  • the solution of the acid chloride (2g dissolved in 10 ml of dichloromethane) prepared in Step 1 was added dropwise and the reaction mixture was allowed to warm to room temperature and washed with water (100 ml).
  • the aqueous extract was extracted with ethyl acetate (3x50 ml) and the ethyl acetate extracts were dried and the residue passed through a 9Og Biotage column eluting with a solvent gradient (50% ethyl acetate/isohexane - 70% ethyl acetate/isohexane). Yield 1.89g.
  • Step 3 Preparation of (4£5i?)-l- ⁇ (3i0-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propanoyl ⁇ -3,4-dimethyl-5-phenylimidazolidin-2-one.
  • TMEDA (11.6g) was added to a suspension of copper iodide (19.4g) in THF (240 ml) under argon and the mixture was stirred for 45 minutes then cooled to -7O 0 C, A solution of 3,5-difluorophenyl magnesium bromide in THF (201.1 ml of a 0.5M solution in THF) was added over 10 minutes and the mixture was stirred at -70°C for 30 minutes.
  • Di-n-butylboron triflate (100.7 ml of IM solution in dichloromethane) was added to a suspension of (4i?,55)-l,5-dimethyl-3- ⁇ (2E)-3-[l-(methylsulfonyl)piperidin-4-yl]prop-2- enoyl ⁇ -4-phenylimidazolidin-2-one (20.4Ig) [Step 2] in THF maintained at-40°C and stirring was continued for 10 minutes and the mixture was cooled to -7O 0 C and added via a cannula to the cuprate suspension prepared in step A.
  • the reaction mixture was stirred at - 7O 0 C for 1 hour and allowed to warm to room temperature, then saturated ammonium chloride solution (200 ml) was added.
  • saturated ammonium chloride solution 200 ml
  • the THF was evaporated and ethyl acetate (200 ml) was added. Air was blown through this mixture for 1 hour.
  • the ethyl acetate layer was collected and the aqueous portion was extracted with ethyl acetate (2x100 ml).
  • the combined ethyl acetate extracts were washed with saturated ammonium chloride solution (2x100 ml), dried and evaporated to dryness.
  • Lithium borohydride (48 ml of 2M solution in THF) was added to a solution of (45',5i?)-l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidm-4-yl]propanoyl ⁇ - 3,4-dimethyl-5-phenylimidazolidin-2-one (25g) in THF (200 ml) and the mixture was heated at 7O 0 C for 3 hours then allowed to cool to room temperature and stirring was continued for 16 hours. Ethanol was added carefully (20 ml) and the reaction mixture was acidified to pH 4 by addition of 2M HCl.
  • Dess-Martin periodinane (5.09g) was added to a solution of (R) 3-(N- methanesulphonylpiperidin-4-yl)-3-(3,5-difluorophenyl)propanol (4.Og) in dichloromethane (100 ml) and the mixture was stirred for 1.5 hours. The reaction mixture was washed with 2M NaOH (2x100 ml) and dried. The solution of the title compound in dichloromethane was used in subsequent reactions.
  • step I 3-(N-trifluoromethylsulphonylpiperidin-4- yl)propenoic acid instead of 3-(N-methanesulphonylpiperidin-4-yl)propenoic acid in step I was prepared (R) 3-(N-trifluoromethylsulphonylpiperidin-4-yl)-3-(3,5- difluorophenyl)propionaldehyde.
  • Step 1 Preparation of tert-buty ⁇ 4- ⁇ 2-[ ⁇ l-[(benzyloxy)carbonyl]piperidin-4- yl ⁇ (ethyl)amino]-2-oxoethyl ⁇ piperazine-l-carboxylate.
  • Step 2 Preparation of the title compound.
  • a solution of tert-butyl 4- ⁇ 2-[ ⁇ l-[(benzyloxy)carbonyl]piperidin-4- yl ⁇ (ethyl)amino]-2-oxoethyl ⁇ piperazine-l-carboxylate (1.98g) in ethanol (20ml) was hydrogenated under a hydrogen filled balloon using 20% Pd(OH) 2 on carbon as catalyst.
  • the reaction mixture was filtered through Celite and the solvent was evaporated under reduced pressure, the residue was purified by passing down a SCX-2 silica column eluting with methanol initially and then with a IM solution of ammonia in methanol.
  • Step 1 Preparation of tert-butyl 4- ⁇ 2-[ ⁇ 1 -[(benzyloxy)carbonyl]piperidin-4- yl ⁇ (ethyl)amino]-2-oxoethyl ⁇ piperidine- 1 -carboxylate.
  • Step 2 Preparation of tert-butyl 4- ⁇ ethyl[( ⁇ [l-(methylsulfonyl)piperidin-4- yl]methyl ⁇ amino)carbonyl]amino ⁇ piperidine-l-carboxylate.
  • Step 1 Preparation of tert-b ⁇ tyl 4-(allyl ⁇ [l-(methylsulfonyl)piperidin-4- yl]acetyl ⁇ amino)piperidine-l-carboxylate
  • Step 1 Preparation of E-(4S, 5i?)-l-(3-[4-methanesulphonylphenyl]acryloyl)-3,4-dimethyl- 5 -phenyl-imidazolidin-2-one
  • Step 2 Preparation of (4S, 5i?)-l-[(#)-3-(4-methanesulphonyl-phenyl)-3-(3,5-di- fluorophenyl)-propionyl] -3 ,4-dimethyl-5 -phenyl-imidazolidin-2-one
  • Step 3 Preparation of (i?)-3-(3,5-difluorophenyl)-3-[4-(methylsulphonyl) ⁇ henyl]propanol
  • Dess-Martin periodinane (5.09g) was added to a solution of (i?)-3-(3,5- difluorophenyl)-3-[4-(methylsulphonyl)phenyl]propanol (3.26g) in dichloromethane (50 ml) and the mixture was stirred for 45 minutes, diluted with an equal volume of dichloromethane and washed with 2M NaOH (2x25 ml) and brine (25 ml) and dried. The solution obtained on filtration of the drying agent was used directly in subsequent steps.
  • Step 1 Preparation of benzyl 4-[(cyclopropylmethyl)amino]piperidine-l-carboxylate
  • Step 3 Preparation of ter ⁇ -butyl (cyclopropylmethyl)piperidin-4-ylcarbamate
  • Step 4 Preparation of tert-butyl (cyclopropylmethyl)(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)carbamate
  • Step 5 Preparation of N-(cyclopropylmethyl)-l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-amine
  • Step 6 Preparation of tert-butyl 4- ⁇ 2-[(cyclopropylmethyl)(l- ⁇ (3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)amino]-2- oxoethyl ⁇ piperazine- 1 -carboxylate
  • Step 1 Preparation of tert-butyl (l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)methylcarbamate
  • Trifluoroacetic acid 25 ml was added to tert-butyl (l- ⁇ (3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl) ⁇ iperidm-4-yl]propyl ⁇ piperidin-4- yl)methylcarbamate (9.7 g) and stirred at room temperature for 1 hour.
  • the trifluoroacetic acid was evaporated off and 2N NaOH (100 ml) added and the mixture extracted with dichloromethane (3x100 ml). The combined extracts were dried over MgSO 4 and evaporated to leave a pale brown gum which was used without further purification.Yield 7.6g.
  • Step 1 Preparation of tert-butyl [l-(methylsulfonyl)pyrrolidin-3-yl] acetate
  • Step 2 Preparation of title compound tert-bntyl [l-(methylsulfonyl)pyrrolidin-3-yl] acetate (1.8g) was dissolved in TFA (20 ml) and stood at room temperature for 1 hour. The TFA was evaporated. The residue was triturated with ether (6x20ml) and the combined ether extracts was evaporated to yield a white solid (yieldl40 mg).
  • Step 1 Preparation of benzyl 4-( ⁇ [(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l-
  • EXAMPLE 18 The ability of compounds to inhibit the binding of MIP-I ⁇ was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with O.lnM iodinated MIP-Ia , scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated MIP- l ⁇ bound to the receptor was determined by scintillation counting.
  • Preferred compounds of formula (I) have an IC 50 of less than 50 ⁇ M.
  • Results from this test for certain compounds of the invention are presented in Table V.
  • Table V the results are presented as Pic50 values.
  • a Pic50 value is the negative log (to base 10) of the IC 50 result, so an IC50 of l ⁇ M (that is 1 x 10 '6 M) gives a Pic50 of 6. If a compound was tested more than once then the data below is an average of the probative tests results.

Abstract

Compounds of formula (I): wherein: when X is NR5, Y is absent or is CH2; when X is CH2, Y is absent, CH2, NR6, O, S, S(O) or S(O)2; Z is a 5- or 6-membered heterocyclyl ring; compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).

Description

CHEMICAL COMPOUNDS
The present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
Pharmaceutically active piperidine derivatives are disclosed in PCT/SEOl/01053, EP-A1-1013276, WOOO/08013, WO99/38514 and WO99/04794.
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or α) and Cys-Cys (C- C, or β) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP- 1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins lα and lβ (MIP- lα and MIP-I β).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO, CXCRl, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above. The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several chemokines, principally "regulated on activation normal T-cell expressed and secreted" (RANTES), macrophage inflammatory proteins (MIP) MIP- lα and MIP-I β and monocyte chemoattractant protein-2 (MCP-2).
This results in the recruitment of cells of the immune system to sites of disease. In many diseases it is the cells expressing CCR5 which contribute, directly or indirectly, to tissue damage. Consequently, inhibiting the recruitment of these cells is beneficial in a wide range of diseases. CCR5 is also a co-receptor for HIV-I and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection.
The present invention provides a compound of formula (I):
Figure imgf000003_0001
wherein
R1 is C1-8 alkyl, C(O)NR10R11, C(O)2R12, NR13C(O)R14, NR15C(O)NR16R17, NR18C(O)2R19, heterocyclyl, aryl or heteroaryl;
R10, R13, R15, R16 and R18 are hydrogen or C1-6 alkyl;
R11, R12, R14, R17 and R19 are Ci-8 alkyl (optionally substituted by halo, hydroxy, Ci-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl (optionally substituted by halo), C5-6 cycloalkenyl,
S(Ci-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), heteroaryl, aryl, heteroaryloxy or aryloxy), aryl, heteroaryl, C3-7 cycloalkyl (optionally substituted by halo, Ci-4 alkyl or Ci-4 haloalkyl), C4-7 cycloalkyl fused to a phenyl ring, C5-7 cycloalkenyl, or heterocyclyl; or
R11, R12, R14 and R17 can also be hydrogen; or R10 and R11, and/or R16 and R17 may join to form a A-, 5- or 6-membered ring which optionally includes a nitrogen, oxygen or sulphur atom, said ring being optionally substituted by Ci-6 alkyl, Ci-6 haloalkyl, S(O)i(Ci-6 alkyl) or C(O)(Ci-6 alkyl);
R2 is C i-6 alkyl, phenyl, heteroaryl or C3-7 cycloalkyl; when X is NR5, Y is absent or is CH2; when X is CH2, Y is absent, CH2, NR6, O, S, S(O) or S(O)2; Z is a 5- or 6-membered heterocyclyl ring; R3, R5 and R6 are, independently, hydrogen or Ci-6 alkyl; R4 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl or C3-6 cycloalkyl; aryl, phenyl and heteroaryl moieties are independently optionally substituted by: halo, cyano, nitro, hydroxy, OC(O)NR20R21, NR22R23, NR24C(O)R25, NR26C(O)NR27R28, S(O)2NR29R30, NR31S(O)2R32, C(O)NR33R34, CO2R36, NR37CO2R38, S(O)qR39, OS(O)2R49, C1-6 alkyl (optionally mono-substituted by S(O)2R50 or C(O)NR51R52), C2-6 alkenyl, C2-6 alkynyl, C3-1O cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy(Ci-6)alkyl, C1-6 alkoxy (optionally mono-substituted by CO2R53, C(O)NR54R55, cyano, heteroaryl or C(O)NHS(O)2R56), NHC(O)NHR57, Ci-6 haloalkoxy, phenyl, phenyl(Ci-4)alkyl, phenoxy, phenylthio, phenylS(O), phenylS(O)2, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(Ci-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(Ci-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, Ci-4 alkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(Ci-4 alkyl), CF3 or OCF3; unless otherwise stated heterocyclyl moieties are independently optionally substituted by: Ci-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, Ci- 4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio, S(O)(Ci-4 alkyl) or S(O)2(Ci-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, (CL4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(Ci-4 alkyl) or S(O)2(Ci-4 alkyl)}], phenyl {optionally substituted by halo, C1-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, OCF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(Ci-4 alkyl)}, heteroaryl {optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio, S(O)(Ci-4 alkyl) or S(O)2(Ci-4 alkyl)}, S(O)2NR40R41, C(O)R42, C(O)2(C1-6 alkyl) (such as tert-butoxycarbonyl), C(O)2(phenyl(Ci-2 alkyl)) (such as benzyloxycarbonyl), C(O)NHR43, S(O)2R44, NHS(O)2NHR45, NHC(O)R46, NHC(O)NHR47 or NHS(O)2R48, provided none of these last four substituents is linked to a ring nitrogen; k, 1, p and q are, independently, O, 1 or 2; R20, R22, R24, R26, R27, R29, R31, R33, R37, R40, R51 and R54 are, independently, hydrogen or
C1-6 alkyl;
R21, R23, R25, R28, R30, R32, R34, R36, R38, R39 5 R41, R42, R43, R44, R45, R46, R47, R48, R49, R50,
R52, R53, R55, R56 and R57 are, independently, C1-6 alkyl (optionally substituted by halo, hydroxy, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-6 cycloalkyl, C5-6 cycloalkenyl, S(Ci-4 alkyl),
S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), heteroaryl, phenyl, heteroaryloxy or phenyloxy), C3-7 cycloalkyl, phenyl or heteroaryl; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(Ci-4 alkyl),
S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, Ci-4 alkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H,
CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(Ci-4 alkyl), CF3 or OCF3;
R21, R23, R25, R28, R30, R34, R35, R36, R41, R42, R43, R45, R46, R47, R52, R53, R55 and R57 may additionally be hydrogen; alternatively, R20 and R21, and/or R22 and R23, and/or R27 and R28, and/or R29 and R30, and/or R33 and R34, and/or R51 and R52 and/or R54 and R55, and/or R40 and R41 may join to form a 5- or 6-membered ring which is optionally substituted with halo, Ci-4 alkyl or phenyl (wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy,
C-4 alkyl, Ci-4 alkoxy, S(O)1nCi-4 alkyl, S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, NHS(O)2(Ci-4 alkyl), NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2s NHC(O)NH2, C(O)NH2, C(O)NH(Ci-4 alkyl), NHC(O)(C1-4 alkyl), CO2H, CO2(Ci-4 alkyl), C(O)(Ci-4 alkyl), CF3,
CHF2, CH2F, CH2CF3 or OCF3); m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.
Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate, succinate or^>-toluenesulphonate. The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates. Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl. Methyl is sometimes abbreviated to Me hereinbelow.
Haloalkyl comprises, for example, one to six, such as one to three, halogen (such as fluorine) atoms, and is, for example, CF3 or CH2CF3.
Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
Phenyl(C1-4 alkyl) is, for example, benzyl, l-(phenyl)eth-l-yl or l-(phenyl)eth-2-yl.
Heteroaryl(C1-4 alkyl) is, for example, pyridinylmethyl, pyrimidinylmethyl or 1- (pyridinyl)eth-2-yl. Phenyl(C1-4 alkoxy) is, for example, benzyloxy or l-(phenyl)eth-l-yloxy.
Aryloxy is, for example, phenoxy.
Heteroaryloxy is, for example, pyridinyloxy or pyrimidinyloxy.
Heteroaryl(C1-4 alkoxy) is, for example, pyridinylmethoxy, pyrimidinylmethoxy or 1 -(pyridinyl)eth-2-oxy . Heteroaryl is an aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [l,2,4]-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzo.[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl (also known as benzo[l,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, a pyrazolopyridine (for example lH-pyrazolo[3,4- b]pyridinyl), quinolinyl, isoquinolinyl, a naphthyridinyl (for example [l,6]naphthyridinyl or [l,8]naphthyridinyl), a benzothiazinyl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
Suitable 5- or 6-membered heterocyclyl rings (the group Z) include rings having one or two nitrogen atoms and, optionally, one oxygen or sulphur atom. Suitable rings are, for example, piperidine, piperazine, morpholine, thiomorpholine or pyrrolidine. In one aspect of the invention Z is piperidine, piperazine or pyrrolidine (such as piperidine or piperazine).
In a further aspect the present invention provides a compound of formula (I) wherein, unless specified otherwise, aryl, phenyl and heteroaryl moieties are independently optionally substituted by one or more of halo, hydroxy, nitro, S(C1-6 alkyl), S(O)(Ci-6 alkyl), S(O)2(C1-6 alkyl), S(O)2NH2, S(O)2NH(C1-6 alkyl), S(O)2N(C1-6 alkyl)2, cyano, C1-6 alkyl, C1-6 alkoxy, CH2S(O)2(C1-6 alkyl), OS(O)2(C1-6 alkyl), OCH2heteroaryl (such as OCH2tetrazolyl), OCH2CO2H, OCH2CO2(C1-6 alkyl), OCH2C(O)NH2, OCH2C(O)NH(C1-6 alkyl), OCH2CN, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)[N-linked heterocyclyl], CO2H, CO2(C1-6 alkyl), NHC(O)(C1-6 alkyl), NHC(O)O(C1-6 alkyl), NHS(O)2(C1-6 alkyl), CF3, CHF2, CH2F, CH2CF3, OCF3, phenyl, heteroaryl, phenyl(C1-4 alkyl), heteroaryl(Ci-4 alkyl), NHC(O)phenyl, NHC(O)heteroaryl, NHC(O)(C1-4 alkyl)phenyl, NHC(O)(C1-4 alkyl)heteroaryl, NHS(O)2phenyl, NHS(O)2heteroaryl, NHS(O)2(Ci-4 alkyl)phenyl, NHS(O)2(C1-4 alkyl)heteroaryl, NHC(O)NH(C1-6 alkyl), NHC(O)NH(C3-7 cycloalkyl),
NHC(O)NHphenyl, NHC(O)NHheteroaryl, NHC(O)NH(Ci-4 alkyl)phenyl or NHC(0)NH(Ci.4 alkyl)heteroaryl; wherein the foregoing phenyl and heteroaryl groups are optionally substituted by halo, hydroxy, nitro, S(C1-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(CM alkyl)2, cyano, Ci-4 alkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), CF3 or OCF3.
In another aspect the present invention provides a compound of formula (I) wherein, unless specified otherwise, aryl, phenyl and heteroaryl moieties are independently optionally substituted by one or more of halo, hydroxy, nitro, S(Ci-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3.
In another aspect of the invention R10, R13, R15, R16 and R18 are hydrogen or Ci-4 alkyl (for example methyl). In yet another aspect R10, R13, R15, R16 and R18 are hydrogen. In a further aspect of the invention R11, R12, R14, R17, R18 and R19 are Ci-8 alkyl
(optionally substituted by halo, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-6 cycloalkyl (optionally substituted by halo), C5-6 cycloalkenyl, S(O)2(Ci-4 alkyl), heteroaryl, phenyl, heteroaryloxy or aryloxy (for example phenoxy)), phenyl, heteroaryl, C3-7 cycloalkyl (optionally substituted by halo or Ci-4 alkyl), C4-7 cycloalkyl fused to a phenyl ring, C5-7 cycloalkenyl, or, heterocyclyl (itself optionally substituted by oxo, C(O)(Ci-6 alkyl), S(O)k(Ci-4 alkyl), halo or CM alkyl); k is 0, 1 or 2; or R10 and R11, and/or R16 and R17 may join to form a 4-, 5- or 6-membered ring which optionally includes a nitrogen, oxygen or sulphur atom, said ring being optionally substituted by C1-6 alkyl or C(O)(C1-6 alkyl).
In yet another aspect of the invention R11, R12, R14, R17 and R19 are Ci-8 alkyl (optionally substituted by halo (such as fluoro)), phenyl (optionally substituted as recited above), C3-6 cycloalkyl (optionally substituted by halo (such as fluoro)) or C-lmked nitrogen containing heterocyclyl (optionally substituted on the ring nitrogen).
In a further aspect R1 is NHC(O)R14, phenyl or heterocyclyl, wherein R14 is as defined above, and phenyl and heterocyclyl are optionally substituted as described above. In another aspect of the invention R1 is NR13C(O)R14, wherein R13 and R14 are as defined above. For example R13 is hydrogen. In yet another aspect of the invention R14 is Ci-8 alkyl (optionally substituted by halo (such as fluoro, for example to form CF3CH2)), phenyl (optionally substituted as recited above), C3-6 cycloalkyl (optionally substituted by halo (such as fluoro, for example to form l,l-difluorocyclohex-4-yl)) or C-linked nitrogen containing heterocyclyl (such as tetrahydropyran or piperidine, optionally substituted on the ring nitrogen). In another aspect the present invention provides a compound of the invention wherein R14 is Ci-8 alkyl (optionally substituted by halo (such as fluoro, for example to form CF3CH2)), phenyl (optionally substituted by halo) or C5-6 cycloalkyl (optionally substituted by halo (such as fluoro, for example to form l,l-difluorocyclohex-4-yl)).
In a further aspect of the invention heterocyclyl of R1 is optionally substituted (such as singly substituted for example on a ring nitrogen atom when present) by Ci-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, OCF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio or S(O)2(Ci-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1.4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, CM alkylthio or S(O)2(Ci-4 alkyl)}], phenyl {optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, OCF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio or S(O)2(Ci-4 alkyl)}, heteroaryl {optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio or S(O)2(C1-4 alkyl)}, S(O)2NR40R41, C(O)R42, C(O)NHR43 or S(O)2R44; wherein R40, R41, R42, R43 and R44 are, independently, hydrogen or C1-6 alkyl.
In yet another aspect of the invention R1 is optionally substituted aryl (such as optionally substituted phenyl) or optionally substituted heteroaryl, wherein the optional substituents are as recited above.
In a further aspect of the invention when R1 is heterocyclyl it is, for example, tetrahydropyran, tetrahydrothiopyran, tetrahydrodioxythiopyran, piperidine, piperazine, pyrrolidine or azetidine. In another aspect when R1 is heterocyclyl it is, for example, piperidine, piperazine, pyrrolidine or azetidine.
In a further aspect of the invention R1 is optionally substituted heterocyclyl, such as optionally substituted: piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, azetidin-1-yl or azetidin-3-yl.
In a still further aspect of the invention the heterocyclyl of R1 is mono-substituted by C1-6 alkyl, C3-7 cycloalkyl, phenyl {optionally substituted by halo (for example fluoro), CL4 alkyl (for example methyl), C1-4 alkoxy (for example methoxy), CF3 or OCF3), S(O)2(C1-4 alkyl) (for example S(O)2CH3, S(O)2CH2CH3 or S(O)2CH(CH3)2), S(O)2(C1-4 fluoroalkyl) (for example S(O)2CF3 or S(O)2CH2CF3), S(O)2phenyl {optionally substituted (such as mono-substituted) by halo (for example chloro), cyano, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, S(O)2(Ci-4 alkyl) (for example S(O)2CH3 or S(O)2CH2CH2CH3) or S(O)2(Ci-4 fiuoroalkyl) (for example S(O)2CH2CF3)), benzyl {optionally substituted by halo (for example chloro or fluoro), Ci-4 alkyl, Ci-4 alkoxy (for example methoxy), CF3 or OCF3), C(O)H, C(O)(Ci-4 alkyl), benzoyl {optionally substituted by halo (for example chloro or fluoro), Ci-4 alkyl (for example methyl), C1-4 alkoxy, CF3 or OCF3), C(O)2(Ci-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl) or C(O)NHphenyl {optionally substituted by halo (for example fluoro), Ci-4 alkyl, C1-4 alkoxy, CF3 or OCF3). Said heterocyclyl can also be mono-substituted by S(O)2N(Ci-4 alkyl)2. In a still further aspect when said heterocyclyl is a 4-substituted piperidin-1-yl, a 1 -substituted piperidin-4-yl, a 4-substituted piperazin-1-yl, a 3-substituted pyrrolidin-1-yl, a 1 -substituted pyrrolidin-3-yl, a 3-substituted azetidin-1-yl or a 1-substituted azetidin-3-yl (for example where said substituent is as recited earlier in this paragraph). In another aspect said heterocyclyl is a 1-substituted piperidin-4-yl or a 4- substituted piperazin-1-yl, wherein the substituent is S(O)2(C1-4 alkyl), S(O)2(Ci-4 haloalkyl), S(O)2(phenyl), S(O)2N(C1-4 alkyl)2 or phenyl.
In another aspect of the invention R1 is piperidinyl or piperazinyl (such as piperidin-4-yl or piperazin-1-yl), either of which is N-substituted by phenyl, S(O)2R39 (wherein R39 is Ci-4 alkyl (such as methyl or ethyl), phenyl or CF3) or S(O)2NR29R30 (wherein R29 and R30 are, independently, Ci-4 alkyl (such as methyl)).
In yet another aspect of the invention R1 is NHC(O)R14 wherein R14 is Ci-4 haloalkyl (for example Ci-4 fluoroalkyl, such as CH2CF3 or CH2CH2CF3), phenyl (optionally substituted by halo) or C3-6 cycloalkyl (substituted by one or two fluoros). In a further aspect of the invention R1 is phenyl optionally substituted by S(O)2R39
(wherein R39 is Ci-4 alkyl (such as methyl)).
In a still further aspect of the invention R1 is heteroaryl (such as pyridinyl) optionally substituted by CF3.
In another aspect of the invention R1 is heterocyclyl (such as tetrahydropyran or tetr ahy drothiopyran) .
In yet another aspect of the invention R2 is phenyl or heteroaryl, either of which is optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, S(O)n(C1-4 alkyl), nitro, cyano or CF3; wherein n is O, 1 or 2, for example O or 2. When R2 is heteroaryl it is, for example, an optionally substituted thiophenyl (that is, thienyl). In a further aspect R2 is phenyl or thienyl, either of which is optionally substituted by halo (such as chloro or fluoro) or CF3.
In a still further aspect R2 is phenyl optionally substituted by halo (such as fluoro) or CF3. For example R2 is phenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-CF3-phenyl, 3,5- dichlorophenyl or 3,5-difluorophenyl. In a still further aspect of the invention R2 is phenyl, 3 -fluorophenyl or 3,5-difluorophenyl.
In another aspect of the invention R3 is hydrogen or methyl. In a further aspect of the invention when R3 is Ci-4 alkyl (such as methyl) the carbon to which R3 is attached has the R absolute configuration. In yet another aspect of the invention R3 is hydrogen.
In a further aspect of the invention R4 is hydrogen, methyl, ethyl, n-propyl, allyl or cyclopropyl. In another aspect R4 is ethyl.
In another aspect X is CH2 and Y is absent.
In yet another aspect X is NH and Y is CH2. In a further aspect Z is heterocyclyl (such as piperidinyl or piperazinyl) optionally substituted (such as on a ring nitrogen) by C(O)(Ci-6 alkyl), C(O)(Ci-6 alkoxy) or S(O)2(C1. 4 alkyl).
In another aspect the present invention provides a compound of formula (Ia):
Figure imgf000011_0001
wherein
R2a is one or 2 halogens (for example two fluoros); R4 is Ci-4 alkyl (for example ethyl or n- propyl); Z1 is CH or N; and Z2 is C(O)(Ci-6 alkyl) (such as acetyl), C(O)(Ci-6 alkoxy) (such as fert-butoxycarbonyl) or S(O)2(Ci-4 alkyl) (such as S(O)2CH3).
In yet another aspect the present invention provides a compound of formula (Ib):
Figure imgf000011_0002
wherein R2a and Z2 are as defined above.
In yet another aspect the present invention provides a compound of formula (Ic):
Figure imgf000012_0001
wherein R2a and Z1 are as defined above; and Z3 is oxygen or N-S(O)2(C1-4 alkyl) (such as N-S(O)2CH3).
In yet another aspect the present invention provides a compound of formula (Id):
Figure imgf000012_0002
wherein R2a and Z2 are as defined above.
In yet another aspect the present invention provides a compound of formula (Ie):
wherein R >2aa, R D4 ,
Figure imgf000012_0003
and Z are as defined above.
In yet another aspect the present invention provides a compound of formula (If):
Figure imgf000013_0001
wherein τ R>4 and Z r?2 are as defined above.
The compounds listed in Tables I, II, III IV, V and VI illustrate the invention.
TABLE I Table I comprises compounds of formula (Ia).
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000015_0002
TABLE II Table II comprises compounds of formula (Ib).
Figure imgf000015_0001
Figure imgf000015_0003
TABLE III Table III comprises compounds of formula (Ic).
Figure imgf000016_0001
Figure imgf000016_0003
TABLE IV Table IV comprises compounds of formula (Id).
Figure imgf000016_0002
Figure imgf000016_0004
TABLE V Table V comprises compounds of formula (Ie)
Figure imgf000017_0001
Figure imgf000017_0003
TABLE VI Table VI comprises compounds of formula (If)
Figure imgf000017_0002
Figure imgf000017_0004
Figure imgf000018_0003
In yet another aspect the invention provides each individual compound listed in the tables above. The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If) can be prepared as shown below.
The compounds of the invention can be prepared by reacting a compound of formula (II):
Figure imgf000018_0001
with a compound of formula (III):
Figure imgf000018_0002
under reductive amination conditions {for example in the presence of a suitable solvent (such as an aliphatic alcohol such as methanol), a suitable organic acid (such as an aliphatic acid, for example acetic acid) and a suitable reducing agent (such as sodium triacetoxyborohydride or sodium cyanoborohydride)} .
Alternatively, a compound of the invention can be prepared by reacting a compound of formula (IV):
R1 R3 2JkJk 1 (IV) wherein the leaving group LG1 is, for example, tosylate, mesylate, triflate or halogen; with a compound of formula (III), under standard literature conditions.
Alternatively, a compound of the invention can be prepared by reacting (V):
Figure imgf000019_0001
with: when X is CH2, a compound of formula (VI):
Figure imgf000019_0002
wherein LG2 is, for example, halogen, an active ester or OH (thus forming a carboxylic acid), activated with a carbodiimide coupling agent such as HATU or the activated product of the reaction of an acid with carbonyldiimidazole; the reaction being carried out in an inert solvent (such as dichloromethane) in the presence of a base (such as triethylamine); OR when X is NH, a compound of formula (VII):
^=N-YN (VII)
O z the reaction being carried out in an inert solvent (such as dichloromethane) in the presence of abase (such as triethylamine); OR when X is NR5, a compound of formula (VIII):
Figure imgf000019_0003
wherein LG3 is halogen or an active ester; the reaction being carried out in an inert solvent (such as dichloromethane) in the presence of a base (such as triethylamine).
A compound of formula (V) can be prepared by deprotecting (IX):
Figure imgf000020_0001
wherein the protecting group PG is, for example, benzyl, Cbz (benzyloxycarbonyl) or tert- butoxycarbonyl, and can be removed by hydrogenation or by treatment with acid (such as trifluoroacetic acid). A compound of formula (IX) can be prepared by reacting (X):
Figure imgf000020_0002
with a compound of formula (II) or (IV) above, employing the conditions outlined above for reacting a compound of formula (II) or (IV) with a compound of formula (III).
A compound of the invention wherein Y is absent, X is CH2 and Z is a N containing heterocycle can be prepared by reacting a compound of formula (XI):
Figure imgf000020_0003
wherein LG3 is halogen (such as bromine), tosylate or mesylate), with an N-containing heterocycle in an inert solvent (such as dichloromethane, dioxane or tetrahydrofuran) in presence of base (such as triethylamine or diisopropylethylamine) at a temperature in the range from ambient to the boiling point of the solvent).
A compound of formula (XI) can be prepared by reaction of a compound of formula (V) with a halo acetic acid, using an acid coupling reagent known in the art, or with a haloacetyl halide.
In a still further aspect the invention provides processes for preparing the compounds of formulae (I), (Ia), (Ib), (Ic) (Id), (Ie) and (If). Many of the intermediates in the processes are novel and these are provided as further features of the invention. The compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
The compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS).
According to a further feature of the invention there is provided a compound of the formula (I), (Ia), (Ib), (Ic), (Id) (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR5 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
The present invention also provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (for example rheumatoid arthritis). [Respiratory disease is, for example, COPD, asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)} or rhinitis {acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}; and is particularly asthma or rhinitis]. In another aspect the present invention provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) (Id)3(Ie) or (If) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
The invention also provides a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis.
In another aspect the present invention provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
The invention further provides the use of a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)} ; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis; (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food- related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man.
The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof.
In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or I(f) or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will comprise, for example, from 0.05 to 99 %w (per cent by weight), such as from 0.05 to 80 %w, for example from 0.10 to 70 %w (such as from 0.10 to 50 %w), of active ingredient, all percentages by weight being based on total composition. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg"1 to lOOmgkg"1 of the compound, preferably in the range of O.lmgkg"1 to 20mgkg"1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof (hereafter Compound X), for therapeutic or prophylactic use in humans:
(a)
Figure imgf000025_0001
(e)
Figure imgf000026_0001
Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β- cyclodextrin may be used to aid formulation.
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
The invention further relates to combination therapies or compositions wherein a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic) (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states. In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of the invention can be combined with a TNF-α inhibitor (such as an anti-TNF monoclonal antibodie (such as Remicade, CDP-870 and D.sub2.E.sub7.), or a TNF receptor immunoglobulin molecule (such as Enbrel.reg.)), a non-selective COX-I / COX-2 inhibitor (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid, indomethacin, sulindac or apazone; a pyrazolone such as phenylbutazone; or a salicylate such as aspirin), a COX-2 inhibitor (such as meloxicam, celecoxib, rofecoxib, valdecoxib or etoricoxib) low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine or auranofm, or parenteral or oral gold.
The present invention still further relates to the combination of a compound of the invention together with:
• a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5- lipoxygenase activating protein (FLAP) antagonist, such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, an N-(5-substituted)-thiophene- 2-alkylsulfonamide, a 2,6-di-tert-butylphenol hydrazones, a methoxytetrahydropyran such as Zeneca ZD-2138, SB-210661, a pyridinyl- substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or quinoline compound such as MK-591,
MK-886 or BAY x l005;
• a receptor antagonist for a leukotriene LTB.sub4., LTC.sub4., LTD.sub4. or LTE.sub4. selected from the group consisting of a phenothiazin-3-one such as L- 651,392; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BIIL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) or BAY x 7195;
• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;
• an antihistaminic H.subl . receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine;
• a gastroprotective H.sub2. receptor antagonist;
• an α.subl .- and α.sub2.-adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride or ethylnorepinephrine hydrochloride;
• an anticholinergic agent such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
• a β.subl.- to β.sub4.-adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate or pirbuterol, or a methylxanthanine including theophylline and aminophylline; sodium cromoglycate; or a muscarinic receptor (Ml, M2, and M3) antagonist;
• an insulin-like growth factor type I (IGF-I) mimetic; • an inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate or mometasone furoate;
• an inhibitor of a matrix metalloprotease (MMP), such as a stromelysin, a collagenase, or a gelatinase or aggrecanase; such as collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin- 1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-Il) or MMP-12;
• a modulator of chemokine receptor function such as CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-
X-C family) and CX3CRl for the C-X3-C family;
• an osteoporosis agent such as raloxifene, droloxifene, lasofoxifene or fosomax;
• an immunosuppressant agent such as FK-506, rapamycin, cyclosporine, azathioprine or methotrexate; or, • an existing therapeutic agent for the treatment of osteoarthritis, for example a nonsteroidal anti-inflammatory agent (hereinafter NSAID's) such as piroxicam or diclofenac, a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen, a fenamate such as mefenamic acid, indomethacin, sulindac or apazone, a pyrazolone such as phenylbutazone, a salicylate such as aspirin, a COX- 2 inhibitor such as celecoxib, valdecoxib, rofecoxib or etoricoxib, an analgesic or intra-articular therapy such as a corticosteroid or a hyaluronic acid such as hyalgan or synvisc, or a P2X7 receptor antagonist.
The present invention still further relates to the combination of a compound of the invention together with: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor including a VLA-4 antagonist; (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kinin-B.subl. - and B.sub2. -receptor antagonist; (x) an anti-gout agent, e.g., colchicine; (xi) a xanthine oxidase inhibitor, e.g., allopurinol; (xii) an uricosuric agent, e.g., probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGFβ); (xv) a platelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) a granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) a capsaicin cream; (xix) a Tachykinin NK. sub 1. and NK.sub3. receptor antagonist selected from the group consisting of NKP-608C; SB-233412 (talnetant); andD-4418; (xx) an elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; (xxi) a TNFα converting enzyme inhibitor (TACE); (xxii) an induced nitric oxide synthase inhibitor (iNOS); or
(xxiii) a chemoattractant receptor-homologous molecule expressed on TH2 cells (a CRTH2 antagonist).
The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (0C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C; (ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5- 30 mm Hg) with a bath temperature of up to 600C; (iii) chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a "Bond Elut" column is referred to, this means a column containing 1Og or 2Og of silica of 40 micron particle size, the silica being contained in a 60ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, California, USA under the name "Mega Bond Elut SI". Where an "Isolute™ SCX column" is referred to, this means a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK. Where "Argonaut™ PS-tra-amine scavenger resin" is referred to, this means a £rø-(2-aminoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA.
(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
(v) yields, when given, are for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vi) when given, 1H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio DMSO (CD3SOCD3) as the solvent unless otherwise stated; coupling constants (J) are given in Hz; (vii) chemical symbols have their usual meanings; SI units and symbols are used; (viii) solvent ratios are given in percentage by volume; (ix) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (APCI) mode using a direct exposure probe; where indicated ionisation was effected by electrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+; (x) LCMS characterisation was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer. The LC comprised water symmetry 4.6x50 column Cl 8 with 5 micron particle size. The eluents were: A, water with 0.05% formic acid and B, acetonitrile with 0.05% formic acid. The eluent gradient went from 95% A to 95% B in 6 minutes. Where indicated ionisation was effected by electrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+ and (xi) the following abbreviations are used:
DMSO dimethyl sulfoxide; DMF N-dimethylformamide;
DCM dichloromethane;
THF tetrahydrofuran;
DIPEA N,N-diisopropylethylamine;
ΝMP N-methylpyrrolidinone; HATU O-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafiuorophosphate; HBTU O-(7-Benzotriazol- 1 -yl)-N,N,N;N'-tetramethyluronium hexafiuorophosphate;
Boc tert-butoxycarbonyl MeOH methanol;
EtOH ethanol;
EtOAc ethyl acetate; MP macro porous; and,
PS polymer supported.
EXAMPLE 1 This Example illustrates the preparation of tert-butyl 4-{2-[(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(ethyl)amino]- 2-oxoethyl}piperazine-l-carboxylate (Compound 1 Table I).
Figure imgf000031_0001
MP-triacetoxyborohydride (2.5g) was added to a solution of (3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propanal (662 mg) (Method A) and fert-butyl 4- {2-[ethyl(piperidin-4-yl)amino]-2-oxoethyl}piperazine- 1 -carboxylate (Method B) (704 mg) in dichloromethane (25 ml) and the mixture was stirred for 18 hours. The reaction mixture was filtered and the resin was washed with a 1:9 mixture of methanol in dichloromethane (50 ml). The combined filtrates were evaporated to dryness and the residue was purified by passing down a 4Og silica column eluted with a solvent gradient of ethyl acetate to 30% methanol-ethyl acetate. The title compound was obtained in 58% yield, LC-MS M+H = 670.
1H NMR: 1.15 (3H, m), 1.20-2.17 (14H, m), 1.42 (9H, s), 2.36-2.54 (6H, m), 2.62 (2H, t), 2.74 (3H, s), 2.90 (2H, m), 3.18 (2H, d), 3.22-3.48 (6H, m), 3.71 (IH, d), 3.79 & 4.29 (IH, m), 3.85 (IH, d), 6.63 (3H, m).
EXAMPLE Ib
In an analogous manner but using fert-butyl 4-{2-[isobutyl(piperidin-4-yl)amino]- 2-oxoethyl}piperazine-l -carboxylate (Method B) instead of tert-butyl 4-{2- [ethyl(piperidin-4-yl)amino]-2-oxoethyl}piperazine-l-carboxylate was prepared tert-butyl 4-{2-[(l-{(3i?)-3-(3,5-difiuorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)(isobutyl)amino]-2-oxoethyl}piperazine-l-carboxylate (Compound 12 Table I), LC-MS M+H = 698
NMR CDC13 0.65 (d, 3H) 0.75 (d, 3H) 1.1-1.3 (m, 3H) 1.4 (s, 9H) 1.45-2.1 (m, 14H) 2.3-2.6 (m, 10H) 2.7 (s, 3H) 2.8-3.2 (m, 4H) 3.3-3.4 (m, 3H) 3.7 (m, IH) 3.8 (m, IH) 6.6 (m, 3H)
Figure imgf000032_0001
EXAMPLE Ic In an analogous manner but using tert-butyl 4-{2-[methyl(piperidin-4-yl)amino]-2- oxoethyl}piperazine-l-carboxylate (Method B) instead of tert-bntyl 4-{2-[ethyl(piperidin- 4-yl)amino]-2-oxoethyl}piperazine-l-carboxylate was prepared tert-butyl 4-{2-[(l-{(3i?)- 3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4- yl)(methyl)amino]-2-oxoethyl}piperazine-l-carboxylate (Compound 20 Table I) ; LC-MS M+H = 656 NMR CDCl3 1.2-1.4 (2H, m) 1.45 (9H, s) 1.5-2.2 (14H, m) 2.35-2.5 (5H, m) 2.6
(IH, m) 2.7 (3H3 s) 2.75-2.95 (5H, m) 3.2 (2H, d) 3.45-3.5 (4H, m) 3.7 (IH, m) 3.75, 4.4 (IH, m) 3.85 (IH, m) 6.7 (3H, m)
Figure imgf000032_0002
EXAMPLE Id
In an analogous manner but using tert-butyl 4-{2-[isobutyl(piperidin-4-yl)amino]-2- oxoethyl}piperazine-l-carboxylate (Method B) instead oftert-butyl 4-{2-[ethyl(piperidin- 4-yl)amino]-2-oxoethy 1} piperazine- 1 -carboxylate and (3i?)-3 -(3 -fluorophenyl)-3 - [ 1 - (methylsulfonyl)piperidin-4-yl]propanal (Method A) was prepared tert-bntyl 4-{2-[(l- {(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4- yl)(isobutyl)amino]-2-oxoethyl}piperazine-l-carboxylate; LC-MS M+H = 680
NMR CDCl3 0.75 (3H, d) 0.85 (3H, d) 1.1-1.35 (4H, m) 1.4 (9H, s) 1.45-2.1 (16H, m) 2.3-2.5 (5H, m) 2.55 (IH, t) 2.65 (3H, s) 2.7-3.05 (4H, m) 3.1 (IH, s) 3.3-3.4 (3H, m) 3.6 (IH, m) 3.8-4 91H, m) 6.7-6.9 (3H, m) 7.2 (IH, m)
Figure imgf000033_0001
EXAMPLE 2
This Example describes the preparation of fers-butyl 4-{2-[(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(ethyl)amino]- 2-oxoethyl}piperidine-l -carboxylate (Compound 2 Table I).
Figure imgf000033_0002
MP-triacetoxyborohydride (2.5g) was added to a solution of (3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propanal (662 mg) (Method A) and tert-butyl 4-{2-[ethyl(piperidin-4-yl)amino]-2-oxoethyl}piperidine-l-carboxylate (Method B) (706 mg) in dichloromethane (25 ml) and the mixture was stirred for 18 hours. The reaction mixture was filtered and the resin was washed with a 1 :9 mixture of methanol in dichloromethane (50 ml). The combined filtrates were evaporated to dryness and the residue was purified by passing down a 4Og silica column eluted with a solvent gradient of ethyl acetate to 10% methanol-ethyl acetate to give the title compound yield, 684 mg, LC- MS M+H = 669.
1H NMR: 1.10-2.23 (25H, m), 1.43 (9H, s), 2.38 (IH, t), 2.51 (IH, t), 2.62 (IH, t), 2.72 (2H, m), 2.73 (3H, s), 2.88 (2H, m), 3.24 (2H, m), 3.48 & 4.38 (IH, m), 3.72 (IH, d), 3.84 (IH, d), 4.08 (2H, m), 6.62 (3H, m).
EXAMPLE 3
This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-piperidin-4-ylacetamide (Compound 3 Table I).
Figure imgf000034_0001
tert-Butyl 4-{2-[(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)(ethyl)amino]-2-oxoethyl}piperidine-l-carboxylate (635 mg) was added to 4M HCl in dioxane (10 ml) and the mixture was allowed to stand for 15 minutes. Methanol (10 ml) was added and the solution was stirred for 45 minutes. The solvent was evaporated to give a white foam, yield 560 mg, LC-MS M+H 569.
1H ΝMR (CDCl3): 1.10-2.14 (23H, m), 2.22 (2H, m), 2.42 (IH, t), 2.54 (IH, t), 2.66 (3H, m), 2.74 (3H, s), 2.88 (2H, m), 3.12 (2H, d), 3.28 (2H, m), 3.50 & 4.38 (IH, m), 3.72 (IH, d), 3.84 (IH, d), 6.64 (3H, m)
Using tert-butyl 4-{2-[(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(ethyl)amino]-2- oxoethyl}piperazine-l-carboxylate (Compound 1 Table I) as starting material there is obtained N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-ethyl-2-piperazin-l-ylacetamide (Compound 4 Table I); LC- MS M+H 570, 1H ΝMR (CDCl3): 1.10-2.14 (18H, m), 2.36-2.56 (6H, m), 2.64 (2H, t), 2.74 (3H, s), 2.78-2.96 (5H, m), 3.14 (2H, d), 3.32 (2H, m), 3.72 (IH, m), 3.78 & 4.28 (IH, m), 3.86 (IH, m), 6.64 (3H, m).
EXAMPLE 3a
Using tert-butyl 4-{2-[(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(isobutyl)amino]-2- oxoethyl}piperazine-l-carboxylate (Compound 12 Table I) as starting material there is obtained N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidm-4-yl)-N-isobutyl-2-piperazin-l-ylacetamide (Compound 13 Table I); LC-MS M+H 598 ΝMR CDCl3 0.7 (d, 3H) 0.8 (d, 3H) 1-2.1 (m, 20 H) 2.3-2.45 (m, 5H) 2.6 (t, IH)
2.7 (s, 3H) 2.75-2.8 (m, 2H) 2.9 (d, IH) 3.1 (m, 2H) 3.7 (d, IH) 3.8 (m, IH) 6.6 (m, 3H)
EXAMPLE 3b
Using tert-butyl 4-{2-[(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(isobutyl)amino]-2- oxoethyl}piperazine-l-carboxylate (Example Id) as starting material was prepared N-(I- {(3i?)-3-(3-fluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N- isobutyl-2-piperazin-l-ylacetamide (Compound 16 Table I); LC-MS M+H 580
ΝMR: CDCl30.75 (3H, d) 0.85 (3H, d) 1.1-2.1 (14H, m) 2.2-2.5 (7H, m) 2.55 (IH, t) 2.65 (3H, s) 2.7-2.9 (8H, m) 2.95 (IH, d) 3.05 (2H, m) 3.6 (IH3 m) 3.7-3.9 (2H, m) 6.6- 6.9 (3H, m) 7.2 (IH, m)
EXAMPLE 3c
Using tert-butyl 4- {2- [ethyl(piperidm-4-yl)amino] -2-oxoethyl} piperazine- 1 - carboxylate was prepared tert-butyl 4-{2-[(l-{(3i?)-3-(3,5-difluoroρhenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(methyl)amino]-2- oxoethyl}piperazine-l-carboxylate (Example Ic) as starting material was prepared N-(I- { (3i?)-3 -(3 , 5-difluorophenyl)-3 - [ 1 -(methylsulfonyl)piperidin-4-yl]propyl} piperidin-4-y I)- N-methyl-2-piperazin-l-ylacetamide; LC-MS M+H 556
EXAMPLE 4 This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-
(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsulfonyl)piperazin-l-yl]acetamide (Compound 5 Table I).
Figure imgf000036_0001
Methanesulphonyl chloride (55 μl) was added to a solution of N-(l-{(3i?)-3-(3,5- difluorophenyi)-3 - [ 1 -(methylsulfony l)piperidin-4-yl]propyl} piperidin-4-y l)-N-ethyl-2- piperazin-1-ylacetamide (200 mg) and triethylamine (143 μl) in dichloromethane (3.5 ml) at 0 0C under argon. The reaction mixture was allowed to warm to room temperature and stirring was continued for 3 hours. The reaction mixture was diluted with dichloromethane (15 ml) and washed with saturated ammonium chloride solution (2x10 ml) and brine (1x1 OmI) and dried. The solvent was evaporated to give the title compound as a white foam, yield 185 mg, LC-MS M+H 648.
1H NMR (CDCl3): 1.10-2.98 (27H, m), 2.74 (3H, s), 2.78 (3H, s), 3.18-3.32 (8H, m), 3.62 & 4.34 (IH, m), 3.72 (IH, d), 3.84 (IH, d), 6.64 (3H5 m).
Using this procedure and starting with N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-
(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-piperidin-4-ylacetamide (Example 3) there is obtained N-(I- {(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[l- (methylsulfonyl)piperidin-4-yl]acetamide (Compound 6 Table I) LC-MS M+H 647, 1H ΝMR (CDCl3): 1.08-2.96 (32H, m), 2.72 (3H, s), 2.74 (3H, s), 3.26 (2H, m), 3.48 & 4.38 (IH, m), 3.72 (IH, d), 3.82 (3H, m), 6.64 (3H, m). Using this procedure and starting with N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}ρiperidin-4-yl)-N-isobutyl-2-piperazin-l- ylacetamide (Example 3a) there is obtained N-(l-{(3i?)-3-(3, 5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-[4- (methylsulfonyl)piperazin-l-yl]acetamide (Compound 14 Table I) LC-MS M+H 676, 1H ΝMR (CDCl3): 0.8 (d, 3H) 0.9 (d, 3H) 1.1-2.2 (m, 16H) 2.4-2.7 (m, 7H) 2.75 (s, 3H) 2.8 (s, 3H) 2.85-3.1 (m, 4H) 3.2-3.4 (m, 6H) 3.6 (m, IH) 3.7 (m, IH) 3.8 (m, IH) 6.6 (m, 3H).
Using this procedure and starting withN-(l-{(3i?)-3-(3-fluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-piperazin-l- ylacetamide (Example 3b) there is obtained N-(l-{(3i?)-3-(3-fluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-[4- (methylsulfonyl)piperazin-l-yl]acetamide (Compound 17 Table I) LC-MS M+H 658, 1H ΝMR (CDCl3): 0.85 (3H, d), 0.95 (3H, d), 1.2-2.2 (17H, m), 2.4 (IH, m), 2.5 (IH, m), 2.6- 2.7 (5H, m), 2.75 (3H, s), 2.78 (3H, s), 2.8-2.95 (2H, m), 3.05 (2H, m), 3.2-3.35 (6H, m), 3.6,4.05 (IH, m), 3.7 (IH, m), 3.85 (IH, m), 6.75-6.95 (3H, m), 7.2 (IH, m).
Using this procedure and starting with N-(cyclopropylmethyl)-N-(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-2-piperazin-l- ylacetamide (Method H) there is obtained N-(cyclopropylmethy I)-N-(I - {(3i?)-3-(3,5- difluorophenyl)-3 - [ 1 -(methylsulfonyl)piperidin-4-yl]propyl} piperidin-4-yl)-2- [4- (methylsulfonyl)piperazin-l-yl]acetamide (Compound 22 Table I) LC-MS M+H 674, 1H NMR (CDCl3): 0.2(d,2H), 0.4 (d, IH), 0.6 (d, IH), 1.5-1.1 (m, 10H), 2.1-1.7 (m, 6H), 1.55 (br, 3H), 2.6-2.3 (m, 6H), 2.55 (s, 3H), 2.6 (s, 3H), 2.9-2.78 (m, 2H), 3.3-3.1 (m, 6H), 3.5 (m, IH), 3.7 (d, IH), 3.8 (d, IH), 6.65 (m, 3H).
Using this procedure and starting withN-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-2-piperazin-l-ylacetamide (Example 3c) there is obtainedN-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-2-[l-
(methylsulfonyl)piρeridin-4-yl]acetamide (Compound 24 Table I) LC-MS M+H 634, 1H ΝMR (CDCl3): 1.2-2.2 (16H, m) 2.4 (IH, m) 2.5 (IH, m) 2.6-2.7 (5H, m) 2.75 (3H, s) 2.8 (3H, s) 2.85 (IH, m) 2.9-2.95 (3H, m) 3.2-3.3 (6H, m) 3.6, 4.4 (IH, m) 3.75 (IH, m) 3.85 (IH, m) 6.7 (3H, m).
Using this procedure and starting withN-(l-{(3i?)-3-(3,5-difiuorophenyi)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-Nl-piperidin-4-ylurea (Method K) there is obtained N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-N1-[l- (methylsulfonyl)piperidin-4-yl]urea (Compound 1 Table VI). LC-MS M+H 676, 1H ΝMR (CDCl3): 0.9 (6H, d) 1.2-2.2 (24H, m) 2.4 (IH, m) 2.5 (IH, m) 2.6 (IH, m) 2.7 (3H, s) 2.75-2.8 (4H, m) 2.9 (2H, m) 3.7-4 (4H, m) 4.25 (IH, d) 6.7 (3H, m).
Using this procedure and starting with N-(I- {(3i?)-3-(3, 5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-N'-piperidin-4-ylurea (Method K) there is obtained N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-N-[l-
(methylsulfonyl)piperidin-4-yl]urea (Compound 4 Table VI). LC-MS M+H 634, 1H ΝMR (CDCl3): 1.3-1.7 (7H, m) 1.9-2.3 (8H, m) 2.4 (IH, m) 2.5 (IH, m) 2.6 (IH, m) 2.7 (7H, m) 2.8 (5H, m) 2.85-2.9 (3H, m) 3.7-3.9 (6H, m) 4.1 (IH, m) 4.2 (IH, d) 6.65 (3H, m).
EXAMPLE 5
This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-N'-{[l- (methylsulfonyl)piperidin-4-yl]methyl}urea (Compound 1 Table II).
Figure imgf000038_0001
PS-triacetoxyborohydride (694 mg) was added to a solution of N-ethyl-iV-{[l-
(methylsulfonyl)piperidin-4-yl]methyl}-N-piperidin-4-ylurea (173 mg) in dichloromethane (10 ml) and stirrd for 18 hours. The reaction mixture was filtered and the filtrate was washed with saturated sodium bicarbonate solution (1x15 ml) and brine (1x15 ml) and dried. The residue obtained on removal of the solvent was purified on a 2Og silica Bond Elut eluted with a solvent gradient of ethyl acetate - 30% methanol/ethyl acetate and the material obtained was passed through a 2Og SCX2 column eluting with methanol initially, then with 10% 7M ammonia in methanol. Evaporation of the methanolic ammonia washings gave the title compound as a white foam, yield 120 mg, LC-MS M+H 662.
1H NMR (CDCl3): 1.2 (t, 3H) 1.2-2.1(m, 19H) 2.4-2.7 (m, 5H) 2.8 (m, 6H) 2.9 (m, 2H) 3.2 (m, 4H) 3.7-3.9 (m, 4H) 4.1 (m, IH) 4.5 (m, IH) 6.6 (m, 3H).
EXAMPLE 6
This Example describes the preparation of N-allyl-N-(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-2-[l- (methylsulfonyl)piperidin-4-yl]acetamide (Compound 7 Table I).
Figure imgf000039_0001
To a solution of (R) 3-(Ν-methanesulphonylpiperidin-4-yl)-3-(3,5- difluorophenyl)propionaldehyde (300mg) in CH2Cl2 (40ml) was added N-allyl-2-[l- (methylsulfonyl)piperidin-4-yl]-N-piperidin-4-ylacetamide hydrochloride (412mg), triethylamine (0.15ml) and sodium triacetoxyborohydride (471mg) and the mixture stirred at room temperature for 18h. The reaction mixture was washed with aqueous sodium bicarbonate (30ml) then brine (30ml) and dried (MgSO4). Preparative HPLC (acetonitrile/water) gave the product as a white solid (340mg), MH+ (659).
ΝMR (DMSO): 1.0-1.3 (m, 2H), 1.35 (d, IH), 1.5-2.0 (m, 6H), 2.0-2.5 (m, 5H), 2.5-2.7 (m, 2H), 2.81 (s, 3H), 2.83 (s, 3H), 2.8-3.1 (m, IH), 3.3-3.7 (m, 5H), 3.7-4.0 (m, 9H), 4.5 (t, IH), 5.0-5.2 (m, 2H)5 5.8-5.9 (m, IH), 7.0 (m, 2H), 7.1 (t, IH). EXAMPLE 7
This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-2-[l-(methylsulfonyl)piperidin-4- yl]-N-propylacetamide (Compound 8 Table I).
Figure imgf000040_0001
A suspension of N-allyl-N-(l-{(3£)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-2-[l-(methylsulfonyl)piperidin-4- yljacetamide (50mg) and palladium on carbon (10%, 20mg) in ethanol (20ml) was stirred under a hydrogen atmosphere at room temperature for 18h. The reaction mixture was filtered through a plug of Celite ® and the filtrate concentrated under reduced pressure to provide the product as a white solid (50mg). MH+ (661).
ΝMR (DMSO): 0.8 (m, 2H), 0.9 (t, 3H), 1.0-1.4 (m, 4H), 1.4-1.8 (m, 4H), 1.8-2.2 (m, 6H), 2.2-2.4 (m, 6H), 2.6-2.8 (m, 6H), 2.85 (s, 3H), 2.9 (s, 3H), 2.9-3.1 (m, 4H), 3.4- 3.6 (m, 6H), 6.9-7.0 (m, 2H), 7.1 (t, IH).
EXAMPLE 8
This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[4- (methylsulphonyl)phenyl]propyl}piperidin-4-yl)-N-ethyl-2-[l-(methylsulphonyl)piperidin- 4-yl]acetamide (Compound 1 Table III).
Figure imgf000040_0002
Diisopropylethylamine (130 μl) was added to a suspension of [1-
(methylsulphonyl)piperidin-4-yl]acetic acid [CAS 423722-27-4] (111 mg) and HATU (228 mg) in dichloromethane (3 ml) and the mixture was stirred for 15 minutes. A solution of 1- {(3i?)-3-(3,5-difluorophenyl)-3-[4-(methylsulphonyl)phenyl]propyl}-N-ethylpiperidin-4- amine (218 mg) in dichloromethane (2 ml) was added and the mixture was stirred for 16 hours. The reaction mixture was diluted with dichloromethane (15 ml) and washed with water (2x20 ml), saturated aqueous sodium bicarbonate solution (2x20 ml), brine (10 ml) and dried. The solvent was evaporated and the residue purified on a silica column eluting with a solvent gradient of ethyl acetate - 20% methanol/ethyl acetate, yield 184 mg, M+H 640.
In an analogous manner but using tetrahydro-2H-pyran-4-ylacetic acid [CAS 85064-61-5] as starting material there is obtainedN-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[4- (methylsulphonyl)phenyl]propyl}piperidin-4-yl)-N-ethyl-2-(tetrahydro-2H-pyran-4- yl)acetamide, M+Η 563, (Compound 2 Table III).
In an analogous manner but using tetrahydro-2H-pyran-4-ylacetic acid [CAS 85064-61-5] and l-{(3JR)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}-N-isobutylpiperidm-4-aniine (Method Η) as starting material there was obtained N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4- yl)-iV-isobutyl-2-(tetrahydro-2H-pyran-4-yl)acetamide (Compound 1 Table V). LC-MS M+Η 598, 1HNMR (CDCl3): 0.75 (d, 3H) 0.8 (d, 3H) 1.1-2.2 (m, 26H) 2.3 (m, IH) 2.4 (t, IH) 2.6 (t, IH) 2.7 (s, 3H) 2.75-2.9 ( m, 2H) 3.4-3.5 (m, 2H) 3.65 (m, IH) 3.8 (m, IH) 3.85 (m, 2H) 6.6 (m, 3H).
In an analogous manner but using tetrahydrofuran-2-ylacetic acid and l-{(3i?)-3- (3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}-N-isobutylpiperidin-4- amine (Method H) as starting material there was obtained N-(l-{(3i?)-3-(3,5- difiuorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2- (tetrahydrofuran-2-yl)acetarnide (Compound 2 Table V). LC-MS M+H 584, 1H ΝMR
(CDCl3): 0.75 (3H, d) 0.85 (3H, d) 1.1-2.15 (22H, m) 2.35 (2H. m) 2.45 (IH, m) 2.55 (IH, m) 2.65 (4H, m) 2.7-2.8 (2H, m) 3.5, 4.1 (IH, m) 3.65 (2H, m) 3.8 (2H, m) 4.2 (IH, m) 6.6 (3H, m).
In an analogous manner but using (l,l-dioxidothiomorpholin-4-yl)acetic acid and l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(metliylsulfonyl)piperidin-4-yl]propyl}-N- isobutylpiperidin-4-amine (Method H) as starting material there was obtained N-(I- {(3i?)- 3 -(3 , 5-difluorophenyl)-3 - [ 1 -(methylsulfonyl)piperidin-4-yl]propyl} piperidin-4-yl)-2-( 1,1- dioxidothiomoφholin-4-yl)-N-isobutylacetamide (Compound 3 Table V). LC-MS M+H 647, 1H ΝMR (CDCl3): 0.9(dt, 6H), 1.4-2.0 (m, 23H), 2.4-2.6 (m, 4H), 2.7 (s, H), 3.1 (br, 5H), 3.35 (s, 2H), 3.7 (d, IH), 3.85 (d, IH), 6.65 (m, 3H).
EXAMPLE 9
This Example describes the preparation of 2-(4-acetylpiperazin-l-yl)-N-(l-{(3i?)-3- (3,5-difluorophenyl)-3-[l-(methylsulphonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N- ethylacetamide (Compound 9 Table I).
Figure imgf000042_0001
Acetic anhydride (66 μl) was added to a stirred solution of N-(I- {(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulphonyl)piperidm-4-yl]propyl}piperidin-4-yl)-N-ethyl-2- piperazin-1-ylacetamide (200 mg) [Example 3, part 2] and triethylamine (143 μl) in dichloromethane (3.5 ml) at 0 0C under an argon atmosphere. The mixture was allowed to warm to room temperature and was stirred for 16 hours.The reaction mixture was diluted with dichloromethane (10 ml) and washed with ammonium chloride solution (2x10 ml) and brine (10 ml) and dried. The residue obtained on evaporation of the solvent was purified by chromatography on a 12g silica cartridge eluting with a solvent gradient of ethyl acetate- 40% methanol/ethyl acetate, yield 105 mg, M+H 612. In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulphonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-piperidin-4-ylacetamide as starting material (Example 3), there is obtained 2-(l-acetylpiperidin-4-yl)-N-(l-{(3i?)-3- (3,5-difluorophenyl)-3-[l-(methylsulphonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N- ethylacetamide (Compound 10 Table I).
In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-piperazin-l- ylacetamide (Compound 13, Table I)) as starting material there is obtained 2-(4- acetylpiperazin-l-yl)-N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-7V-isobutylacetamide (Compound 15 table I) LC-MS M+H 640, 1H ΝMR (CDCl3): 0.8 (d, 3H) 0.9 (d, 3H) 1.1-2.2 (m, 24H) 2.4-2.65 (m 7H) 2.7 (m, 3H) 2.8-3.2 (m, 4H) 3,45 (m, IH) 3.6 (m, IH) 3.7 (m, IH) 3.8 (m, IH).
In an analogous manner but using N-(l-{(3i?)-3-(3-fluorophenyl)-3-[l-
(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-piperazin-l- ylacetamide (Compound 16 Table I) as starting material there is obtained 2-(4- acetylpiperazin- 1 -yl)-N-( 1 - { (3i?)-3 -(3 -fluorophenyl)-3 - [ 1 -(methy lsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-isobutylacetamide (Compound 19 table I) LC-MS M+H 622, 1H ΝMR (CDCl3): 0.85 (3H, d) 0.95 (3H, d) 1.2-2.0 (15H, m) 2.05 (3H, s) 2.1 (IH, m) 2.35 (IH, m) 2.5-2.65 (6H, m) 2.75 (3H, s) 2.8-2.95 (2H, m) 3.1 (2H, m) 3.2 (2H, m) 3.45 (2H, m) 3.5, 4.05 (IH, m) 3.6-3.75 (3H, m) 3.85 (IH, m) 6.8-6.95 (3H, m) 7.25 (IH, m).
In an analogous manner but using N-(cyclopropylmethyl)-N-(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-2-piperazin-l- ylacetamide (Method H) as starting material there is obtained 2-(4-acetylpiperazin-l-yl)-N- (cyclopropylmethyl)-N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]proρyl}piperidin-4-yl)acetamide (Compound 23 Table I) LC-MS M+H 638, 1H ΝMR (CDCl3): 0.3(d,2H), 0.5 (d, IH), 0.65 (d, IH), 1.2-1.55 (m, 8H), 1.65 (br, 3H), 1.75-2.05 (m, 4H), 2.1 (s, 3H), 2.4-2.7 (m, 8H), 2.75 (s, 3H), 2.85-2.95 (m, 2H), 3.0-3.3 (m, 5H), 3.45-3.6 (m, 4H), 3.75 (d, IH), 3.85 (d, IH), 6.65 (m, 3H). In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-2-piperazin-l-ylacetamide (Example 3c) as starting material there is obtained 2-(4-acetylpiperazin-l-yl)-N-(l-{(3i?)- 3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N- methylacetamide (Compound 26 Table I) LC-MS M+H 598, 1H ΝMR (CDCl3): 1.2-2.05 (15H, m) 2.1 (3H, s) 2.4 (IH, m) 2.45-2.65 (6H, m) 2.7 (3H, s) 2.8-2.95 ((5H, m) 3.2 (2H, d) 3.4-3.5 ((2H, m) 3.6-3.7 (2H, m) 3.75 (IH, m) 3.85 (IH, m) 4.4 (IH, m) 6.7 (3H, m).
In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-Nl-piperidin-4-ylurea (Method K) as starting material there is obtained N'-(l-acetylpiperidin-4-yl)-N-(l-{(3i?)-3- (3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N- isobutylurea (Compound 3 Table VI) ) LC-MS M+H 640, 1H ΝMR (CDCl3): 0.95 (6H, d) 1.2-2.1 (21H, m) 2.15 (3H, s) 2.35 (IH, m) 2.5 (IH, m 2.6 (IH5 m) 2.7 (4H, m) 2.8-2.9 (4H, m) 3.15 (IH, m) 3.75 (2H, m) 3.8-4 (3H, m) 4.2 (IH, d) 4.5 (IH, m) 6.65 (3H, m).
EXAMPLE 10
This Example describes the preparation of N-(I- {(3i?)-3-(3,5-difluorophenyl)-3-[4- (methylsulphonyl)phenyl]propyl}piperidin-4-yl)-N-ethyl-2-morpholin-4-ylacetamide (Compound 3 Table III).
Figure imgf000044_0001
Step 1: Preparation of 2-bromo-N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[4- (methylsulphonyl)phenyl]propyl}piperidin-4-yl)-N-ethylacetamide
Figure imgf000045_0001
A solution of l-{(3i?)-3-(3,5-difluorophenyl)-3-[4-
(methylsulphonyl)phenyl]propyl}-N-ethylpiperidin-4-amine (Method F) (314 mg) and triethylamine (200 μl) in dichloromethane (3.5 ml) was added to a stirred solution of bromoacetyl chloride (72 μl) in dichloromethane (3.5 ml) under argon at 0 0C. The mixture was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was diluted with dichloromethane (10 ml) washed with ammonium chloride solution (2x15 ml), brine (15 ml) and dried. The brown foam (339 mg) [M+H 558] obtained on evaporation of the solvent was used directly in Step 2.
Step 2: Preparation of the title compound
A mixture of 2-bromo-N-(l-{(3i?)-3-(3,5-difiuorophenyl)-3-[4-
(methylsulphonyl)phenyl]propyl}piperidin-4-yl)-N-ethylacetamide (170 mg), morpholine (53 μl) and potassium carbonate (126 mg) in dioxane (3.1 ml) was stirred at room temperature for 30 minutes then warmed to 50 0C for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane (15 ml), washed with water (2x15 ml), brine (15 ml) and dried. The residue obtained on evaporation of the solvent was purified on a 12g silica cartridge eluting with a solvent gradient of ethyl acetate - 30% methanol/ethyl acetate (yield 58 mg, M+H 564).
EXAMPLE Il
This Example describes the preparation of N-[l-((3i?)-3-(3,5-difluorophenyl)-3-{l- [(trifluoromethyl)sulfonyl]piperidin-4-yl}propyl)piperidin-4-yl]-N-ethyl-2-[l- (methylsulfonyl)piperidin-4-yl]acetamide (Compound 11 Table I)
Figure imgf000046_0001
Step 1: Preparation of tøt-butyl 4-{2-[[l-((3i?)-3-(3,5-difluoroplienyl)-3-{l- [(trifluoromethyl)sulfonyl]piperidin-4-yl}propyl)piperidin-4-yl](ethyl)amino]-2- oxoethyl}piperidine- 1 -carboxylate
Figure imgf000046_0002
To a solution of (3i?)-3-(3,5-difluorophenyl)-3-{l-
[(trifluoromethyl)sulfonyl]piperidin-4-yl}propanal (271mg,) (Method A) and fer/-butyl 4- {2-[ethyl(piperidin-4-yl)amino]-2-oxoethyl}piperidine-l -carboxylate (Method C) in dichloromethane (7ml) was added glacial acetic acid (50μL) and sodium triacetoxyborohydride (178mg) and the resulting mixture was stirred for 18 hours. The mixture was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organics were dried and evaporated to a give a solid which was purified by silica chromatography eluting with a gradient of ethyl acetate / isohexane (0 to 20%) to give the subtitled compound as a white solid (yield 270mg) M+H 723.
Step 2: Preparation of the title compound
To a solution of of ferf-butyl 4-{2-[[l-((3i?)-3-(3,5-difluoroρhenyl)-3-{l- [(trifluoromethyl)sulfonyl]piperidin-4-yl} propyl)piperidin-4-yl] (ethyl)amino] -2- oxoethyl}piperidine-l-carboxylate (270mg) in methanol (ImI) was added 4N HCl in dioxane (4ml) and the resulting mixture was stirred for 1 hour. The mixture was concentrated and partitioned between dichloromethane and 2M NaOH and the aqueous was extracted with further dichloromethane (3x). The organics were dried and evaporated to dryness. The residue was dissolved in dichloromethane (4ml), cooled to 50C under an argon atmosphere. Triethylamine (104μl) and methanesulphonyl chloride (44μl) was added and the mixture was allowed to warm to room temperature and to stir for 18 hours. The mixture was diluted with dichloromethane and washed with saturated ammonium chloride (2x). The organics were dried and evaporated to a gum which was purified by silica chromatography eluting with a gradient of methanol / dichloromethane (0:100 to 20:80) to give the titled compound as a white solid (121mg). LC-MS M+H 701 1H NMR (CDCl3): 1.06 - 2.29 (m, 26H), 2.42 (m, IH), 2.67 (t, 2H), 2.76 (s, 3H), 2.78 (m, IH), 2.89 (t, IH), 3.00 (t, IH), 3.28 (m, 2H), 3.48 and 4.37 (m, IH), 3.78 (m, 2H), 3.87 (m, IH), 4.00 (m, IH), 6.66 (m, 3H).
EXAMPLE 12
This Example describes the preparation of methyl 4-{2-[(l-{(3i?)-3-(3- fluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidm-4-yl)(isobutyl)amino]- 2-oxoethyl}piperazine-l-carboxylate (Compound 18 Table I)
Figure imgf000047_0001
To a solution of N-(l-{(3i?)-3-(3-fluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-isobutyl-2-piperazin-l-ylacetamide (Compound 16 Table I) (329 mg) and triethylamine (104 uL) in dichloromethane (25 ml) was added methyl chloroformate (53 uL). The reaction mixture was stirred at room temperature for 24 hours, washed with 2Ν NaOH (2x25 ml), dried over MgSO4 and evaporated. The residue was purified by silica chromatography eluting with a gradient of ethyl acetate to 35% methanol/ethyl acetate to give the title compound as a solid. Yield 159 mg. LC-MS M+H 638 1HNMR (CDCl3): 0.85 (3H, d) 0.95 (3H, d) 1.2-2.2 (18H, m) 2.4 (IH, m) 2.5 (4H, m) 2.6 (IH, m) 2.7 (3H, s) 2.8-2.95 (2H, m) 3.05 (2H, m) 3.2 (2H, m) 3.45 (3H, m) 3.5, 4.05 (IH, m) 3.7 (4H, m) 3.85 (IH, m) 6.8-6.95 (3H, m) 7.25 (IH, m).
In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-
(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-2-piperazin-l-ylacetamide (Example 3c) as starting material there was obtained methyl 4-{2-[(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4- yl)(methyl)amino]-2-oxoethyl}piperazine-l-carboxylate (Compound 25 Table I) LC-MS M+H 614, 1H NMR (CDCl3): 1.15-2.1 (16H, m) 2.35-2.5 (5H, m) 2.6 (IH, m) 2.75 (3H, s) 2.8-2.95 (5H, m) 3.15 (2H, d) 3.45-3.55 (4H, m) 3.7 (4H, m) 3.75, 4.4 (IH, m) 3.85 (IH, m) 6.7 (3H, m).
In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-piperazin- 1 - ylacetamide (Compound 13 Table I) as starting material there was obtained methyl 4-{2- [( 1 - { (3i?)-3 -(3 , 5-difluorophenyl)-3 - [ 1 -(methylsulfonyl)piperidin-4-yl]propyl} piperidin-4- yl)(isobutyl)amino]-2-oxoethyl}piperazine-l-carboxylate (Compound 27 Table I) LC-MS M+H 656, 1HNMR (CDCl3): 0.35 (m, 3H), 0.9 (m, 3H), 1.2-2.1 (m, 17H), 2.35-2.55 (m, 6H), 2.65 (m, IH), 2.8 (s, 3H), 2.9 (m, 2H), 3.1 (m, 2H), 3.2 (d, 2H), 3.5 (m, 4H), 3.7 (s, 3H), 3.75 (d, IH), 3.85 (d, IH), 6.65 (m, 3H).
In an analogous manner but using N-(cyclopropylmethyl)-N-(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-2-piperazin-l- ylacetamide (Method H) as starting material there was obtained methyl 4- {2-
[(cyclopropylmethyl)(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)amino]-2-oxoethyl}piperazine-l-carboxylate (Compound 28 Table I) LC-MS M+H 654, 1H ΝMR (CDCl3): 0.25 (m, 2H), 0.45 (d, IH), 0.6 (d, IH), 1.0- 2.1 (m, 12H), 2.35-2.65 (m, 9H), 2.7 (s, 3H), 2.8 (s, IH), 2.9 (m, 2H), 3.1-3.25 (m, 5H), 3.45 (m, 5) 3.7 (s, 3H), 3.75 (d, IH), 3.85 (d, IH), 6.65 (m, 3H). In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-N'-piperidin-4-ylurea (Method K) as starting material there was obtained methyl 4-({[(l-{(3i?)-3-(3,5- difluorophenyl)-3 - [ 1 -(methylsulfonyl)piperidin-4-yl]propyl} piperidin-4- yl)(isobutyl)amino]carbonyl}amino)piperidine-l-carboxylate (Compound 2 Table VI). LC- MS M+H 656, 1H ΝMR (CDCl3): 0.9 (6H, d) 1.2-2.2 (19H, m) 2.35 (IH, m) 2.5 (IH, m) 2.6 (IH, m) 2.75 (3H, s) 2.8-2.95 (6H, m) 3.65 (3H, s) 3.7 (IH, m) 3.85 (2H, m) 3.9-4.15 (3H, m) 4.2 (IH, d) 6.7 (3H, m).
In an analogous manner but using N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-
(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-N'-piperidin-4-ylurea (Method K) as starting material there was obtained methyl 4-({[(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4- yl)(methyl)amino]carbonyl}amino)piperidine-l-carboxylate (Compound 5 Table VI). LC- MS M+H 656, 1H ΝMR (CDCl3):
EXAMPLE 13
This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-[4-(2- methoxyethyl)piperazin-l-yl]acetamide (Compound 21 Table I)
Figure imgf000049_0001
To a solution of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin- 4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-piperazin-l-ylacetamide (Compound 13 table I) (105mg) and triethylamine (0.033ml) in dichloromethane (10ml) was added. 2-chloroethyl methyl ether (0.018ml). The reaction mixture was stirred at room temperature for 18 hours, washed with 2N NaOH (2x1 OmI), dried over MgSO4, filtered and evaporated to dryness. The residue was dissolved in MeOH (10ml) and poured onto a SCX2 cartridge and eluted with MeOH (6x20ml), then IM NH3/methanol (6x50ml). The combined ammonia fractions were evaporated to yield an oil which was transferred to a vial in dichloromethane/methanol solution, evaporated to dryness using a Genevac to yield an oil and high vacuumed dried to give the titled compound as a foam. Yield 44mg LC-MS M+H 656, 1H NMR (CDCl3): 0.85 (d, 3H) 0.9 (d, 3H), 1.2-1.5 (m, 4H), 1.6-2.1 (m, 22H), 2.35-2.65 (m, 7H), 2.7 (s, 3H), 2.8-3.2 (m, 8H), 3.75 (d, IH), 3.85 (d, IH), 6.65 (m, 3H).
EXAMPLE 14
This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-methyl-2-[l- (methylsulfonyl)piperidin-4-yl]acetamide (Compound 30 table I)
Figure imgf000050_0001
[1 -(methylsulfonyl)piperidin-4-yl] acetic acid (117 mg) and HATU (202 mg) were dissolved in DMF (10 ml) and triethylamine (149 uL) was added. The reaction mixture was stirred at room temperature for 10 minutes. l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}-N-methylpiperidin-4-amine (Method I) (250 mg) was added and the reaction stirred at room temperature for 18 hours. The solvent was removed by evaporation. The residue was dissolved in dichloromethane (25 ml) and washed with 2Ν NaOH (2x25 ml), dried over MgSO4 and evaporated. The residue was purified by chromatography eluting with ethyl acetate to30% methanol/ethyl acetate. Yield 105 mg LC-MS M+H 633, 1H NMR (CDCl3): 1.2-2.15 (21H, m) 2.25 (2H, d) 2.4 (IH, s) 2.5 (IH, s) 2.6-2.7 (3H, m) 2.75 (3H, s) 2.78 (3H, s) 2.8-2.95 (5H, m) 3.5,4.45 (IH, m) 3.7- 3.9 (4H, m) 6.65 (3H, m). In an analogous manner but using l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}-N-isobutylpiperidin-4-amine (Method I) there was obtained N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl} piperidin-4-y l)-N-isobutyl-2- [ 1 -(methylsulfonyl)piperidin-4-yl] acetamide (Compound 29 Table I) LC-MS M+H 675, 1H ΝMR (CDCl3): 0.85 (3H, d) 0.9 (3H5 d) 1.2- 2.15 (21H, m) 2.25 (2H, d) 2.4 (IH, m) 2.5 (IH, m) 2.65 (3H, m) 2.75 (3H, s) 2.78 (3H, s) 2.8-2.9 (2H, m) 3.05 (IH, m) 3.1 (IH, m) 3.45, 4.1 (IH, m) 3.7-3.9 (4H, m) 6.65 (3H, m).
EXAMPLE 15
This Example describes the preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-isobutyl-2-[l- (methylsulfonyl)pyrrolidin-3-yl]acetamide (Compound 4 Table V)
Figure imgf000051_0001
[l-(methylsulfonyl)pyrrolidin-3-yl] acetic acid (Method J) (93 mg) was dissolved in dichloromethane (20ml) and carbonyldiimidazole (73mg) was added. The reaction mixture was stirred at room temperature for 2hours. l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piρeridin-4-yl]propyl}-N-isobutylpiperidin-4-amine (Method I) (212 mg) was then added and the mixture stirred at room temperature for 24 hours. The solvent was evaporated and the residue dissolved in dichloromethane (25 ml) and washed with 2Ν NaOH (2x20 ml), dried over MgSO4 and evaporated. The residue was purified by silica chromatography, eluting with a gradient of ethyl acetate to 30% methanol/ethyl acetate to give the titled compound as a white foam. Yield 16 mg. LC-MS M+H 661.
In an analogous manner but using l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}-N-ethylpiperidin-4-amine there was obtained N-(I- {(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)- N-ethyl-2-[l-(methylsulfonyl)ρyrrolidin-3-yl]acetamide (Compound 5 Table V). LC-MS M+H 633, 1E NMR (CDCl3): 1-2.2 (m, 23H) 2.3-2.6 (m, 5H) 2.7 (s, 3H) 2.75 (s, 3H) 2.8- 2.9 (m, 2H) 3.2 (m, 3H) 3.35-3.5 (m, 2H) 3.65 (m,lH) 3.8 (m, IH) 6.6 (m, 3H).
EXAMPLE 16
This Example describes the preparation N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[(25)-l- (methylsulfonyl)pyrrolidin-2-yl]acetamide
Figure imgf000052_0001
Step 1: Preparation of tert-butyl (2-S)-2-{2-[(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(ethyl)amino]-2- oxoethyl} pyrrolidine- 1 -carboxylate
Figure imgf000052_0002
To a solution of [(25)-l-(fer/-butoxycarbonyl)pyrrolidin-2-yl]acetic acid (399 mg) and HATU (343 mg) in DMF (10 ml) was added triethylamine (182 mg) and the resulting mixture was stirred at room temperature for 10 minutes. l-{(3i?)-3-(3,5-difiuorophenyl)-3- [l-(methylsulfonyl)piperidin-4-yl]propyl}-N-ethylpiperidin-4-amine was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with 2N NaOH (2x10 ml), dried over MgSO4 and evaporated. The residue was purified by silica chromatography eluting with a gradient of ethyl acetate to 20% methanol/ethyl acetate to yield the subtitled compound as a gum (500 mg). LC-MS M+H 655, 1H NMR (CDCl3): 1-1.3 (m, 8H) 1.4 (s, 9H) 1.45-2.1 (m, 18H) 2.6 (m, 3H) 2.7 (s, 3H) 2.7-2.9 (m, 2H) 3.0-3.4 (m, 4H) 3.65 (d, IH) 3.8 (d, IH) 6.6 (m, 3H).
Step 2: Preparation of N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-ethyl-2-[(25)-pyrrolidin-2-yl]acetamide
Figure imgf000053_0001
tørt-butyl (25)-2-{2-[(l-{(3JR)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)(ethyl)amino]-2- oxoethyl} pyrrolidine- 1 -carboxylate (400 mg) was dissolved in TFA (10 ml) and stood at room temperature for 1 hour. The TFA was evaporated and the residue dissolved in dichloromethane (50 ml) and washed with 2Ν NaOH, dried over MgSO4 and evaporated to yield the subtitled compound (350 mg) as a glass which was used without further purification. LC-MS M+H 555, 1H NMR (CDCl3): 1.0- 2.1 (m, 23H) 2.2-2.6 (m 7H) 2.7 (s, 3H) 2.75-2.95 (m, 2H) 3.2 (m, 2H) 3.4 (m IH) 3.65 (d, IH) 3.8 (d, IH) 6.6 (m, 3H).
Step 3: Preparation of title compound
N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-ethyl-2-[(2>S)-pyrrolidm-2-yl]acetamide (250 mg) was dissolved in dichloromethane (20 ml) and triethylamine (45 mg) was added. Methane sulfonyl chloride (51 mg) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 2N NaOH (2x20 ml), dried over MgSO4 and evaporated. The residue was dissolved in dichloromethane (10 ml) and poured onto a 20 g SCX2 cartridge and eluted with methanol (6x20 ml) and IM NH3/methanol (6x20 ml). The combined ammonia washings were evaporated to yield the titled compound as a glass (112mg). LC-MS M+H 633, 1H NMR (CDCl3): 1.0-2.0 (m, 19H) 2.6 (m, 6H) 2.65 (s, 3H) 2.7 (s, 3H) 2.75-3.2 (m, 3H) (m, 3H) 3.3-3.6 (m, 3H) 3.65 (d, IH) 3.8 (d, IH) 3.95 (m, IH) 6.6 (m, 3H).
EXAMPLE 17
This Example describes the preparation N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-3-[l- (methylsulfonyl)piperidm-4-yl]propanamide
Figure imgf000054_0001
Step 1: Preparation of (2£)-N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl} piperidin-4-yl)-N-ethyl-3 - [ 1 - (methylsulfonyl)piperidin-4-yl]acrylamide
Figure imgf000054_0002
(2£)-3-[l-(methylsulfonyl)piperidin-4-yl]acrylic acid (181 mg) and HATU (342 mg) were dissolved in DMF (10 ml) and triethylamine (91 mg) added. The reaction was stirred at room temperature for 20 minutes. {(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}-N-ethylpiperidin-4-amine (Method I) was added and the reaction stirred at room temperature for 24 hours. The solvent was evaporated and the residue dissolved in dichloromethane (50 ml) and washed with 2Ν NaOH, dried over MgS 04 and evaporated. The residue was purified by silica chromatography eluting with a gradient of ethyl aceate to 25% methanol/ethyl acetate to give the subtitled compound as a glass (yield 420mg). LC-MS M+H 659, 1H NMR (CDCl3): 1.1-2.1 (m, 22H) 2.2-2.6 (m, 7H) 2.65 (s, 3H) 2.7 (m, 3H) 2.8 (m, IH) 3.2-3.4 (m, 3H) 3.6-3.9 (m, 4H) 6.1 (d, IH) 6.6 (m, 3H) 6.8 (m, IH).
Step 2: Preparation of title compound
(2£)-N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-ethyl-3-[l-(methylsulfonyl)piperidin-4-yl]acrylamide (300 mg) was dissolved in ethanol (25 ml) and purged with argon, 20% palladium hydroxide (50 mg) was added and the reaction purged with argon and filled with hydrogen from a balloon. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was purged with argon and filtered through celite and evaporated to give the title compound as a solid (yield 214mg). LC-MS M+H 661, 1H NMR (CDCl3): 1.1-2.6 (m, 33H) 2.65 (s, 3H) 2.7 (s, 3H) 2.8-2.9 (m, 2H) 3.2 (m, 2H) 3.6-3.8 (m, 4H) 6.6 (m, 3H)
Method A Preparation of (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propanal
Figure imgf000055_0001
Step 1 Preparation of (2£)-3-[l-(methylsulfonyl)piperidin-4-yl]acryloyl chloride.
Figure imgf000056_0001
Oxalyl chloride (5.1 g) was added to a solution of (2E)-S-[I-
(methylsulfonyl)piperidin-4-yl]acrylic acid (9.4g) in dichloromethane containing 2-3 drops of DMF and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness and the residue obtained was used directly in the next step.
Step 2 Preparation of (4i?,55)-l,5-dimethyl-3-{(2JE)-3-[l-(methylsulfonyl)piperidin-4- yl]prop-2-enoyl} ^-phenylimidazolidin^-one.
Figure imgf000056_0002
Lithium bis(trimethylsilyl)amide (8 ml of a IM solution in THF) was added dropwise to a suspension of (4R,5S)-l,5-dimethyl-4-phenyl-2-imidazolidinone (1.52g) in THF (20 ml) under argon at -100C. The reaction mixture was stirred at -100C for 10 minutes, allowed to warm to 00C and maintained at this temperature for 10 minutes then cooled again to -10°C. The solution of the acid chloride (2g dissolved in 10 ml of dichloromethane) prepared in Step 1 was added dropwise and the reaction mixture was allowed to warm to room temperature and washed with water (100 ml). The aqueous extract was extracted with ethyl acetate (3x50 ml) and the ethyl acetate extracts were dried and the residue passed through a 9Og Biotage column eluting with a solvent gradient (50% ethyl acetate/isohexane - 70% ethyl acetate/isohexane). Yield 1.89g. LC-MS MH+ 406, NMR (CDCl3): 0.8 (d, 3H), 1.5-1.6 (m, 3H), 1.9 (m, 2H), 2.3 (m, IH), 2.7 (m, 2H), 2.75 (s, 3H), 2.8 (s, 3H)S 3.75 (m, 2H), 3.9 (m, IH), 5.3 (d, IH), 6.85 (d-d, IH), 7.1 (d, IH)3 7.2- 7.35 (m, 3H), 7.45 (d, IH). Step 3 Preparation of (4£5i?)-l-{(3i0-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propanoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one.
Figure imgf000057_0001
Step A
TMEDA (11.6g) was added to a suspension of copper iodide (19.4g) in THF (240 ml) under argon and the mixture was stirred for 45 minutes then cooled to -7O0C, A solution of 3,5-difluorophenyl magnesium bromide in THF (201.1 ml of a 0.5M solution in THF) was added over 10 minutes and the mixture was stirred at -70°C for 30 minutes. Step B
Di-n-butylboron triflate (100.7 ml of IM solution in dichloromethane) was added to a suspension of (4i?,55)-l,5-dimethyl-3-{(2E)-3-[l-(methylsulfonyl)piperidin-4-yl]prop-2- enoyl}-4-phenylimidazolidin-2-one (20.4Ig) [Step 2] in THF maintained at-40°C and stirring was continued for 10 minutes and the mixture was cooled to -7O0C and added via a cannula to the cuprate suspension prepared in step A. The reaction mixture was stirred at - 7O0C for 1 hour and allowed to warm to room temperature, then saturated ammonium chloride solution (200 ml) was added. The THF was evaporated and ethyl acetate (200 ml) was added. Air was blown through this mixture for 1 hour. The ethyl acetate layer was collected and the aqueous portion was extracted with ethyl acetate (2x100 ml). The combined ethyl acetate extracts were washed with saturated ammonium chloride solution (2x100 ml), dried and evaporated to dryness. The residue was purified by chromatography on silica eluting with a solvent gradient of ethyl acetate-isohexane (1:1) to neat ethyl acetate to give the subtitled compound as a white solid, yield 25g, NMR (CDCl3) 0.78 (d, 3H), 1.2-1.6 (m, 6H), 1.9 (m, IH), 2.4-2.65 (m, 2H), 2.75 (s, 3H), 2.85 (s, 3H), 3-3.2 (m, 2H), 3.7-3.9 (m, 4H), 5.2 (d, IH), 6.6(m, 3H), 6.85 (m, 2H), 7.2 (m, 3H). Step 4 Preparation of (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propan-l-ol
Figure imgf000058_0001
Lithium borohydride (48 ml of 2M solution in THF) was added to a solution of (45',5i?)-l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidm-4-yl]propanoyl}- 3,4-dimethyl-5-phenylimidazolidin-2-one (25g) in THF (200 ml) and the mixture was heated at 7O0C for 3 hours then allowed to cool to room temperature and stirring was continued for 16 hours. Ethanol was added carefully (20 ml) and the reaction mixture was acidified to pH 4 by addition of 2M HCl. The THF was evaporated and the residue dissolved in dichloromethane (100 ml) and this was washed with water (100 ml) and dried. The solvent was removed and the product was purified by chromatography on a Biotage 65 column eluted with a 1:1 mixture of ethyl acetate/isohexane. Yield 13g, NMR (CDCl3): 1.2-1.8 (m, 5H), 1.95-2.2 (m, 2H), 2.5-2.7 (m, 3H), 2.75 (s, 3H), 3.3-3.6 (m, 2H), 3.7 -3.9 (m, 2H), 6.65 (m, 3H).
Step 5 Preparation of title compound.
Dess-Martin periodinane (5.09g) was added to a solution of (R) 3-(N- methanesulphonylpiperidin-4-yl)-3-(3,5-difluorophenyl)propanol (4.Og) in dichloromethane (100 ml) and the mixture was stirred for 1.5 hours. The reaction mixture was washed with 2M NaOH (2x100 ml) and dried. The solution of the title compound in dichloromethane was used in subsequent reactions.
In an analogous manner but using 3-(N-trifluoromethylsulphonylpiperidin-4- yl)propenoic acid instead of 3-(N-methanesulphonylpiperidin-4-yl)propenoic acid in step I was prepared (R) 3-(N-trifluoromethylsulphonylpiperidin-4-yl)-3-(3,5- difluorophenyl)propionaldehyde.
Figure imgf000059_0001
In an analogous manner but using 3 -fluorophenyl magnesium bromide instead of 3,5-difluorophenyl magnesium bromide in Step 3 was prepared (3i?)-3-(3-fluorophenyl)-3- [ 1 -(methylsulfonyl)piperidin-4-yl]propanal
Figure imgf000059_0002
Method B
Preparation of ter/-butyl 4-{2-[ethyl(piperidin-4-yl)amino]-2-oxoethyl}piperazine-l- carboxylate.
Figure imgf000059_0003
Step 1: Preparation of tert-buty\ 4-{2-[{l-[(benzyloxy)carbonyl]piperidin-4- yl}(ethyl)amino]-2-oxoethyl}piperazine-l-carboxylate.
Figure imgf000059_0004
Diisopropylethylamine (1.3 ml) was added to a slurry of [4-(tert- butoxycarbonyl)piperazin-l-yl]acetic acid dihydrate (1.12g) [154478-71-6] in dichloromethane (16 ml) followed by HATU (1.82g) and the mixture was stirred under argon for 30 minutes. A solution of benzyl 4-(ethylarnino)piperidine-l-carboxylate (1.05g) [159874-38-1] in dichloromethane (4 ml) was added and the mixture was stirred for 24 hours, then diluted with dichloromethane (25 ml), washed consecutively with 2M NaOH (2x20 ml) and brine (1x20 ml) and dried. The solvent was evaporated and the residue was purified on a 4Og silica column eluted with a solvent gradient made up of ethyl acetate to 5% methanol: ethyl acetate. The yellow oil obtained was used directly in the next stage, LC-MS M+H 489 plus a HATU derived impurity M+H 175.
1H NMR (CDCl3): 1.12 (3H, m), 1.44 (9H, s), 1.54-1.74 (8H, m), 2.48 (4H, d), 3.19-3.38 (4H, m), 3.44 (4H, d), 4.30 (IH, m), 5.14 (2H, s). 7.36 (5H, s).
Step 2: Preparation of the title compound. A solution of tert-butyl 4-{2-[{l-[(benzyloxy)carbonyl]piperidin-4- yl}(ethyl)amino]-2-oxoethyl}piperazine-l-carboxylate (1.98g) in ethanol (20ml) was hydrogenated under a hydrogen filled balloon using 20% Pd(OH)2 on carbon as catalyst. The reaction mixture was filtered through Celite and the solvent was evaporated under reduced pressure, the residue was purified by passing down a SCX-2 silica column eluting with methanol initially and then with a IM solution of ammonia in methanol. The methanolic ammonia fractions were evaporated to dryness to give the title compound as an oil, yield 1.3g, LC-MS M+H 335. 1H NMR (CDCl3): 1.18 (3H, m), 1.44 (9H, s), 1.72 (8H, m), 2.48 (3H, m), 2.70 (IH, m), 3.22 (2H, m), 3.32 (2H, m), 3.46 (4H, m), 3.92 & 4.38 (IH, m). In an analogous manner but using benzyl 4-(isobutylamino)piperidine-l- carboxylate instead of benzyl 4-(ethylamino)piperidine-l-carboxylate in Step 1 was prepared tert-butyl 4- {2-[isobutyl(piperidin-4-yl)amino]-2-oxoethyl}piperazine- 1 - carboxylate
In an analogous manner but using benzyl 4-(methylamino)piperidine-l -carboxylate instead of benzyl 4-(ethylamino)piperidine-l -carboxylate in Step 1 was prepared tert-butyl 4-{2-[isobutyl(piperidin-4-yl)amino]-2-oxoethyl}piperazine-l-carboxylate Method C
Preparation of tert-butyl 4-{2-[ethyl(piperidin-4-yl)amino]-2-oxoethyl}piperidme-l- carboxylate.
Figure imgf000061_0001
Step 1 : Preparation of tert-butyl 4- {2-[ { 1 -[(benzyloxy)carbonyl]piperidin-4- yl} (ethyl)amino]-2-oxoethyl} piperidine- 1 -carboxylate.
Figure imgf000061_0002
l-Chloro-N,N-2-trimethylpropenylamine (891 μl) was added to a solution of [1- (tert-butoxycarbonyi)piperidm-4-yi]acetic acid (1.6Og) [157688-46-5] in dichloromethane (10 ml) and the mixture was stirred for 2 hours. An additional equivalent of l-chloro-N,N- 2-trimethylpropenylamine was added and stirring continued for 3 hours. A solution of benzyl 4-(ethylamino)piperidine-l -carboxylate (1.735g) and triethylamine (1.84 ml) in dichloromethane (30 ml) was added and the mixture was stirred for 16 hours then diluted with dichloromethane (30 ml) and washed with saturated ammonium chloride solution (2x25ml), 2M NaOH (2x25 ml) and brine (25 ml) and dried. Removal of the solvent gave an orange oil, LC-MS M+H (-Boc) 388. The material was used directly in step 2.
Step 2: Preparation of the title compound.
A solution of tert-butyl 4-{2-[{l-[(benzyloxy)carbonyl]piperidin-4- yl}(ethyl)amino]-2-oxoethyl}piperidine-l-carboxylate (3.Ig) in ethanol (30ml) was hydrogenated under a hydrogen filled balloon using 20% Pd(OH)2 on carbon as catalyst. The reaction mixture was filtered through Celite and the solvent was evaporated under reduced pressure. The residue was purified by passing down a SCX-2 5Og silica column eluting with methanol initially and then with a IM solution of ammonia in methanol. The methanolic ammonia fractions were evaporated to dryness to give the title compound as an oil, yield 2.08g, 1H NMR (CDCl3): 1.14 (3H, m), 1.44 (9H, s), 1.52-1.78 (8H, m), 2.10 (IH, m), 2.22 (2H, m), 2.70 (4H, m), 3.14 (2H, m), 3.28 (2H, m), 3.62 & 4.48 (IH, m), 4.10 (2H, m).
Following the procedures outlined above and using benzyl 4-
(ethylamino)piperidine- 1 -carboxylate and [ 1 -(fert-butoxycarbonyl)piperidin-4-yl]acetic acid [157688-46-5] as starting materials there is obtained benzyl 4-[{[4-(tert- butoxycarbonyl)piperidin- 1 -yl] acetyl} (ethyl)amino]piperidine- 1 -carboxylate.
Method D
Preparation of N-ethyl-N1- { [ 1 -(methylsulfonyl)piperidin-4-yl]methyl} -N-piperidin-4-ylurea
Figure imgf000062_0001
Step 1. Preparation of 2,2,2-trichloro-N-{[l-(methylsulfonyl)piperidin-4- yl]methyl} acetamide
Figure imgf000062_0002
Trichloroacetyl chloride (0.41 ml) was added to a solution of {[1-
(methylsulfonyl)piperidin-4-yl]methyl}amine (700 mg) [325153-03-5] in dichloromethane (20 ml) containing pyridine (0.59 ml) and DMAP (73 mg) and the mixture was stirred for 3 hours then washed with water (1x15ml), brine (1x15 ml) and dried. The residue obtained on removal of the solvent was purified on a 2Og silica Bond Elut eluted with a solvent gradient of 1:1 ethyl acatate/hexane to ethyl acetate to give 2,2,2-trichloro-N-{[l- (methylsulfonyl)piperidin-4-yl]methyl}acetamide, yield 578 mg, LC-MS M+H 337/339.
1H ΝMR (CDCl3): 1.3-1.5 (m, 2H) 1.8 (m, 3H) 2.7 (m, 3H) 3.3 (m, 2H) 3.8 (m, 2H) 6.8 (bs, IH).
Step 2: Preparation of tert-butyl 4-{ethyl[({[l-(methylsulfonyl)piperidin-4- yl]methyl}amino)carbonyl]amino}piperidine-l-carboxylate.
Figure imgf000063_0001
A solution of 2,2,2-trichloro-N-{[l-(methylsulfonyl)piperidin-4- yl]methyl}acetamide (578 mgs) in DMA (3 ml) was added to a stirred solution of tert- butyl 4-(ethylamino)piperidine-l-carboxylate (521 mg) in DMA (7 ml) followed by DBU (0.34 ml) and the mixture was stirred at 85 0C for 4 hours. The solvent was evaporated and the residue was purified on a 2Og silica Bond Elut eluted with a solvent gradient of 1 ;1 ethyl acetate/hexane to ethyl acetate. Yield 770 mg, LC-MS M+H 469. 1H ΝMR (CDCl3): 1.2 (m, 3H) 1.4 (m, 2H) 1,5 (s, 9H) 1.6 (m, 3H) 1.8 (m, IH) 2.1
(m, 3H) 2.6-2.8 (m, 5H) 2.9 (m, 3H) 3.0 (s, 3H) 3.1-3.2(m, 3H) 3.8 (m, IH) 4.2 (m, IH).
Step 3: Preparation of the title compound
TFA (5 ml) was added to a solution of tert-butyl 4-{ethyl[({[l- (methylsulfonyl)piperidin-4-yl]methyl}amino)carbonyl]amino}piperidine-l-carboxylate (750 mg) in dichloromethane (20 ml) and the mixture was stirred for 1 hour. The solvent was evaporated and the residue was redissolved in 2M NaOH (1x15 ml) and extracted with dichloromethane (2x15 ml). The dichloromethane extracts were dried and the solvent removed to give the title compound, yield 480 mg, LC-MS M+H 347. Method E
Preparation of N-allyl-2-[l-(methylsulfonyl)piperidin-4-yl]-N-piperidin-4-ylacetamide hydrochloride
Figure imgf000064_0001
Step 1: Preparation of tert-bυtyl 4-(allyl{[l-(methylsulfonyl)piperidin-4- yl]acetyl}amino)piperidine-l-carboxylate
Figure imgf000064_0002
To a solution of [l-(methylsulfonyl)piρeridin-4-yl] acetic acid [CAS 423722-27-4] (0.8g) in CH2Cl2 (20ml) was added l-chloro-N,N-2-trimethylpropenylamine (0.53ml) and the mixture stirred at room temperature for 2h. A solution of tert-bnty\ 4-
(allylamino)piperidine-l-carboxylate [CAS 235420-68-5] (770mg) and triethylamine (ImI) in CH2Cl2 (10ml) was then added and the mixture stirred at room temperature for 18h. The reaction mixture was poured into aqueous NaHCO3 (50ml) and extracted with CH2Cl2 (2 x 100ml). The combined extracts were washed with brine (100ml) and dried (MgSO4). Concentration under reduced pressure gave the crude product as a clear oil (1.5g), M+H+ (344, M+- BOC).
NMR (CDCl3): 1.2-1.5 (m, 3H), 1.4 (s, 9H), 1.6 (d, 2H), 1.8-1.9 (m, 4H), 2.6-2.8 (m, 3H), 2.8 (s, 3H), 3.7-3.8 (m, 4H), 4.1-4.3 (m, 2H), 5.1-5.3 (m, 2H), 5.7-5.9 (m, IH).
Step 2: Preparation of the title compound.
A solution of tert-butyl 4-(allyl{[l-(methylsulfonyl)piperidin-4- yl] acetyl} amino)piperidine-l-carboxylate (800mg) in CH2Cl2 (20ml) and saturated methanolic hydrogen chloride (15ml) was stirred at room temperature for 18h. The reaction mixture was concentrated under reduced pressure to give the crude product as a hygroscopic white solid (560mg). M+H+ (344.3).
NMR (DMSO): 1.1-1.3 (m, 2H), 1.5-2.1 (m, 8H), 2.2 (d, IH), 2.4 (d, IH), 2.7 (m, 3H), 2.8 (s, 3H), 2.9-3.0 (m, 3H), 3.3 (d, 2H), 3.9 (br m, 2H), 4.5 (m, IH), 5.0-5.3 (m, 2H), 5.8-5.9 (m, IH).
Method F
Preparation of l-{(3i?)-3-(3,5-difluorophenyl)-3-[4-(methylsulphonyl)phenyl]propyl}-N- ethylpiperidin-4-amine
Figure imgf000065_0001
Sodium triacetoxyborohydride (2.54g) was added in portions to a solution of (R)-3-
(3,5-difluorophenyl)-3-[4-(methylsulphonyl)phenyl]propanal in dichloromethane (3.2g in 50 ml, Method G) and tert-butyl ethyl(piperidin-4-yl)carbamate (2.28g) [CAS 313977-45- 6] in dichloromethane (50 ml) containing acetic acid (0.2 ml) and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (2x25 ml) and brine (25 ml) and dried. The residue obtained on evaporation of the solvent was purified on a silica column eluting with 5% methanol/ethyl acetate, yield 4.18g, M+H 537.
Method G
Preparation of (i?)-3-(3,5-difluorophenyl)-3-[4-(methylsulphonyl)phenyl]propanal
Figure imgf000065_0002
Step 1: Preparation of E-(4S, 5i?)-l-(3-[4-methanesulphonylphenyl]acryloyl)-3,4-dimethyl- 5 -phenyl-imidazolidin-2-one
Figure imgf000066_0001
To a stirred solution of 3-(4-methanesulphonylphenyl)acrylic acid (7.14g) in DCM (1OmL) was added thionyl chloride (3mL) dropwise and the resulting mixture was stirred at room temperature for 18h. To this solution was added DIPEA (5.04mL) dropwise at room temperature. The resulting solution was added to a stirred solution of (4R, 5S)-l,5- dimethyl-4-phenyl-imidazolidin-2-one (5.Og) in DCM (2OmL) and DIPEA (4.58mL) and the resulting mixture stirred at room temperature for 4h. The mixture was washed with water and brine, pre-absorbed onto a Bond Elut and eluted with a gradient of isohexane to ethyl acetate giving the sub-titled compound as a solid (7.61g, 73%).
NMR (CDCl3): 0.84 (d, 3H), 2.89 (s, 3H), 3.04 (s, 3H), 3.98 (m, IH), 5.42 (d, IH), 7.20 (m, 2H), 7.32 (m, 3H), 7.69 (d, IH), 7.74 (d, 2H), 7.93 (d, 2H), 8.31 (d, IH); MS: 399.
Step 2: Preparation of (4S, 5i?)-l-[(#)-3-(4-methanesulphonyl-phenyl)-3-(3,5-di- fluorophenyl)-propionyl] -3 ,4-dimethyl-5 -phenyl-imidazolidin-2-one
Figure imgf000066_0002
To a mixture of copper (I) iodide (5.0Ig) and THF (9OmL) was added N,N,N',N'- tetramethylethylenediamine (4.2mL) and the resulting mixture was stirred at room temperature for lOmin. then cooled to -780C. 3,5-Difluorophenylmagnesium bromide (52mL, 0.5M in THF) was added and the resulting mixture stirred at -780C for 30min. A solution of di-rc-butylboron triflate (15.8mL, IM in diethyl ether) and (E)-(4S, 5i?)-l-(3-[4- methanesulphonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-one (5.2 g) in THF (9OmL) was added gradually and the resulting mixture was stirred whilst allowing to warm to room temperature for 18h. The reaction mixture was washed with saturated aqueous ammonium chloride then concentrated tetrasodium EDTA solution and evaporated to give a yellow solid. This was triturated with diethyl ether giving the subtitled compound (4.04 g, 60%) as a white powder.
NMR: 0.78 (d, 3H), 2.83 (s, 3H), 3.26 (s, 3H), 3.75 (dd, IH), 4.05 (m, 2H), 4.80 (t, IH), 5.35 (d, IH), 7.10 (m, 3H), 7.20 (m, 2H), 7.35 (m, 3H), 7.73 (d, 2H), 7.93 (d, 2H); LC-MS: 513.
Step 3: Preparation of (i?)-3-(3,5-difluorophenyl)-3-[4-(methylsulphonyl)ρhenyl]propanol
Figure imgf000067_0001
To a mixture of (4S, 5i?)-l-[(i?)-3-(4-methanesulphonyl-phenyl)-3-(3,5- difiuorophenyl)-propionyl]-3,4-dimethyl-5-phenyl-imidazolidin-2-one (57g) and THF (50OmL) at 2O0C was added lithium borohydride (2M in THF, 8OmL) gradually. The resulting mixture was heated to reflux for Ih, cooled to 5°C and the reaction quenched by the gradual addition of 2M hydrochloric acid (20OmL). The mixture was extracted with diethyl ether and the extracts dried and concentrated. The residue was triturated with ethyl acetate (20OmL) and the resulting mixture filtered. The filtrate was concentrated and purified by silica column chromatography (eluting with ethyl acetate) to give the sub-titled compound as an oil (25.5g).
NMR (CDCl3): 1.65 (br s, IH), 2.3 (m, 2H), 3.55 (m, 2H), 4.3 (t, IH), 6.7 (m, IH), 6.75 (m, 2H), 7.25 (d, 2H), 7.9 (d, 2H).
Step 4: Preparation of the title compound
Dess-Martin periodinane (5.09g) was added to a solution of (i?)-3-(3,5- difluorophenyl)-3-[4-(methylsulphonyl)phenyl]propanol (3.26g) in dichloromethane (50 ml) and the mixture was stirred for 45 minutes, diluted with an equal volume of dichloromethane and washed with 2M NaOH (2x25 ml) and brine (25 ml) and dried. The solution obtained on filtration of the drying agent was used directly in subsequent steps.
Method H
Preparation of N-(cyclopropylmethyl)-N-( 1 - {(3i?)-3 -(3 ,5-difluorophenyl)-3 -[ 1 - (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-2-piperazin-l-ylacetamide
Figure imgf000068_0001
Step 1: Preparation of benzyl 4-[(cyclopropylmethyl)amino]piperidine-l-carboxylate
Figure imgf000068_0002
To a solution of benzyl-4-oxopiperidine-l-carboxylate (1Og) in dichloromethane (250ml) was added (cyclopropylmethyl)amine (6.09g) and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C and sodium triacetoxyborohydride (10.9g) was added. The mixture was allowed to reach room temperature and then stirred for 18 hours. The reaction was quenched with 2Ν NaOH (100ml). The organic phase was dried over MgSO4, filtered and evaporated to dryness to yield an oil, which was vacuum dried. (Yield 12.Ig).
CDC13: 0.1 (m, 2H), 0.6 (m, 2H), 0.85 (m, IH), 1.15 (tar, 3H), 1.7 (br, 2H), 2.4 (m, 2H), 2.52 (m, IH), 2.89 (br, 2H), 4.0 (br, 2H), 5.02 (s, 2H), 7.25 (m, 5H). Step 2: Preparartion of benzyl 4-[(tert- butoxycarbonyl)(cyclopropylmethyl)amino]piperidine-l-carboxylate
Figure imgf000069_0001
To a solution of benzyl 4-[(cyclopropylmethyl)amino]piperidine-l-carboxylate (12.05g) and triethylamine (6.98ml) in dichloromethane (250ml) was added di tert-bntyl dicarbonate (10.9g, in 3 portions over 20 minutes. The reaction mixture was stirred at room temperature for 18 hours.The reaction mixture was washed with 2N NaOH (2x100ml), dried over MgSO4, filtered and evaporated to dryness to give an oil which was used without further purification. Yield 17g. LC-MS (M+H-Boc) = 288
Step 3: Preparation of ter^-butyl (cyclopropylmethyl)piperidin-4-ylcarbamate
Figure imgf000069_0002
To a solution of benzyl 4-[(tert- butoxycarbonyl)(cyclopropylmethyl)amino]piperidine-l-carboxylate(17g) m ethanol (200ml) was added 20% palladium hydroxide on carbon (1.7g) and the resulting reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through Celite and evaporated to dryness to yield an oil which was used without further purification. Yield 10.79g.
NMR CDCl3: 0.25 (m, 2H), 0.45 (m, 2H), 0.95 (m, IH), 1.45 (s, 9H), 1.6 (m, IH), 1.7 (m, 2H), 1.85 (m, 2H), 2.65 (m, 2H), 3.0 (m,2H), 3.1 (m, 2H),
Step 4: Preparation of tert-butyl (cyclopropylmethyl)(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)carbamate
Figure imgf000070_0001
A solution of (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propanal (6.6g) in dichloromethane (100ml) was added to a solution of tert-butyl (cyclopropylmethyl) piperidin-4-ylcarbamate (5.08g) in dichloromethane (100ml). Sodium triacetoxyborohydride (5.09g) was added and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with 2M NaOH (2x150ml), dried over MgSO4 and filtered. PS-isocyanate resin (1.2mm/g; 5g) was added to the filtrate and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and evaporated to dryness to yield a colourless oil which was used without further purification. Yield 12.4g. LC-MS (M+H-Boc) = 570.
NMR CDCl3: 0.25 (m, 2H), 0.5 (m, 2H), 0.95 (m, IH), 1.2-1.4 (m, 4H), 1.45(s, 9H), 1.6- 2.6(m, 17H), 2.75 (s, 3H), 2.95 (br, 3H), 3.7 (d, IH), 3.85 (d, IH), 6.65 (m, 3H).
Step 5: Preparation of N-(cyclopropylmethyl)-l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl} piperidin-4-amine
Figure imgf000070_0002
ter^butyl (cyclopropylmethyl)(l-{(3i?)-3-(3,5-difluorophenyi)-3-[l- (niethylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)carbamate ( 11.4g) was dissolved in TFA (150ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (150ml) and 2NaOH (150ml). The aqueous layer was extracted with further dichloromethane (3x100ml). The organic extracts were combined, dried (MgSO4), filtered and evaporated to dryness to yield an oil which was used without further purification. Yield 8.28g. LC-MS (M+H) = 470.NMR CDCl3 0.1 (m, IH), 0.5 (m,2H), 0.95-2.1 (m,16H), 2.3-2.7 (m,8H), 2.75 (s,3H), 2.8 (m,lH), 3.65 (d,lH), 3.8 (d,lH), 6.65 (m,3H).
Step 6: Preparation of tert-butyl 4-{2-[(cyclopropylmethyl)(l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)amino]-2- oxoethyl} piperazine- 1 -carboxylate
Figure imgf000071_0001
[4-(tert-butoxycarbonyl)piperazin-l-yl]acetic acid (518mg) and HATU (804mg) were dissolved in DMF (40ml) and triethylamine (0.9ml) was added. The reaction mixture was stirred for 10 minutes at room temperature and then N-(cyclopropylmethyl)-l-{(3i?)-3- (3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-amine (994mg) was added. The reaction mixture was stirred at room temperature for 24 hours and evaporated to dryness. The residual oil was dissolved in dichloromethane (100ml), washed with 2M NaOH (2x100ml), dried over MgSO4, filtered and evaporated to dryness to yield a yellow oil which was purified by combiflash chromatography using a 12g Redisep column and eluting with 0-25% MeOH/ethyl acetate gradient to yield an oil. Yield 250mg. LC-MS (M+H) = 696. NMR CDCl3 0.25 (m, 2H), 0.4 (d, 2H), 0.6 (d, 2H), 1.2-1.4 (m, 2H), 1.45 (s, 9H), 1.6 (br, 3H), 1.8 (m, 2H), 2.0 (m, 4H), 2.3-2.7 (m, 10H), 2.75 (s, 3H), 2.90 (m, 2H), 3.05-3.3 (m, 4H), 3.4 (m, 4H), 3.5 (s, IH), 3.7 (d, IH), 3.85 (d, IH), 6.65 (m, 3H).
Step 7: Preparation of title compound
A solution of tert-butyl 4-{2-[(cyclopropylmethyl)(l-{(3i?)-3-(3,5-difiuorophenyl)- 3-[l-(metb.ylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)amino]-2-oxoethyl}piperazine- 1-carboxylate (231mg) in TFA (10ml) was stirred for 1 hour. The reaction mixture was evaporated to dryness and partitioned between 2M NaOH (15ml) and dichloromethane (3x15ml). The organic phase was collected, dried over MgSO4, filtered and evaporated to dryness to yield the title compound as an oil. Yield 195mg. LC-MS (M+H) 596. NMR CDCl3: 0.3 (d, 2H), 0.55 (dd, 2H), 1.3-2.65 (m, 24H), 2.75 (s, 3H), 2.95 (m, 7H), 3.2 (m, 4H), 3.75 (d, IH), 3.85 (d, IH), 6.65 (m, 3H).
Method I
Preparation of l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}-N-methylpiperidin-4-amine
Figure imgf000072_0001
Step 1: Preparation of tert-butyl (l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)methylcarbamate
Figure imgf000073_0001
To a solution of tert-bntyl methyl(piperidin-4-yl)carbamate (CAS 188174-17-6) (4 g) and (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propanal (Method A)
(6.2g) in dichloromethane (100 ml) was added sodium triacetoxyborohydride (4.7 g). The reaction mixture was stirred at room temperature for 24 hours and then washed with 2N NaOH (2x100 ml), dried over MgSO4 and evaporated. The residue was purified by silica chromatography eluting with a gradient of ethylacetate to20% methanol/ethyl acetate to yield the sub titled compound as a pale brown oil.Yield 9.7g LC-MS (M+H) 530. NMR CDCl3: 1.2-1.35 (m, 3H) 1.4 (s, 9H) 1.6 (m, 7H) 1.9-2.1 (m, 6H) 2.35 (m, IH) 2.5 (m, IH) 2.6 (m, IH) 2.7 (s, 3H) 2.75 (s, 3H) 2.8-2.9 (m, 2H) 3.7 (m, IH) 3.85 (m, IH) 6.6 (m, 3H).
Step 2: Preparation of title compound.
Trifluoroacetic acid (25 ml) was added to tert-butyl (l-{(3i?)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)ρiperidm-4-yl]propyl}piperidin-4- yl)methylcarbamate (9.7 g) and stirred at room temperature for 1 hour. The trifluoroacetic acid was evaporated off and 2N NaOH (100 ml) added and the mixture extracted with dichloromethane (3x100 ml). The combined extracts were dried over MgSO4 and evaporated to leave a pale brown gum which was used without further purification.Yield 7.6g. LC-MS (M+H) 430 NMR CDCl3: 1.2-2.2 (m, 15H) 2.4 (m, 2H) 2.45 (s, 3H) 2.5-2.7 (m, 3H) 2.75 (s, 3H) 2.8 (m, IH) 3.7 (m, IH) 3.85 (m, IH) 6.65 (m, 3H).
In s similar manner but using tert-butyl isobutyl(piperidin-4-yl)carbamate in Step 1 was prepared l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}-N- isobutylpiperidin-4-amine. In s similar manner but using tert-butyl ethyl(piperidin-4-yl)carbamate in Step 1 was prepared l-{(3JR)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}-N- ethylpiperidin-4-amine
Method J
Preparation of [l-(methylsulfonyl)pyrrolidin-3-yl)acetic acid
Figure imgf000074_0001
Step 1: Preparation of tert-butyl [l-(methylsulfonyl)pyrrolidin-3-yl] acetate
Figure imgf000074_0002
To a solution of fert-butylpyrrolidin-3-yl- acetate (Ig) and triethylamine (0.85 ml) in dichloromethane (50ml) was added methanesulfonylchloride (0.48ml). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with 2N NaOH (2x20ml), dried over MgSO4 and evaporated to yield a mobile oil (yield 1.8g) which was used without further purification.
Step 2: Preparation of title compound tert-bntyl [l-(methylsulfonyl)pyrrolidin-3-yl] acetate (1.8g) was dissolved in TFA (20 ml) and stood at room temperature for 1 hour. The TFA was evaporated. The residue was triturated with ether (6x20ml) and the combined ether extracts was evaporated to yield a white solid (yieldl40 mg). LC-MS (M-H) 206 NMR CDCl3: 1.6 (m, IH) 2.15 (m, IH) 2.4 (m, 2H) 2.6 (m, IH) 2.75 (s, 3H) 2.9 (m, IH) 3.25 (m, IH) 3.4 (m, IH) 3.6 (m, IH).
Method K
Preparation of N-( 1 - { (3i?)-3 -(3 ,5-difluorophenyl)-3 -[I -(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-isobutyl-N-piperidin-4-ylurea
Figure imgf000075_0001
Step 1: Preparation of benzyl 4-({[(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-
(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4- yl)(isobutyl)amino]carbonyl}amino)piperidine-l-carboxylate
Figure imgf000075_0002
1 - { (3i?)-3 -(3 , 5-difluorophenyl)-3 - [ 1 -(methylsulfonyl)piperidin-4-yl]propyl} -N- isobutylpiperidin-4-amine (Method I) (600 mg) was dissolved in dichloromethane (25 ml) and benzyl 4-isocyanatopiperidine-l-carboxylate (331 mg) added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto a 2Og SCX2 cartridge and eluted with methanol (6x20 ml) and IM ammonia/methanol (6x20 ml). The combined ammonia washings were evaporated to a gum which was purified by silica chromatography eluting with a gradient of ethyl acetate to 20% methanol/ethyl acetate to give the subtitled compound as a solid. Yield 750 mg. LC-MS (M+H) 732 NMR CDCl3: 0.85 (6H, d) 1.21.7 (1OH, m) 1.8-2.1 (9H, m) 2.35 (IH, m) 2.5 (IH, m) 2.6 (IH, m) 2.7 (3H, s) 2.8-95 (5H, m) 3.7 (IH, m) 3.8 (2H, m) 3.95 (IH, m) 4.05-4.2 (4H, m) 5.2 (2H, s) 6.7 (3H, m) 7.35 (5H, m). Step 2: preparation of title compound
Benzyl ^({[(l-KS^-S-CS^-difluoropheny^-S-Cl-Cmethylsulfony^piperidin-^ yl]propyl}piperidin-4-yl)(isobutyl)amino]carbonyl}amino)piperidine-l-carboxylate (600 mg) was dissolved in ethanol (50 ml) and purged with argon. 20% Palladium hydroxide (100 mg) was added and the reaction purged with argon. Hydrogen was introduced from a balloon and the reaction was stirred under a hydrogen atmosphere for 24 hours. The reaction was purged with argon, filtered through celite and evaporated to give the title compound. Yield 500 mg LC-MS (M+H) 598 NMR CDCl3: 0.9 (6H, d) 1.1-2.2 (17H, m) 2.4 (IH, m) 2.5 (IH, m) 2.55-2.77 (4H, m) 2.75 (3H, s) 2.8-2.9 (4H, m) 3.05 (2H, m) 3.7- 3.8 (3H, m) 3.85 (IH, m) 3.95 (IH, m) 4.25 (IH, m) 6.7 (3H, m).
In an analogous manner but using l-{(3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl}-N-methylpiperidin-4-amine in Step 1 there was obtained N-(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl}piperidin-4-yl)-N-methyl-Nl-piperidin-4-ylurea LC-MS (M+H) 556 ΝMR
CDCl3: 1.2-2.3 (16H, m) 2.35-2.65 (5H, m) 2.7 (3H, s) 2.75 (3H, s) 2.8-2.95 (2H, m) 3.05 (2H, m) 3.7 (4H, m) 3,75 (IH, m) 4.15 (IH, m) 4.2 (IH, d) 6.7 (3H, m).
EXAMPLE 18 The ability of compounds to inhibit the binding of MIP-I α was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with O.lnM iodinated MIP-Ia , scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated MIP- lα bound to the receptor was determined by scintillation counting.
Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated MIP-Ia was calculated (IC5o). Preferred compounds of formula (I) have an IC50 of less than 50μM.
Results from this test for certain compounds of the invention are presented in Table V. In Table V the results are presented as Pic50 values. A Pic50 value is the negative log (to base 10) of the IC50 result, so an IC50 of lμM (that is 1 x 10'6M) gives a Pic50 of 6. If a compound was tested more than once then the data below is an average of the probative tests results.
Table VII
Figure imgf000077_0001
Figure imgf000077_0002

Claims

Claims
1. A compound of formula (I) :
Figure imgf000078_0001
wherein
R1 is C1-8 alkyl, C(O)NR10R11, C(O)2R12, NR13C(O)R14, NR15C(O)NR16R17,
NR18C(O)2R19, heterocyclyl, aryl or heteroaryl;
R10, R13, R15, R16 and R18 are hydrogen or C1-6 alkyl;
R11, R12, R14, R17 and R19 are C1-8 alkyl (optionally substituted by halo, hydroxy, C1- 6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl (optionally substituted by halo), Cs-6 cycloalkenyl, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), heteroaryl, aryl, heteroaryloxy or aryloxy), aryl, heteroaryl, C3-7 cycloalkyl (optionally substituted by halo, C1-4 alkyl or C1-4 haloalkyl), C4-7 cycloalkyl fused to a phenyl ring, C5-7 cycloalkenyl, or heterocyclyl; or R11, R12, R14 and R17 can also be hydrogen; or R10 and R11, and/or R16 and R17 may join to form a A-, 5- or 6-membered ring which optionally includes a nitrogen, oxygen or sulphur atom, said ring being optionally substituted by C1-6 alkyl, C1-6 haloalkyl, S(O)](C1-6 alkyl) or C(O)(C1-6 alkyl); R2 is C1-6 alkyl, phenyl, heteroaryl or C3-7 cycloalkyl; when X is NR5, Y is absent or is CH2; when X is CH2, Y is absent, CH2, NR6, O, S, S(O) or S(O)2;
Z is a 5- or 6-membered heterocyclyl ring;
R3, R5 and R6 are, independently, hydrogen or C1-6 alkyl;
R4 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl or C3-6 cycloalkyl; aryl, phenyl and heteroaryl moieties are independently optionally substituted by: halo, cyano, nitro, hydroxy, OC(O)NR20R21, NR22R23, NR24C(O)R25, NR26C(O)NR27R28, S(O)2NR29R30, NR31S(O)2R32, C(O)NR33R34, CO2R36, NR37CO2R38, S(O)qR39, OS(O)2R49, C1-6 alkyl (optionally mono-substituted by S(O)2R50 or C(O)NR51R52), C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-6 haloalkyl, Ci-6 alkoxy(C1-6)alkyl, C1-6 alkoxy (optionally mono-substituted by CO2R53, C(O)NR54R55, cyano, heteroaryl or C(O)NHS(O)2R56), NHC(O)NHR57, C1-6 haloalkoxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenylS(O), phenylS(O)2, phenyl(Ci-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(Ci-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(Ci-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Cj-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, Ci-4 alkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), CF3 or OCF3; unless otherwise stated heterocyclyl moieties are independently optionally substituted by: Ci-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, OCF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, C]-4 alkylthio, S(O)(Ci-4 alkyl) or S(O)2(Ci-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, Ci-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio, S(O)(Cj-4 alkyl) or S(O)2(Ci-4 alkyl)}], phenyl {optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, OCF3, (Ci-4 alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio, S(O)(Ci-4 alkyl) or S(O)2(Ci-4 alkyl)}, heteroaryl {optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF3, (CM alkyl)C(O)NH, S(O)2NH2, Ci-4 alkylthio, S(O)(Ci-4 alkyl) or S(O)2(Ci-4 alkyl)}, S(O)2NR40R41, C(O)R42, C(O)2(Ci- 6 alkyl) (such as tert-butoxycarbonyl), C(O)2(phenyl(Ci-2 alkyl)) (such as benzyloxycarbonyl), C(O)NHR43, S(O)2R44, NHS(O)2NHR45, NHC(O)R46, NHC(O)NHR47 or NHS(O)2R48, provided none of these last four substituents is linked to a ring nitrogen; k, 1, p and q are, independently, O, 1 or 2;
R20, R22, R24, R26, R27, R29, R31, R33, R37, R40, R51 and R54 are, independently, hydrogen or Ci-6 alkyl;
R21, R23, R25, R28, R30, R32, R34, R36, R38, R39, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R52, R53, R55, R56 and R57 are, independently, Cj-6 alkyl (optionally substituted by halo, hydroxy, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-6 cycloalkyl, C5-6 cycloalkenyl, S(Ci-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), heteroaryl, phenyl, heteroaryloxy or phenyloxy), C3-7 cycloalkyl, phenyl or heteroaryl; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(Ci-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Ci-4 alkyl)2, cyano, Ci-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(C1-4 alkyl),
NHC(O)(Ci-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(Ci-4 alkyl), CF3 or OCF3; R21, R23, R25, R28, R30, R34, R35, R36, R41, R42, R43, R45, R46, R47, R52, R53, R55 and R57 may additionally be hydrogen; alternatively, R20 and R21, and/or R22 and R23, and/or R27 and R28, and/or R29 and R30, and/or R33 and R34, and/or R51 and R52 and/or R54 and R55, and/or R40 and R41 may join to form a 5- or 6-membered ring which is optionally substituted with halo, Ci.4 alkyl or phenyl (wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, Ci-4 alkyl, Ci-4 alkoxy, S(O)1nCi-4 alkyl, S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Cj-4 alkyl)2, NHS(O)2(Ci-4 alkyl), NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, NHC(O)NH2, C(O)NH2, C(O)NH(C1-4 alkyl), NHC(O)(Ci-4 alkyl), CO2H, CO2(C1-4 alkyl), C(O)(Ci-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3); m is O, 1 or 2; or a pharmaceutically acceptable salt thereof.
2. A compound of the formula (I) according to claim 1 wherein R1 is heterocyclyl.
3. A compound of the formula (I) according to claim 1 or claim 2 wherein R1 is piperidinyl or piperazinyl, either of which is N-substituted by phenyl, S(O)2R39 (wherein R39 is Ci-4 alkyl, phenyl or CF3) or S(O)2NR29R30 (wherein R29 and R30 are, independently, C1-4 alkyl).
4. A compound of the formula (I) according to claims 1 to 3 wherein R2 is phenyl or heteroaryl, either of which is optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy,
S(O)n(Ci-4 alkyl), nitro, cyano or CF3; wherein n is O, 1 or 2.
5. A compound of the formula (I) according to claims 1 to 4 wherein R4 is hydrogen,methyl, ethyl, n-propyl, allyl or cyclopropyl
6. A compound of the formula (I) according to claims 1 to 5 wherein Z is piperidinyl or piperazinyl, optionally substituted (such as on a ring nitrogen) by C(O)(Ci-6 alkyl), C(O)(C1-6 alkoxy) or S(O)2(C1-4 alkyl).
7. A processes for preparation of a compound of the formula (I) as claimed in claim 1 which comprises :- (a) reacting a compound of formula (II):
Figure imgf000081_0001
with a compound of formula (III):
Figure imgf000081_0002
under reductive amination conditions, with a suitable organic acid and a suitable reducing agent ; or
(b) reacting a compound of formula (IV):
Figure imgf000081_0003
wherein the leaving group LG1 is tosylate, mesylate, triflate or halogen; with a compound of formula (III); or (c) reacting a compound of the formula (V):
Figure imgf000081_0004
with: when X is CH2, a compound of formula (VI):
Figure imgf000082_0001
wherein LG2 is halogen, an active ester or OH activated with a carbodiimide coupling agent, or the activated product of the reaction of an acid with carbonyldiimidazole; the reaction being carried out in an inert solvent in the presence of a base;
OR when X is NH, a compound of formula (VII):
^F=N-YN (VII)
O z the reaction being carried out in an inert solvent in the presence of a base; OR when X is NR5, a compound of formula (VIII):
Figure imgf000082_0002
wherein LG3 is halogen or an active ester; the reaction being carried out in an inert solvent in the presence of a base; wherein R1, R2 R3, R4 and R5 are as defined in claim 1.
8. A pharmaceutical composition which comprises a compound as claimed in claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A compound as claimed in claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use as a medicament.
10. A compound as claimed in claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy.
11. A method of treating a CCR5 mediated disease state comprising administering to a patient in need of such treatment an effective amount of a compound as claimed in claims 1 to 6, or a pharmaceutically acceptable salt thereof.
PCT/GB2005/004841 2004-12-20 2005-12-15 Chemical compounds WO2006067385A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP05818258A EP1833792A1 (en) 2004-12-20 2005-12-15 Substituted piperidine compounds for use as ccr5 modulators
JP2007546181A JP2008524188A (en) 2004-12-20 2005-12-15 Chemical compound
US11/793,436 US20080200460A1 (en) 2004-12-20 2005-12-15 Chemical Compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0403106A SE0403106D0 (en) 2004-12-20 2004-12-20 Chemical compounds
SE0403106-8 2004-12-20

Publications (1)

Publication Number Publication Date
WO2006067385A1 true WO2006067385A1 (en) 2006-06-29

Family

ID=34075238

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2005/004841 WO2006067385A1 (en) 2004-12-20 2005-12-15 Chemical compounds

Country Status (6)

Country Link
US (1) US20080200460A1 (en)
EP (1) EP1833792A1 (en)
JP (1) JP2008524188A (en)
CN (1) CN101124203A (en)
SE (1) SE0403106D0 (en)
WO (1) WO2006067385A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007057643A1 (en) * 2005-11-16 2007-05-24 Astrazeneca Ab Process for preparing beta- (fluorophenyl) -propanoate ester derivatives
WO2009010478A2 (en) * 2007-07-13 2009-01-22 Euroscreen S.A. Use of piperidine derivatives as agonists of chemokine receptor activity
US7625905B2 (en) 2006-09-18 2009-12-01 Roche Palo Alto Llc Octahydro-pyrrolo[3,4-c]pyrrole CCR5 receptor antagonists
US10577363B2 (en) 2014-09-10 2020-03-03 Epizyme, Inc. Substituted piperidine compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1013276A1 (en) * 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalkanes as CCR5 modulators
WO2001087839A1 (en) * 2000-05-17 2001-11-22 Astrazeneca Ab Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1013276A1 (en) * 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalkanes as CCR5 modulators
WO2001087839A1 (en) * 2000-05-17 2001-11-22 Astrazeneca Ab Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007057643A1 (en) * 2005-11-16 2007-05-24 Astrazeneca Ab Process for preparing beta- (fluorophenyl) -propanoate ester derivatives
US7625905B2 (en) 2006-09-18 2009-12-01 Roche Palo Alto Llc Octahydro-pyrrolo[3,4-c]pyrrole CCR5 receptor antagonists
WO2009010478A2 (en) * 2007-07-13 2009-01-22 Euroscreen S.A. Use of piperidine derivatives as agonists of chemokine receptor activity
WO2009010478A3 (en) * 2007-07-13 2010-03-04 Euroscreen S.A. Use of piperidine derivatives as agonists of chemokine receptor activity
US10577363B2 (en) 2014-09-10 2020-03-03 Epizyme, Inc. Substituted piperidine compounds

Also Published As

Publication number Publication date
EP1833792A1 (en) 2007-09-19
SE0403106D0 (en) 2004-12-20
JP2008524188A (en) 2008-07-10
CN101124203A (en) 2008-02-13
US20080200460A1 (en) 2008-08-21

Similar Documents

Publication Publication Date Title
US7615555B2 (en) Piperidine derivatives as modulators of chemokine receptor CCR5
US20060167048A1 (en) N-4-piperidinyl compounds as ccr5 modulators
CA2570893A1 (en) Novel piperidine/8-azabicyclo [3.2.1] octan derivatives as moduilators of chemokine receptor ccr5
US20060189650A1 (en) Novel piperidine derivatives as modulators of chemokine receptor ccr5
CA2571087A1 (en) Novel piperidine derivates as modulators of chemokine receptor ccr5
US7294636B2 (en) Chemical compounds
WO2006067385A1 (en) Chemical compounds
US20060069120A1 (en) Novel piperidine derivaties as modulators of chemokine receptor ccr5
US20060052413A1 (en) Novel piperidine derivatives as modulators of chemokine receptor ccr5
EP1648871B1 (en) Piperidine or 8-aza-bicyclo 3.2.1 oct-3-yl derivatives useful as modulators of chemokine receptor activity
EP1654229B1 (en) Piperidine derivatives as ccr5 receptor modulators
WO2005058881A1 (en) Chemical compounds
ZA200504616B (en) Novel piperidine derivatives as modulators of chemokine receptor CCR5

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2005818258

Country of ref document: EP

Ref document number: 11793436

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2007546181

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 5372/DELNP/2007

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 200580048478.0

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2005818258

Country of ref document: EP