WO2005090348A1 - Pyrazolo ’3,4-b! pyridine compounds, and their use as phosphodiesterase type 4 (pde4) inhibitors - Google Patents

Pyrazolo ’3,4-b! pyridine compounds, and their use as phosphodiesterase type 4 (pde4) inhibitors Download PDF

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WO2005090348A1
WO2005090348A1 PCT/GB2005/000983 GB2005000983W WO2005090348A1 WO 2005090348 A1 WO2005090348 A1 WO 2005090348A1 GB 2005000983 W GB2005000983 W GB 2005000983W WO 2005090348 A1 WO2005090348 A1 WO 2005090348A1
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formula
compound
salt
ring
sub
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PCT/GB2005/000983
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French (fr)
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David George Allen
Diane Mary Coe
Caroline Mary Cook
Michael Dennis Dowle
Christopher David Edlin
Julie Nicole Hamblin
Martin Redpath Johnson
Paul Spencer Jones
Mika Kristian Lindvall
Charlotte Jane Mitchell
Alison Judith Redgrave
Naimisha Trivedi
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Glaxo Group Limited
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Priority to EP05718036A priority Critical patent/EP1751151A1/en
Priority to JP2007503402A priority patent/JP2007529485A/en
Priority to US10/598,940 priority patent/US20080021058A1/en
Publication of WO2005090348A1 publication Critical patent/WO2005090348A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to pyrazolo[3,4-b]pyridine compounds, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds.
  • the invention also relates to the use of the pyrazolo[3,4-b]pyridine compounds in therapy, for example as inhibitors of phosphodiesterase type IN (PDE4) and/or for the treatment and/or prophylaxis of inflammatory and or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.
  • PDE4 phosphodiesterase type IN
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • asthma chronic obstructive pulmonary disease
  • rheumatoid arthritis allergic rhinitis
  • the 4-amino group NR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl (e.g.
  • NR3R4 can alternatively be a 5-6- membered heterocyciic group in which an additional nitrogen is present such as 25 pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl.
  • the compounds are mentioned as being central nervous system depressants useful as ataractic agents or tranquilisers, as having antiinflammatory and analgesic properties.
  • the compounds are mentioned as increasing the intracellular concentration of adenosine-3',5'- cyclic monophosphate and for alleviating the symptoms of asthma. 30 H. Hoehn et al., J. Heterocycl.
  • Chem., 1972, 9(2), 235-253 discloses a series of 1H- pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives with 4-hydroxy, 4-chloro, 4-alkoxy, 4-hydrazino, and 4-amino substituents.
  • Japanese laid-open patent application JP-2002-20386-A (Ono Yakuhin Kogyo KK) published on 23 January 2002 discloses pyrazolopyridine compounds of the following 40 formula: wherein R 1 denotes 1) a group -OR 6 , 2) a group -SR 7 , 3) a C2-8 alkynyl group, 4) a nitro group, 5) a cyano group, 6) a Cl-8 alkyl group substituted by a hydroxy group or a Cl-8 alkoxy group, 7) a phenyl group, 8) a group -C(O)R 8 , 9) a group -SO 2 NR 9 R 10 , 10) a group -NR 1 ⁇ R 12 , 11) a group -NR 13 C(O)R 14 or 12) a group -CE NR 15 .
  • R 1 denotes 1) a group -OR 6 , 2) a group -SR 7 , 3) a C2-8
  • R 6 and R 7 denote i) a hydrogen atom, ii) a Cl-8 alkyl group, iii) a Cl-8 alkyl group substituted by a Cl-8 alkoxy group, iv) a trihalomethyl group, v) a C3-7 cycloalkyl group, vi) a Cl-8 alkyl group substituted by a phenyl group or vii) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms.
  • R 2 denotes 1) a hydrogen atom or 2) a Cl-8 alkoxy group.
  • R 3 denotes 1) a hydrogen atom or 2) a Cl-8 alkyl group.
  • R 4 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group, 5) a phenyl group which may be substituted by 1-3 halogen atoms or 6) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms.
  • R 5 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3- 7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group or 5) a phenyl group which may be substituted by 1-3 substituents.
  • group R 3 a hydrogen atom is preferred.
  • group R ⁇ methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are preferred.
  • the compounds of JP-2002-20386-A are stated as having PDE4 inhibitory activity and as being useful in the prevention and/or treatment of inflammatory diseases and many other diseases,
  • EP 0 076 035 Al discloses pyrazolo[3,4-b]pyridine derivatives as central nervous system depressants useful as tranquilisers or ataractic agents for the relief of anxiety and tension states.
  • WO 02/060900 A2 appears to disclose, as MCP-1 antagonists for treatment of allergic, inflammatory or autoimmune disorders or diseases, a series of bicyclic heterocyciic compounds with a -C(O)-NR4-C(O)-NR5R6 substituent, including isoxazolo[5,4- bjpyridines and lH-pyrazolo[3,4-b]pyridines (named as pyrazolo[5,4-b]pyridines) with the -C(O)-NR 4 -C(O)-NR 5 R 6 group as the 5-substituent and optionally substituted at the 1-, 3-, 4-, and/or 6-positions.
  • Bicyclic heterocyciic compounds with a -C(O)N ⁇ -2 substituent instead of the -C(O)-NR4-C(O)-NR5R6 substituent are alleged to be disclosed in WO 02/060900 as intermediates in the synthesis of the -C(O)- R 4 -C(O)-NR 5 R 6 substituted compounds.
  • WO 00/15222 discloses inter alia pyrazolo[3,4-b]pyridines having inter alia a C(O)-X ⁇ group at the 5-position and a group ⁇ at the 4-position of the ring system.
  • X can for example be -OR9, -N(R9)(RIQ) or
  • E ⁇ can for example be -N ⁇ -Aj -cycloalkyl, -N ⁇ -Ai -substituted cycloalkyl, or -N ⁇ -Ai-heterocyclo; wherein Aj is an alkylene or substituted alkylene bridge of 1 to 10 carbons and A2 can for example be a direct bond or an alkylene or substituted alkylene bridge of 1 to 10 carbons.
  • the compounds are disclosed as being useful as inhibitors of cGMP phosphodiesterase, especially PDE type V, and in the treatment of various cGMP-associated conditions such as erectile dysfunction.
  • Rl is C 1 _ 4 alkyl, C ⁇ fluoroalkyl, -CH 2 CH 2 OH or -CH 2 CH 2 CO2C 1 .2alkyl;
  • R2 is a hydrogen atom (H), methyl or C ⁇ fluoroalkyl
  • R3 is optionally substituted C3.8cycloa.kyl or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc);
  • n and n 2 independently are 1 or 2; and in which Y is O, S, SO2, or NRIO;
  • R3 is a bicyclic group (dd) or (ee):
  • R 4 is a hydrogen atom (H); C ⁇ gal yl; C ⁇ _ 3 fluoroalkyl; or C2_6 a lkyl substituted by one substituent Rl 1.
  • R 5 can be: a hydrogen atom (H); Ci .galkyl; C ⁇ _ 8 fluoroalkyl; C3. gcycloalkyl optionally substituted by a C ⁇ alkyl group; -(CH2) n 4 -C3_gcycloalkyl optionally substituted, in the -(CH-2) n 4 - moiety or in the C3_gcycloalkyl moiety, by a Cj_2 alkyl group, wherein n 4 is 1, 2 or 3; C2_6alkyl substituted by one or two independent substituents R 1 1 ; -(CH2) n U -C(O)R 16 ; -(CH 2 ) n 12 -C(O)NR 12 R 13 ; -CHR 19 -C(O)NR 12 Rl3; -(CH 2 ) n 12 -C(O)OR 16 ; -(CH 2 ) n 12 -C(O)OR 16 ; -(CH
  • each R ⁇ independently of any other R6 present, is: a halogen atom; C ⁇ alkyl; C ⁇ fluoroalkyl; C ⁇ alkoxy; C ⁇ _2iTuoroalkoxy; C3_6cycloalkyloxy;
  • n* 4 is 0 or 1; cyano (CN); Ar ⁇ b- or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C ⁇ _2alkyl, C ⁇ fluoroalkyl, C ⁇ _2alkoxy or Cifluoroalkoxy; or two adjacent R ⁇ taken together can be -O-(CM ⁇ 2)-O- or
  • n 14 is 1 or 2.
  • G is O or S or NR 9 wherein R 9 is a hydrogen atom (H), C ⁇ _4alkyl or C ⁇ _4fluoroalkyl; none, one, two or three of J, L, M and Q are nitrogen; and the remaining of J, L, M and Q are independently CH or CR ⁇ where R ⁇ , independently of any other R" present, is as defined therein.
  • pyrazolo[3,4-b]pyridine compounds of formula (I) and salts thereof disclosed in PCT/EP03/11814 are disclosed as being inhibitors of phosphodiesterase type IN (PDE4), and as being useful for the treatment and/or prophylaxis of an inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, or allergic rhinitis.
  • COPD chronic obstructive pulmonary disease
  • asthma chronic obstructive pulmonary disease
  • rheumatoid arthritis or allergic rhinitis
  • the present invention therefore provides a compound of formula (I) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
  • W is Ar, -CR >4 RT ⁇ 5 Ar or a group (y) or (yl) wherein:
  • R 1 is Ci _4alkyl, C ⁇ _ fluoroalkyl, or -CH2CH2OH;
  • R 2 is C 2-6 alkyl, C 3-6 cyclo alkyl or -(CH 2 )n 4 C 3-6 cycloalkyl, wherein n 4 is 1 or 2;
  • R 3 is optionally substituted C3_8cycloalkyl or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc); (aa) (bb) (cc) in which n* and n 2 independently are 1 or 2; and in which Y is O, S, SO2, or NRlO; where R 10 is a hydrogen atom (H), Chalky ] , C ⁇ fluoroalkyl, CH2C(O)NH2, C(O)NH 2 , C(O)NHMe, C(O)-C ⁇ _ 2 alkyl, C(O)-C ⁇ fluoroalkyl or -C(O)-CH 2 O-C ⁇ _ 2 alkyl;
  • NHR 2 1 substituent is not substituted at the R 3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R 3 ring carbon bonded to the Y group of the heterocyciic group (aa), (bb) or (cc);
  • R 3 when R 3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, then the cycloalkenyl is optionally substituted with one substituent being fluoro or C j ⁇ alkyl or two substituents independently being fluoro or methyl , and the R 3 ring carbon bonded to the -NH- group of formula (I) does not partake in the cycloalkenyl double bond;
  • R 3 is a bicyclic group of sub-formula (ee): ( ee ' wherein NI, Y 2 and Y 3 independently are CH2 or oxygen (O) provided that no more than one of Y , Y 2 and Y 3 is oxygen (O);
  • R 4 and R 5 are independently a hydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, C ⁇ . 2 fl oroalkyl, cyclopropyl, -CH OR 4a -CH(Me)OR 4a , or -CH2CH 2 OR 4a , wherein R 4a is a hydrogen atom (H), methyl (Me), or Ci fluoroalkyl such as CF3 or CHF2.
  • A is C-R6A nitrogen (N) or nitrogen-oxide (N + -O")
  • B is C-R6B, nitrogen (N) or nitrogen-oxide (N + -O ⁇ )
  • D is C-R6D 5 nitrogen (N) or nitrogen-oxide (N + -O ⁇ )
  • E is C-R6E 5 nitrogen (N) or nitrogen-oxide (N + -O ⁇ )
  • F is C-R6F, nitrogen (N) or nitrogen-oxide (N+-O-),
  • R6B ? R6D ⁇ R6E gjyj R6F independently are: a hydrogen atom (H), a halogen atom; C ⁇ _6alkyl (e.g. C ⁇ alkyl or C ⁇ -2 alkyl); C ⁇ _4fluoroalkyl (e.g. C ⁇ _2fluoroalkyl); C3_6cycloalkyl; C ⁇ alkoxy (e.g. C ⁇ alkoxy); C ⁇ _2fluoroalkoxy;
  • R 16a -S(O) 2 -NR 15a - e.g. C 1 . 2 alkyl-S(O)2-NH-
  • n* 4 is 0 or 1; cyano (-CN); Ar 5b ; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, Cj_2 alkyl, C ⁇ fluoroalkyl, C ⁇ _2alkoxy or Cifluoroalkoxy;
  • A, B, D, E and F are independently C-H (carbon-hydrogen), C-F
  • G is O or S or NR 9 wherein R 9 is a hydrogen atom (H), C ⁇ _4alkyl, or C ⁇ _2fluoroalkyl; J is C-R 6 J, C-[connection point to formula (I)], or nitrogen (N), L is C-R L 5 C-[connection point to formula (I)], or nitrogen (N), M is C-R6 , C-[connection point to formula (I)], or nitrogen (N), Q is C-R Q, C-[connection point to formula (I)], or nitrogen (N),
  • R ⁇ J, R6L R6M an ⁇ ⁇ R6Q independently are: a hydrogen atom (H), a halogen atom; Ci ⁇ alkyl (e.g. Chalky.); C 1.3 fluoroalkyl (e.g. C ⁇ fluoroalkyl); C3_6cycloalkyl; C ⁇ alkoxy (e.g. C ⁇ _2alkoxy); C ⁇ fluoroalkoxy; C3_6cycloalkyloxy;
  • OH (including any tautomer thereof); or phenyl optionally substituted by one or two substituents independently being fluoro, chloro, C ⁇ alkyl, C ⁇ fluoroalkyl, C ⁇ _2alkoxy or Cifluoroalkoxy;
  • two or more of J, L, M and Q are independently C-H, C-F, C-C ⁇ _2 a ⁇ kyl (e.g.
  • R 7 and R 8 are independently a hydrogen atom (H); C ⁇ alkyl (e.g. C ⁇ _2 alkyl such as methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two substituents independently being: fluoro, chloro, C ⁇ _2alkyl, C ⁇ fluoroalkyl, C ⁇ _2 alkoxy or Ci fluoroalkoxy;
  • R 7 and R 8 together are -(CH 2 ) n 6 - or -C(O)-(CH 2 ) n 7 - or -C(O)-(CH 2 ) n 10 -C(O)- or -(CH 2 )n 8 -X 7 -(CH 2 )n 9 - or -C(O)-X 7 -(CH 2 ) n 10 - in which: n 6 is 3, 4, 5 or 6 (suitably n6 is 4 or 5), n 7 is 2, 3, 4, or 5 (suitably n 7 is 3 or 4), n 8 and n 9 and n ⁇ independently are 2 or 3 (suitably independently 2), and X 7 is O or NRI 4 ;
  • R 7a is a hydrogen atom (H) or C ⁇ _4alkyl (suitably H or C ⁇ _2 alkyl, more suitably H or methyl);
  • R 8a is a hydrogen atom (H) or methyl (suitably H); 14 ⁇ R17 and Rl7a independently are: a hydrogen atom (H); C ⁇ alkyl (e.g. C ⁇ a-kyl); C 1 _ fluoroalkyl (e.g. CF3); cyclopropyl; -C(O)-C 1 _4alkyl (e.g. -C(O)Me); -C(O)NR 7a R a (e.g. -C(O)NH 2 ); or -S(O) 2 -C 1 . 4 alkyl (e.g. -S(O) 2 Me) (preferably, R* 4 , R 17 and/or R 17a independently is/are: H; C ⁇ _2alkyl; or -C(O)Me);
  • R 15a is a hydrogen atom (H) or C ⁇ alkyl (e.g. H, *Bu or C i _2alkyl such as methyl; preferably R 15a is H or C ⁇ .2alkyl, more preferably H);
  • Rl 6a is:
  • C3_6cycloalkyl e.g. C5_6cycloalkyl
  • C3_6cycloalkyl-CH2- e.g. C5_6cycloalkyl-CH2-
  • pyridinyl e.g.
  • pyridin-2-yl optionally substituted on a ring carbon atom by one of: a halogen atom, Cj_2 alkyl, C ⁇ fluoroalkyl, C ⁇ _2 alkoxy or Cifluoroalkoxy; Ar5c ; phenyl optionally substituted by one or two substituents independently being: a halogen atom, C ⁇ _2alkyl, C ⁇ fluoroalkyl, C ⁇ _2alkoxy or Cifluoroalkoxy; benzyl optionally substituted on its ring by one or two substituents independently being: a halogen atom, C ⁇ _2 alkyl, Cj fluoroalkyl, C ⁇ _2alkoxy or Cifluoroalkoxy; or a 4-, 5-, 6- or 7-membered saturated heterocyciic ring connected at a ring-carbon and containing one or two ring-hetero-atoms independently selected from O, S, and N; wherein any ring
  • R 3 ⁇ independent of other R 3 ⁇ , is a hydrogen atom (H), C ⁇ _4alkyl or C3_6cycloalkyl;
  • Ar ⁇ b and Ar ⁇ c independently is/are a 5-membered aromatic heterocyciic ring containing one O, S or NR ⁇ a m the 5-membered ring, wherein the 5-membered ring can optionally additionally contain one or two N atoms, and wherein the heterocyciic ring is optionally substituted on a ring carbon atom by one of: a halogen atom, C ⁇ _2alkyl, Ci fluoroalkyl,
  • an "alkyl” group or moiety may be straight-chain or branched.
  • Alkyl groups for example C ⁇ .galkyl or C ⁇ .galkyl or C ⁇ _4alkyl or C ⁇ _3alkyl or
  • C ⁇ _2 alkyl which maybe employed include Ci. ⁇ alkyl or C ⁇ alkyl or C 1.3 alkyl or C j _2 alkyl such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl or any branched isomers thereof such as isopropyl, t-butyl, sec-butyl, isobutyl, 3-methylbutan-2-yl, 2-ethylbutan-l-yl, or the like.
  • a corresponding meaning is intended for "alkoxy", "alkylene", and like terms derived from alkyl.
  • alkoxy such as C ⁇ alkoxy or Ci _4alkoxy or
  • C ⁇ _2alkoxy includes methoxy, ethoxy, propyloxy, and oxy derivatives of the alkyls listed above.
  • Alkylsulfonyl such as C ⁇ _4alkylsulfonyl includes methylsulfonyl
  • alkylsulfonyloxy such as C ⁇ alkylsulfonyloxy includes methanesulfonyloxy
  • Cycloalkyl for example C3_gcycloalkyl, includes cyclopropyl, cyclobuiyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • a first cyclobuiyl for example C3_gcycloalkyl
  • cyclopentyl for example C3_gcycloalkyl
  • cyclohexyl cycloheptyl
  • cyclooctyl cyclooctyl
  • C3_gcycloalkyl group is C3_6cycloalkyl or Cs.gcycloalkyl , that is contains a 3-6 membered or 5-6 membered carbocyclic ring.
  • "Fluoroalkyl” includes alkyl groups with one, two, three, four, five or more fluorine substituents, for example Ci_4fluoroalkyl or C .3 fluoroalkyl or C ⁇ fluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF2CH2-), 2-fluoroethyl
  • Fluoroalkoxy includes Cifluoroalkoxy or Cifluoroalkoxy such as trifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy, etc.
  • Fluoroalkylsulfonyl such as C ⁇ _4fluoroalkylsulfonyl includes trifluoromethanesulfonyl, pentafluoroethylsulfonyl, etc.
  • a halogen atom present in compounds, for example in the compounds of formula (I), means a fluorine, chlorine, bromine or iodine atom ("fluoro", “chloro”, “bromo” or “iodo"), for example fluoro, chloro or bromo.
  • fluorine chlorine, bromine or iodine atom
  • chloro chloro or bromo
  • atom or moiety A is "bonded” or “attached” to atom or moiety B, it means that atom/moiety A is directly bonded to atom/moiety B usually by means of a covalent bond or a double covalent bond, and excludes A being indirectly attached to B via one or more intermediate atoms/moieties (e.g. excludes A-C- B); unless it is clear from the context that another meaning is intended.
  • Rl When Rl is C ⁇ alkyl or C ⁇ _3fluoroalkyl, it can be straight-chained or branched. Where Rl is Cj_4alkyl then it can for example be methyl, ethyl, n-propyl, isopropyl or n-butyl.
  • Rl when Rl is C ⁇ _3fluoroalkyl, then Rl can for example be C ⁇ fluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl; or Rl can be C2fluoroalkyl such as pentafluoroethyl or more preferably Cifluoroalkyl-GH j- such as 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF 2 CH2-), or 2-fluoroethyl (CH 2 FCH 2 -).
  • Cifluoroalkyl-GH j- such as 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF 2 CH2-), or 2-fluoroethyl (CH 2 FCH 2 -).
  • R 1 is C ⁇ _3alkyl (e.g. methyl, ethyl or n-propyl), C ⁇ fluoroalkyl or
  • R 1 is more preferably C ⁇ _ 3 alkyl, C ⁇ fluoroalkyl, or -CH 2 CH 2 OH. Still more preferably, R 1 is C2_3alkyl (e.g. ethyl or n-propyl), C2fluoroalkyl (e.g. Cifluoroalkyl-CH2- such as CF3-CH2-) or -CH2CH2OH; in particular ethyl, n-propyl or -CH2CH2OH. Yet more preferably, Rl is C2alkyl or C2fluoroalkyl. Rl is most preferably ethyl.
  • R 1 include ethyl.
  • R 2 is C 2-4 alkyl, C 3-5 cycloalkyl or -CH 2 cyclopropyl.
  • R 2 include ethyl, propyl, cyclopropyl, cyclobutyl, cyclop entyl and cyclopropylmethyl.
  • R 3 there is one substituent or no substituent.
  • R 3 is the optionally substituted C3_gcycloalkyl or the optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc).
  • R 3 when R 3 is optionally substituted C3_g cycloalkyl, it is not unsubstituted Cscycloalkyl, i.e. not unsubstituted cyclopentyl. In this case, more suitably, R 3 is optionally substituted Cg.gcycloalkyl.
  • R 3 is optionally substituted C3_gcycloalkyl, it is more preferably optionally substituted C6-7cycloalkyl or optionally substituted C ⁇ cycloalkyl (i.e. cyclohexyl).
  • R 3 is optionally substituted C3_gcycloalkyl
  • C3_gcycloalkyl e.g. C ⁇ - cycloalkyi
  • R 26 is Chalky!
  • C3_gcycloalkyl e.g. C ⁇ - cycloalkyl
  • R 3 is optionally substituted C3_gcycloalkyl
  • R 3 is optionally substituted C3_gcycloalkyl
  • the C3_gcycloalkyl in R 3 , can be unsubstituted.
  • R 3 is optionally substituted C3_gcycloalkyl or optionally substituted
  • C5_7cycloalkenyl e.g. optionally substituted C5_gcycloalkyl or C5_7cycloalkyl, such as optionally substituted Cgcycloalkyl (optionally substituted cyclohexyl) or optionally substituted cyclohexenyl
  • the one or two optional substituents if present suitably can comprise a substituent (for example is or are substituent(s)) at the 3-, 4- and/or 5- position(s), e.g. at the 3- and/or 4- position(s), of the R 3 cycloalkyl or cycloalkenyl ring.
  • R 3 is not substituted (other than optionally by alkyl or fluoroalkyl) at the ring atom connecting to the -NH- in formula (I), and R 3 is not substituted (other than optionally by alkyl, fluoroalkyl or NHR 1) at the two ring atoms either side of (bonded to) the connecting atom.
  • R 3 is optionally substituted C3_gcycloalkyl or optionally substituted
  • R 3 is not substituted at the ring atom connecting to the -NH- in formula (I), and R 3 is not substituted at the two ring atoms either side of (bonded to) the connecting atom.
  • the one or two optional R 3 substituents if present can comprise a substituent (for example is or are substituent(s)): (a) at the 3 -position of a R 3 cyclobutyl ring, or (b) at the 3- and/or 4- position(s) of a R 3 cyclopentyl or cyclopentenyl ring, or
  • R 3 is optionally substituted C3_gcycloalkyl, any OH, alkoxy, fluoroalkoxy,
  • any OH, alkoxy, fluoroalkoxy, -CH2CH2OH or -CH2NHR 22 substituent can be: at the 3-position of a R 3 cyclobutyl ring; or at the 3- or 4- position of a R 3 Cscycloalkyl (cyclopentyl) ring; or at the 3-, 4- or
  • any OH, alkoxy, fluoroalkoxy, -CH2CH2OH or -CH2NHR 22 substituent is at the 3- or 4- position of a R 3 C5cycloalkyl
  • C 5 _ 7 cycloalkenyl, any -C(O)OR 23 , -C(O)NHR 24 , -C(O)R 2 5 , -CH 2 OH, or fluoro substituent is: at the 3-position of a R 3 cyclobutyl ring; or at the 3- or 4- position of a R 3 C5cycloalkyl (cyclopentyl) or cyclopentenyl ring; or at the 3-, 4- or 5- position, preferably at the 4-position, of a R 3 C ⁇ cycloalkyl (cyclohexyl) or cyclohexenyl ring; or at the 3-, 4-, 5- or 6- position of a R 3 cycloheptyl or cycloheptenyl ring, or at the 3-, 4-, 5-, 6- or 7- position of a R 3 cyclooctyl ring.
  • Any -C(O)OR 23 , -C(O)NHR 24 , -C(O)R 25 , -CH2OH, or fluoro substituent is suitably at the 3-, 4- or 5- position, more suitably at the 4-position, of a R 3 Cgcycloalkyl (cyclohexyl) or cyclohexenyl ring. It is particularly preferable for any -C(O)NHR 24 substituent to be at the 4-position of a R 3 cyclohexyl ring.
  • any NHR 2 1 substituent is at any position other than the 1 -position (the ring atom connecting to the -NH- in formula (I)), e.g. at the 3-, 4-, 5-, 6-, 7- or 8- position.
  • any NFIR 2 substituent is at the 2-, 3-, 5- or 6- position, or more preferably at the 3- or 5- position, of a R 3 cyclohexyl ring.
  • any alkyl or fluoroalkyl substituent can for example be at the 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- position, for example at the 1-, 2-, 3-, 5- or 6- position, e.g. the
  • any alkyl or fluoroalkyl substituent is at the 1-, 2-, 3-, 5- or 6- position, or more preferably at the 1-, 3- or 5- position, of a R 3 cyclohexyl or cyclohexenyl ring.
  • R 3 cycloalkyl e.g. C ⁇ .gcycloalkyl e.g. cyclohexyl
  • any such substituent is at the 4-position of a R 3 cyclohexyl ring.
  • R 3 is optionally substituted C3_gcycloalkyl (e.g. Cg- cycloalkyl)
  • the optional substituent can for example be at the 3- or 4- position, of the R 3 cyclohexyl ring.
  • any alkyl or fluoroalkyl substituent is preferably at the 1-, 3- or 5- position of a R 3 cyclohexyl ring.
  • R 3 can for example be 4-hydroxy- cyclohexyl (i.e. 4-hydroxycyclohexan-l-yl), 4-methylcyclohexyl, 3-fluorocyclohexyl, 2- aminocyclohexyl, 3-(HO(O)C)cyclohexyl or 3-oxocyclohexyl, but R 3 is more preferably cyclohexyl (i.e. unsubstituted), cycloheptyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl) (e.g.
  • 4-oxo-cyclohexyl i.e. 4- oxocyclohexan- 1 -yl
  • 4-(hydroxyimino)cyclohexyl i.e. 4-(hydroxyimino)cyclohexan- 1 - yl
  • 4-(C ⁇ _2alkoxyimino)cyclohexyl 4-(aminocarbonyl)cyclohexyl (i.e.
  • 4-(aminocarbonyl)cyclohexan-l-yl) (e.g. in a cis configuration), 1-methylcyclohexyl, 3-methylcyclohexyl, 4,4-(difluoro)cyclohexyl, or 3-aminocyclohexyl.
  • R 3 is most preferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl) (e.g. in a cis configuration), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-l-yl), 4- (hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-l-yl), or 4-(aminocarbonyl)cyclohexyl (i.e. 4-(aminocarbonyl)cyclohexan-l-yl) (e.g. in a cis configuration).
  • cyclohexyl i.e. unsubstituted
  • 3-hydroxy-cyclohexyl i.e. 3-hydroxycyclohexan-l-yl
  • 4-oxo-cyclohexyl i.e. 4-o
  • R 3 is optionally substituted Cscycloalkyl (optionally substituted cyclopentyl)
  • R 3 can for example be cyclopentyl (i.e. unsubstituted) or more suitably 3-hydroxy- cyclopentyl.
  • the R 3 cyclohexenyl can be optionally substituted cyclohex-3-en-l-yl.
  • R 3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl
  • the R 3 cycloalkenyl is optionally substituted with one or two substituents independently being fluoro or methyl.
  • the R 3 cycloalkenyl e.g. cyclohexenyl
  • the R 3 cycloalkenyl is optionally substituted with one substituent being fluoro or C ⁇ _2alkyl (preferably fluoro or methyl); more preferably the R 3 cycloalkenyl (e.g. cyclohexenyl) is substituted with one fluoro substituent or is unsubstituted.
  • the R 3 optionally substituted cycloalkenyl can be cyclohex-3-en-l-yl (i.e. unsubstituted) or 4-fluoro-cyclohex-3-en-l-yl.
  • the optional substiruent(s) can for example be at the 1-, 2-, 3-, 4-, 5- or 6- position(s) of the cycloalkenyl ring.
  • R 3 is the heterocyciic group of sub-fo ⁇ nula (aa), (bb) or (cc), then Y is preferably O or NRIO, most preferably O.
  • R 10 is a hydrogen atom (H), methyl, ethyl, C(O)NH2, C(O)-C ⁇ _ 2 alkyl or C(O)-C ⁇ fluoroalkyl. .
  • R 10 is not C ⁇ alkyl or C ⁇ _2fluoroalkyl.
  • R 10 is not CH 2 C(O)NH2.
  • R 10 is a hydrogen atom (H), C(O)NH2, C(O)-C ⁇ _2alkyl (e.g. C(O)methyl) or C(O)-C ⁇ fluoroalkyl (e.g. C(O)-CF 3 ). Still more preferably R 10 is H, C(O)NH2 or C(O)methyl; for example C(O)NH 2 .
  • R 3 is the heterocyciic group of sub-formula (aa), (bb) or (cc)
  • R 3 is the heterocyciic group of sub-formula (aa) or (bb), more preferably of sub- formula (bb).
  • n is preferably 1.
  • n 2 is preferably 1. That is, six-membered rings are preferred in the R 3 heterocyciic group.
  • the heterocyciic group of sub-formula (aa), (bb) or (cc) is unsubstituted on a ring carbon.
  • Y is NR 0, R 0 is not a substituent on a ring carbon.
  • any alkyl or fluoroalkyl substituent can for example be at the 1-, 2-, 3-, 4-, 5- or 6- position, e.g. the 1-position, of the R 3 heterocyciic ring, for example at the 1-, 3- or 5- position of a six-membered R 3 heterocyciic ring.
  • any OH substituent can be: at the 5-position of a six-membered R 3 heterocyciic group of sub-formula (cc) wherein n 2 is 1; at the 5- or 6- position of a seven-membered R 3 heterocyciic group of sub- formula (cc) wherein n 2 is 2; or at the 6- position of a seven-membered R 3 heterocyciic group of sub-formula (bb) wherein n is 2.
  • R 3 heterocyciic ring at numerical positions as described herein for when R 3 is optionally substituted C5_7cycloalkyl, all necessary changes to the wording being made.
  • R 3 is the heterocyciic group of sub-formula (aa) and Y is NRlO
  • RlO is not C(O)-C ⁇ _2alkyl, C(O)-C ⁇ fluoroalkyl or -C(O)-CH 2 O-C 1 _ 2 alkyl.
  • R 10 is optionally not C(O)NHMe, C(O)-C ⁇ _ 2 alkyl, C(O)-C ⁇ fluoroalkyl or
  • Y is O, S, SO2 or NH when R 3 is the heterocyciic group of sub-formula (aa).
  • R 3 is the heterocyciic group of sub-formula (bb), n* is 1, and Y is NR 0 (e.g.
  • NHR 3 is 10 is not C ⁇ _2alkyl or Cifluoroalkyl. More preferably, when R 3 is the heterocyciic group of sub-formula (bb) wherein n is 1 or 2 and Y is N IO, then R 0 is preferably not Chalky! or Cifluoroalkyl.
  • R 3 when R 3 is the heterocyciic group of sub-formula (bb), then preferably Y is O, S, SO 2 or NR 10 wherein R 10 is H, C(O)NH , C(O)-C 1 . 2 alkyl (e.g. C(O)methyl) or C(0)-C ⁇ fluoroalkyl (e.g. C(O)-CF 3 ), or more preferably R 10 is H, C(O)NH2 or C(O)Me, for example C(O)NH2 or C(O)Me most preferably CONH 2 .
  • R 10 is H, C(O)NH2 or C(O)Me, for example C(O)NH2 or C(O)Me most preferably CONH 2 .
  • R 3 is the heterocyciic group of sub-formula (cc)
  • Y is O, S, S0 2 or NR 1 () wherein R 10 is H, C(O)NH 2 , C(O)-C 1 . 2 alkyl (e.g.
  • ⁇ U-® can for example be H, C(O)NH 2 or C(O)Me, for example H.
  • Y is O or N lO.
  • R 3 is optionally substituted C3_gcycloalkyl (e.g. C ⁇ .ycycloalkyl) or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc), then a substituent can be in the cis or trans configuration with respect to the -NH- group of formula (I) to which R 3 is attached (bonded); this includes mixtures of configurations wherem the stated configuration is the major component.
  • C3_gcycloalkyl e.g. C ⁇ .ycycloalkyl
  • R 3 optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc)
  • an OH or -C(O)NHR 24 substituent on C ⁇ cycloalkyl can for example be in the cis configuration and/or a NHR 2 1 substituent on C6_7cycloalkyl can for example be in the cis or trans configuration, with respect to the
  • NHR 3 is of sub-formula (a), (al), (b), (c), (c 1), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (g), (gl), (g2), (g3), (g4), (h), (i), (j), (k), (kl), (k2), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (p), (pi), (p2), (p3), (p4), (p5), ( P 6), (p7), (p8), (p9), (pl0), (pl l) or (q):
  • NHR 3 is of sub-foi ula (c), (cl), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (gl), (g4), (h), (i), (j), (k), (kl), (k2), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (p), (p2), (p5), (p6), (p7), (p9), (plO), (pi 1) or (q).
  • NHR 3 is of sub-formula (c), (cl), (c 4), (c 5), (h), (i), (j), (k), (k2), (ml), (m2), (n), (o), (o2), (o3), (p2), (p5), (p6), (p9), (pi 1) or (q).
  • NHR 3 can for example be of sub-formula (c), (pll), (h), (k), (k2), (n), (o), (o2) or (p9); or still more preferably (c), (pll), (h), (k2), (n), (o), (o2) or (p9).
  • R 3 is tetrahydro-2H-pyran-4-yl or l-(aminocarbonyl)-4-piperidinyl; that is NHR 3 is most preferably of sub-formula (h) or (k2), as shown above.
  • R 3 is a 4-(aminocarbonyl)cyclohexyl (i.e. 4-(aminocarbonyl)cyclohexan- 1 -yl) group of sub-formula (aa), or an N-aminocarbonyl- piperidinyl or an N-aminocarbonyl-pyrrolidinyl or a tetrahydropyranyl group of sub- formula (bb);
  • cyclohexyl group of sub-formula (aa) or the piperidinyl, pyrrolidinyi or tetrahydropyranyl groups of sub-formula (bb) may be further optionally substituted with one or two substituents independently selected from C ⁇ lkyl; Cifluoroalkyl; CH 2 OH; -C(O)OR 23 wherein R 23 is H or C ⁇ alkyl; -C(O)NHR 23 ; or fluoro; on any ring carbon; as well as, on the C2, C3, C5 and C6 of the cyclohexyl group of (aa), the C2 or C6 of the piperidinyl ring or the C5 of the pyrrolidinyi ring of (bb), a substituent selected from OH; C ⁇ _2fluoroalkoxy; or alkoxy.
  • R include tetrahydro-2H-pyran-4-yl.
  • NHR 3 is of sub-formula (n), then preferably it is in the cis configuration, i.e. preferably it is a ct 1 y-(3-hydroxycyclohexan-l-yl)amino group, e.g. in any enantiomeric form or mixture of forms such as a racemic mixture.
  • NHR 3 is of sub-formula (p9), then preferably it is in the cis configuration, i.e. preferably it is a ct-?-[4-(aminocarbonyl)cyclohexan-l-yl] amino group.
  • R 4 is Cifluoroalkyl
  • it can be Cifluoroalkyl such as monofluoromethyl, difluoromethyl or trifluoromethyl.
  • R 4a can suitably be a hydrogen atom (H) or methyl (Me), more suitably H.
  • R 4 can for example be a hydrogen atom (H); methyl, ethyl, Cifluoroalkyl, -CH2OH, -CH(Me)OH, -CH2CH2OH, or -CH2OMe; or preferably a hydrogen atom (H), methyl, ethyl, -CH2OH, or -CTJ ⁇ OMe . More preferably, R 4 is H, methyl, ethyl, -CH2OH, or -CH 2 OMe.
  • R 4 include H, methyl and ethyl.
  • R$ is a hydrogen atom (H), methyl, ethyl, n-propyl, or iso-propyl.
  • R 5 include H.
  • A is C-R 6A
  • B is C- R 6B
  • D is C- R 6D
  • E is C- R 6E .
  • Representative examples of (y) include 2,3-dihydro-lH-inden-2-yl.
  • Ar has the sub-formula (x).
  • two or more (more preferably three or more) of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine) or nitrogen (N).
  • three or more of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine), nitrogen (N), or nitrogen-oxide (N+-O").
  • two or more (e.g. three or more) of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine), or nitrogen (N); and one or more (e.g. two or more) others of A, B, D, E and F are independently C-H (carbon- hydrogen), C-F (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe, or nitrogen (N).
  • two or more (e.g. three or more) of A, B, D, E and F are C-H (carbon-hydrogen); and one or more (e.g. two or more) others of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe, or nitrogen (N).
  • two or more are C-H.
  • no more than one (more preferably none) of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N + -O ⁇ ).
  • none of A, B, D, E and F are nitrogen-oxide (N+-O").
  • Ar has the sub-formula (x) which is sub-formula (xl), (x2), (x3), (x4), (x5), (x6), (x7), (x8), (x9), (xlO), (xll), (xl2), (xl3), (xl4), ( l5) or (xl6):
  • Ar has the sub-formula (x) which is sub-formula (xl), (x2), (x3), (x8), (xl3), or (xl4). Still more preferably, Ar has the sub-formula (x) which is sub-formula (xl), (x8), (xl3), or (xl4). Most preferably, Ar has the sub-formula (x) which is sub- formula (xl).
  • R 6A , R 6B , R 6D , R 6E and or R 6F independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, C4alkyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, isopropoxy, Ci fluoroalkoxy (e.g.
  • R ⁇ A R B ? R6D ? R6E and/or R ⁇ F independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, isobutyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, isopropoxy, C fluoroalkoxy (e.g.
  • R ⁇ A 5 R ⁇ B, R6D ; R6E and/or R ⁇ F independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, difluoromethoxy, OH or MeS(O)2--
  • sub-formula (x) e.g. in sub-formula (xl), suitably, one, two or three of R ⁇ B, R6D ⁇ d R6E aj-g other than a hydrogen atom (H).
  • R ⁇ A and R ⁇ F are independently a hydrogen atom (H), a fluorine atom (F), or methyl.
  • R6A and R6F can be a hydrogen atom (H).
  • the ring or ring system is unsubstituted, monosubstituted, disubstituted or trisubstituted, preferably the ring or ring system is monosubstituted or disubstituted.
  • sub-formula (xl) for monosubstitution of the ring or ring system, then the one substituent selected from R6A R6B ? 6D 5 R6E an d R ⁇ F is suitably present at the 3- or 4-position with respect to the -(CR R 5 )- side-chain (i.e. D is CR 6D where R 6D is other than H), or is a 2-methyl 2-ethyl, 2-fluoro or 2-chloro substituent.
  • i sub-fo ⁇ nula (x) e.g. in sub-formula (xl), for disubstitution of the ring or ring system, then 3,4-disubstirution, 2,4-disubstitution, 2,3- disubstitution or 3,5-disubstitution is suitable.
  • Ar has the sub-formula (xl) and is: phenyl, monoalkyl- phenyl-, mono(fluoroalkyl)-phenyl-, monohalo-phenyl-, monoalkoxy-phenyl-, mono(fluoroalkoxy)-phenyl-, mono(N,N-dimethylamino)-phenyl-, mono(methyl-SO2-NH-)-phenyl-, mono(methyl-S ⁇ 2-)-phenyl-, dialkyl-phenyl-, monoalkyl-monohalo-phenyl-, mono(fluoroalkyl)-monohalo-phenyl-, dihalo-phenyl-, dihalo-monoalkyl-phenyl-, dihalo-mono(hydroxymethyl)-phenyl- (e.g.
  • Ar is of sub-formula (xl) and is: monoalkyl-phenyl-, mono(fluoroalkyl)-phenyl-, monohalo-phenyl-, monoalkoxy-phenyl-, mono(fluoroalkoxy)-phenyl-, dialkyl-phenyl-, monoalkyl-monohalo-phenyl-, dihalo- phenyl- or dihalo-monoalkyl-phenyl-.
  • Ar is:
  • diC ⁇ _3alkyl-phenyl- or diC ⁇ _2alkyl-phenyl- or dimethyl-phenyl- such as 3,4-dimethyl- phenyl-, 2,4-dimethyl-phenyl-, 3,5-dimethyl-phenyl-, 2,3-dimethyl-phenyl- or 2,5- dimethyl-phenyl-; for example 3,4-dimethyl-phenyl-, 2,4-dimethyl-phenyl-, 2,3-dimethyl- phenyl- or 3,5-dimethyl-phenyl-;
  • monoC _3alkyl-monohalo-phenyl- such as monoC _2alkyl-monohalo-phenyl- and/or monoC ⁇ _3alkyl-monochloro-phenyl- or monoC ⁇ _3alkyl-monofluoro-phenyl-, for example 4-methyl-3-chloro-phenyl-, 3-methyl-4-chloro-phenyl-, or 2-methyl-4-chloro-phenyl-;
  • dihalo-phenyl- such as 2-chloro-4-fluorophenyl- or 2,4-difluoro-phenyl- or 4-bromo- 2-fluorophenyl- or preferably 4-chloro-2-fluorophenyl-; for example dichloro-phenyl- such as 3,4-dichloro-phenyl- or 2,4-dichloro-phenyl- or 2,6-dichloro-phenyl- or preferably 2,3-dichloro-phenyl-; or
  • Ar has the sub-formula (z).
  • J, L, M and Q are independently C-H, C-F, C-C ⁇ _2alkyl (e.g. C-Me), C- [connection point to formula (I)], or nitrogen (N).
  • no more than two (for example no more than one) of J, L, M and Q are nitrogen (N).
  • Q is C- [connection point to formula (I)].
  • R 9 is a hydrogen atom (H) or methyl.
  • R ⁇ 1 , R ⁇ L R6M and/or R ⁇ Q independently is or are: a hydrogen atom (H); fluoro; chloro; C ⁇ _2alkyl (e.g. methyl); Cifluoroalkyl (e.g. CF3); C ⁇ _2alkoxy (methoxy); Ci fluoroalkoxy (e.g. CF2HO-); OH (including any tautomer thereof); or phenyl optionally substituted by one substituent being fluoro, methyl, Cifluoroalkyl, methoxy or Ci fluoroalkoxy.
  • H hydrogen atom
  • fluoro chloro
  • C ⁇ _2alkyl e.g. methyl
  • Cifluoroalkyl e.g. CF3
  • C ⁇ _2alkoxy methoxy
  • Ci fluoroalkoxy e.g. CF2HO-
  • OH including any tautomer thereof
  • phenyl optionally substituted by one substituent being flu
  • R ⁇ L R6M a ⁇ l( ⁇ / or R6Q independently is or are H, OH (including any keto tautomer thereof), or more preferably C ⁇ _2alkyl (e.g. methyl) or Cifluoroalkyl.
  • sub-formula (z) can suitably be one of the following:
  • Ar is phenyl and R6 ⁇ , R6 B , R6 D , R6 E and R6 F are independently H, C ⁇ - alkyl, C ⁇ -2 alkoxy or halogen.
  • Representative examples of Ar include 4-chloro-2-methylphenyl, 4-methoxyphenyl, 3,4- dimethylphenyl, 4-chlorophenyl, and phenyl.
  • the compound of formula (I) or the salt thereof is a compound of formula (IA) or a salt thereof:
  • Formula (IA) means that more than 50% of the compound or salt present has the stereochemistry shown at the carbon atom bearing the R 4 and R ⁇ groups.
  • the stereochemistry at the carbon atom bearing the R 4 and R ⁇ groups is such that there is an enantiomeric excess (e.e.) of 50% or more at the carbon atom bearing the R 4 and R ⁇ groups (ignoring the stereochemistry at any other carbon atoms). More preferably, the enantiomeric excess (e.e.) is 70% or more or 80% or more, still more preferably 90% or more, yet more preferably 95% or more, at the carbon atom bearing the R 4 and R-> groups (ignoring the stereochemistry at any other carbon atoms).
  • Enantiomeric excess (e.e.) is defined as the percentage of the major isomer present minus the percentage of the minor isomer present. For example, if 95% of major isomer is present and 5% of the minor isomer is present, then the e.e. would be 90%.
  • R 4 is not a hydrogen atom (H).
  • R 4 can for example be methyl, ethyl, C fluoroalkyl (such as CF 3 ), -CH 2 OH, or -CH 2 OMe.
  • R ⁇ is a hydrogen atom (H) and R 4 is not a hydrogen atom (H).
  • the compound of formula (I) or the salt thereof is: N-[(4-chloro-2-methylphenyl)methyl]-6-cyclopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
  • the compound of formula (I) or the salt thereof is one of Examples 1 to 29, as a compound or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
  • the structures of these specific compounds are given in Examples 1 to 29 hereinafter, and their names are given in the Examples section.
  • the invention provides a compound of formula (I) or a salt thereof selected from the group consisting of:
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt.
  • a hydrobromide hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-to
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline- earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the the compound of formula (I).
  • non-pharmaceutically acceptable salts eg. oxalates
  • oxalates may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of formula (I). Also included within the scope of the invention are all solvates, hydrates and complexes of compounds and salts of the invention.
  • Certain groups, substituents, compounds or salts included in the present invention may be present as isomers.
  • the present invention includes within its scope all such isomers, including racemates, enantiomers and mixtures thereof. ha the compounds or salts, pharmaceutical compositions, uses, methods of treatment/prophylaxis, methods of preparing, etc. according to the present invention, where a defined isomeric configuration e.g. stereochemical configuration is described or claimed, the invention includes a mixture comprising (a) a major component of the compound or salt which is in the described or claimed configuration, together with (b) one or more minor components of the compound or salt which is/are not in the described or claimed configuration.
  • the major component of the compound or salt which is in the described or claimed configuration represents 70% or more, or 75% or more, more preferably 85%) or more, still more preferably 90% or more, yet more preferably 95% or more, yet more preferably 98% or more, of the total amount of compound or salt present in the mixture on a molarity basis.
  • the percentage of one isomeric / stereochemical component in a mixture of different isomeric / stereochemical components, and if appropriate enantiomeric and/or diastereomeric excesses, can be measured using techniques known in the art. Such methods include the following: (1) Measurement using NMR (e.g. ⁇ H NMR) spectroscopy in the presence of chiral agent.
  • the chiral agent can be: i) an optically pure reagent which reacts with the compound/salt e.g. to form a mixture of diastereomers, ii) a chiral solvent, iii) a chiral molecule which forms a transient species (e.g. diastereomeric species) with the compound/salt, or iv) a chiral shift reagent. See e.g. J. March, "Advanced Organic
  • a chiral shift reagent can be a chiral lanthanide shift reagent such as tris[3-trifluoroacetyl- ⁇ - camphorato]europium-(III) or others as described in Morrill, "Lanthanide Shift Reagents in Stereochemical Analysis", VCH, New York, 1986. Whatever the chiral agent is that is used, usually, the relative integrals (intensities) for the NMR peaks of a given atom or group in different isomers can provide a measurement of the relative amounts of each isomer present. (2) Measurement using chiral chromatography, especially on an analytical scale.
  • a suitable chiral column which separates the different isomeric components can be used to effect separation, e.g. using gas or liquid chromatography such as HPLC, and/or e.g. on an analytical scale.
  • the peaks for each isomer can be integrated (area under each peak); and a comparison or ratio of the integrals for the different isomers present can give a measurement of the percentage of each isomeric component present. See for example: "Chiral Chromatography", Separation Science Series Author: T.E. Beesley and R.P.W. Scott, John Wiley & Sons, Ltd., Chichester, UK, 1998, electronic Book ISBN: 0585352690, Book ISBN: 0471974277.
  • optically active acid chloride or acid anhydride can be via formation of an acid or base addition salt of the compound by treatment of the compound with an optically-active acid or base, such as + or - di-para-toluoyl tartaric acid.
  • separation of the resulting isomers e.g. diastereomers, can be using gas or liquid chromatography (usually non-chiral); or (especially with isomeric salts) can be by selective crystallisation of a single isomeric e.g. diastereoisomeric salt. Determination of isomeric ratios and/or excesses can be using chromatography peak areas or measurement of mass of each separated isomer. See e.g. J.
  • Certain of the groups, e.g. heteroaromatic ring systems, included in compounds of formula (I) or their salts may exist in one or more tautomeric forms.
  • the present invention includes within its scope all such tautomeric forms, including mixtures.
  • the compound of formula (I) can optionally have a molecular weight of 1000 or less, for example 800 or less, in particular 650 or less or 600 or less.
  • Molecular weight here refers to that of the unsolvated "free base” compound, that is excluding any molecular weight contributed by any addition salts, solvent (e.g. water) molecules, etc.
  • the activated compound can be the acid chloride.
  • This can be formed from the carboxylic acid (II) e.g. by reaction with thionyl chloride, either in an organic solvent such as chloroform or without solvent.
  • the activated compound can be an activated ester wherein the leaving group X S
  • the latter activated compound of formula (III) can be formed from the carboxylic acid (II) either:
  • reaction (a) by reaction of the carboxylic acid with a carbodiimide such as EDC, which is 1-ethyl- 3-(3'-dimethylaminopropyl)carbodiimide and is also l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, or a salt thereof e.g. hydrochloride salt, preferably followed by reaction of the resulting product with 1-hydroxybenzotriazole (HOBT); reaction (a) usually being carried out in the presence of a solvent (preferably anhydrous) such as dimethyl formamide (DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25 °C);
  • a solvent preferably anhydrous
  • DMF dimethyl formamide
  • acetonitrile e.g. about 20 to about 25 °C
  • room temperature e.g. about 20 to about 25 °C
  • a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane or
  • Compounds of formula (IN) can be prepared according to a method, for example as described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027, by reaction of a compound of formula (N) with an amine of formula R 3 ⁇ H 2 .
  • the reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane, l-methyl-2-pyrrolidinone (NMP) or acetonitrile.
  • the reaction may require heating e.g. to ca. 60-180°C, for example ca. 140-160°C:
  • the 4-chloro substituent in the compound of formula (V) can be replaced by another halogen atom, such as a bromine atom, or by another suitable leaving group which is displaceable by an amine of formula R 3 NH 2.
  • the leaving group can, for example, be an alkoxy group -OR such as -OC ⁇ - 4 alkyl (in particular -OEt) or a group -O-S(O)2-R 3 ⁇ , wherein R ⁇ is C ⁇ _galkyl (e.g. C ⁇ _4alkyl or C ⁇ _2 lkyl such as methyl), Ci.gfluoroalkyl (e.g.
  • Cifluoroalkyl or Cifluoroalkyl such as CF3 or C4F9), or phenyl wherein the phenyl is optionally substituted by one or two of independently Chalky., halogen or C ⁇ _2alkoxy (such as phenyl or 4-methyl-phenyl).
  • the reaction may be carried out with or without solvent and may require heating.
  • Compounds of formula (I) can be prepared by reaction of a compound of formula (XI) with an amine of formula R 3 NH 2 .
  • the reaction is preferably carried out in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, THF, dioxane or acetonitrile.
  • a base such as triethylamine or N,N-diisopropylethylamine
  • organic solvent such as ethanol, THF, dioxane or acetonitrile.
  • the reaction may require heating, e.g. to ca. 60-100 °C or ca. 80-90 °C, for example for 8-48 or 12-24 hours:
  • Compounds of formula (XI) can be prepared in a two step procedure as described by Bare et. al. inJ Med. Chem. 1989, 32, 2561-2573. This process involves, first, reaction of a compound of formula (XII) with thionyl chloride (or another agent suitable for forming an acid chloride from a carboxylic acid), either in an organic solvent such as chloroform or THF, or as a neat solution. This reaction may require heating and the thus-formed intermediate may or may not be isolated.
  • Step two involves reaction with an amine of formula WNH 2 , in an organic solvent such as THF or chloroform and may also involve the use of a base such as triethylamine or diisopropylethylamine:
  • Compounds of formula (XII) can be prepared by hydrolysis of an ester of formula (V) according to the method described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027. This procedure preferably involves reaction with a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:
  • a base such as sodium hydroxide or potassium hydroxide
  • a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:
  • the 4-chloro substituent in the compound of formula (IN) can be replaced by another halogen atom, such as a bromine atom.
  • Compounds of formula (IN) can be prepared by reaction of a compound of formula (XIII) with an alkylating agent of formula R ⁇ -X 4 , where X 4 is a leaving group displaceable by the 1 -position pyrazolopyridine nitrogen atom of the compound of formula (XIII):
  • a suitable alkylating agent of fo ⁇ nula R ⁇ -X 4 can be used.
  • X 4 can be a halogen atom such as a chlorine atom or more preferably a bromine or iodine atom, or X 3 can be -O-S(O)2-R 3 ⁇ wherein R 3 ⁇ is Ci.galkyl (e.g. C ⁇ _4alkyl or C _2alkyl such as methyl), Ci. ⁇ fluoroalkyl (e.g.
  • the reaction is preferably carried out in the presence of a base; the base can for example comprise or be potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, or a basic resin or polymer such as polymer-bound 2-tert-butylimino-2-diethylamino-l,3-dimethyl- perhydro-l,3,2-diazaphosphorine.
  • the reaction is preferably carried out in the presence of a solvent, e.g. an organic solvent such as DMF; the solvent is preferably anhydrous.
  • the reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane or acetonitrile.
  • the reaction may require heating e.g. to ca. 60- 100°C, for example ca. 80-90°C:
  • Process D Conversion of one compound of formula (I)-(IV) or salt thereof into another compound of formula (I)-(IV) or salt thereof
  • One compound of formula ( ⁇ )-(IN) or salt thereof can be converted into another compound of formula (I)-(IN) or salt thereof.
  • This conversion preferably comprises or is one or more of the following processes DI to D7: D 1. Conversion of a ketone into the corresponding oxime.
  • the oxidation process can comprise or be oxidation of an alcohol to a ketone (e.g. using Jones reagent) or oxidation of an alcohol or a ketone to a carboxylic acid.
  • a reduction process for example reduction of a ketone or a carboxylic acid to an alcohol.
  • Alkylation for example alkylation of an amine or of a hydroxy group.
  • the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal such as a human.
  • the compound or salt can be for use in the treatment and/or prophylaxis of any of the diseases / conditions described herein (e.g. for use in the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal) and/or for use as a phosphodiesterase inhibitor e.g. for use as a phosphodiesterase 4 (PDE4) inhibitor.
  • "Therapy" may include treatment and/or prophylaxis.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal such as a human, e.g. for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.
  • a method of treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal (e.g. human) in need thereof e.g. a method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal (e.g. human) in need thereof, which method comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt thereof.
  • Phosphodiesterase 4 inhibitors are thought to be useful in the treatment and/or prophylaxis of a variety of diseases / conditions, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: asthma, chronic obstructive pulmonary disease (COPD) (e.g.
  • COPD chronic obstructive pulmonary disease
  • chronic bronchitis and/or emphysema chronic bronchitis and/or emphysema
  • atopic dermatitis urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple sclerosis, cognitive impairment (e.g. in a neurological disorder such as Alzheimer's disease), depression, or pain. Ulcerative colitis and/or Crohn's disease are collectively often referred to as inflammatory bowel disease.
  • the inflammatory and/or allergic disease is preferably chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD or asthma in a mammal (e.g. human).
  • COPD chronic obstructive pulmonary disease
  • asthma rheumatoid arthritis
  • allergic rhinitis in a mammal
  • the treatment and/or prophylaxis is of COPD or asthma in a mammal (e.g. human).
  • PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M.A.Giembycz, Drugs, Feb. 2000, 59(2), 193-212; Z. Huang et al, Current Opinion in Chemical Biology, 2001, 5: 432-438; H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466- 473; and references cited in the aforementioned publications).
  • PDE4 inhibitors are thought to be effective in the treatment of COPD.
  • S.L. Wolda Emerging Drugs, 2000, 5(3), 309-319
  • Z. Huang et al. Current Opinion in Chemical Biology, 2001, 5: 432-438
  • H.J.Dyke et al. Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13
  • C.Burnouf et al. Current Pharmaceutical Design, 2002, 8(14), 1255-1296
  • A.M.Doherty Current Opinion Chem. Biol, 1999, 3(4), 466- 473
  • references cited in the aforementioned publications and G. Krishna et al.,
  • COPD ulcerative colitis
  • PDE4 inhibitors are thought to be effective in the treatment of allergic rhinitis (e.g. see B.M. Schmidt et al., J. Allergy & Clinical Immunology, 108(4), 2001, 530-536).
  • PDE4 inhibitors are thought to be effective in the treatment of rheumatoid arthritis and multiple sclerosis (e.g. see H.J.Dyke et al, Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; and A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466-473; and references cited in these publications). See e.g. A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466-473 and references cited therein for atopic dermatitis use.
  • PDE4 inhibitors have been suggested as having analgesic properties and thus being effective in the treatment of pain (A.Kumar et al., Indian J. Exp. Biol, 2000, 38(1), 26- 30).
  • the treatment and/or prophylaxis can be of cognitive impairment e.g. cognitive impairment in a neurological disorder such as Alzheimer's disease.
  • the treatment and/or prophylaxis can comprise cognitive enhancement e.g. in a neurological disorder. See for example: H.T.Zhang et al. in: Psychopharmacology, June 2000, 150(3), 311-316 and Neuropsychopharmacology, 2000, 23(2), 198-204; and T. Egawa et al., Japanese J. Pharmacol, 1997, 75(3), 275-81.
  • PDE4 inhibitors such as rolipram have been suggested as having antidepressant properties (e.g. J. Zhu et al, CNS Drug Reviews, 2001, 7(4), 387-398; O'Donnell, Expert Opinion on Investigational Drugs, 2000, 9(3), 621-625; and H.T. Zhang et al., Neuropsychopharmacology, October 2002, 27(4), 587-595).
  • the compounds of the present invention are usually administered as a pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein.
  • the invention also provides a method of preparing a phamiaceutical composition comprising a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients, the method comprising mixing the compound or salt with the one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention also provides a pharmaceutical composition prepared by said method.
  • the compounds of formula (I) and/or the pharmaceutical composition may be administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration.
  • the pharmaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration.
  • the pharmaceutical composition is suitable for inhaled or oral administration, e.g. to a mammal such as a human.
  • Inhaled administration involves topical administration to the lung e.g. by aerosol or dry powder composition. Oral administration to a human is most preferred.
  • a pharmaceutical composition suitable for oral administration can be liquid or solid; for example it can be a syrup, suspension or emulsion, a tablet, a capsule or a lozenge.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations.
  • the carrier can for example be or include lactose, cellulose (for example microcrystalline cellulose), or mannitol.
  • the tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example a binding agent such as hydroxypropylmethylcellulose or povidone (polyvinylpyrollidone), a lubricant e.g. an alkaline earth metal stearate such as magnesium stearate, and/or a tablet disintegrant such as sodium starch glycollate, croscarmellose sodium, or crospovidone (cross-linked polyvinylpyrollidone).
  • a binding agent such as hydroxypropylmethylcellulose or povidone (polyvinylpyrollidone)
  • a lubricant e.g. an alkaline earth metal stearate such as magnesium stearate
  • a tablet disintegrant such as sodium starch glycollate, croscarmellose sodium, or crospovidone (cross-linked polyvinylpyr
  • the phannaceutical composition being a tablet can be prepared by a method comprising the steps of: (i) mixing the compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, with the one or more pharmaceutically acceptable carriers and/or excipients, (ii) compressing the resulting mixture (which is usually in powder form) into tablets, and (iii) optionally coating the tablet with a tablet film-coating material.
  • a pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures. For example, pellets or powder containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule.
  • a dispersion or suspension can be prepared using any suitable pharmaceutically acceptable carrier, for example an aqueous gum or an oil and the dispersion or suspension then filled into a soft gelatin capsule.
  • the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human.
  • a parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil.
  • the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.
  • Compositions for nasal or inhaled administration may conveniently be formulated as aerosols, drops, gels or dry powders.
  • Aerosol formulations can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non- aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
  • a metering valve metered dose inhaler
  • the dosage form comprises an aerosol dispenser
  • it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide, or an organic propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC).
  • CFC chlorofluorocarbon
  • HFC hydrofluorocarbon
  • Suitable CFC propellants include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane.
  • Suitable HFC propellants include 1,1,1,2,3,3,3- heptafluoropropane and 1,1,1,2-tetrafluoroethane.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation.
  • Micronisation usually involves subjecting the compound/salt to collisional and/or abrasional forces in a fast-flowing circular or spiral/vortex-shaped airstream often including a cyclone component.
  • the preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns, e.g. about 1 to about 7 microns (e.g. as measured using laser diffraction).
  • the compound or salt of formula (I) it is preferable for the compound or salt of formula (I) to have a particle size defined by: a D10 of about 0.3 to about 3 microns (e.g. about 0.5 to about 2 microns, or about 1 micron), and/or a D50 of about 0.5 to about 10 microns or about 1 to about 7 microns (e.g. about 2 to about 5 microns or about 2 to about 4 microns), and/or a D90 of about 1 to about 30 microns or about 2 to about 20 microns or about 3 to about 15 microns (e.g. about 5 to about 15 microns or about 5 to about 10 microns); for example as measured using laser diffraction.
  • a D10 of about 0.3 to about 3 microns e.g. about 0.5 to about 2 microns, or about 1 micron
  • a D50 of about 0.5 to about 10 microns or about 1 to about 7 microns e.g. about 2 to about
  • D90, D50 and D10 respectively mean that 90%, 50% and 10%) of the material is less than the micron size specified.
  • D50 is the median particle size.
  • DN90, DN50 and DN10 respectively mean that 90%, 50% and 10% by volume of the material is less than the micron size specified.
  • DM90, DM50 and DM10 respectively mean that 90%, 50% and 10% by weight of the material is less than the micron size specified.
  • Laser diffraction measurement of particle size can use a dry method (wherein a suspension of the compound/salt in an airflow crosses the laser beam) or a wet method [wherein a suspension of the compound/salt in a liquid dispersing medium, such as isooctane or (e.g. if compound is soluble in isooctane) 0.1% Tween 80 in water, crosses the laser beam].
  • particle size is preferably calculated using the Fraunhofer calculation; and/or preferably a Malvern Mastersizer or Sympatec apparatus is used for measurement.
  • particle size measurement and/or analysis by laser diffraction can use any or all of (preferably all of) the following: a Malvern Mastersizer longbed version, a dispersing medium of 0.1% Tween 80 in water, a stir rate of ca. 1500 rpm, ca. 3 mins sonification prior to final dispersion and analysis, a 300 RF (Reverse Fourier) lens, and/or the Fraunhofer calculation with Malvern software.
  • a Malvern Mastersizer longbed version a dispersing medium of 0.1% Tween 80 in water
  • a stir rate of ca. 1500 rpm ca. 3 mins sonification prior to final dispersion and analysis
  • a 300 RF (Reverse Fourier) lens a Fraunhofer calculation with Malvern software.
  • the pharmaceutical composition is a dry powder inhalable composition.
  • a dry powder inhalable composition can comprise a powder base such as lactose or starch, the compound of formula (I) or salt thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine, mannitol, trehalose and/or magnesium stearate.
  • the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof.
  • the lactose is preferably lactose hydrate e.g.
  • the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g. 10-300 microns e.g.
  • the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50%) or more of the lactose particles being less than 40-70 microns in diameter. Most importantly, it is preferable that about 3 to about 30% (e.g. about 10%) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter.
  • a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).
  • the compound of formula (I) or salt thereof is present in about 0.1% to about 70% (e.g. about 1% to about 50%, e.g. about 5% to about 40%, e.g. about 20 to about 30%) by weight of the composition.
  • An illustrative non-limiting example of a dry powder inhalable composition follows:
  • Dry Powder Formulation Example - Dry powder Lactose Blend Preparation Using a size-reduced e.g. micronised form of the compound of formula (I) or salt thereof, the dry powder blend is prepared by mixing the required amount of the compound/salt (e.g. 10 mg, 1% w/w) with inhalation-grade lactose containing 10% fines (e.g. 990 mg, 99% w/w) in a TeflonTM (polytetrafluoroethene) pot in a Mikro-dismembrator ball-mill (but without a ball bearing) at % speed (ca. 2000-2500 rpm) for about 4 hours at each blend concentration.
  • the Mikro-dismembrator available from B.
  • a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel-openable on demand and the dose, e.g. of the dry powder composition, can be administered by inhalation via a device such as the DISKUS TM device, marketed by GlaxoSmithKline.
  • the DISKUS TM inhalation device is usually substantially as described in GB 2,242,134 A.
  • At least one container for the pharmaceutical composition in powder form (the at least one container preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: means defining an opening station for the said at least one container; means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the phamiaceutical composition in powder form from the opened container.
  • the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human.
  • a or each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • a or each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • a pha ⁇ naceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g.
  • a pharmaceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g. human) in a daily nasal or inhaled dose of: 0.0001 to 5 mg/kg/day or 0.0001 to 1 mg/kg/day, e.g.
  • the pharmaceutically acceptable compounds or salts of the invention is preferably administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day e.g.
  • the compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a ⁇ 2 adrenoreceptor agonist, an anti-histamine, an anti-allergic or an anti-inflammatory agent.
  • a ⁇ 2 adrenoreceptor agonist for example, an anti-histamine, an anti-allergic or an anti-inflammatory agent.
  • the invention thus provides, in a further aspect, a combination comprising a compound of fonnula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent, for example, a ⁇ 2 -adrenoreceptor agonist, an anti-histamine, an anti-allergic, an anti-inflammatory agent or an antiinfective agent.
  • another therapeutically active agent for example, a ⁇ 2 -adrenoreceptor agonist, an anti-histamine, an anti-allergic, an anti-inflammatory agent or an antiinfective agent.
  • the ⁇ 2 -adrenoreceptor agonist is salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline, or a salt thereof (e.g. pharmaceutically acceptable salt thereof), for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • Long-acting ⁇ 2 -adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 12-24 hour period such as salmeterol or formoterol.
  • the ⁇ 2 -adrenoreceptor agonist is for inhaled administration, e.g. once per day and/or for simultaneous inhaled administration; and more preferably the ⁇ 2 -adrenoreceptor agonist is in particle-size-reduced form e.g. as defined herein.
  • the ⁇ 2 -adrenoreceptor agonist combination is for treatment and/or prophylaxis of COPD or asthma.
  • Salmeterol or a pharmaceutically acceptable salt thereof, e.g. salmeterol xinofoate is preferably administered to humans at an inhaled dose of 25 to 50 micrograms twice per day (measured as the free base).
  • the combination with a ⁇ 2 -adrenoreceptor agonist can be as described in WO 00/12078.
  • Preferred long acting ⁇ 2 -adrenoreceptor agonists include those described in WO 02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933.
  • Especially preferred long-acting ⁇ 2 -adrenoreceptor agonists include compounds of formula(XX) (described in WO 02/066422):
  • R 11X is -XSO 2 NR 16x R 17X wherein X is -(CH 2 ) p ⁇ - or C -6 alkenylene;
  • R 16x and R 17X are independently selected from hydrogen, C ⁇ -6 alkyl, C 3 - 7 cycloalkyl,
  • R 16x and R 17X are each optionally substituted by one or two groups selected from halo, C ⁇ - 6 alkyl, C ⁇ - 6 haloalkyl, C ⁇ - alkoxy, hydroxy- substituted C ⁇ - 6 alkoxy, -CO 2 R 18x , -SO NR 18X R 19X , -CONR 18X R 19X , -NR 18 C(O)R 19X , or a 5-, 6- or 7-membered heterocylic ring; R 18X and R 19X are independently selected from hydrogen, C ⁇ - 6 alkyl,
  • R 12X and R 13X are independently selected from hydrogen, C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy, halo, phenyl, and C ⁇ - 6 haloalkyl; and R 14X and R 15X are independently selected from hydrogen and C ⁇ - 4 alkyl with the proviso that the total number of carbon atoms in R 14X and R 15X is not more than 4.
  • Preferred ⁇ 2 -adrenoreceptor agonists disclosed in WO 02/066422 include:
  • a preferred ⁇ 2 -adrenoreceptor agonist disclosed in WO 03/024439 is: 4- ⁇ (lR)-2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-l-hydroxyethyl ⁇ -2- (hydroxymethyl)phenol.
  • a combination of a compound of formula (I) or salt together with an anti-histamine is preferably for oral administration (e.g. as a combined composition such as a combined tablet), and can be for treatment and/or prophylaxis of allergic rhinitis.
  • anti- histamines include methapyrilene, or HI antagonists such as cetirizine, loratadine (e.g. Clarityn TM ⁇ desloratadine (e.g. Clarinex TM) or fexofenadine (e.g. Allegra M)
  • the invention also provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic compound, e.g. a muscarinic (M) receptor antagonist in particular an M , M2, M1/M2, or
  • an anticholinergic compound e.g. a muscarinic (M) receptor antagonist in particular an M , M2, M1/M2, or
  • M3 receptor antagonist more preferably a M3 receptor antagonist, still more preferably a M3 receptor antagonist which selectively antagonises (e.g. antagonises 10 times or more strongly) the M3 receptor over the M and/or M2 receptor.
  • anticholinergic compounds / muscarinic (M) receptor antagonist with PDE4 inhibitors see for example WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 Al and US 2002/052312 Al, and some or all of these publications give examples of anticholinergic compounds / muscarinic (M) receptor antagonists which may be used with the compounds of formula (I) or salts, and/or suitable pharmaceutical compositions.
  • the muscarinic receptor antagonist can comprise or be an ipratropium salt (e.g. ipratropium bromide), an oxitropium salt (e.g. oxitropium bromide), or more preferably a tiotropium salt (e.g. tiotropium bromide); see e.g. EP 418 716 Al for tiotropium.
  • an ipratropium salt e.g. ipratropium bromide
  • an oxitropium salt e.g. oxitropium bromide
  • tiotropium salt e.g. tiotropium bromide
  • the anticholinergic compound or muscarinic (M) receptor antagonist e.g. M3 receptor antagonist
  • M3 receptor antagonist is preferably for inhaled administration, more preferably in particle-size- reduced form e.g. as defined herein. More preferably, both the muscarinic (M) receptor antagonist and the compound of formula (I) or the phannaceutically acceptable salt thereof are for inhaled administration.
  • the anticholinergic compound or muscarinic receptor antagonist and the compound of formula (I) or salt are for simultaneous administration.
  • the muscarinic receptor antagonist combination is preferably for treatment and/or prophylaxis of COPD.
  • Suitable combinations include, for example, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another anti- inflammatory agent such as an anti-inflammatory corticosteroid; or a non-steroidal anti- inflammatory drag (NSAID) such as a leukotriene antagonist (e.g. montelukast), an iNOS inhibitor, a tryptase inhibitor, a elastase inhibitor, a beta-2 integrin antagonist, a adenosine 2a agonist, a CCR3 antagonist, or a 5-lipoxogenase inhibitor; or an antiinfective agent (e.g. an antibiotic or an antiviral).
  • An iNOS inhibitor is preferably for oral administration.
  • Suitable iNOS inhibitors include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875.
  • Suitable CCR3 inliibitors include those disclosed in WO 02/26722.
  • the anti-inflammatory corticosteroid is fluticasone, fluticasone propionate (e.g.
  • the anti-inflammatory corticosteroid is a compound as described in WO 02/12266 Al, then preferably it is Example 1 therein ⁇ wMch is 6 ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-ll ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester ⁇ or Example 41 therein ⁇ which is 6 ⁇ ,9 ⁇ -difluoro- 11 ⁇ -hydroxy- 16 ⁇ -methyl- 17 ⁇ -[(4-methyl- 1 ,3 -thiazole-5- carbonyl)oxy]-3-oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester ⁇ , or a pharmaceutically acceptable salt thereof.
  • the anti-inflammatory corticosteroid is preferably for intranasal or inhaled administration.
  • Fluticasone propionate is preferred and is preferably for inhaled administration to a human either (a) at a dose of 250 micrograms once per day or (b) at a dose of 50 to 250 micrograms twice per day.
  • a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with ⁇ 2 -adrenoreceptor agonist and an anti-inflammatory corticosteroid, for example as described in WO 03/030939 Al.
  • this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis.
  • the ⁇ 2 -adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 Al.
  • the ⁇ 2 -adrenoreceptor agonist is salmeterol or a pharmaceutically acceptable salt thereof (e.g. salmeterol xinafoate) and the anti- inflammatory corticosteroid is fluticasone propionate.
  • compositions comprising a combination as defined above together with one or more pharmaceutically acceptable carriers and/or excipients represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical composition.
  • the combination as defined herein can be for simultaneous inhaled administration and is disposed in a combination inhalation device.
  • a combination inhalation device is another aspect of the invention.
  • Such a combination inhalation device can comprise a combined pharmaceutical composition for simultaneous inhaled administration (e.g. dry powder composition), the composition comprising all the individual compounds of the combination, and the composition being incorporated into a plurality of sealed dose containers mounted longitudinally in a strip or ribbon inside the inhalation device, the containers being rupturable or peel-openable on demand; for example such inhalation device can be substantially as described in GB 2,242,134 A (DISKUS TM) and/or as described above.
  • DISKUS TM substantially as described in GB 2,242,134 A
  • the combination inhalation device can be such that the individual compounds of the combination are administrable simultaneously but are stored separately (or wholly or partly stored separately for triple combinations), e.g. in separate pharmaceutical compositions, for example as described in PCT/EP03/00598 filed on 22 January 2003, published as WO 03/061743 (e.g. as described in the claims thereof e.g. claim 1).
  • the invention also provides a method of preparing a combination as defined herein, the method comprising either (a) preparing a separate pharmaceutical composition for administration of the individual compounds of the combination either sequentially or simultaneously, or (b) preparing a combined pharmaceutical composition for administration of the individual compounds of the combination simultaneously, wherein the pharmaceutical composition comprises the combination together with one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention also provides a combination as defined herein, prepared by a method as defined herein.
  • Preferred compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D, preferably PDE4B) more strongly than they inhibit PDE3 and/or more strongly than they inhibit PDE5 and/or more strongly than they inhibit PDE6.
  • PDE4 e.g. PDE4B and/or PDE4D, preferably PDE4B
  • Human recombinant PDE4B in particular the 2B splice variant thereof (HSPDE4B2B), is disclosed in WO 94/20079 and also M.M. McLaughlin et al, "A low Km, rolipram- sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterisation of recombinant protein, and tissue distribution of mRNA", J. Biol. Chem., 1993, 268, 6470-6476.
  • human recombinant PDE4B is described as being expressed in the PDE- deficient yeast Saccharomyces cerevisiae strain GL62, e.g. after induction by addition of 150 uM CUSO4, and 100,000 x g supernatant fractions of yeast cell lysates are described for use in the harvesting of PDE4B enzyme.
  • HSPDE4D3A Human recombinant PDE4D (HSPDE4D3A) is disclosed in P. A. Baecker et al, "Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phoshodiesterase (PDE IN D )", Gene, 1994, 138, 253-256.
  • Human recombinant PDE5 is disclosed in K. Loughney et al., "Isolation and characterisation of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase", Gene, 1998, 216, 139-147.
  • PDE3 can be purified from bovine aorta, e.g. as described by H. Coste and P. Grondin, "Characterisation of a novel potent and specific inhibitor of type V phosphodiesterase", Biochem. Pharmacol, 1995, 50, 1577-1585.
  • PDE6 can be purified from bovine retina, e.g. as described by: P. Catty and P. Deterre, "Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis", Eur. J. Biochem., 1991, 199, 263-269; A. Tar et al. "Purification of bovine retinal cGMP phosphodiesterase", Methods in Enzymology, 1994, 238, 3-12; and/or D. Srivastava et al. "Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cyclic GMP phosphodiesterase", Biochem. J, 1995, 308, 653-658. Inhibition of PDE 3, PDE 4B, PDE 4D, PDE 5 or PDE 6 activity: radioactive Scintillation Proximity Assay (SPA)
  • SPA radioactive Scintillation Proximity Assay
  • test compounds (as a solution in DMSO, preferably about 2 microlitre (ul) volume of DMSO solution) are preincubated at ambient temperature (room temperature, e.g.
  • Plates containing assay mixture are mixed on an orbital shaker for 5 minutes and incubated at ambient temperature for 1 hour.
  • Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ 0150) are added ( ⁇ lmg per well) to terminate the assay. Plates are sealed and shaken and allowed to stand at ambient temperature for 35 minutes to lhour (preferably 35 minutes) to allow the beads to settle.
  • Bound radioactive product is measured using a WALLAC TRILUX 1450 Microbeta scintillation counter. For inhibition curves, 10 concentrations (1.5nM - 30uM) of each compound are assayed. Curves are analysed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom) Results are expressed as pIC 5 o values.
  • PDE4B or PDE4D inhibition can be measured in the following Fluorescence Polarisation (FP) assay:
  • FP Fluorescence Polarisation
  • EVIAP Fluorescence Polarisation (FP) assay IMAP Explorer kit, available from Molecular Devices Corporation, Sunnydale, CA, USA; Molecular Devices code: R8062
  • the IMAP FP assay is able to measure PDE activity in an homogenous, non-radioactive assay format.
  • the FP assay uses the ability of immobilised trivalent metal cations, coated onto nanoparticles (tiny beads), to bind the phosphate group of Fl-AMP that is produced on the hydrolysis of fluorescein-labelled (FI) cyclic adenosine mono-phosphate (Fl-cAMP) to the non-cyclic Fl-AMP form. Fl-cAMP does not bind. Binding of Fl-AMP product to the beads (coated with the immobilised trivalent cations) slows the rotation of the bound Fl-AMP and leads to an increase in the fluorescence polarisation ratio of parallel to perpendicular light. Inhibition of the PDE reduces/inhibits this signal increase. Test compounds (small volume, e.g. ca.
  • 0.5 to 1 ul, preferably ca. 0.5 ul, of solution in DMSO are preincubated at ambient temperature (room temperature, e.g. 19- 23 °C) in black 384-well microtitre plates (supplier: NUNC, code 262260) with PDE enzyme in lOmM Tris-HCl buffer pH 7.2, lOmM MgCl 2 , 0.1% (w/v) bovine serum albumin, and 0.05% NaN 3 for 10-30 minutes.
  • the enzyme level is set by experimentation so that reaction is linear throughout the incubation.
  • Fluorescein adenosine 3 ',5 '-cyclic phosphate (from Molecular Devices Corporation, Molecular Devices code: R7091) is added to give about 40nM final concentration (final assay volume usually ca. 20-40 ul, preferably ca. 20 ul). Plates are mixed on an orbital shaker for 10 seconds and incubated at ambient temperature for 40 minutes. IMAP binding reagent (as described above, from Molecular Devices Corporation, Molecular Devices code: R7207) is added (60ul of a 1 in 400 dilution in binding buffer of the kit stock solution) to terminate the assay. Plates are allowed to stand at ambient temperature for 1 hour.
  • the Fluorescence Polarisation (FP) ratio of parallel to perpendicular light is measured using an AnalysfT pj a te reader (from Molecular Devices Corporation). For inhibition curves, 10 concentrations (1.5nM - 30uM) of each compound are assayed. Curves are analysed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom). Results are expressed as pIC 50 values. In the FP assay, all reagents are dispensed using MultidropTM (available from Thermo Labsystems Oy, Ratastie 2, PO Box 100, Vantaa 01620, Finland).
  • the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly.
  • the PIC50 inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units, for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R.Mobbs et al., "Comparison of the EVIAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity", poster presented at 2003 Molecular Devices UK & Europe User Meeting, 2nd October 2003, Down Hall, Harlow, Essex, United Kingdom).
  • Biological Data obtained for some of the Examples are as follows, based on current measurements only. In each of the SPA and FP assays, absolute accuracy of measurement is not possible, and the readings given are accurate only up to about ⁇ 0.5 of a log unit, depending on the number of readings made and averaged:
  • Room temperature this is usually in the range of about 20 to about 25 °C.
  • Solvent B 0.1% formic acid + lOmMolar ammonium acetate
  • Injection Volume 1ml; or more preferably 0.5 ml Solvent A : 0.1% formic acid
  • Solvent B 95% acetonitrile + 5% formic acid; or more usually 99.95% acetonitrile +
  • Example 2-6 were prepared from Intermediate 20 and the appropriate amine WNH 2 using a similar procedure to that used for the preparation of Example 1 :
  • Example 12-16 were prepared from Intermediate 22 and the appropriate amine WNH 2 using a similar procedure to that used for the preparation of Example 1:

Abstract

The invention provides a compound of formula (I) or a salt thereof: formula (I) wherein W is Ar, -CR4R5Ar or a group (y) or (y1), wherein Ar is (x) or (z): formulae (x), (z), (y), (y1) R1 is C1-4alkyl, C1-3fluoroalkyl or CH2CH2OH. R2 is C2-6alkyl, C3-6cycloalkyl or -(CH2)n4-C3-6cycloalkyl; and R3 is optionally substituted C3-8cycloalkyl, optionally substituted mono unsaturated C5-7cycloalkenyl, an optionally substituted heterocyclic group (aa), (bb) or (cc) (in which Y is O, S, SO2, or NR10), or a bicyclic group (ee): formulae (aa), (bb), (cc), (ee). The invention also relates to the use of the compounds in therapy as inhibitors of phosphodiesterase type IV (PDE4), and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.

Description

PYRAZOLO ' 3 , 4-B ! PYRIDINE COMPOUNDS , AND THEIR USE AS PHOSPHODIESTERASE TYPE 4 ( PDE4 ) INHIBITORS
The present invention relates to pyrazolo[3,4-b]pyridine compounds, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds. The invention also relates to the use of the pyrazolo[3,4-b]pyridine compounds in therapy, for example as inhibitors of phosphodiesterase type IN (PDE4) and/or for the treatment and/or prophylaxis of inflammatory and or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.
10 Background to the Invention
US 3,979,399, US 3,840,546, and US 3,966,746 (E.R.Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxamides wherein the 4-amino group 15 ΝR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR3R4 can alternatively be a 3-6-membered heterocyciic group such as pyrrolidino, piperidino and piperazino. The compounds are disclosed as central nervous system depressants useful as ataractic, analgesic and hypotensive agents.
20 US 3,925,388, US 3,856,799, US 3,833,594 and US 3,755,340 (E.R.Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxylic acids and esters. The 4-amino group NR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR3R4 can alternatively be a 5-6- membered heterocyciic group in which an additional nitrogen is present such as 25 pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl. The compounds are mentioned as being central nervous system depressants useful as ataractic agents or tranquilisers, as having antiinflammatory and analgesic properties. The compounds are mentioned as increasing the intracellular concentration of adenosine-3',5'- cyclic monophosphate and for alleviating the symptoms of asthma. 30 H. Hoehn et al., J. Heterocycl. Chem., 1972, 9(2), 235-253 discloses a series of 1H- pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives with 4-hydroxy, 4-chloro, 4-alkoxy, 4-hydrazino, and 4-amino substituents.
35 CA 1003419, CΗ 553 799 and T.Denzel, Archiv der Pharmazie, 1974, 307(3), 177-186 disclose 4,5-disubstituted lH-pyrazolo[3,4-b]pyridines unsubstituted at the 1-position.
Japanese laid-open patent application JP-2002-20386-A (Ono Yakuhin Kogyo KK) published on 23 January 2002 discloses pyrazolopyridine compounds of the following 40 formula:
Figure imgf000004_0001
wherein R1 denotes 1) a group -OR6, 2) a group -SR7, 3) a C2-8 alkynyl group, 4) a nitro group, 5) a cyano group, 6) a Cl-8 alkyl group substituted by a hydroxy group or a Cl-8 alkoxy group, 7) a phenyl group, 8) a group -C(O)R8, 9) a group -SO2NR9R10, 10) a group -NR1 ^R12, 11) a group -NR13C(O)R14 or 12) a group -CE NR15. R6 and R7 denote i) a hydrogen atom, ii) a Cl-8 alkyl group, iii) a Cl-8 alkyl group substituted by a Cl-8 alkoxy group, iv) a trihalomethyl group, v) a C3-7 cycloalkyl group, vi) a Cl-8 alkyl group substituted by a phenyl group or vii) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R2 denotes 1) a hydrogen atom or 2) a Cl-8 alkoxy group. R3 denotes 1) a hydrogen atom or 2) a Cl-8 alkyl group. R4 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group, 5) a phenyl group which may be substituted by 1-3 halogen atoms or 6) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R5 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3- 7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group or 5) a phenyl group which may be substituted by 1-3 substituents. In group R3, a hydrogen atom is preferred. In group R^ , methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are preferred. The compounds of JP-2002-20386-A are stated as having PDE4 inhibitory activity and as being useful in the prevention and/or treatment of inflammatory diseases and many other diseases,
l,3-Dimethyl-4-(arylamino)-pyrazolo[3,4-b]pyridines with a 5-C(O)NJΪ2 substituent similar or identical to those in JP-2002-20386-A were disclosed as orally active PDE4 inhibitors by authors from Ono Pharmaceutical Co. in: H. Ochiai et al., Bioorg. Med. Chem. Lett, 5th January 2004 issue, vol. 14(1), pp. 29-32 (available on or before 4th December 2003 from the Web version of the journal: "articles in press").
EP 0 076 035 Al (ICI Americas) discloses pyrazolo[3,4-b]pyridine derivatives as central nervous system depressants useful as tranquilisers or ataractic agents for the relief of anxiety and tension states.
The compound cartazolate, ethyl 4-(n-butylamino)-l-ethyl-lH-pyrazolo[3,4-b]-pyridine- 5-carboxylate, is known. J.W. Daly et al., Med. Chem. Res., 1994, 4, 293-306 and D. Shi et al., Drug Development Research, 1997, 42, 41-56 disclose a series of 4- (amino)substituted lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives, including ethyl 4-cyclopentylamino-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate, and their affinities and antagonist activities at A - and A2A-adenosine receptors, and the latter paper discloses their affinities at various binding sites of the GABA^-receptor channel. S. Schenone et al., Bioorg. Med. Chem. Lett., 2001, 11, 2529-2531, and F. Bondavalli et al, J. Med. Chem., 2002, vol. 45 (Issue 22, 24 October 2002, allegedly published on Web
09/24/2002), pp. 4875-4887 disclose a series of 4-amino- l-(2-chloro-2-phenylethyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters as Aj-adenosine receptor ligands.
WO 02/060900 A2 appears to disclose, as MCP-1 antagonists for treatment of allergic, inflammatory or autoimmune disorders or diseases, a series of bicyclic heterocyciic compounds with a -C(O)-NR4-C(O)-NR5R6 substituent, including isoxazolo[5,4- bjpyridines and lH-pyrazolo[3,4-b]pyridines (named as pyrazolo[5,4-b]pyridines) with the -C(O)-NR4-C(O)-NR5R6 group as the 5-substituent and optionally substituted at the 1-, 3-, 4-, and/or 6-positions. Bicyclic heterocyciic compounds with a -C(O)NΗ-2 substituent instead of the -C(O)-NR4-C(O)-NR5R6 substituent are alleged to be disclosed in WO 02/060900 as intermediates in the synthesis of the -C(O)- R4-C(O)-NR5R6 substituted compounds.
WO 00/15222 (Bristol-Myers Squibb) discloses inter alia pyrazolo[3,4-b]pyridines having inter alia a C(O)-Xι group at the 5-position and a group Ε at the 4-position of the ring system. Amongst other things, X can for example be -OR9, -N(R9)(RIQ) or
-N(R5)(-A2-R2), and E^ can for example be -NΗ-Aj -cycloalkyl, -NΗ-Ai -substituted cycloalkyl, or -NΗ-Ai-heterocyclo; wherein Aj is an alkylene or substituted alkylene bridge of 1 to 10 carbons and A2 can for example be a direct bond or an alkylene or substituted alkylene bridge of 1 to 10 carbons. The compounds are disclosed as being useful as inhibitors of cGMP phosphodiesterase, especially PDE type V, and in the treatment of various cGMP-associated conditions such as erectile dysfunction. Compounds with a cycloalkyl or heterocyclo group directly attached to -NΗ- at the 4-position of the pyrazolo[3,4-b]pyridine ring system and/or having PDE4 inhibitory- activity do not appear to be disclosed in WO 00/15222.
Copending patent application PCT/EP03/11814, filed on 12 September 2003 in the name of Glaxo Group Limited, and incorporated herein by reference, discloses pyrazolo[3,4- bjpyridine compounds or salts thereof with a 4-NΗR^ group and a 5-C(O)-X group, according to this formula (I):
Figure imgf000006_0001
wherein:
Rl is C1_4alkyl, C^ fluoroalkyl, -CH2CH2OH or -CH2CH2CO2C1.2alkyl;
R2 is a hydrogen atom (H), methyl or C\ fluoroalkyl;
R3 is optionally substituted C3.8cycloa.kyl or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc);
Figure imgf000006_0002
(aa) (bb) (cc) in which n and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NRIO;
or R3 is a bicyclic group (dd) or (ee):
Figure imgf000006_0003
and wherein X is NR4R5 or OR5a.
In PCT/EP03/11814, R4 is a hydrogen atom (H); C^gal yl; Cι_3fluoroalkyl; or C2_6alkyl substituted by one substituent Rl 1.
In PCT/EP03/11814, R5 can be: a hydrogen atom (H); Ci .galkyl; Cι_8 fluoroalkyl; C3. gcycloalkyl optionally substituted by a C^alkyl group; -(CH2)n 4-C3_gcycloalkyl optionally substituted, in the -(CH-2)n 4- moiety or in the C3_gcycloalkyl moiety, by a Cj_2 alkyl group, wherein n4 is 1, 2 or 3; C2_6alkyl substituted by one or two independent substituents R1 1; -(CH2)n U-C(O)R16; -(CH2)n 12-C(O)NR12R13; -CHR19-C(O)NR12Rl3; -(CH2)n 12-C(O)OR16; -(CH2)n 12-C(O)OH; -CHR19-C(O)OR16; -CHRl9_C(O)OH; -(CH2)n 12-SO2-NR1 Rl3; -(CH2)n12-SO2R16; or -(CH2)n 12-CN; -(CH2)n 13-Het; or optionally substituted phenyl. Alternatively, in PCT/EP03/11814, R5 can have the sub-formula (x), (y), (yl) or (z):
Figure imgf000007_0001
(x) (y) (yl) (z)
wherein in sub-formula (x), n = 0, 1 or 2; in sub-formula (y) and (yl), m = 1 or 2; and in sub-formula (z), r = 0, 1 or 2; and wherein in sub-formula (x) and (y) and (yl), none, one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+-O~) provided that no more than one of A, B, D, E and F is nitrogen-oxide, and the remaining of A, B, D, E and F are independently CH or CR^; and provided that when n is 0 in sub- formula (x) then one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N^-O-) and no more than one of A, B, D, E and F is nitrogen-oxide;
In PCT/EP03/11814, each R^, independently of any other R6 present, is: a halogen atom; C^alkyl; C^fluoroalkyl; C^alkoxy; Cι_2iTuoroalkoxy; C3_6cycloalkyloxy;
-C(O)R16a; -C(O)OR30; -S(O)2-R16a; R16a-S(O)2-NR15a-; R7R8N-S(O)2-;
Cι _2alkyl-C(O)-R15aN-S(O)2-; Cι _4alkyl-S(O)-; Ph-S(O)-; R7R8N-CO-;
-NR15-C(O)R16; R7R8N; OH; C^alkoxymethyl; Cι _4alkoxyethyl;
C1_2alkyl-S(O)2-CH2-; R7R8N-S(O)2-CH2-; C1.2alkyl-S(O)2-NR15a-CH2-; -CH2-OH; -CH2CH2-OH; -CH2-NR7R8; -CH2-CH2-NR7R8; -CH2-C(O)OR30;
-CH2-C(O)- R7R8; -CH2- R15a-C(O)-Cι_3alkyl; -(CH2)n 14-Het1 where n*4 is 0 or 1; cyano (CN); Ar^b- or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, Cι_2alkyl, C\ fluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy; or two adjacent R^ taken together can be -O-(CMβ2)-O- or
-O-(CH2)n 14-0- where n14 is 1 or 2.
hi PCT/EP03/11814, in sub-formula (z), G is O or S or NR9 wherein R9 is a hydrogen atom (H), Cι_4alkyl or Cι_4fluoroalkyl; none, one, two or three of J, L, M and Q are nitrogen; and the remaining of J, L, M and Q are independently CH or CR^ where R^, independently of any other R" present, is as defined therein.
The pyrazolo[3,4-b]pyridine compounds of formula (I) and salts thereof disclosed in PCT/EP03/11814 are disclosed as being inhibitors of phosphodiesterase type IN (PDE4), and as being useful for the treatment and/or prophylaxis of an inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, or allergic rhinitis.
The Invention
We have now found new pyrazolo[3,4-b]pyridine compounds, having a -C(O)-NH-W substituent at the 5-position of the pyrazolo[3,4-b]pyridine ring system, which compounds inhibit phosphodiesterase type IN (PDE4).
The present invention therefore provides a compound of formula (I) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
Figure imgf000009_0001
wherein:
W is Ar, -CR >4 RTΪ 5 Ar or a group (y) or (yl) wherein:
Figure imgf000009_0002
(X) (z)
Figure imgf000009_0003
wherein m = 1 or 2
R1 is Ci _4alkyl, Cι_ fluoroalkyl, or -CH2CH2OH;
R2 is C2-6alkyl, C3-6cyclo alkyl or -(CH2)n4C3-6cycloalkyl, wherein n4 is 1 or 2;
R3 is optionally substituted C3_8cycloalkyl or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc);
Figure imgf000010_0001
(aa) (bb) (cc) in which n* and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NRlO; where R10 is a hydrogen atom (H), Chalky], C^fluoroalkyl, CH2C(O)NH2, C(O)NH2, C(O)NHMe, C(O)-Cι_2alkyl, C(O)-Cι fluoroalkyl or -C(O)-CH2O-Cι_2alkyl;
and wherein in R3 the C3_gcycloalkyl or the heterocyciic group of sub-formula (aa), (bb) or (cc) is optionally substituted on a ring carbon with one or two substituents independently being oxo (=O); OH; Cι_2alkoxy; Cι_2fluoroalkoxy; NHR21 wherein R2 is a hydrogen atom (H) or C 1^.4 straight-chain alkyl; C^ lkyl; Cι_2fluoroalkyl; -CH2OH; -CH2CH2OH; -CH2NHR22 wherein R22 is H or C 1 _2alkyl; -C(O)OR23 wherein R23 is H or Cι_2alkyl; -C(O)NHR24 wherein R24 is H or C^alkyl; -C(O)R25 wherein R2^ is Cj_ 2 alkyl; fluoro; hydroxyimino (=N-OH); or (Cι_4alkoxy)imino
(=N-OR2^ where R ^ is Ci^alkyl); and wherein any OH, alkoxy, fluoroalkoxy or
NHR21 substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyciic group (aa), (bb) or (cc);
and wherein, when R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, then the cycloalkenyl is optionally substituted with one substituent being fluoro or Cj^alkyl or two substituents independently being fluoro or methyl , and the R3 ring carbon bonded to the -NH- group of formula (I) does not partake in the cycloalkenyl double bond;
Figure imgf000010_0002
or R3 is a bicyclic group of sub-formula (ee): (ee' wherein NI, Y2 and Y3 independently are CH2 or oxygen (O) provided that no more than one of Y , Y2 and Y3 is oxygen (O);
and wherein: R4 and R5 are independently a hydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, Cι.2fl oroalkyl, cyclopropyl, -CH OR4a -CH(Me)OR4a, or -CH2CH2OR4a, wherein R4a is a hydrogen atom (H), methyl (Me), or Ci fluoroalkyl such as CF3 or CHF2.
and wherein, in sub-formula (x) (y) and (yl):
A is C-R6A nitrogen (N) or nitrogen-oxide (N+-O"), B is C-R6B, nitrogen (N) or nitrogen-oxide (N+-O~), D is C-R6D5 nitrogen (N) or nitrogen-oxide (N+-O~), E is C-R6E5 nitrogen (N) or nitrogen-oxide (N+-O~), F is C-R6F, nitrogen (N) or nitrogen-oxide (N+-O-),
wherein, R6B? R6D} R6E gjyj R6F independently are: a hydrogen atom (H), a halogen atom; Cι _6alkyl (e.g. C^alkyl or C\-2 alkyl); Cι _4fluoroalkyl (e.g. Cι_2fluoroalkyl); C3_6cycloalkyl; C^alkoxy (e.g. C^alkoxy); Cι_2fluoroalkoxy;
C3.6cycloalkyloxy; -C(O)R16a; -C(O)OR30; -SfO^-R16a (e.g. Cι_2alkyl-S(O)2-);
R16a-S(O)2-NR15a- (e.g. C1.2alkyl-S(O)2-NH-); R7R8N-S(O)2-;
C1.2alkyl-C(O)-R15aN-S(O)2-; Cι_4alkyl-S(O)-, Ph-S(O)-, R7R8N-CO-;
-NR15-C(O)R16a; R7R8N; nitro (-NO2); OH (including any tautomer thereof); Cι_4alkoxymethyl; Cι_4alkoxyethyl; Cι_2alkyl-S(O)2-CH2-; R7R8N-S(O) -CH2-;
C1.2alkyl-S(O)2-NR15a-CH2-; -CH2-OH; -CH2CH2-OH; -CH2-NR7R8;
-CH2-CH2-NR7R8; -CH2-C(O)OR30; -CH2-C(O)-NR7R8;
-CH2-NR15a-C(O)-Cι_3alkyl; -(CH2)n 14-Hetl where n*4 is 0 or 1; cyano (-CN); Ar5b; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, Cj_2 alkyl, C\ fluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy;
and/or two adjacent groups selected from R^A R6B5 R6D? R6E ^d R6F are taken together and are: -CH=CH-CH=CH2- -(CH2)n 14a- where n*4a is 3, 4 or 5 (e.g. 3 or 4), -O-(CMe2)-O- -O-(CH2)n 14b-O- where n*4b is 1 or 2; -CH=CH-NR15b-;
-N=CH-NR15 -; -CH=N-NR15 -; -N=N-NR15b-; -CH=CH-O-; -N=CH-O-; -CH=CH-S-; or -N-CH-S-; wherein R*5b 1S H or C^alkyl;
provided that: two or more of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F
(carbon-fluorine), nitrogen (N), or nitrogen-oxide (N+-O-); and no more than two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+-O~), and no more than one of A, B, D, E and F is nitrogen-oxide (N+-O~); and wherein, in sub-formula (z):
G is O or S or NR9 wherein R9 is a hydrogen atom (H), Cι_4alkyl, or Cι_2fluoroalkyl; J is C-R6J, C-[connection point to formula (I)], or nitrogen (N), L is C-R L5 C-[connection point to formula (I)], or nitrogen (N), M is C-R6 , C-[connection point to formula (I)], or nitrogen (N), Q is C-R Q, C-[connection point to formula (I)], or nitrogen (N),
wherein, R^J, R6L R6M anς\ R6Q independently are: a hydrogen atom (H), a halogen atom; Ci^alkyl (e.g. Chalky.); C 1.3 fluoroalkyl (e.g. C^fluoroalkyl); C3_6cycloalkyl; C^^alkoxy (e.g. Cι_2alkoxy); C^fluoroalkoxy; C3_6cycloalkyloxy;
OH (including any tautomer thereof); or phenyl optionally substituted by one or two substituents independently being fluoro, chloro, C^alkyl, C\ fluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy;
provided that: two or more of J, L, M and Q are independently C-H, C-F, C-Cι_2aιkyl (e.g.
C-Me), C- [connection point to formula (I)], or nitrogen (N); and no more than three of J, L, M and Q are nitrogen (N);
and wherein:
R7 and R8 are independently a hydrogen atom (H); C^alkyl (e.g. Cχ_2 alkyl such as methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two substituents independently being: fluoro, chloro, Cι_2alkyl, C\ fluoroalkyl, Cι_2 alkoxy or Ci fluoroalkoxy;
or R7 and R8 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 10-C(O)- or -(CH2)n8-X7-(CH2)n9- or -C(O)-X7-(CH2)n 10- in which: n6 is 3, 4, 5 or 6 (suitably n6 is 4 or 5), n7 is 2, 3, 4, or 5 (suitably n7 is 3 or 4), n8 and n9 and n^ independently are 2 or 3 (suitably independently 2), and X7 is O or NRI4;
R7a is a hydrogen atom (H) or Cι_4alkyl (suitably H or Cι_2 alkyl, more suitably H or methyl);
R8a is a hydrogen atom (H) or methyl (suitably H); 14} R17 and Rl7a independently are: a hydrogen atom (H); C^alkyl (e.g. C^a-kyl); C 1 _ fluoroalkyl (e.g. CF3); cyclopropyl; -C(O)-C 1 _4alkyl (e.g. -C(O)Me); -C(O)NR7aR a (e.g. -C(O)NH2); or -S(O)2-C1.4alkyl (e.g. -S(O)2Me) (preferably, R*4, R17 and/or R17a independently is/are: H; Cι_2alkyl; or -C(O)Me);
R15a , independent of other R15a, is a hydrogen atom (H) or C^alkyl (e.g. H, *Bu or C i _2alkyl such as methyl; preferably R15a is H or C \ .2alkyl, more preferably H);
Rl6a is:
Cι„6alkyl (e-S- Cι_4alkyl or C^ lkyl);
C3_6cycloalkyl (e.g. C5_6cycloalkyl) optionally substituted by one oxo (=O), OH or Cι_2 lkyl substituent (e.g. optionally substituted at the 3- or 4-position of a C5_6cycloalkyl ring; and/or preferably unsubstituted C3_6cycloalkyl); C3_6cycloalkyl-CH2- (e.g. C5_6cycloalkyl-CH2-); pyridinyl (e.g. pyridin-2-yl) optionally substituted on a ring carbon atom by one of: a halogen atom, Cj_2 alkyl, C\ fluoroalkyl, Cι _2 alkoxy or Cifluoroalkoxy; Ar5c; phenyl optionally substituted by one or two substituents independently being: a halogen atom, Cι_2alkyl, C\ fluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy; benzyl optionally substituted on its ring by one or two substituents independently being: a halogen atom, Cι_2 alkyl, Cj fluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy; or a 4-, 5-, 6- or 7-membered saturated heterocyciic ring connected at a ring-carbon and containing one or two ring-hetero-atoms independently selected from O, S, and N; wherein any ring-nitrogens which are present are present as NR27 where R27 is H, Cι_2 lkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one
Cι_2alkyl or oxo (=O) substituent, provided that any oxo (=O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
R3^, independent of other R3^, is a hydrogen atom (H), Cι_4alkyl or C3_6cycloalkyl;
Ar^b and Ar^c independently is/are a 5-membered aromatic heterocyciic ring containing one O, S or NR^a m the 5-membered ring, wherein the 5-membered ring can optionally additionally contain one or two N atoms, and wherein the heterocyciic ring is optionally substituted on a ring carbon atom by one of: a halogen atom, Cι_2alkyl, Ci fluoroalkyl,
-CH2OH, -CH2-OCι_2 alkyl, OH (including the keto tautomer thereof) or - CH2-NR28R29 wherein R28 and R29 independently are H or methyl; and
Hetl , is a 4-, 5-, 6- or 7-membered saturated heterocyciic ring connected at a ring-carbon and containing one or two ring-hetero-atoms independently selected from O, S, and N; wherein any ring-nitrogens which are present are present as NR31 where R31 is H, Cι_2alkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one Cι_2 lkyl or oxo (=O) substituent, provided that any oxo (=O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen. In compounds, for example in the compounds of formula (I) (or formula (IA) or formula (IB), see later), an "alkyl" group or moiety may be straight-chain or branched. Alkyl groups, for example C^.galkyl or C^.galkyl or Cι_4alkyl or Cι_3alkyl or
Cι_2 alkyl, which maybe employed include Ci.βalkyl or C^alkyl or C 1.3 alkyl or Cj_2 alkyl such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl or any branched isomers thereof such as isopropyl, t-butyl, sec-butyl, isobutyl, 3-methylbutan-2-yl, 2-ethylbutan-l-yl, or the like. A corresponding meaning is intended for "alkoxy", "alkylene", and like terms derived from alkyl. For example, "alkoxy" such as C^alkoxy or Ci _4alkoxy or
Cι_2alkoxy includes methoxy, ethoxy, propyloxy, and oxy derivatives of the alkyls listed above. "Alkylsulfonyl" such as Cι_4alkylsulfonyl includes methylsulfonyl
(methanesulfonyl), ethylsulfonyl, and others derived from the alkyls listed above. "Alkylsulfonyloxy" such as C^alkylsulfonyloxy includes methanesulfonyloxy
(methylsulfonyloxy), ethanesulfonyloxy, et al
"Cycloalkyl", for example C3_gcycloalkyl, includes cyclopropyl, cyclobuiyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, a
C3_gcycloalkyl group is C3_6cycloalkyl or Cs.gcycloalkyl , that is contains a 3-6 membered or 5-6 membered carbocyclic ring. "Fluoroalkyl" includes alkyl groups with one, two, three, four, five or more fluorine substituents, for example Ci_4fluoroalkyl or C .3 fluoroalkyl or C^fluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF2CH2-), 2-fluoroethyl
(CH2FCH2-), etc. "Fluoroalkoxy" includes Cifluoroalkoxy or Cifluoroalkoxy such as trifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy, etc. "Fluoroalkylsulfonyl" such as Cι_4fluoroalkylsulfonyl includes trifluoromethanesulfonyl, pentafluoroethylsulfonyl, etc.
A halogen atom ("halo") present in compounds, for example in the compounds of formula (I), means a fluorine, chlorine, bromine or iodine atom ("fluoro", "chloro", "bromo" or "iodo"), for example fluoro, chloro or bromo. When the specification states that atom or moiety A is "bonded" or "attached" to atom or moiety B, it means that atom/moiety A is directly bonded to atom/moiety B usually by means of a covalent bond or a double covalent bond, and excludes A being indirectly attached to B via one or more intermediate atoms/moieties (e.g. excludes A-C- B); unless it is clear from the context that another meaning is intended.
When Rl is C^alkyl or Cι_3fluoroalkyl, it can be straight-chained or branched. Where Rl is Cj_4alkyl then it can for example be methyl, ethyl, n-propyl, isopropyl or n-butyl. When Rl is Cι_3fluoroalkyl, then Rl can for example be C\ fluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl; or Rl can be C2fluoroalkyl such as pentafluoroethyl or more preferably Cifluoroalkyl-GH j- such as 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF2CH2-), or 2-fluoroethyl (CH2FCH2-).
Preferably, R1 is Cι_3alkyl (e.g. methyl, ethyl or n-propyl), C^fluoroalkyl or
-CH CH2OH. R1 is more preferably Cι_3alkyl, C ^fluoroalkyl, or -CH2CH2OH. Still more preferably, R1 is C2_3alkyl (e.g. ethyl or n-propyl), C2fluoroalkyl (e.g. Cifluoroalkyl-CH2- such as CF3-CH2-) or -CH2CH2OH; in particular ethyl, n-propyl or -CH2CH2OH. Yet more preferably, Rl is C2alkyl or C2fluoroalkyl. Rl is most preferably ethyl.
Representative examples of R1 include ethyl.
In another aspect of the invention R2 is C2-4alkyl, C3-5cycloalkyl or -CH2cyclopropyl.
Representative examples of R2 include ethyl, propyl, cyclopropyl, cyclobutyl, cyclop entyl and cyclopropylmethyl.
Preferably, in R3 there is one substituent or no substituent.
In one embodiment, R3 is the optionally substituted C3_gcycloalkyl or the optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc).
In one optional embodiment, when R3 is optionally substituted C3_g cycloalkyl, it is not unsubstituted Cscycloalkyl, i.e. not unsubstituted cyclopentyl. In this case, more suitably, R3 is optionally substituted Cg.gcycloalkyl.
When R3 is optionally substituted C3_gcycloalkyl, it is more preferably optionally substituted C6-7cycloalkyl or optionally substituted Cβcycloalkyl (i.e. cyclohexyl).
Suitably, when R3 is optionally substituted C3_gcycloalkyl, then R3 is C3_gcycloalkyl (e.g. C6_7cycloalkyl) optionally substituted with one or two substituents independently being oxo (=O); OH; Cjalkoxy; Ci fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy); NHR2^ wherein R2^ is a hydrogen atom (H) or Cι_2alkyl (more preferably R2^ is H); C^alkyl such as methyl; Cifluoroalkyl such as -CH2F or -CHF2;
-CH2OH; -CH2NHR22 wherein R22 is H; -C(O)OR23 wherein R23 is H or methyl;
-C(O)NHR24 wherein R24 is H or methyl; -C(O)R25 wherein R25 is methyl; fluoro; hydroxyimino (=N-OH); or (Cι_4alkoxy)imino (=N-OR26 where R ^ is C^alkyl); and wherein any OH, alkoxy, fluoroalkoxy or NHR21 substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyciic group (aa), (bb) or (cc).
Preferably, when R3 is optionally substituted C3_gcycloalkyl, then R3 is C3_gcycloalkyl (e.g. Cβ- cycloalkyi) optionally substituted with one or two substituents independently being oxo (=O); OH; NHR2 wherein R2 is a hydrogen atom (H); Ci^alkyl such as methyl; Ci fluoroalkyl such as -CH-2F or -CHF2; -C(O)OR23 wherein R23 is H or methyl; -C(O)NHR24 wherein R24 is H or methyl; fluoro; hydroxyimino (=N-OH); or (Cι_2alkoxy)imino (=N-OR26 where R26 is Chalky!).
More preferably, when R3 is optionally substituted C3_gcycloalkyl, then R3 is C3_gcycloalkyl (e.g. Cβ- cycloalkyl) optionally substituted with one or two substituents independently being oxo (=O); OH; NHR21 wherein R is a hydrogen atom (H); methyl; -CH2F; -CHF2; -C(O)OR23 wherein R23 is H; -C(O) HR24 wherein R24 is H or methyl (preferably H); fluoro; hydroxyimino (=N-OH); or methoxyimino (=N-OR2^ where R ^ is methyl).
Still more preferably, when R3 is optionally substituted C3_gcycloalkyl, then R3 is C3_gcycloalkyl (e.g. C6_7cycloalkyl) optionally substituted with one or two substituents independently being oxo (=O); OH; methyl; -C(O)NHR24 wherein R24 is H; fluoro; hydroxyimino (=N-OH); or methoxyimino (=N-OR2^ where R2^ is methyl).
Yet more preferably, when R3 is optionally substituted C3_gcycloalkyl, then R3 is C3_gcycloalkyl (e.g. C6_7cycloalkyl) optionally substituted with one or two substituents independently being OH; -C(O)NHR24 wherein R24 is H; oxo (=O) or hydroxyimino (-N-OH).
In one optional embodiment, in R3, the C3_gcycloalkyl can be unsubstituted.
When R3 is optionally substituted C3_gcycloalkyl or optionally substituted
C5_7cycloalkenyl, e.g. optionally substituted C5_gcycloalkyl or C5_7cycloalkyl, such as optionally substituted Cgcycloalkyl (optionally substituted cyclohexyl) or optionally substituted cyclohexenyl, the one or two optional substituents if present suitably can comprise a substituent (for example is or are substituent(s)) at the 3-, 4- and/or 5- position(s), e.g. at the 3- and/or 4- position(s), of the R3 cycloalkyl or cycloalkenyl ring.
(In this connection and generally herein, the 1 -position of the R3 ring, e.g. of the R3 cycloalkyl or cycloalkenyl ring is deemed to be the connection point to the -NH- in formula (I) = the ring atom connecting to the -NH- in formula (I)). Suitably, for R3, and in particular when R3 is optionally substituted C3_gcycloalkyl or optionally substituted C5_7cycloalkenyl, R3 is not substituted (other than optionally by alkyl or fluoroalkyl) at the ring atom connecting to the -NH- in formula (I), and R3 is not substituted (other than optionally by alkyl, fluoroalkyl or NHR 1) at the two ring atoms either side of (bonded to) the connecting atom. For example, suitably, for R3, and in particular when R3 is optionally substituted C3_gcycloalkyl or optionally substituted
C5-7cycloalkenyl, R3 is not substituted at the ring atom connecting to the -NH- in formula (I), and R3 is not substituted at the two ring atoms either side of (bonded to) the connecting atom.
Suitably, for R3, and in particular when R3 is optionally substituted C3_gcycloalkyl or optionally substituted C5_7cycloalkenyl, the one or two optional R3 substituents if present can comprise a substituent (for example is or are substituent(s)): (a) at the 3 -position of a R3 cyclobutyl ring, or (b) at the 3- and/or 4- position(s) of a R3 cyclopentyl or cyclopentenyl ring, or
(c) at the 3-, 4- and/or 5- position(s) of a R3 cyclohexyl or cyclohexenyl ring, or
(d) at the 3-, 4-, 5- and/or 6- position(s) of a R3 cycloheptyl or cycloheptenyl ring, or
(e) at the 3-, 4-, 5-, 6- and/or 7- position(s) of a R3 cyclooctyl ring, and/or (f) at the 1-, 2- and/or highest-numbered- position(s) of a R3 cycloalkyl or cycloalkenyl ring, for alkyl or fluoroalkyl substituent(s), and/or
(g) at the 2- and or highest-numbered- position(s) of a R3 cycloalkyl or cycloalkenyl ring, for NHR 1 or fluoro substituent(s).
When R3 is optionally substituted C3_gcycloalkyl, any OH, alkoxy, fluoroalkoxy,
-CH2CH2OH or -CH2NHR22 substituent (particularly any OH substituent) is suitably at the 3-, 4- or 5- position, e.g. 3- or 5-position, of the R3 cycloalkyl (e.g. Cg.gcycloalkyl) ring. Optionally, any OH, alkoxy, fluoroalkoxy, -CH2CH2OH or -CH2NHR22 substituent (particularly any OH substituent) can be: at the 3-position of a R3 cyclobutyl ring; or at the 3- or 4- position of a R3 Cscycloalkyl (cyclopentyl) ring; or at the 3-, 4- or
5- position, of a R3 Cβcycloalkyl (cyclohexyl) ring e.g. at the 3- or 5-position of a R3 cyclohexyl ring especially for any OH substituent; or at the 3-, 4-, 5- or 6- position of a R3 cycloheptyl ring, or at the 3-, 4-, 5-, 6- or 7- position of a R3 cyclooctyl ring. Suitably, any OH, alkoxy, fluoroalkoxy, -CH2CH2OH or -CH2NHR22 substituent (particularly any OH substituent) is at the 3- or 4- position of a R3 C5cycloalkyl
(cyclopentyl) ring; or more suitably at the 3-, 4- or 5- position, still more suitably at the 3- or 5-position, of a R3 Cgcycloalkyl (cyclohexyl) ring. Suitably, when R3 is optionally substituted C3_gcycloalkyl or optionally substituted
C5_7cycloalkenyl, any -C(O)OR23, -C(O)NHR24, -C(O)R25 , -CH2OH, or fluoro substituent is: at the 3-position of a R3 cyclobutyl ring; or at the 3- or 4- position of a R3 C5cycloalkyl (cyclopentyl) or cyclopentenyl ring; or at the 3-, 4- or 5- position, preferably at the 4-position, of a R3 Cβcycloalkyl (cyclohexyl) or cyclohexenyl ring; or at the 3-, 4-, 5- or 6- position of a R3 cycloheptyl or cycloheptenyl ring, or at the 3-, 4-, 5-, 6- or 7- position of a R3 cyclooctyl ring. Any -C(O)OR23, -C(O)NHR24, -C(O)R25 , -CH2OH, or fluoro substituent, e.g. any -C(O)NHR24 or fluoro substituent, is suitably at the 3-, 4- or 5- position, more suitably at the 4-position, of a R3 Cgcycloalkyl (cyclohexyl) or cyclohexenyl ring. It is particularly preferable for any -C(O)NHR24 substituent to be at the 4-position of a R3 cyclohexyl ring.
When R3 is optionally substituted C3_gcycloalkyl, any NHR21 substituent is at any position other than the 1 -position (the ring atom connecting to the -NH- in formula (I)), e.g. at the 3-, 4-, 5-, 6-, 7- or 8- position. Preferably, any NFIR2 substituent is at the 2-, 3-, 5- or 6- position, or more preferably at the 3- or 5- position, of a R3 cyclohexyl ring.
When R3 is optionally substituted C3_gcycloalkyl or optionally substituted C5_7cycloalkenyl, any alkyl or fluoroalkyl substituent can for example be at the 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- position, for example at the 1-, 2-, 3-, 5- or 6- position, e.g. the
1 -position, of the R3 ring. Preferably, any alkyl or fluoroalkyl substituent is at the 1-, 2-, 3-, 5- or 6- position, or more preferably at the 1-, 3- or 5- position, of a R3 cyclohexyl or cyclohexenyl ring.
When R3 is optionally substituted C3_gcycloalkyl, any oxo (=O), hydroxyimino
(=N-OH); or (Ci _4alkoxy)imino (=N-OR2^) substituent is suitably at the 3-, 4- or 5- position, e.g. at the 4-position, of the R3 cycloalkyl (e.g. Cβ.gcycloalkyl e.g. cyclohexyl) ring. Preferably any such substituent is at the 4-position of a R3 cyclohexyl ring.
When R3 is optionally substituted C3_gcycloalkyl (e.g. Cg- cycloalkyl), R3 is preferably cyclohexyl (i.e. unsubstituted); or cycloheptyl (i.e. unsubstituted); or cyclohexyl substituted by one substituent being oxo (=O), OH, NETR2 , Cι_2alkyl, C ^fluoroalkyl,
-CH2OH, -C(O)OR23, -C(O)NHR24, -C(O)R25, fluoro, hydroxyimino (=N-OH), or
(Cι_4alkoxy)imino (=N-OR2^); or cyclohexyl substituted by two fluoro substituents. More preferably, R3 is cyclohexyl (i.e. unsubstituted); or cycloheptyl (i.e. unsubstituted); or cyclohexyl substituted by one substituent being oxo (=O), OH, NHR21, Cι_2 alkyl,
Cι_2fluoroalkyl, -C(O)OR23, -C(O)NHR24, fluoro, hydroxyimino (=N-OH), or
(Cι_2alkoxy)imino (=N-OR26 wherein R ^ is C^alkyl); or cyclohexyl substituted by two fluoro substituents. Still more preferably R3 is cyclohexyl (i.e. unsubstituted) or cyclohexyl substituted by one oxo (=O), hydroxyimino (=N-OH), -C(O)NH2, methyl or
OH substituent. The optional substituent can for example be at the 3- or 4- position, of the R3 cyclohexyl ring. Preferably, any OH substituent is preferably at the 3 -position of a R3 cyclohexyl ring, and/or any oxo (=O), hydroxyimino (=N-OH), (Cι_4alkoxy)imino
(=N-OR26) or -C(O)NH2 substituent is preferably at the 4-position of a R3 cyclohexyl ring, and/or any alkyl or fluoroalkyl substituent is preferably at the 1-, 3- or 5- position of a R3 cyclohexyl ring.
When R3 is optionally substituted Cβ- cycloalkyl, R3 can for example be 4-hydroxy- cyclohexyl (i.e. 4-hydroxycyclohexan-l-yl), 4-methylcyclohexyl, 3-fluorocyclohexyl, 2- aminocyclohexyl, 3-(HO(O)C)cyclohexyl or 3-oxocyclohexyl, but R3 is more preferably cyclohexyl (i.e. unsubstituted), cycloheptyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl) (e.g. in a cis configuration), 4-oxo-cyclohexyl (i.e. 4- oxocyclohexan- 1 -yl), 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan- 1 - yl), 4-(Cι_2alkoxyimino)cyclohexyl, 4-(aminocarbonyl)cyclohexyl (i.e.
4-(aminocarbonyl)cyclohexan-l-yl) (e.g. in a cis configuration), 1-methylcyclohexyl, 3-methylcyclohexyl, 4,4-(difluoro)cyclohexyl, or 3-aminocyclohexyl.
When R3 is optionally substituted Cβ^cycloalkyl, R3 is most preferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl) (e.g. in a cis configuration), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-l-yl), 4- (hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-l-yl), or 4-(aminocarbonyl)cyclohexyl (i.e. 4-(aminocarbonyl)cyclohexan-l-yl) (e.g. in a cis configuration).
When R3 is optionally substituted Cscycloalkyl (optionally substituted cyclopentyl), R3 can for example be cyclopentyl (i.e. unsubstituted) or more suitably 3-hydroxy- cyclopentyl.
When R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, preferably it is optionally substituted mono-unsaturated-Cs.gcycloalkenyl, more preferably optionally substituted mono-unsaxurated-Cβcycloalkenyl (i.e. optionally substituted mono-unsaturated-cyclohexenyl = optionally substituted cyclohexenyl). For example, the R3 cyclohexenyl can be optionally substituted cyclohex-3-en-l-yl.
When R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, in one optional embodiment the R3 cycloalkenyl is optionally substituted with one or two substituents independently being fluoro or methyl. Preferably, in this embodiment, if there are two substituents then they are not both methyl. In another optional embodiment, the R3 cycloalkenyl (e.g. cyclohexenyl) is optionally substituted with one substituent being fluoro or Cι_2alkyl (preferably fluoro or methyl); more preferably the R3 cycloalkenyl (e.g. cyclohexenyl) is substituted with one fluoro substituent or is unsubstituted. For example, the R3 optionally substituted cycloalkenyl can be cyclohex-3-en-l-yl (i.e. unsubstituted) or 4-fluoro-cyclohex-3-en-l-yl.
For R3 cycloalkenyl, the optional substiruent(s) can for example be at the 1-, 2-, 3-, 4-, 5- or 6- position(s) of the cycloalkenyl ring.
When R3 is the heterocyciic group of sub-foπnula (aa), (bb) or (cc), then Y is preferably O or NRIO, most preferably O.
Suitably, R10 is a hydrogen atom (H), methyl, ethyl, C(O)NH2, C(O)-Cι_2alkyl or C(O)-Cιfluoroalkyl. . Preferably, R10 is not C^alkyl or Cι_2fluoroalkyl. Suitably R10 is not CH2C(O)NH2.
More preferably, R10 is a hydrogen atom (H), C(O)NH2, C(O)-Cι _2alkyl (e.g. C(O)methyl) or C(O)-Cι fluoroalkyl (e.g. C(O)-CF3). Still more preferably R10 is H, C(O)NH2 or C(O)methyl; for example C(O)NH2. When R3 is the heterocyciic group of sub-formula (aa), (bb) or (cc), then it is preferable that R3 is the heterocyciic group of sub-formula (aa) or (bb), more preferably of sub- formula (bb).
In sub-formula (bb), n is preferably 1. In sub-formula (cc), n2 is preferably 1. That is, six-membered rings are preferred in the R3 heterocyciic group.
Suitably, in R3, the heterocyciic group of sub-formula (aa), (bb) or (cc) is unsubstituted on a ring carbon. (In this connection, where Y is NR 0, R 0 is not a substituent on a ring carbon).
h the R3 heterocyciic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents preferably comprise (e.g. is or independently are) OH; oxo (=O); Ci^alkyl
(e.g. methyl) or Cι_ 2 fluoroalkyl (e.g. Ci fluoroalkyl such as -CH2F or -CHF2). More preferably, in the R3 heterocyciic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents comprise (e.g. is or independently are) C^alkyl (e.g. methyl) or oxo; most preferably the one or two optional substituents comprise (e.g. is or are) oxo (=0). i the R3 heterocyciic group of sub-formula (aa), (bb) or (cc), any oxo (=O) substituent is preferably on a carbon atom bonded (adjacent) to Y, e.g. is on a carbon atom bonded (adjacent) to Y only when Y is O or NR^. In the R3 heterocyciic group of sub-formula (aa), (bb) or (cc), any oxo (=O) substituent can suitably be at the 2-, 3-, 4-, 5- or 6- position of the R3 heterocyciic ring. For example any oxo (=O) substituent(s) can be: at the 2-, 4- or 5- position(s) (e.g. 2-position or 4- position, or two oxo substituents at 2- and 4- positions) of a R3 heterocyciic group of sub- formula (aa), at the 2-, 4-, 5- or 6- position(s) (e.g. 4-position) of a six-membered R3 heterocyciic group of sub-formula (cc) wherein n2 is 1, at the 2-, 3-, 5-, 6- or 7- position(s) (e.g. 5-position) of a seven-membered R3 heterocyciic group of sub-formula (bb) wherein n is 2, or at the 2-, 4-, 5-, 6- or 7- position(s) (e.g. 2-position) of a seven- membered R3 heterocyciic group of sub-formula (cc) wherein n2 is 2.
(In this connection and generally herein, the 1 -position of the R3 heterocyciic ring is deemed to be the connection point to the -NH- in formula (I) = the ring atom connecting to the -NH- in formula (I), and the remaining positions of the ring are then numbered so that the ring heteroatom takes the lowest possible number).
In the R3 heterocyciic group of sub-formula (aa), (bb) or (cc), any alkyl or fluoroalkyl substituent can for example be at the 1-, 2-, 3-, 4-, 5- or 6- position, e.g. the 1-position, of the R3 heterocyciic ring, for example at the 1-, 3- or 5- position of a six-membered R3 heterocyciic ring.
In the R3 heterocyciic group of sub-formula (aa), (bb) or (cc), any OH substituent can be: at the 5-position of a six-membered R3 heterocyciic group of sub-formula (cc) wherein n2 is 1; at the 5- or 6- position of a seven-membered R3 heterocyciic group of sub- formula (cc) wherein n2 is 2; or at the 6- position of a seven-membered R3 heterocyciic group of sub-formula (bb) wherein n is 2.
Any other substituents of the R3 heterocyciic group can optionally be positioned on the
R3 heterocyciic ring at numerical positions as described herein for when R3 is optionally substituted C5_7cycloalkyl, all necessary changes to the wording being made.
In the R3 heterocyciic group of sub-formula (aa), (bb) or (cc), preferably, only Cι_2alkyl, Cifluoroalkyl, fluoro or oxo (=O) substitution or no substitution is allowed independently at each of the 2- and highest-numbered- positions of the R3 heterocyciic ring (e.g. at each of the 2- and 6- positions of a six-membered R3 heterocyciic ring), and/or only Cι_2alkyl, Cι_2fluoroalkyl or fluoro substitution or no substitution is allowed at the 1-ρosition of the R3 heterocyciic ring.
When R3 is the heterocyciic group of sub-formula (aa) and Y is NRlO, then RlO is not C(O)-Cι_2alkyl, C(O)-Cι fluoroalkyl or -C(O)-CH2O-C1_2alkyl. According to one optional embodiment when R3 is the heterocyciic group of sub-formula (aa) and Y is NR10 then R10 is optionally not C(O)NHMe, C(O)-Cι _2alkyl, C(O)-Cι fluoroalkyl or
-C(O)-CH2O-Cι.2alkyl.
In one preferable embodiment, Y is O, S, SO2 or NH when R3 is the heterocyciic group of sub-formula (aa).
When R3 is the heterocyciic group of sub-formula (bb), n* is 1, and Y is NR 0 (e.g.
when NHR3 is
Figure imgf000022_0001
10 is not Cι_2alkyl or Cifluoroalkyl. More preferably, when R3 is the heterocyciic group of sub-formula (bb) wherein n is 1 or 2 and Y is N IO, then R 0 is preferably not Chalky! or Cifluoroalkyl.
In one embodiment, when R3 is the heterocyciic group of sub-formula (bb), then preferably Y is O, S, SO2 or NR10 wherein R10 is H, C(O)NH , C(O)-C1.2alkyl (e.g. C(O)methyl) or C(0)-Cι fluoroalkyl (e.g. C(O)-CF3), or more preferably R10 is H, C(O)NH2 or C(O)Me, for example C(O)NH2 or C(O)Me most preferably CONH2.
In one optional embodiment, when R3 is the heterocyciic group of sub-formula (cc), then optionally Y is O, S, S02 or NR1 () wherein R10 is H, C(O)NH2, C(O)-C1.2alkyl (e.g.
C(O)methyl) or C(O)-Cχ fluoroalkyl (e.g. C(O)-CF3). In this case ΕU-® can for example be H, C(O)NH2 or C(O)Me, for example H.
Optionally, for sub-formula (bb) and/or for sub-formula (cc), Y is O or N lO.
When R3 is optionally substituted C3_gcycloalkyl (e.g. Cβ.ycycloalkyl) or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc), then a substituent can be in the cis or trans configuration with respect to the -NH- group of formula (I) to which R3 is attached (bonded); this includes mixtures of configurations wherem the stated configuration is the major component. For example, an OH or -C(O)NHR24 substituent on C^cycloalkyl can for example be in the cis configuration and/or a NHR21 substituent on C6_7cycloalkyl can for example be in the cis or trans configuration, with respect to the
-NH- group of formula (I) to which R3 is attached (bonded), including mixtures of configurations wherein the stated configuration is the major component.
When R3 is a bicyclic group of sub-formula (ee), then preferably γl, Y2 and Y3 are all CH2. Preferably, NHR3 is of sub-formula (a), (al), (b), (c), (c 1), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (g), (gl), (g2), (g3), (g4), (h), (i), (j), (k), (kl), (k2), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (p), (pi), (p2), (p3), (p4), (p5), (P6), (p7), (p8), (p9), (pl0), (pl l) or (q):
Figure imgf000024_0001
(a) (a1) (b) (c) (c1) (c2)
Figure imgf000024_0002
(c3) (c4) (C5) (C6) (c7)
Figure imgf000024_0003
( ) (e) (f) (9) (gi) (g2) (g3) (g4)
Figure imgf000024_0004
(h) (i)
Figure imgf000024_0005
Figure imgf000024_0006
In the sub-formulae (a) to (q) etc above, the -NH- connection point of the NHR3 group to the 4-position of the pyrazolopyridine of formula (I) is underlined.
Preferably, NHR3 is of sub-foi ula (c), (cl), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (gl), (g4), (h), (i), (j), (k), (kl), (k2), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (p), (p2), (p5), (p6), (p7), (p9), (plO), (pi 1) or (q). More preferably, NHR3 is of sub-formula (c), (cl), (c 4), (c 5), (h), (i), (j), (k), (k2), (ml), (m2), (n), (o), (o2), (o3), (p2), (p5), (p6), (p9), (pi 1) or (q). NHR3 can for example be of sub-formula (c), (pll), (h), (k), (k2), (n), (o), (o2) or (p9); or still more preferably (c), (pll), (h), (k2), (n), (o), (o2) or (p9). Most preferably, R3 is tetrahydro-2H-pyran-4-yl or l-(aminocarbonyl)-4-piperidinyl; that is NHR3 is most preferably of sub-formula (h) or (k2), as shown above. In another aspect of the invention R3 is C3_gcycloalkyl (e.g. C^cycloalkyl) optionally substituted with one or two substituents independently being oxo (=O); OH; methyl; -C(O)NHR24 wherein R24 is H; fluoro; hydroxyimino (=N-OH); or methoxyimino (=N-OR26 where R26 is methyl).
In another aspect of the invention R3 is a 4-(aminocarbonyl)cyclohexyl (i.e. 4-(aminocarbonyl)cyclohexan- 1 -yl) group of sub-formula (aa), or an N-aminocarbonyl- piperidinyl or an N-aminocarbonyl-pyrrolidinyl or a tetrahydropyranyl group of sub- formula (bb);
Figure imgf000025_0001
(aa) (bb) wherein Y is O or NCONH2 and n* is 0 or 1 ;
and wherein the cyclohexyl group of sub-formula (aa) or the piperidinyl, pyrrolidinyi or tetrahydropyranyl groups of sub-formula (bb) may be further optionally substituted with one or two substituents independently selected from C^ lkyl; Cifluoroalkyl; CH2OH; -C(O)OR23 wherein R23 is H or C^alkyl; -C(O)NHR23; or fluoro; on any ring carbon; as well as, on the C2, C3, C5 and C6 of the cyclohexyl group of (aa), the C2 or C6 of the piperidinyl ring or the C5 of the pyrrolidinyi ring of (bb), a substituent selected from OH;
Figure imgf000025_0002
Cι_2fluoroalkoxy; or alkoxy.
Representative examples of R include tetrahydro-2H-pyran-4-yl. When NHR3 is of sub-formula (n), then preferably it is in the cis configuration, i.e. preferably it is a ct1y-(3-hydroxycyclohexan-l-yl)amino group, e.g. in any enantiomeric form or mixture of forms such as a racemic mixture.
When NHR3 is of sub-formula (p9), then preferably it is in the cis configuration, i.e. preferably it is a ct-?-[4-(aminocarbonyl)cyclohexan-l-yl] amino group.
Where R4 is Cifluoroalkyl, then it can be Cifluoroalkyl such as monofluoromethyl, difluoromethyl or trifluoromethyl.
R4a can suitably be a hydrogen atom (H) or methyl (Me), more suitably H.
R4 can for example be a hydrogen atom (H); methyl, ethyl, Cifluoroalkyl, -CH2OH, -CH(Me)OH, -CH2CH2OH, or -CH2OMe; or preferably a hydrogen atom (H), methyl, ethyl, -CH2OH, or -CTJ^OMe . More preferably, R4 is H, methyl, ethyl, -CH2OH, or -CH2OMe.
Representative examples of R4 include H, methyl and ethyl.
In another aspect of the invention, R$ is a hydrogen atom (H), methyl, ethyl, n-propyl, or iso-propyl.
Representative examples of R5 include H.
In another aspect of the invention, in sub-formulae (y) and (yl) m is 1, A is C-R6A, B is C- R6B, D is C- R6D and E is C- R6E.
Representative examples of (y) include 2,3-dihydro-lH-inden-2-yl.
It is preferable that Ar has the sub-formula (x).
Preferably, in sub-formula (x), two or more (more preferably three or more) of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine) or nitrogen (N).
Preferably, in sub-formula (x), three or more of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine), nitrogen (N), or nitrogen-oxide (N+-O").
Preferably, in sub-formula (x), two or more (e.g. three or more) of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine), or nitrogen (N); and one or more (e.g. two or more) others of A, B, D, E and F are independently C-H (carbon- hydrogen), C-F (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe, or nitrogen (N). More preferably, in sub-formula (x), two or more (e.g. three or more) of A, B, D, E and F are C-H (carbon-hydrogen); and one or more (e.g. two or more) others of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe, or nitrogen (N).
Preferably, in sub-formula (x), two or more (e.g. three or more, e.g. four or more) of A, B, D, E and F are C-H.
Preferably, in sub-formula (x), no more than one (more preferably none) of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+-O~).
Preferably, in sub-formula (x), none of A, B, D, E and F are nitrogen-oxide (N+-O").
Preferably, Ar has the sub-formula (x) which is sub-formula (xl), (x2), (x3), (x4), (x5), (x6), (x7), (x8), (x9), (xlO), (xll), (xl2), (xl3), (xl4), ( l5) or (xl6):
Figure imgf000027_0001
(x10) (x11 )
Figure imgf000027_0002
(x13) (x14) (x15) (x16) More preferably, Ar has the sub-formula (x) which is sub-formula (xl), (x2), (x3), (x8), (xl3), or (xl4). Still more preferably, Ar has the sub-formula (x) which is sub-formula (xl), (x8), (xl3), or (xl4). Most preferably, Ar has the sub-formula (x) which is sub- formula (xl).
In sub-formula (x), preferably, R6A, R6B, R6D, R6E and or R6F, independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, C4alkyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, isopropoxy, Ci fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy), cyclohexyloxy; cyclopentyloxy; nitro (-NO2), OH, Cι_3alkylS(O)2- (such as MeS(O)2-), Cι_3alkylS(O)2-NH- such as Me-S(O)2-NH-, Me2N-S(O)2-, H2N-S(O)2-, -CONH2, -CONHMe, -C(O)OH, cyano (-CN), NMe2, or Cι_2alkyl-S(O)2-CH2- sucb as Me-S(O)2-CH2-.
More preferably, R^A R B? R6D? R6E and/or R^F, independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, isobutyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, isopropoxy, C fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy), nitro (-NO2), OH, Cι_3alkylS(O)2- such as MeS(O)2-, Cι_2alkylS(O)2-NH- such as Me-S(O)2-NH-, -CONH2, cyano (-CN), or Cι„2alkylS(O)2-CH2- such as Me-S(O)2-CH2.
Still more preferably, R^A5 R^B, R6D; R6E and/or R^F, independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, difluoromethoxy, OH or MeS(O)2--
When two adjacent groups selected from R^A R B3 6D5 R6E mc R6F are taken together, then, preferably, when taken together they are: -CH=CH-CH=CH2- -(CH2)n 14a- where n 4a is 3, 4 or 5 (e.g. 3 or 4), -O-(CMe2)-O- -O-(CH2)n 14b-O- where nl4b is 1 or 2; -CH=CH-NR15b-; -N=CH-NR15b-; -N=N-NR15 wherein R^b is H or C _2 lkyl (preferably R^b js jj). More preferably, in this embodiment, two adjacent groups selected from R^A? R6B} 6D5 R6E a cι R6F are taken together and are: -CH=CH-CH= H2- or -(CH2)n 14a- where n14 is 3, 4 or 5 (e.g. 3 or 4).
In sub-formula (x), e.g. in sub-formula (xl), suitably, one, two or three of R^B, R6D ^d R6E aj-g other than a hydrogen atom (H).
In sub-formula (x), e.g. in sub-formula (xl), preferably, one or both of R^A and R^F are independently a hydrogen atom (H), a fluorine atom (F), or methyl. For example, one or both of R6A and R6F can be a hydrogen atom (H). In sub-formula (x), e.g. in sub-formula (xl), suitably the ring or ring system is unsubstituted, monosubstituted, disubstituted or trisubstituted, preferably the ring or ring system is monosubstituted or disubstituted. hi sub-formula (x), e.g. in sub-formula (xl), for monosubstitution of the ring or ring system, then the one substituent selected from R6A R6B? 6D5 R6E and R^F is suitably present at the 3- or 4-position with respect to the -(CR R5)- side-chain (i.e. D is CR6D where R6D is other than H), or is a 2-methyl 2-ethyl, 2-fluoro or 2-chloro substituent. i sub-foπnula (x), e.g. in sub-formula (xl), for disubstitution of the ring or ring system, then 3,4-disubstirution, 2,4-disubstitution, 2,3- disubstitution or 3,5-disubstitution is suitable.
In one preferable embodiment, Ar has the sub-formula (xl) and is: phenyl, monoalkyl- phenyl-, mono(fluoroalkyl)-phenyl-, monohalo-phenyl-, monoalkoxy-phenyl-, mono(fluoroalkoxy)-phenyl-, mono(N,N-dimethylamino)-phenyl-, mono(methyl-SO2-NH-)-phenyl-, mono(methyl-Sθ2-)-phenyl-, dialkyl-phenyl-, monoalkyl-monohalo-phenyl-, mono(fluoroalkyl)-monohalo-phenyl-, dihalo-phenyl-, dihalo-monoalkyl-phenyl-, dihalo-mono(hydroxymethyl)-phenyl- (e.g. 2,3-dichloro-6- (hydroxymethyl)-phenyl-), or dialkoxy-phenyl- such as 3,4-dimethoxy-phenyl-. The substituents can preferably be further defined, as defined in preferable embodiments herein.
In one preferable embodiment, Ar is of sub-formula (xl) and is: monoalkyl-phenyl-, mono(fluoroalkyl)-phenyl-, monohalo-phenyl-, monoalkoxy-phenyl-, mono(fluoroalkoxy)-phenyl-, dialkyl-phenyl-, monoalkyl-monohalo-phenyl-, dihalo- phenyl- or dihalo-monoalkyl-phenyl-.
More preferably, in this embodiment, Ar is:
- monoCι_4alkyl-phenyl- or monoC _3alkyl-phenyl- such as 4-Cι_4alkyl-phenyl- (e.g.
4-Cι_3alkyl-phenyl-) or 2-Cι_2alkyl-phenyl-; - monoCifluoroalkyl-phenyl- such as 4-C fluoroalkyl-phenyl-;
- monoCι_3alkoxy-phenyl- such as 4-Cι_3alkoxy-phenyl- or 3-Cι_3alkoxy-phenyl-;
- mono(C fluoroalkoxy)-phenyl- such as 4-Cifluoroalkoxy-phenyl-;
- diCι_3alkyl-phenyl- or diCι_2alkyl-phenyl- or dimethyl-phenyl- such as 3,4-dimethyl- phenyl-, 2,4-dimethyl-phenyl-, 3,5-dimethyl-phenyl-, 2,3-dimethyl-phenyl- or 2,5- dimethyl-phenyl-; for example 3,4-dimethyl-phenyl-, 2,4-dimethyl-phenyl-, 2,3-dimethyl- phenyl- or 3,5-dimethyl-phenyl-;
- monoC _3alkyl-monohalo-phenyl-, such as monoC _2alkyl-monohalo-phenyl- and/or monoCι_3alkyl-monochloro-phenyl- or monoCι_3alkyl-monofluoro-phenyl-, for example 4-methyl-3-chloro-phenyl-, 3-methyl-4-chloro-phenyl-, or 2-methyl-4-chloro-phenyl-;
- dihalo-phenyl- such as 2-chloro-4-fluorophenyl- or 2,4-difluoro-phenyl- or 4-bromo- 2-fluorophenyl- or preferably 4-chloro-2-fluorophenyl-; for example dichloro-phenyl- such as 3,4-dichloro-phenyl- or 2,4-dichloro-phenyl- or 2,6-dichloro-phenyl- or preferably 2,3-dichloro-phenyl-; or
- dihalo-monoCι_2alkyl-phenyl- e.g. 2,4-dichloro-6-methyl-phenyl-.
In an alternative embodiment, Ar has the sub-formula (z).
Preferably, in sub-formula (z), three or more (for example all) of J, L, M and Q are independently C-H, C-F, C-Cι_2alkyl (e.g. C-Me), C- [connection point to formula (I)], or nitrogen (N).
Preferably, in sub-formula (z), no more than two (for example no more than one) of J, L, M and Q are nitrogen (N).
Suitably, Q is C- [connection point to formula (I)].
Suitably, R9 is a hydrogen atom (H) or methyl.
Suitably, R^1, R^L R6M and/or R^Q independently is or are: a hydrogen atom (H); fluoro; chloro; Cι_2alkyl (e.g. methyl); Cifluoroalkyl (e.g. CF3); Cι_2alkoxy (methoxy); Ci fluoroalkoxy (e.g. CF2HO-); OH (including any tautomer thereof); or phenyl optionally substituted by one substituent being fluoro, methyl, Cifluoroalkyl, methoxy or Ci fluoroalkoxy. More SuitablyR^J, R^L R6M aιl(ι/or R6Q independently is or are H, OH (including any keto tautomer thereof), or more preferably Cι_2alkyl (e.g. methyl) or Cifluoroalkyl.
When Ar has the sub-formula (z), then sub-formula (z) can suitably be one of the following:
Figure imgf000030_0001
In another aspect of the invention Ar is phenyl and R6Λ, R6B, R6D, R6E and R6F are independently H, Cι- alkyl, Cι-2alkoxy or halogen. Representative examples of Ar include 4-chloro-2-methylphenyl, 4-methoxyphenyl, 3,4- dimethylphenyl, 4-chlorophenyl, and phenyl.
Preferably, the compound of formula (I) or the salt thereof is a compound of formula (IA) or a salt thereof:
Figure imgf000031_0001
wherein
Figure imgf000031_0002
(X) (z) ,
Formula (IA) means that more than 50% of the compound or salt present has the stereochemistry shown at the carbon atom bearing the R4 and R^ groups.
Preferably, the stereochemistry at the carbon atom bearing the R4 and R^ groups is such that there is an enantiomeric excess (e.e.) of 50% or more at the carbon atom bearing the R4 and R^ groups (ignoring the stereochemistry at any other carbon atoms). More preferably, the enantiomeric excess (e.e.) is 70% or more or 80% or more, still more preferably 90% or more, yet more preferably 95% or more, at the carbon atom bearing the R4 and R-> groups (ignoring the stereochemistry at any other carbon atoms).
"Enantiomeric excess" (e.e.) is defined as the percentage of the major isomer present minus the percentage of the minor isomer present. For example, if 95% of major isomer is present and 5% of the minor isomer is present, then the e.e. would be 90%.
In another aspect of the invention in formula (IA) R4 is not a hydrogen atom (H). In this aspect in formula (IA), R4 can for example be methyl, ethyl, C fluoroalkyl (such as CF3), -CH2OH, or -CH2OMe.
In another aspect of the invention in formula (IA) R^ is a hydrogen atom (H) and R4 is not a hydrogen atom (H).
It is particularly preferred that the compound of formula (I) or the salt thereof is: N-[(4-chloro-2-methylphenyl)methyl]-6-cyclopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
6-cyclopropyl-l-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide;
6-cyclopropyl- 1 -ethyl-N- {[4-(methyloxy)phenyl]methyl} -4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
6-cyclopropyl-N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide; N-[ 1 -(4-chlorophenyl)ethyl]-6-cyclopropyl- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
N-[ 1 -(4-chlorophenyl)propyl] -6-cyclopropyl- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
1 -ethyl-N-(phenylmethyl)-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5-carboxamide;
1 -ethyl-N- {[4-(methyloxy)phenyl]methyl} -6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
N-[(4-chloro-2-methylphenyl)methyl]-l-ethyl-6-propyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide; N-[(3 ,4-dimethylphenyl)methyl] - 1 -ethyl-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide; l,6-diethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide; l,6-diethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide;
N-[(3,4-dimethylphenyl)methyl]-l,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide; N-(2,3-dihydro-lH-inden-2-yl)-l,6-diethyl-4-(tetrahydro-2H-ρyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide;
N-[l-(4-chlorophenyl)propyl]-l,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide;
6-cyclobutyl-l-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide;
6-cyclobutyl- 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl} -4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
6-(cyclopropylmethyl)-N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-
4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide; 6-cyclobutyl-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide;
N-[(4-chloro-2-methylphenyl)methyl]-6-cyclobutyl-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide; N-[l-(4-chlorophenyl)ethyl]-6-cyclobutyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
N-[ 1 -(4-chlorophenyl)propyl] -6-cyclobutyl- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5-carboxamide; 6-(cyclopropylmethyl)- 1 -ethyl-N-(phenyhnethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
6-(cyclopropylmethyl)-N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-
4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide;
6-(cyclopropylmethyl)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-l H-pyrazolo [3, 4-b]pyridine-5 -carboxamide;
N-[l-(4-chlorophenyl)ethyl]-6-(cyclopropylmethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide;
6-cycloρentyl-l-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide; or 6-cyclopentyl-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide.
or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
The structures of these specific compounds are given in Examples 1 to 29 hereinafter.
Alternatively, it is particularly preferred that the compound of formula (I) or the salt thereof is one of Examples 1 to 29, as a compound or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. The structures of these specific compounds are given in Examples 1 to 29 hereinafter, and their names are given in the Examples section.
In a further aspect the invention provides a compound of formula (I) or a salt thereof selected from the group consisting of:
N-[(4-chloro-2-methylphenyl)methyl]-6-cyclopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide;
6-cyclopropyl-l-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide;
6-cyclopropyl- 1 -ethyl-N- {[4-(methyloxy)phenyl]methyl} -4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3,4-b]pyridine-5-carboxamide;
6-cyclopropyl-N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide;
N-[l-(4-chlorophenyl)ethyl]-6-cyclopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide; or N-[l-(4-chlorophenyl)propyl]-6-cyclopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide;
or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. Because of their potential use in medicine, the salts of the compounds of formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts. A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration. Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline- earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the the compound of formula (I). Other non-pharmaceutically acceptable salts, eg. oxalates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of formula (I). Also included within the scope of the invention are all solvates, hydrates and complexes of compounds and salts of the invention.
Certain groups, substituents, compounds or salts included in the present invention may be present as isomers. The present invention includes within its scope all such isomers, including racemates, enantiomers and mixtures thereof. ha the compounds or salts, pharmaceutical compositions, uses, methods of treatment/prophylaxis, methods of preparing, etc. according to the present invention, where a defined isomeric configuration e.g. stereochemical configuration is described or claimed, the invention includes a mixture comprising (a) a major component of the compound or salt which is in the described or claimed configuration, together with (b) one or more minor components of the compound or salt which is/are not in the described or claimed configuration. Preferably, in such a mixture, the major component of the compound or salt which is in the described or claimed configuration represents 70% or more, or 75% or more, more preferably 85%) or more, still more preferably 90% or more, yet more preferably 95% or more, yet more preferably 98% or more, of the total amount of compound or salt present in the mixture on a molarity basis. The percentage of one isomeric / stereochemical component in a mixture of different isomeric / stereochemical components, and if appropriate enantiomeric and/or diastereomeric excesses, can be measured using techniques known in the art. Such methods include the following: (1) Measurement using NMR (e.g. ^H NMR) spectroscopy in the presence of chiral agent. One can measure a nuclear magnetic resonance (NMR) spectrum (preferably a *H NMR spectrum, and/or a solution-phase NMR spectrum e.g. in CDCI3 or D6-DMSO solvent) of the compound/salt mixture in the presence of a suitable chiral agent which "splits" the NMR peaks of a given atom in different isomers into different peak positions. The chiral agent can be: i) an optically pure reagent which reacts with the compound/salt e.g. to form a mixture of diastereomers, ii) a chiral solvent, iii) a chiral molecule which forms a transient species (e.g. diastereomeric species) with the compound/salt, or iv) a chiral shift reagent. See e.g. J. March, "Advanced Organic
Chemistry", 4th edn., 1992, pages 125-126 and refs. 138-146 cited therein. A chiral shift reagent can be a chiral lanthanide shift reagent such as tris[3-trifluoroacetyl-< - camphorato]europium-(III) or others as described in Morrill, "Lanthanide Shift Reagents in Stereochemical Analysis", VCH, New York, 1986. Whatever the chiral agent is that is used, usually, the relative integrals (intensities) for the NMR peaks of a given atom or group in different isomers can provide a measurement of the relative amounts of each isomer present. (2) Measurement using chiral chromatography, especially on an analytical scale. A suitable chiral column which separates the different isomeric components can be used to effect separation, e.g. using gas or liquid chromatography such as HPLC, and/or e.g. on an analytical scale. The peaks for each isomer can be integrated (area under each peak); and a comparison or ratio of the integrals for the different isomers present can give a measurement of the percentage of each isomeric component present. See for example: "Chiral Chromatography", Separation Science Series Author: T.E. Beesley and R.P.W. Scott, John Wiley & Sons, Ltd., Chichester, UK, 1998, electronic Book ISBN: 0585352690, Book ISBN: 0471974277. (3) Separation of pre-existing diastereomeric mixtures which are compounds/salts of the invention can be achieved (usually directly, without derivatisation) using separation techniques such as gas or liquid chromatography. Diastereomeric ratios and/or excesses can thereby be derived e.g. from the relative peak areas or relative separated masses. (4) Conversion with a chiral / optically-active agent and subsequent separation of the resulting isomers, e.g. diastereomers. Conversion can be via derivatisation of a derivatisable group (e.g. -OH, -NHR) on the compound/salt with an optically-active derivatising group (e.g. optically active acid chloride or acid anhydride); or can be via formation of an acid or base addition salt of the compound by treatment of the compound with an optically-active acid or base, such as + or - di-para-toluoyl tartaric acid. After derivatisation, separation of the resulting isomers e.g. diastereomers, can be using gas or liquid chromatography (usually non-chiral); or (especially with isomeric salts) can be by selective crystallisation of a single isomeric e.g. diastereoisomeric salt. Determination of isomeric ratios and/or excesses can be using chromatography peak areas or measurement of mass of each separated isomer. See e.g. J. March, "Advanced Organic Chemistry", 4th edn., 1992, pages 120-121 and 126, and refs. 105-115 and 147-149 cited therein. (5) Measurement of optical activity [alpha] of mixture and comparison with optical activity of pure isomer [alpha]max if available (e.g. see J. March, "Advanced
Organic Chemistry", 4th edn., 1992, page 125 and refs. 138-139 cited therein). This assumes a substantially linear relationship between [alpha] and concentration.
Certain of the groups, e.g. heteroaromatic ring systems, included in compounds of formula (I) or their salts may exist in one or more tautomeric forms. The present invention includes within its scope all such tautomeric forms, including mixtures.
Especially when intended for oral medicinal use, the compound of formula (I) can optionally have a molecular weight of 1000 or less, for example 800 or less, in particular 650 or less or 600 or less. Molecular weight here refers to that of the unsolvated "free base" compound, that is excluding any molecular weight contributed by any addition salts, solvent (e.g. water) molecules, etc.
The following processes can be used to make the compounds of the invention:
Figure imgf000036_0001
Process A
To form a compound of formula (I) wherein W = -CR >4 Rτ>5 Ar, a carboxylic acid of formula (II) can be converted into an activated compound of formula (III) wherein X1 = a leaving group substitutable by an amine (as defined below) and subsequently the activated compound can be reacted with an amine of formula ArCR4R5NH2:
Figure imgf000037_0001
For example, the activated compound (the compound of formula (III)) can be the acid chloride. This can be formed from the carboxylic acid (II) e.g. by reaction with thionyl chloride, either in an organic solvent such as chloroform or without solvent. Alternatively, the activated compound (the compound of formula (III)) can be an activated ester wherein the leaving group X S
Figure imgf000037_0002
The latter activated compound of formula (III) can be formed from the carboxylic acid (II) either:
(a) by reaction of the carboxylic acid with a carbodiimide such as EDC, which is 1-ethyl- 3-(3'-dimethylaminopropyl)carbodiimide and is also l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, or a salt thereof e.g. hydrochloride salt, preferably followed by reaction of the resulting product with 1-hydroxybenzotriazole (HOBT); reaction (a) usually being carried out in the presence of a solvent (preferably anhydrous) such as dimethyl formamide (DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25 °C);
or:
(b) by reaction with 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-Azabenzotriazol-l-yl)-N,N,N',N,-tetramethyluronium hexafluorophosphate (HATT ) ,in the presence of a base such as diisopropylethylamine (1Pr2-SIEt = DIPEA), and usually in the presence of a solvent such as dimethyl formamide
(DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25 °C). Compounds of formula (II) can be prepared by hydrolysis of an ester of formula (IN). This procedure preferably involves reaction of (IN) with either:
(a) a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane or
(b) an acid such as hydrochloric acid in a solvent e.g. an aqueous solvent such as aqueous dioxane:
Figure imgf000038_0001
( IV ) ( II )
Compounds of formula (IN) can be prepared according to a method, for example as described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027, by reaction of a compound of formula (N) with an amine of formula R3ΝH2. The reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane, l-methyl-2-pyrrolidinone (NMP) or acetonitrile. The reaction may require heating e.g. to ca. 60-180°C, for example ca. 140-160°C:
Figure imgf000038_0002
(V) (IV)
Compounds of formula (V) are also described in the above reference and can be prepared by reaction of a compound of formula (VI) with, for example, diethyl[chloro(cyclopropyl)methylene]malonate (Nil) (where X3 = Et) with heating, followed by reaction with phosphorous oxychloride, again with heating:
Figure imgf000039_0001
( VI ) ( V )
Compounds of formula (Nil) are also described in the above reference and can be prepared by reaction of a malonate derivative, for example diethyl(cyclopropylcarbonyl)malonate (NlTi), with phosphorus oxychloride in the presence of a base such as tributylamine. The reaction may require heating, e.g. to ca 80- 130°C, for example ca. 100-120°C:
Figure imgf000039_0002
( VII ) ( VIII )
Compounds of formula (Nil) are also described in the above reference and can be prepared by reaction of diethyl malonate (IX) with magnesium powder followed by an acid chloride, for example cyclopropylcarbonyl chloride (X).
Figure imgf000039_0003
Where the desired amino pyrazole of formula (NI) is not commercially available, preparation can be achieved using methods described by Dorgan et. al. in J. Chem. Soc, Perkin Trans. 1, (4), 938-42; 1980, by reaction of cyanoethylhydrazine with a suitable aldehyde of formula R40CHO in a solvent such as ethanol, with heating, followed by reduction with, for example sodium in a solvent such as t-butanol. R ^ should be chosen so as to contain one less carbon atom than R , for example R4^ = methyl will afford Rl = ethyl.
Figure imgf000040_0001
( VI )
In an alternative embodiment of Process A, the 4-chloro substituent in the compound of formula (V) can be replaced by another halogen atom, such as a bromine atom, or by another suitable leaving group which is displaceable by an amine of formula R3NH2. The leaving group can, for example, be an alkoxy group -OR such as -OCι-4alkyl (in particular -OEt) or a group -O-S(O)2-R3^, wherein R ^ is Cι_galkyl (e.g. Cι_4alkyl or Cι_2 lkyl such as methyl), Ci.gfluoroalkyl (e.g. Cifluoroalkyl or Cifluoroalkyl such as CF3 or C4F9), or phenyl wherein the phenyl is optionally substituted by one or two of independently Chalky., halogen or Cι_2alkoxy (such as phenyl or 4-methyl-phenyl). The reaction may be carried out with or without solvent and may require heating.
Process B
Compounds of formula (I) can be prepared by reaction of a compound of formula (XI) with an amine of formula R3NH2. The reaction is preferably carried out in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, THF, dioxane or acetonitrile. The reaction may require heating, e.g. to ca. 60-100 °C or ca. 80-90 °C, for example for 8-48 or 12-24 hours:
Figure imgf000040_0002
( XI ) ( I )
Compounds of formula (XI) can be prepared in a two step procedure as described by Bare et. al. inJ Med. Chem. 1989, 32, 2561-2573. This process involves, first, reaction of a compound of formula (XII) with thionyl chloride (or another agent suitable for forming an acid chloride from a carboxylic acid), either in an organic solvent such as chloroform or THF, or as a neat solution. This reaction may require heating and the thus-formed intermediate may or may not be isolated. Step two involves reaction with an amine of formula WNH2, in an organic solvent such as THF or chloroform and may also involve the use of a base such as triethylamine or diisopropylethylamine:
Figure imgf000041_0001
( Xll ) ( XI )
Compounds of formula (XII) can be prepared by hydrolysis of an ester of formula (V) according to the method described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027. This procedure preferably involves reaction with a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:
Figure imgf000041_0002
( V ) ( XII )
In an alternative embodiment of Process B, the 4-chloro substituent in the compound of formula (IN) can be replaced by another halogen atom, such as a bromine atom.
Process C
Compounds of formula (IN) can be prepared by reaction of a compound of formula (XIII) with an alkylating agent of formula R^-X4, where X4 is a leaving group displaceable by the 1 -position pyrazolopyridine nitrogen atom of the compound of formula (XIII):
Figure imgf000042_0001
A suitable alkylating agent of foπnula R^-X4 can be used. For example, X4 can be a halogen atom such as a chlorine atom or more preferably a bromine or iodine atom, or X3 can be -O-S(O)2-R3^ wherein R3^ is Ci.galkyl (e.g. Cι_4alkyl or C _2alkyl such as methyl), Ci.βfluoroalkyl (e.g. Cifluoroalkyl or C _2fluoroalkyl such as CF3 or C4F9), or phenyl wherein the phenyl is optionally substituted by one or two of independently Cι_2alkyl, halogen or Cι_2alkoxy (such as phenyl or 4-methyl-phenyl). The reaction is preferably carried out in the presence of a base; the base can for example comprise or be potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, or a basic resin or polymer such as polymer-bound 2-tert-butylimino-2-diethylamino-l,3-dimethyl- perhydro-l,3,2-diazaphosphorine. The reaction is preferably carried out in the presence of a solvent, e.g. an organic solvent such as DMF; the solvent is preferably anhydrous.
Compounds of formula (XIII) can be prepared, using a method analogous to that used for the preparation of compounds (IN), by reaction of a compound of formula (N) (R1 = H) with an amine of formula R3ΝH2. The reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane or acetonitrile. The reaction may require heating e.g. to ca. 60- 100°C, for example ca. 80-90°C:
Figure imgf000042_0002
(V) (XIII)
Process D: Conversion of one compound of formula (I)-(IV) or salt thereof into another compound of formula (I)-(IV) or salt thereof
One compound of formula (ι)-(IN) or salt thereof can be converted into another compound of formula (I)-(IN) or salt thereof. This conversion preferably comprises or is one or more of the following processes DI to D7: D 1. Conversion of a ketone into the corresponding oxime.
D2. An oxidation process. For example, the oxidation process can comprise or be oxidation of an alcohol to a ketone (e.g. using Jones reagent) or oxidation of an alcohol or a ketone to a carboxylic acid.
D3. A reduction process, for example reduction of a ketone or a carboxylic acid to an alcohol.
D4. Alkylation, for example alkylation of an amine or of a hydroxy group.
D5. Hydrolysis, e.g. hydrolysis of an ester to the corresponding carboxylic acid or salt thereof.
D6. Deprotection, e.g. deprotection (e.g. deacylation or t-butyloxycarbonyl (BOC) removal) of an amine group.
D7. Formation of an ester or amide, for example from the corresponding carboxylic acid.
The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal such as a human. The compound or salt can be for use in the treatment and/or prophylaxis of any of the diseases / conditions described herein (e.g. for use in the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal) and/or for use as a phosphodiesterase inhibitor e.g. for use as a phosphodiesterase 4 (PDE4) inhibitor. "Therapy" may include treatment and/or prophylaxis.
Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal such as a human, e.g. for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.
Also provided is a method of treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal (e.g. human) in need thereof, e.g. a method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal (e.g. human) in need thereof, which method comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt thereof. Phosphodiesterase 4 inhibitors are thought to be useful in the treatment and/or prophylaxis of a variety of diseases / conditions, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: asthma, chronic obstructive pulmonary disease (COPD) (e.g. chronic bronchitis and/or emphysema), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple sclerosis, cognitive impairment (e.g. in a neurological disorder such as Alzheimer's disease), depression, or pain. Ulcerative colitis and/or Crohn's disease are collectively often referred to as inflammatory bowel disease.
In the treatment and/or prophylaxis, the inflammatory and/or allergic disease is preferably chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD or asthma in a mammal (e.g. human).
PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M.A.Giembycz, Drugs, Feb. 2000, 59(2), 193-212; Z. Huang et al, Current Opinion in Chemical Biology, 2001, 5: 432-438; H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466- 473; and references cited in the aforementioned publications).
PDE4 inhibitors are thought to be effective in the treatment of COPD. For example, see S.L. Wolda, Emerging Drugs, 2000, 5(3), 309-319; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466- 473; and references cited in the aforementioned publications; and G. Krishna et al.,
Expert Opinion on Investigational Drugs, 2004, 13(3), 255-267 (see especially pp. 259- 261 and refs. 102-111 and 201 therein). COPD is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (e.g., see S.L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).
PDE4 inhibitors are thought to be effective in the treatment of allergic rhinitis (e.g. see B.M. Schmidt et al., J. Allergy & Clinical Immunology, 108(4), 2001, 530-536).
PDE4 inhibitors are thought to be effective in the treatment of rheumatoid arthritis and multiple sclerosis (e.g. see H.J.Dyke et al, Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; and A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466-473; and references cited in these publications). See e.g. A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466-473 and references cited therein for atopic dermatitis use.
PDE4 inhibitors have been suggested as having analgesic properties and thus being effective in the treatment of pain (A.Kumar et al., Indian J. Exp. Biol, 2000, 38(1), 26- 30).
In the invention, the treatment and/or prophylaxis can be of cognitive impairment e.g. cognitive impairment in a neurological disorder such as Alzheimer's disease. For example, the treatment and/or prophylaxis can comprise cognitive enhancement e.g. in a neurological disorder. See for example: H.T.Zhang et al. in: Psychopharmacology, June 2000, 150(3), 311-316 and Neuropsychopharmacology, 2000, 23(2), 198-204; and T. Egawa et al., Japanese J. Pharmacol, 1997, 75(3), 275-81.
PDE4 inhibitors such as rolipram have been suggested as having antidepressant properties (e.g. J. Zhu et al, CNS Drug Reviews, 2001, 7(4), 387-398; O'Donnell, Expert Opinion on Investigational Drugs, 2000, 9(3), 621-625; and H.T. Zhang et al., Neuropsychopharmacology, October 2002, 27(4), 587-595).
For use in medicine, the compounds of the present invention are usually administered as a pharmaceutical composition. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients. The pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein. The invention also provides a method of preparing a phamiaceutical composition comprising a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients, the method comprising mixing the compound or salt with the one or more pharmaceutically acceptable carriers and/or excipients. The invention also provides a pharmaceutical composition prepared by said method. The compounds of formula (I) and/or the pharmaceutical composition may be administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration. Accordingly , the pharmaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration. More preferably, the pharmaceutical composition is suitable for inhaled or oral administration, e.g. to a mammal such as a human. Inhaled administration involves topical administration to the lung e.g. by aerosol or dry powder composition. Oral administration to a human is most preferred. A pharmaceutical composition suitable for oral administration can be liquid or solid; for example it can be a syrup, suspension or emulsion, a tablet, a capsule or a lozenge. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent. A pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations. The carrier can for example be or include lactose, cellulose (for example microcrystalline cellulose), or mannitol. The tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example a binding agent such as hydroxypropylmethylcellulose or povidone (polyvinylpyrollidone), a lubricant e.g. an alkaline earth metal stearate such as magnesium stearate, and/or a tablet disintegrant such as sodium starch glycollate, croscarmellose sodium, or crospovidone (cross-linked polyvinylpyrollidone). The phannaceutical composition being a tablet can be prepared by a method comprising the steps of: (i) mixing the compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, with the one or more pharmaceutically acceptable carriers and/or excipients, (ii) compressing the resulting mixture (which is usually in powder form) into tablets, and (iii) optionally coating the tablet with a tablet film-coating material. A pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures. For example, pellets or powder containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule. Alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutically acceptable carrier, for example an aqueous gum or an oil and the dispersion or suspension then filled into a soft gelatin capsule. Preferably the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human. A parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Alternatively, the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration. Compositions for nasal or inhaled administration may conveniently be formulated as aerosols, drops, gels or dry powders. Aerosol formulations, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non- aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide, or an organic propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane. Suitable HFC propellants include 1,1,1,2,3,3,3- heptafluoropropane and 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also take the form of a pump-atomiser.
For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. Micronisation usually involves subjecting the compound/salt to collisional and/or abrasional forces in a fast-flowing circular or spiral/vortex-shaped airstream often including a cyclone component. The preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns, e.g. about 1 to about 7 microns (e.g. as measured using laser diffraction). For example, it is preferable for the compound or salt of formula (I) to have a particle size defined by: a D10 of about 0.3 to about 3 microns (e.g. about 0.5 to about 2 microns, or about 1 micron), and/or a D50 of about 0.5 to about 10 microns or about 1 to about 7 microns (e.g. about 2 to about 5 microns or about 2 to about 4 microns), and/or a D90 of about 1 to about 30 microns or about 2 to about 20 microns or about 3 to about 15 microns (e.g. about 5 to about 15 microns or about 5 to about 10 microns); for example as measured using laser diffraction.
In particle size measurements, D90, D50 and D10 respectively mean that 90%, 50% and 10%) of the material is less than the micron size specified. D50 is the median particle size. DN90, DN50 and DN10 respectively mean that 90%, 50% and 10% by volume of the material is less than the micron size specified. DM90, DM50 and DM10 respectively mean that 90%, 50% and 10% by weight of the material is less than the micron size specified.
Laser diffraction measurement of particle size can use a dry method (wherein a suspension of the compound/salt in an airflow crosses the laser beam) or a wet method [wherein a suspension of the compound/salt in a liquid dispersing medium, such as isooctane or (e.g. if compound is soluble in isooctane) 0.1% Tween 80 in water, crosses the laser beam]. With laser diffraction, particle size is preferably calculated using the Fraunhofer calculation; and/or preferably a Malvern Mastersizer or Sympatec apparatus is used for measurement. For example, particle size measurement and/or analysis by laser diffraction can use any or all of (preferably all of) the following: a Malvern Mastersizer longbed version, a dispersing medium of 0.1% Tween 80 in water, a stir rate of ca. 1500 rpm, ca. 3 mins sonification prior to final dispersion and analysis, a 300 RF (Reverse Fourier) lens, and/or the Fraunhofer calculation with Malvern software.
For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the pharmaceutical composition is a dry powder inhalable composition. Such a composition can comprise a powder base such as lactose or starch, the compound of formula (I) or salt thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine, mannitol, trehalose and/or magnesium stearate. Preferably, the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof. The lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is preferably inhalation-grade and/or fine-grade lactose. Preferably, the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g. 10-300 microns e.g. 50-300 microns) in diameter, and/or 50%> or more of the lactose particles being less than 100 microns in diameter. Optionally, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50%) or more of the lactose particles being less than 40-70 microns in diameter. Most importantly, it is preferable that about 3 to about 30% (e.g. about 10%) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands). hi the dry powder inhalable composition, preferably, the compound of formula (I) or salt thereof is present in about 0.1% to about 70% (e.g. about 1% to about 50%, e.g. about 5% to about 40%, e.g. about 20 to about 30%) by weight of the composition. An illustrative non-limiting example of a dry powder inhalable composition follows:
Dry Powder Formulation Example - Dry powder Lactose Blend Preparation Using a size-reduced e.g. micronised form of the compound of formula (I) or salt thereof, the dry powder blend is prepared by mixing the required amount of the compound/salt (e.g. 10 mg, 1% w/w) with inhalation-grade lactose containing 10% fines (e.g. 990 mg, 99% w/w) in a Teflon™ (polytetrafluoroethene) pot in a Mikro-dismembrator ball-mill (but without a ball bearing) at % speed (ca. 2000-2500 rpm) for about 4 hours at each blend concentration. The Mikro-dismembrator (available from B. Braun Biotech International, Schwarzenberger Weg 73-79, D-34212 Melsungen, Germany; www.bbraunbiotech.com) comprises a base with an upwardly-projecting and sidewardly- vibratable arm to which is attached the Teflon TM p0t_ χhe vibration of the arm achieves blending. Other blends: 10% w/w compound/salt (50 mg) + 90% w/w lactose (450 mg, inhalation-grade lactose containing 10% fines). Serial dilution of the 1% w/w blend can achieve e.g. 0.1% and 0.3% w/w blends. Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel-openable on demand and the dose, e.g. of the dry powder composition, can be administered by inhalation via a device such as the DISKUS TM device, marketed by GlaxoSmithKline. The DISKUS ™ inhalation device is usually substantially as described in GB 2,242,134 A. In such device at least one container for the pharmaceutical composition in powder form (the at least one container preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: means defining an opening station for the said at least one container; means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the phamiaceutical composition in powder form from the opened container.
Preferably the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human. In the pharmaceutical composition, a or each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. A or each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. A phaπnaceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g. human) in a daily oral or parenteral dose of 0.001 mg to 50 mg per kg body weight per day (mg/kg/day), for example 0.01 to 20 mg/kg/day or 0.03 to 10 mg/kg/day or 0.1 to 2 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. A pharmaceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g. human) in a daily nasal or inhaled dose of: 0.0001 to 5 mg/kg/day or 0.0001 to 1 mg/kg/day, e.g. 0.001 to 1 mg/kg/day or 0.001 to 0.3 mg/kg/day or 0.001 to 0.1 mg/kg/day or 0.005 to 0.3 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The pharmaceutically acceptable compounds or salts of the invention is preferably administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day e.g. 2 to 500 mg per day, or a nasal or inhaled dose of 0.001 to 300 mg per day or 0.001 to 50 mg per day or 0.01 to 30 mg per day or 0.01 to 5 mg per day or 0.02 to 2 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
The compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a β2 adrenoreceptor agonist, an anti-histamine, an anti-allergic or an anti-inflammatory agent.
The invention thus provides, in a further aspect, a combination comprising a compound of fonnula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent, for example, a β2-adrenoreceptor agonist, an anti-histamine, an anti-allergic, an anti-inflammatory agent or an antiinfective agent.
Preferably, the β2-adrenoreceptor agonist is salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline, or a salt thereof (e.g. pharmaceutically acceptable salt thereof), for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β2-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 12-24 hour period such as salmeterol or formoterol. Preferably, the β2-adrenoreceptor agonist is for inhaled administration, e.g. once per day and/or for simultaneous inhaled administration; and more preferably the β2-adrenoreceptor agonist is in particle-size-reduced form e.g. as defined herein. Preferably, the β2-adrenoreceptor agonist combination is for treatment and/or prophylaxis of COPD or asthma. Salmeterol or a pharmaceutically acceptable salt thereof, e.g. salmeterol xinofoate, is preferably administered to humans at an inhaled dose of 25 to 50 micrograms twice per day (measured as the free base). The combination with a β2-adrenoreceptor agonist can be as described in WO 00/12078.
Preferred long acting β2-adrenoreceptor agonists include those described in WO 02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933.
Especially preferred long-acting β2-adrenoreceptor agonists include compounds of formula(XX) (described in WO 02/066422):
Figure imgf000050_0001
or a salt or solvate thereof, wherein in formula (XX): mx is an integer of from 2 to 8; nx is an integer of from 3 to 11 , with the proviso that mx + nx is 5 to 19,
R11X is -XSO2NR16xR17X wherein X is -(CH2)p χ- or C -6 alkenylene;
R16x and R17X are independently selected from hydrogen, Cι-6alkyl, C3-7cycloalkyl,
C(O)NR18XR19X, phenyl, and phenyl (C1-4alkyl)-, or R16x and R17X, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring, and R16x and R17X are each optionally substituted by one or two groups selected from halo, Cι-6alkyl, Cι-6haloalkyl, Cι- alkoxy, hydroxy- substituted Cι-6alkoxy, -CO2R18x, -SO NR18XR19X, -CONR18XR19X, -NR18 C(O)R19X, or a 5-, 6- or 7-membered heterocylic ring; R18X and R19X are independently selected from hydrogen, Cι-6alkyl,
C3-6cycloalkyl, phenyl, and phenyl (C1-4alkyl)-; and px is an integer of from 0 to 6, preferably from 0 to 4;
R12X and R13X are independently selected from hydrogen, Cι-6alkyl, Cι-6alkoxy, halo, phenyl, and Cι-6haloalkyl; and R14X and R15X are independently selected from hydrogen and Cι-4alkyl with the proviso that the total number of carbon atoms in R14X and R15X is not more than 4.
Preferred β2-adrenoreceptor agonists disclosed in WO 02/066422 include:
3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide and
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide.
A preferred β2-adrenoreceptor agonist disclosed in WO 03/024439 is: 4-{(lR)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-l-hydroxyethyl}-2- (hydroxymethyl)phenol.
A combination of a compound of formula (I) or salt together with an anti-histamine is preferably for oral administration (e.g. as a combined composition such as a combined tablet), and can be for treatment and/or prophylaxis of allergic rhinitis. Examples of anti- histamines include methapyrilene, or HI antagonists such as cetirizine, loratadine (e.g. Clarityn TM^ desloratadine (e.g. Clarinex TM) or fexofenadine (e.g. Allegra M)
The invention also provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic compound, e.g. a muscarinic (M) receptor antagonist in particular an M , M2, M1/M2, or
M3 receptor antagonist, more preferably a M3 receptor antagonist, still more preferably a M3 receptor antagonist which selectively antagonises (e.g. antagonises 10 times or more strongly) the M3 receptor over the M and/or M2 receptor. For combinations of anticholinergic compounds / muscarinic (M) receptor antagonist with PDE4 inhibitors, see for example WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 Al and US 2002/052312 Al, and some or all of these publications give examples of anticholinergic compounds / muscarinic (M) receptor antagonists which may be used with the compounds of formula (I) or salts, and/or suitable pharmaceutical compositions. For example, the muscarinic receptor antagonist can comprise or be an ipratropium salt (e.g. ipratropium bromide), an oxitropium salt (e.g. oxitropium bromide), or more preferably a tiotropium salt (e.g. tiotropium bromide); see e.g. EP 418 716 Al for tiotropium.
The anticholinergic compound or muscarinic (M) receptor antagonist, e.g. M3 receptor antagonist, is preferably for inhaled administration, more preferably in particle-size- reduced form e.g. as defined herein. More preferably, both the muscarinic (M) receptor antagonist and the compound of formula (I) or the phannaceutically acceptable salt thereof are for inhaled administration. Preferably, the anticholinergic compound or muscarinic receptor antagonist and the compound of formula (I) or salt are for simultaneous administration. The muscarinic receptor antagonist combination is preferably for treatment and/or prophylaxis of COPD.
Other suitable combinations include, for example, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another anti- inflammatory agent such as an anti-inflammatory corticosteroid; or a non-steroidal anti- inflammatory drag (NSAID) such as a leukotriene antagonist (e.g. montelukast), an iNOS inhibitor, a tryptase inhibitor, a elastase inhibitor, a beta-2 integrin antagonist, a adenosine 2a agonist, a CCR3 antagonist, or a 5-lipoxogenase inhibitor; or an antiinfective agent (e.g. an antibiotic or an antiviral). An iNOS inhibitor is preferably for oral administration. Suitable iNOS inhibitors (inducible nitric oxide synthase inhibitors) include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Suitable CCR3 inliibitors include those disclosed in WO 02/26722.
In a combination comprising a compound of fonnula (I) or a pharmaceutically acceptable salt thereof together with an anti-inflammatory corticosteroid (which is preferably for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis), then preferably the anti-inflammatory corticosteroid is fluticasone, fluticasone propionate (e.g. see US patent 4,335,121), beclomethasone, beclomethasone 17-propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof, ciclesonide, budesonide, flunisolide, or a compound as described in WO 02/12266 Al (e.g. as claimed in any of claims 1 to 22 therein), or a pharmaceutically acceptable salt of any of the above. If the anti-inflammatory corticosteroid is a compound as described in WO 02/12266 Al, then preferably it is Example 1 therein {wMch is 6 ,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-llβ-hydroxy-16α-methyl-3- oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester} or Example 41 therein {which is 6α,9α-difluoro- 11 β-hydroxy- 16α-methyl- 17α-[(4-methyl- 1 ,3 -thiazole-5- carbonyl)oxy]-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester}, or a pharmaceutically acceptable salt thereof. The anti-inflammatory corticosteroid is preferably for intranasal or inhaled administration. Fluticasone propionate is preferred and is preferably for inhaled administration to a human either (a) at a dose of 250 micrograms once per day or (b) at a dose of 50 to 250 micrograms twice per day.
Also provided is a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with β2-adrenoreceptor agonist and an anti-inflammatory corticosteroid, for example as described in WO 03/030939 Al. Preferably this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis. The β2-adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 Al. Most preferably, in this "triple" combination, the β2-adrenoreceptor agonist is salmeterol or a pharmaceutically acceptable salt thereof (e.g. salmeterol xinafoate) and the anti- inflammatory corticosteroid is fluticasone propionate.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus a pharmaceutical composition comprising a combination as defined above together with one or more pharmaceutically acceptable carriers and/or excipients represent a further aspect of the invention.
The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical composition.
In one embodiment, the combination as defined herein can be for simultaneous inhaled administration and is disposed in a combination inhalation device. Such a combination inhalation device is another aspect of the invention. Such a combination inhalation device can comprise a combined pharmaceutical composition for simultaneous inhaled administration (e.g. dry powder composition), the composition comprising all the individual compounds of the combination, and the composition being incorporated into a plurality of sealed dose containers mounted longitudinally in a strip or ribbon inside the inhalation device, the containers being rupturable or peel-openable on demand; for example such inhalation device can be substantially as described in GB 2,242,134 A (DISKUS TM) and/or as described above. Alternatively, the combination inhalation device can be such that the individual compounds of the combination are administrable simultaneously but are stored separately (or wholly or partly stored separately for triple combinations), e.g. in separate pharmaceutical compositions, for example as described in PCT/EP03/00598 filed on 22 January 2003, published as WO 03/061743 (e.g. as described in the claims thereof e.g. claim 1).
The invention also provides a method of preparing a combination as defined herein, the method comprising either (a) preparing a separate pharmaceutical composition for administration of the individual compounds of the combination either sequentially or simultaneously, or (b) preparing a combined pharmaceutical composition for administration of the individual compounds of the combination simultaneously, wherein the pharmaceutical composition comprises the combination together with one or more pharmaceutically acceptable carriers and/or excipients.
The invention also provides a combination as defined herein, prepared by a method as defined herein.
BIOLOGICAL TEST METHODS
PDE 3, PDE 4B, PDE 4D, PDE 5, PDE 6 Primary assay methods
The activity of the compounds can be measured in the assay methods shown below. Preferred compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D, preferably PDE4B) more strongly than they inhibit PDE3 and/or more strongly than they inhibit PDE5 and/or more strongly than they inhibit PDE6.
PDE enzyme sources and literature references
Human recombinant PDE4B, in particular the 2B splice variant thereof (HSPDE4B2B), is disclosed in WO 94/20079 and also M.M. McLaughlin et al, "A low Km, rolipram- sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterisation of recombinant protein, and tissue distribution of mRNA", J. Biol. Chem., 1993, 268, 6470-6476. For example, in Example 1 of WO 94/20079, human recombinant PDE4B is described as being expressed in the PDE- deficient yeast Saccharomyces cerevisiae strain GL62, e.g. after induction by addition of 150 uM CUSO4, and 100,000 x g supernatant fractions of yeast cell lysates are described for use in the harvesting of PDE4B enzyme.
Human recombinant PDE4D (HSPDE4D3A) is disclosed in P. A. Baecker et al, "Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phoshodiesterase (PDE IND)", Gene, 1994, 138, 253-256.
Human recombinant PDE5 is disclosed in K. Loughney et al., "Isolation and characterisation of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase", Gene, 1998, 216, 139-147.
PDE3 can be purified from bovine aorta, e.g. as described by H. Coste and P. Grondin, "Characterisation of a novel potent and specific inhibitor of type V phosphodiesterase", Biochem. Pharmacol, 1995, 50, 1577-1585.
PDE6 can be purified from bovine retina, e.g. as described by: P. Catty and P. Deterre, "Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis", Eur. J. Biochem., 1991, 199, 263-269; A. Tar et al. "Purification of bovine retinal cGMP phosphodiesterase", Methods in Enzymology, 1994, 238, 3-12; and/or D. Srivastava et al. "Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cyclic GMP phosphodiesterase", Biochem. J, 1995, 308, 653-658. Inhibition of PDE 3, PDE 4B, PDE 4D, PDE 5 or PDE 6 activity: radioactive Scintillation Proximity Assay (SPA)
The ability of compounds to inhibit catalytic activity at PDE4B or 4D (human recombinant), PDE3 (from bovine aorta), PDE5 (human recombinant) or PDE6 (from bovine retina) is determined by Scintillation Proximity Assay (SPA) in 96-well format. Test compounds (as a solution in DMSO, preferably about 2 microlitre (ul) volume of DMSO solution) are preincubated at ambient temperature (room temperature, e.g. 19- 23°C) in Wallac Isoplates (code 1450-514) with PDE enzyme in 50mM Tris-HCl buffer pH 7.5 , 8.3mM MgCl2, 1.7mM EGTA, 0.05% (w/v) bovine serum albumin for 10-30 minutes (usually 30 minutes). The enzyme concentration is adjusted so that no more than 20% hydrolysis of the substrate defined below occurs in control wells without compound, during the incubation. For the PDE3, PDE4B and PDE4D assays, [5',8-3H]Adenosine 3',5'-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.559; or Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, UK) is added to give 0.05uCi per well and ~ lOnM final concentration. For the PDE5 and PDE6 assays, [8- H]Guanosine 3',5'-cychc phosphate (Amersham Pharmacia Biotech, code TRK.392) is added to give 0.05uCi per well and ~ 36nM final concentration. Plates containing assay mixture, preferably approx. 100 ul volume of assay mixture, are mixed on an orbital shaker for 5 minutes and incubated at ambient temperature for 1 hour. Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ 0150) are added (~lmg per well) to terminate the assay. Plates are sealed and shaken and allowed to stand at ambient temperature for 35 minutes to lhour (preferably 35 minutes) to allow the beads to settle. Bound radioactive product is measured using a WALLAC TRILUX 1450 Microbeta scintillation counter. For inhibition curves, 10 concentrations (1.5nM - 30uM) of each compound are assayed. Curves are analysed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom) Results are expressed as pIC5o values.
In an alternative to the above radioactive SPA assay, PDE4B or PDE4D inhibition can be measured in the following Fluorescence Polarisation (FP) assay:
Inhibition ofPDE4B orPDE4D activity: Fluorescence Polarisation (FP) assay The ability of compounds to inhibit catalytic activity at PDE4B (human recombinant) or PDE4D (human recombinant) is determined by EVIAP Fluorescence Polarisation (FP) assay (IMAP Explorer kit, available from Molecular Devices Corporation, Sunnydale, CA, USA; Molecular Devices code: R8062) in 384-well format. The IMAP FP assay is able to measure PDE activity in an homogenous, non-radioactive assay format. The FP assay uses the ability of immobilised trivalent metal cations, coated onto nanoparticles (tiny beads), to bind the phosphate group of Fl-AMP that is produced on the hydrolysis of fluorescein-labelled (FI) cyclic adenosine mono-phosphate (Fl-cAMP) to the non-cyclic Fl-AMP form. Fl-cAMP does not bind. Binding of Fl-AMP product to the beads (coated with the immobilised trivalent cations) slows the rotation of the bound Fl-AMP and leads to an increase in the fluorescence polarisation ratio of parallel to perpendicular light. Inhibition of the PDE reduces/inhibits this signal increase. Test compounds (small volume, e.g. ca. 0.5 to 1 ul, preferably ca. 0.5 ul, of solution in DMSO) are preincubated at ambient temperature (room temperature, e.g. 19- 23 °C) in black 384-well microtitre plates (supplier: NUNC, code 262260) with PDE enzyme in lOmM Tris-HCl buffer pH 7.2, lOmM MgCl2, 0.1% (w/v) bovine serum albumin, and 0.05% NaN3 for 10-30 minutes. The enzyme level is set by experimentation so that reaction is linear throughout the incubation. Fluorescein adenosine 3 ',5 '-cyclic phosphate (from Molecular Devices Corporation, Molecular Devices code: R7091) is added to give about 40nM final concentration (final assay volume usually ca. 20-40 ul, preferably ca. 20 ul). Plates are mixed on an orbital shaker for 10 seconds and incubated at ambient temperature for 40 minutes. IMAP binding reagent (as described above, from Molecular Devices Corporation, Molecular Devices code: R7207) is added (60ul of a 1 in 400 dilution in binding buffer of the kit stock solution) to terminate the assay. Plates are allowed to stand at ambient temperature for 1 hour. The Fluorescence Polarisation (FP) ratio of parallel to perpendicular light is measured using an AnalysfT pjate reader (from Molecular Devices Corporation). For inhibition curves, 10 concentrations (1.5nM - 30uM) of each compound are assayed. Curves are analysed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom). Results are expressed as pIC50 values. In the FP assay, all reagents are dispensed using MultidropTM (available from Thermo Labsystems Oy, Ratastie 2, PO Box 100, Vantaa 01620, Finland).
For a given PDE4 inhibitor, the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly. However, in a regression analysis of 100 test compounds (not necessarily compounds of the invention), the PIC50 inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units, for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R.Mobbs et al., "Comparison of the EVIAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity", poster presented at 2003 Molecular Devices UK & Europe User Meeting, 2nd October 2003, Down Hall, Harlow, Essex, United Kingdom).
Biological Data obtained for some of the Examples (PDE4B inhibitory activity, either as one reading or as an average of ca. 2-6 readings) are as follows, based on current measurements only. In each of the SPA and FP assays, absolute accuracy of measurement is not possible, and the readings given are accurate only up to about ± 0.5 of a log unit, depending on the number of readings made and averaged:
All of the Examples have been tested for PDE4B inhibition using the radioactive SPA assay or the FP assay or in a similar assay. All of the Examples tested have PDE4B inhibitory activities in the range of pIC50 = about 7 (± about 0.5) to about 9 (± about 0.5). All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
EXAMPLES
The various aspects of the invention will now be described by reference to the following examples. These examples are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In this section, "hitermediates" represent syntheses of intermediate compounds intended for use in the synthesis of the "Examples".
Abbreviations used herein:
CC14 carbon tetrachloride
DCM dichloromethane
DMF dimethyl formamide DP EA diisopropylethyl amine Φ^NEt)
EtOAc ethyl acetate Et2O diethyl ether
Et3N triethylamine
EtOH ethanol
HATU O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl hydrogen chloride/hydrochloric acid
Na2SO4 sodium sulfate
NaHCO3 sodium bicarbonate
NMP l-methyl-2-pyrrolidinone
PhCH3 toluene PPA polyphosphoric acid
HPLC high pressure liquid chromatography
SPE solid phase extraction NMR nuclear magnetic resonance (in which: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, H = no. of protons)
LCMS liquid chromatography/mass spectroscopy
TLC thin layer chromatography h hours TRET retention time
Room temperature this is usually in the range of about 20 to about 25 °C.
General Experimental Details
Machine Methods used herein:
LCMS (liquid chromatography/mass spectroscopy) Waters ZQ mass spectrometer operating in positive ion electrospray mode, mass range
100-1000 amu.
UN wavelength : 215-330nM
Column : 3.3cm x 4.6mm ID, 3μm ABZ+PLUS Flow Rate : 3ml/min
Injection Volume : 5μl
Solvent A : 95% acetonitrile + 0.05% formic acid
Solvent B : 0.1% formic acid + lOmMolar ammonium acetate
Gradient : 0% A/0.7min, 0-100% A/3.5min, 100% A/l.lmin, 100-0% A 0.2min It should be noted that retention times (TRET) quoted herein may vary slightly (+/-
O.lmin.) when samples were run on different Waters machines, even though the same type of column and identical flow rates, injection volumes, solvents and gradients were used.
Mass directed autoprep HPLC The prep column used was a Supelcosil ABZplus (10cm x 2.12cm)
(usually 10cm x 2.12cm x 5 μm).
UN wavelength : 200-320nM
Flow : 20ml/min
Injection Volume: 1ml; or more preferably 0.5 ml Solvent A : 0.1% formic acid
Solvent B : 95% acetonitrile + 5% formic acid; or more usually 99.95% acetonitrile +
0.05% formic acid
Gradient : 100% A lmin, 100-80% A/9min, 80-1% A 3.5min, 1% A/1.4min, 1-
100%A/0.1min
Intermediates and Examples
All reagents not detailed in the text below are commercially available from established suppliers such as Sigma- Aldrich. The addresses of the suppliers for some of the starting materials mentioned in the Intermediates and Examples below or the Assays above are as follows:
- Aldrich (catalogue name), Sigma-Aldrich Company Ltd., Dorset, United Kingdom, telephone: +44 1202 733114; Fax: +44 1202 715460; ukcustsv@,eurnotes.sial.com: or - Aldrich (catalogue name), Sigma-Aldrich Corp., P.O. Box 14508, St. Louis, MO 63178-9916, USA; telephone: 314-771-5765; fax: 314-771-5757; [email protected]: or Aldrich (catalogue name), Sigma-Aldrich Chemie Gmbh, Munich, Germany; telephone: +49 89 6513 0; Fax: +49 89 6513 1169; [email protected].
- Bionet Research Ltd; Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ UK - Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA (CAS 38041-19-9) Lancaster Synthesis Ltd., Newgate, White Lund, Morecambe, Lancashire LA3 3DY, United Kingdom Matrix Scientific, P.O. Box 25067, Columbia, SC 29224-5067, USA Trans World Chemicals, Inc., 14674 Southlawn Lane, Rockville, MD 20850, USA
Figure imgf000061_0001
Figure imgf000062_0002
Cyclopropylacetyl chloride
D Prepared from cyclopropyl acetic acid according to the procedure outlined in:
Bouzoubaa, Mohamed; Leclerc, Gerard; Decker, Nicole; Schwartz, Jean; Andermann, Guy; J.Med.Chem; 1984, 27 (10); 1291-1294.
Intermediate 1 : Diethyl (cyclopropylcarbonyl)malonate
Figure imgf000062_0001
A solution of diethyl malonate (6ml) in EtOΗ (20ml) was added to solid magnesium powder (lg) and CC14 (1ml) at such a rate as to maintain a constant reflux. Et2O (20ml) was added and the mixture was heated under reflux for 2h. The solvents were removed under reduced pressure and the residue was azeotroped with PhCΗ3 (2x10ml). The solid residue was dissolved in Et2O (40ml) and the solution was added to a cooled solution of cylopropane carbonyl chloride (3.6ml), maintaining the temperature between 0 and 5°C. The mixture was allowed to warm slowly to room temperature and stirred for 16 hours. The mixture was treated with 5% aqueous sulphuric acid solution (100ml), with stirring. The organic phase was separated, washed with saturated aqueous NaHCO3 (2x75ml), dried over anhydrous Na2SO4, filtered and the filtrate evaporated to dryness to leave Intermediate 1 as a colourless oil (7.74g). LCMS showed MET1" = 229; TRET = 2.79min.
Similarly prepared from diethyl malonate were the following:
Figure imgf000063_0001
Figure imgf000063_0003
Intermediates 7-11
These intermediates were prepared using a modification of the procedure developed by O.E.O. Hormi and described in Synthetic Commun; 1986, 16, 997 - 1002.
Intermediate 7: Diethyl [chloro(cyclopropyl)methy!ene] malonate
Figure imgf000063_0002
A mixture of intermediate 1 (lg), phosphorus oxychloride (10ml) and tributylamine (1.1ml) was stirred at 110°C for 5h. The volatile organics were removed under reduced pressure. The mixture was dissolved in Et2O (20ml) and n-hexane was added until two layers formed. The top layer was collected. More n-hexane was added until two layers formed again. This procedure was repeated once more. The combined Et2O extracts were washed with dilute aqueous HCl (IM, 2x50ml), dilute aqueous NaOH (IM, 2x50ml) and water (2x50ml), dried over anhydrous Na2SO4, filtered and evaporated to give intermediate 7 as a pale yellow oil (0.87g). LCMS showed MH+ = 249; TRET = 3.49min.
Similarly prepared from Intermediates 3-6 were the following:
Figure imgf000064_0001
Figure imgf000064_0003
Intermediate 12: Ethyl 4-chloro-6-cycIopropvl-l-ethyl-l-H-pvrazolof3,4-61pvridine- 5-carboxylate
Figure imgf000064_0002
A mixture of intermediate 7 (6.75g), Et3N (2.88ml) and 5-amino-l -ethyl pyrazole (3.28g) in PhCH3 (40ml) was heated at reflux for 16 hours. The solvent was removed under reduced pressure and the residue was treated with phosphorus oxychloride (50ml). The reaction mixture was heated at 110°C for 16 hours. The phosphorus oxychloride was removed under reduced pressure and the residue was partitioned between EtOAc (50ml) and saturated aqueous NaHCO3 (50ml). The organic layer was collected, dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a 50g SiO2 SPE cartridge, eluting with 5%EtOAc: 95 %> cyclohexane, to give Intermediate 12 as a yellow oil (1.53g). LCMS showed MH+ = 294; TRET = 3.4min.
Similarly prepared from Intermediates 8-11 were the following:
Figure imgf000065_0001
Figure imgf000065_0003
Intermediate 17 ; Ethyl-4-chloro-6-cvclopentvI-l-ethyl- IH-pyrazolo F3,4-Z>1 pyridϊne- 5-carboxylate
Figure imgf000065_0002
A mixture of Intermediate 2 (1.6g) and 5-amino-l-ethyl pyrazole (0.69g) in PPA (12ml) was heated at 120°C for 3h. The mixture was poured into water (50ml) and extracted with Et2O (3x75ml). The organic extracts were combined, dried (Na2SO4), filtered and the filtrate concentrated to leave a yellow oil. Phosphorus oxychloride (50ml) was added to the oil. The mixture was heated at 110° for 16h. The phosphorus oxychloride was removed and the residue was partitioned between EtOAc (50ml) and saturated aqueous NaΗCO3 (25ml). The organic layer was collected, dried (Na2SO4), filtered and the filtrate was concentrated to leave Intennediate 17 as a tan solid (lOOmg). LCMS showed MH+ = 322; TREτ = 3.96min.
Intermediate 18: 4-Aminotetrahydropyran Commercially available from Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA (CAS 38041-19-9)
H2N— ( O Intermediate 19: Ethyl 6-cyclopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3,4-b] pyridine-5-carboxylate
Figure imgf000066_0001
A solution of Intermediate 12 (0.76g), Intermediate 18 (0.36g) and DIPEA (0.65ml) in NMP (8ml) was heated at 150°C for 16h. The mixture was allowed to cool and partitioned between EtOAc (100ml) and water (20ml). The organic layer was collected, dried (Na2SO4), filtered and concentrated to give a dark gum. The gum was purified on a 20g SiO2 SPE cartridge, eluting with 10%EtOAc : 90% Cyclohexane to give hitennediate 18 as a pale yellow solid (0.35g). LCMS showed MH+ = 359; TRET = 3.43min.
Similarly prepared from Intermediates 13-17 were the following:
Figure imgf000066_0002
Figure imgf000066_0003
Intermediate 25: 6-CycIopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lJΪ- pyrazolo[3,4~Z>]pyridine-5-carboxylic acid
Figure imgf000067_0001
A solution of intermediate 19 (0.35g) in EtOH (60ml) was treated with a solution of NaOH (0.75g) in water (20ml) and the reaction mixture was heated at 60°C for 16h. The solvents were removed under reduced pressure, the residue was suspended in water (5ml) and the pH of the solution was adjusted to 3 (IM HCl). The resultant suspension was extracted with EtOAc (2x30ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give Intermediate 25 as a white solid (0.30g). LCMS showed MH+ = 331; TRET = 2.41min
Similarly prepared from Intermediates 21-25 were the following:
Figure imgf000067_0002
Figure imgf000067_0003
Table of Examples
Example Name
Figure imgf000068_0001
Figure imgf000069_0002
Example 1 : N (4-chloro-2-methvlphenvI)methyl1-6-cvclopropvl-l-ethvl-4- (tetrahydro-2H-pyran-4-yIamino)-liϊ-pyrazolo[3,4-A]pyridine-5-carboxamide
Figure imgf000069_0001
A solution of Intermediate 20 (30mg) in DMF (2ml) was treated with HATU (35mg) and DIPEA (lOOμL). The solution was allowed to stand at 22°C for lOmin. then treated with 2-methyl-4-chloro benzylamine (supplier: Matrix Scientific) (14mg) and allowed to stand at 22°C for 16h. The solvent was evaporated and the residue was partitioned between DCM (5ml) and saturated aqueous NaHCO3 (2ml). The organic phase was collected through a hydrophobic frit and evaporated. The residue was purified by mass directed autoprep. HPLC to give Example las a white solid (14.9mg). LCMS showed MH+ = 468; TREτ = 3.45min.
The following Examples 2-6 were prepared from Intermediate 20 and the appropriate amine WNH2 using a similar procedure to that used for the preparation of Example 1 :
Figure imgf000070_0001
Figure imgf000070_0003
The following Examples 7-11 were prepared from Intermediate 21 and the appropriate amine WNH2 using a similar procedure to that used for the preparation of Example 1 :
Figure imgf000070_0002
Figure imgf000070_0004
Figure imgf000071_0002
The following Examples 12-16 were prepared from Intermediate 22 and the appropriate amine WNH2 using a similar procedure to that used for the preparation of Example 1:
Figure imgf000071_0001
Figure imgf000071_0003
The following Examples 17-23 were prepared from Intermediate 23 and the appropriate amine WNH using a similar procedure to that used for the preparation of Example 1 :
Figure imgf000072_0001
Figure imgf000072_0002
The following Examples 24-27 were prepared from Intermediate 24 and the appropriate amine WNH2 using a similar procedure to that used for the preparation of Example 1 :
Figure imgf000073_0001
Figure imgf000073_0003
The following Examples 28-29 were prepared from Intermediate 24 and the appropriate amine WNH using a similar procedure to that used for the preparation of Example 1 :
Figure imgf000073_0002
Figure imgf000073_0004

Claims

1. A compound of formula (I) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
Figure imgf000074_0001
wherein:
W is Ar, -CR >4τ R>5 Ar or a group (y) or (yl) wherein:
Figure imgf000074_0002
(x) (z)
Figure imgf000074_0003
wherein m = 1 or 2
R1 is Ci _4alkyl, Cι_3 fluoroalkyl, or -CH2CH2OH;
R^ is C2_6alkyl, C3_6"cycloalkyl or -(CH2)n^C3_6cycloalkyl, wherein n^ is 1 or 2;
R3 is optionally substituted C3_gcycloalkyl or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc);
Figure imgf000075_0001
(aa) (bb) (cc) in which n1 and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NR10; where R10 is a hydrogen atom (H), C^alkyl, Cifluoroalkyl, CH2C(O)NH2, C(O)NH2, C(O)NHMe, C(O)-C1_2alkyl, C(O)-Cχ fluoroalkyl or -C(O)-CH2O-Cι_2alkyl;
and wherein in R3 the C3_gcycloalkyl or the heterocyciic group of sub-formula (aa), (bb) or (cc) is optionally substituted on a ring carbon with one or two substituents independently being oxo (=O); OH; Cχ_2 alkoxy; Cχ_2fluoroalkoxy; NHR^l wherein R2 is a hydrogen atom (H) or Cχ.4 straight-chain alkyl; Cχ_2 alkyl; Cχ.2fluoroalkyl; -CH2OH; -CH2CH2OH; -CH2NHR22 wherein R22 is H or C 1.2alkyl; -C(O)OR23 wherein R23 is H or C^alkyl; -C(O)NHR24 wherein R24 is H or Ci^alkyl; -C(O)R25 wherein R2^ is Cχ_2alkyl; fluoro; hydroxyimino (=N-OH); or (Cχ.4alkoxy)imino
(=N-OR2^ where R2^ is Cχ_4alkyl); and wherein any OH, alkoxy, fluoroalkoxy or
NHR 1 substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyciic group (aa), (bb) or (cc);
and wherein, when R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, then the cycloalkenyl is optionally substituted with one substituent being fluoro or Cχ_2 alkyl or two substituents independently being fluoro or methyl , and the R3 ring carbon bonded to the -NH- group of formula (I) does not partake in the cycloalkenyl double bond;
Figure imgf000075_0002
or R3 is a bicyclic group of sub-formula (ee): (ee) wherein γl, Y2 and Y3 independently are CH2 or oxygen (O) provided that no more than one of γl, Y2 and Y3 is oxygen (O);
and wherein:
R4 and R5 are independently a hydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, C 1 _2fluoroalkyl, cyclopropyl, -CH2OR4a, -CH(Me)OR4a or -CH2CH2OR4a wherein
R a is a hydrogen atom (H), methyl (Me), or Cifluoroalkyl such as CF3 or CHF2- and wherein, in sub-formula (x) (y) and (yl):
A is C-R6A, nitrogen (N) or nitrogen-oxide (N+-O_), B is C-R6B, nitrogen (N) or nitrogen-oxide (N+-O"), D is C-R6D, nitrogen (N) or nitrogen-oxide (N+-O"), E is C-R^E. nitrogen (N) or nitrogen-oxide (N+-O"), F is C-R6F nitrogen (N) or nitrogen-oxide (N^-O"),
wherein, R6A? R6B? R6D5 R6E a^j R6F independently are: a hydrogen atom (H), a halogen atom; Ci.galkyl; Cx ^fluoroalkyl; C3_6cycloalkyl; Cχ_4alkoxy;
Figure imgf000076_0001
C3_6cycιoaιkyloxy; -C(O)R16a; -C(O)OR30; -S(O)2-R16a;
Rl6a.S(o)2-NRl5a.; R7R8N.S(0)2 C1.2alkyl-C(O)-R15aN-S(O)2-; Cχ_4alkyl-S(O)-,
Ph-S(O)-, R?R8N-CO-; -NR!5-C(O)R16a; R?R8N; nitro (-NO2); OH (including any tautomer thereof); C \ _4alkoxymethyl; C \ _4alkoxyethyl; C \ _2alkyl-S(O)2-CH2-;
R7R8N-S(O)2-CH2-; Cι_2alkyl-S(O)2-NR15a-CH2-; -CH2-OH; -CH2CH2-OH;
-CH2-NR7R8; -CH2-CH2-NR7R8; -CH2-C(O)OR30; -CH2-C(O)-NR7R8;
-CH2-NR15a-C(O)-C1.3alkyl; -(CH2)n 14-Het1 where n14 is 0 or 1; cyano (-CN); Ar5 ; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C \ _2alkyl,
Cx fluoroalkyl, Cχ_2alkoxy or C fluoroalkoxy;
and/or two adjacent groups selected from R6A? R6B; R6DS R6E an(χ R6F ΆXQ taken together and are: -CH=CH-CH=CH2- -(CH2)n 14a- where n14a is 3, 4 or 5, -O- (CMe2)-O- -O-(CH2)n 14b-O- where nl4 is 1 or 2; -CH=CH-NR15b-; -N=CH-NR15b-; -CH=N-NRl5b.; -N=N-NR15b-; -CH=CH-O-; -N=CH-O-; -CH=CH-S-; or -N=CH-S-; wherein R15b is H or Cχ.2alkyl;
provided that: two or more of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F
(carbon-fluorine), nitrogen (N), or nitrogen-oxide ST^-O-); and no more than two of A, B, D, E and F are independently nitrogen or nitrogen-oxide OST^-O"), and no more than one of A, B, D, E and F is nitrogen-oxide (N^-O-);
and wherein, in sub-formula (z):
G is O or S or NR9 wherein R9 is a hydrogen atom (H), C _4alkyl, or Cχ_2fluoroalkyl; J is C-R^J, C-[connection point to formula (I)], or nitrogen (N), L is C-R6L? C- [connection point to formula (I)], or nitrogen (N), M is C-R6M C-[connection point to formula (I)], or nitrogen (N), Q is C-R6Q, C- [connection point to formula (I)], or nitrogen (N),
wherein, R^J, R6L R6M and R^Q independently are: a hydrogen atom (H), a halogen atom; Cχ_4alkyl; C .3 fluoroalkyl; C3_6cycloalkyl; Cχ_4alkoxy; Cχ_2fluoroalkoxy; C3_6cycloalkyloxy; OH (including any tautomer thereof); or phenyl optionally substituted by one or two substituents independently being fluoro, chloro, C _2alkyl, Cx fluoroalkyl, Cχ_2alkoxy or C fluoroalkoxy;
provided that: two or more of J, L, M and Q are independently C-H, C-F, C-Cχ_2 alkyl,
C-[connection point to formula (I)], or nitrogen (N); and no more than three of J, L, M and Q are nitrogen (N);
and wherein:
R7 and R8 are independently a hydrogen atom (H); Cχ_4alkyl; C3_6cycloalkyl; or phenyl optionally substituted by one or two substituents independently being: fluoro, chloro, C _2 alkyl, C x fluoroalkyl, C x _2alkoxy or C x fluoroalkoxy;
or R7 and R8 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 10-C(O)- or -(CH2)n 8-X7-(CH2)n9- or -C(O)-X7-(CH2)n 10- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5, n8 and n^ and n^ independently are 2 or 3, and X7 is O or NR^4;
R7a is a hydrogen atom (H) or Cχ_4alkyl;
R a is a hydrogen atom (H) or methyl;
R 4, R 7 and R*7a independently are: a hydrogen atom (H); Cχ_4alkyl; Cχ_2fluoroalkyl (e.g. CF3); cyclopropyl; -C(O)-Cχ.4alkyl; -C(O)NR7aR8a; or -S(O)2-Cx.4alkyl;
Rl5a s independent of other R^^a, {s a hydrogen atom (H) or Cχ_4alkyl;
R16a is: Cχ_6alkyl;
C3_6cycloalkyl optionally substituted by one oxo (=O), OH or Cχ_2alkyl substituent;
C3_6cycloalkyl-CH2-; pyridinyl optionally substituted on a ring carbon atom by one of: a halogen atom, C x _2 alkyl, C x fluoroalkyl, C x _2 alkoxy or C fluoroallcoxy; Ar5c; phenyl optionally substituted by one or two substituents independently being: a halogen atom, Cχ_2alkyl, Cx fluoroalkyl, Cχ_2alkoxy or C fluoroalkoxy; benzyl optionally substituted on its ring by one or two substituents independently being: a halogen atom, C _2alkyl, Cx fluoroalkyl, Cχ_2 alkoxy or C fluoroalkoxy; or a 4-, 5-, 6- or 7-membered saturated heterocyciic ring connected at a ring-carbon and containing one or two ring-hetero-atoms independently selected from O, S, and N; wherein any ring-nitrogens which are present are present as NR27 where R27 is H, C _2 lkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one Cχ_2alkyl or oxo (=O) substituent, provided that any oxo (=O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
R ^, independent of other R3^, is a hydrogen atom (H), Cχ_4alkyl or C3_6cycloalkyl;
Ar^b and Ar^c independently is/are a 5-membered aromatic heterocyciic ring containing one O, S or NR^a m the 5-membered ring, wherein the 5-membered ring can optionally additionally contain one or two N atoms, and wherein the heterocyciic ring is optionally substituted on a ring carbon atom by one of: a halogen atom, Cχ_2alkyl, C fluoroalkyl,
-CH2OH, -CH2-OC _2 alkyl, OH (including the keto tautomer thereof) or -CH2-NR28R 9 wherein R28 and R29 independently are H or methyl; and
Hefl , is a 4-, 5-, 6- or 7-membered saturated heterocyciic ring connected at a ring-carbon and containing one or two ring-hetero-atoms independently selected from O, S, and N; wherein any ring-nitrogens which are present are present as NR3^ where R3^ is H, Cχ_2 lkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one
Cχ_2 alkyl or oxo (=O) substituent, provided that any oxo (=O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen.
2. A compound or salt as claimed in claim 1, wherein Rl is C2_3alkyl, C2fluoroalkyl or -CH2CH2OH.
3. A compound or salt as claimed in claim 2, wherein R is ethyl, n-propyl or -CH2CH2OH.
4. A compound or salt as claimed in claim 3, wherein R* is ethyl.
5. A compound or salt as claimed in claim 1, 2, 3 or 4, wherein R2 is C2_4alkyl, C3-5cycloalkyl or -CH2cyclopropyl.
6. A compound or salt as claimed in claim 5, wherein R2 is ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.
7. A compound or salt as claimed in any preceding claim, wherein in R3 there is one substituent or no substituent.
8. A compound or salt as claimed in any preceding claim, wherein R3 is the optionally substituted C3_8cycloalkyl or the optionally substituted heterocyciic group of sub-formula (aa), (bb) or (cc).
9. A compound or salt as claimed in any preceding claim, wherein, when R3 is optionally substituted C3_gcycloalkyl, it is optionally substituted cyclohexyl.
10. A compound or salt as claimed in any preceding claim, wherein, when R3 is optionally substituted C3_gcycloalkyl, then R3 is Cβ. cycloalkyl optionally substituted with one or two substituents independently being oxo (=O); OH; NHR21 wherein R2* is a hydrogen atom (H); methyl; -CH2F; -CHF ; -C(O)OR23 wherein R23 is H;
-C(O)NHR24 wherein R24 is H; fluoro; hydroxyimino (=N-OH); or methoxyimino (=N-OR26 where R26 is methyl).
11. A compound or salt as claimed in any claim 10, wherein, when R3 is optionally substituted C3_8cycloalkyl, then R3 is C6_7cycloalkyl optionally substituted with one or two substituents independently being OH; -C(O)NHR24 wherein R24 is H; oxo (=O) or hydroxyimino (=N-OH).
12. A compound or salt as claimed in any preceding claim, wherein, for R3, the one or two optional R3 substituents if present is or are substituent(s):
(a) at the 3-position of a R3 cyclobutyl ring, or
(b) at the 3- and/or 4- position(s) of a R3 cyclopentyl or cyclopentenyl ring, or (c) at the 3-, 4- and/or 5- position(s) of a R3 cyclohexyl or cyclohexenyl ring, or
(d) at the 3-, 4-, 5- and/or 6- position(s) of a R3 cycloheptyl or cycloheptenyl ring, or
(e) at the 3-, 4-, 5-, 6- and/or 7- position(s) of a R3 cyclooctyl ring, and/or
(f) at the 1-, 2- and/or highest-numbered- position(s) of a R3 cycloalkyl or cycloalkenyl ring, for alkyl or fluoroalkyl substituent(s), and/or
(g) at the 2- and/or highest-numbered- position(s) of a R3 cycloalkyl or cycloalkenyl ring, for NHR21 substituent(s).
13. A compound or salt as claimed in any preceding claim, wherein, when R3 is the heterocyciic group of sub-formula (aa), (bb) or (cc), then Y is O or NR^O.
14. A compound or salt as claimed in any preceding claim, wherein RlO is H, C(O)NH2 or C(O)methyl.
15. A compound or salt as claimed in claim 14, wherein R 0 is C(O)NH2-
16. A compound or salt as claimed in any preceding claim, wherein, when R3 is the heterocyciic group of sub-formula (aa), (bb) or (cc), then R3 is the heterocyciic group of sub-formula (bb) and n is 1.
17. A compound or salt as claimed in any preceding claim, wherein, in R3, the heterocyciic group of sub-formula (aa), (bb) or (cc) is unsubstituted on a ring carbon.
18. A compound or salt as claimed in any preceding claim, wherein:
when R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, it is mono-unsaturated-cyclohexenyl optionally substituted with one or two substituents independently being fluoro or methyl.
and when R3 is a bicyclic group of sub-formula (ee), then γl, Y2 and Y3 are all CH2.
19. A compound or salt as claimed in any preceding claim, wherein NHR3 is of sub- formula (a), (al), (b), (c), (c 1), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (g), (gl), (g2), (g3), (g4), (h), (i), (j), (k), (kl), (k2), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (p), (pi), (p2), (p3), (p4), (p5), (p6), (p7), (p8), (p9), (plO), (pll) or (q):
Figure imgf000081_0001
(c3) (c4) (c5) (c6) (c7)
Figure imgf000081_0002
(d) (e) (f) (g) (gD (g2) (g3) (g4)
Figure imgf000081_0003
(h) (i)
Figure imgf000081_0004
Figure imgf000081_0005
Figure imgf000081_0006
(q) (o1) (o2) (o3)
20. A compound or salt as claimed in claim 19, wherein NHR3 is of sub-formula (c), (cl), (c 4), (c 5), (h), (i), 0), (k), (k2), (ml), (m2), (n), (o), (o2), (o3), (p2), (p5), (p6), (p9), (pl l) or (q).
21. A compound or salt as claimed in claim 19, wherein NHR3 is of sub-formula (c), (pl l), (h), (k2), (n), (o), (o2) or (p9).
22. A compound or salt as claimed in claim 19, 20 or 21, wherein: when NHR3 is of sub-formula (n), then it is in the cis configuration, i.e. it is a cis- (3-hydroxycyclohexan-l-yl)amino group; and when NHR3 is of sub-formula (p9), then it is in the cis configuration, i.e. it is a ct_?-[4-(aminocarbonyl)cyclohexan-l-yl]amino group.
23. A compound or salt as claimed in claim 19, wherein NHR3 is of sub-formula (h) or (k2), that is R3 is tetrahydro-2H-pyran-4-yl or l-(aminocarbonyl)-4-piperidinyl.
24. A compound or salt as claimed in any preceding claim, wherein R4 is a hydrogen atom (H); methyl, ethyl, Cx fluoroalkyl, -CH2OH, -CH(Me)OH, -CH2CH2OH, or -CH2OMe.
25. A compound or salt as claimed in claim 24, wherein R4 is a hydrogen atom (H), methyl, ethyl, -CH2OH, or -CH2OMe.
26. A compound or salt as claimed in any preceding claim, wherein R^ is a hydrogen atom (H), methyl, ethyl, n-propyl, or iso-propyl.
27. A compound or salt as claimed in any preceding claim, wherein, in sub-formula (x): two or more of A, B, D, E and F are C-H (carbon-hydrogen); and one or more others of A, B, D, E and F are independently C-H (carbon-hydrogen), C-F . (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe, or nitrogen (N); no more than one of A, B, D, E and F is nitrogen; and none of A, B, D, E and F are nitrogen-oxide (N+-O~).
28. A compound or salt as claimed in any preceding claim, wherein Ar has the sub- formula (x).
29. A compound or salt as claimed in claim 28, wherein Ar has the sub-formula (x), and the sub-formula (x) is sub-formula (xl), (x2), (x3), (x4), (x5), (x6), (x7), (x8), (x9),
(xlO), (xll), (xl2), (xl3), (xl4), (xl5) or (xl6):
Figure imgf000083_0001
(x13) (x14) (x15) (x16)
30. A compound or salt as claimed in claim 29, wherein Ar has the sub-formula (x), and the sub-fonnula (x) is sub-formula (xl).
31. A compound or salt as claimed in claim 30, wherein Ar is of sub-formula (xl) and is: monoalkyl-phenyl-, mono(fluoroalkyl)-phenyl-, monohalo-phenyl-, monoalkoxy-phenyl-, mono(fluoroalkoxy)-phenyl-, dialkyl-phenyl-, monoalkyl-monohalo-phenyl-, dihalo-phenyl- or dihalo-monoalkyl-phenyl-.
32. A compound or salt as claimed in claim 31, wherein Ar is: monoC _4alkyl-phenyl-; monoC x fluoroalkyl-phenyl-; monoC _3alkoxy-phenyl-; mono(C fluoroalkoxy)-phenyl-; diC x _3alkyl-phenyl-; monoCχ_3 alkyl-monohalo-phenyl-; dihalo-phenyl-; or dihalo-monoCχ_2alkyl-phenyl-
33. A compound or salt as claimed in any preceding claim, wherein, in sub-formula (x), R6A, R6B, R6D, R6E and R6F, independently of each other, are: a hydrogen atom (H), a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, difluoromethoxy, OH or MeS(O)2-.
34. A compound or salt as claimed in any preceding claim, wherein R9 is a hydrogen atom (H) or methyl; R6J, R6L R6M and R^Q independently are H, OH (including any keto tautomer thereof), Cχ_2 alkyl or Cx fluoroalkyl; and when Ar has the sub-formula (z), then sub-formula (z) is one of the following:
Figure imgf000084_0001
35. A compound or salt as claimed in claim 1, which is one of Examples 1 to 29, as a compound or a pharmaceutically acceptable salt thereof.
36. A compound or salt as claimed in any preceding claim, for use as an active therapeutic substance in a mammal.
37. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 35, and one or more pharmaceutically acceptable carriers and/or excipients.
38. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 35, in the manufacture of a medicament for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal.
39. The use as claimed in claim 38, wherein the inflammatory and/or allergic disease is chronic obstructive pulmonary disease (COPD), asthma, rheumatoid artliritis or allergic rhinitis in a human.
40. A method of treatment and/or prophylaxis of an inflammatory and or allergic disease in a human in need thereof, which method comprises administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 35.
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Publication number Priority date Publication date Assignee Title
WO2007122165A1 (en) 2006-04-20 2007-11-01 Glaxo Group Limited Novel compounds
WO2007150016A2 (en) 2006-06-23 2007-12-27 Smithkline Beecham Corporation Il-8 receptor antagonist
WO2008009735A1 (en) * 2006-07-21 2008-01-24 Glaxo Group Limited Pyrazolo (3, 4-b) pyridine derivatives as pde4 inhibitors
WO2008015437A1 (en) * 2006-08-01 2008-02-07 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as pde4 inhibitors
WO2008118724A1 (en) 2007-03-23 2008-10-02 Smithkline Beecham Corporation Indole carboxamides as ikk2 inhibitors
US7528148B2 (en) 2002-12-23 2009-05-05 Glaxo Group Limited Pyrazolo[3,4-B]pyridine compounds, and their use as phosphodiesterase inhibitors
WO2009147187A1 (en) 2008-06-05 2009-12-10 Glaxo Group Limited 4-carboxamide indazole derivatives useful as inhibitors of p13-kinases
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US7709497B2 (en) 2004-03-16 2010-05-04 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compound, and its use as a PDE4 inhibitor
WO2010097248A1 (en) 2009-01-13 2010-09-02 Glaxo Group Limited Pyrimidinecarboxamide derivatives as inhibitors of syk kinase
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WO2011110575A1 (en) 2010-03-11 2011-09-15 Glaxo Group Limited Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases
WO2011143106A1 (en) 2010-05-10 2011-11-17 Gilead Sciences, Inc. Bi - functional pyrazolopyridine compounds
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
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WO2012032067A1 (en) 2010-09-08 2012-03-15 Glaxo Group Limited Polymorphs and salts of n- [5- [4- (5- { [(2r,6s) -2, 6 - dimethyl - 4 -morpholinyl] methyl} - 1, 3 - oxazol - 2 - yl) - 1h- inda zol-6-yl] -2- (methyloxy) - 3 - pyridinyl] methanesulfonamide
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WO2012055846A1 (en) 2010-10-27 2012-05-03 Glaxo Group Limited Polymorphs and salts of 6-(1h-indol-4-yl)-4-(5- { [4-(1-methylethyl)-1-pi perazinyl] methyl} -1,3-oxazol-2-yl)-1h-indazole as pi3k inhibitors for use in the treatment of e.g. respiratory disorders
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2015055690A1 (en) 2013-10-17 2015-04-23 Glaxosmithkline Intellectual Property Development Limited Pi3k inhibitor for treatment of respiratory disease
WO2015055691A1 (en) 2013-10-17 2015-04-23 Glaxosmithkline Intellectual Property Development Limited Pi3k inhibitor for treatment of respiratory disease
EP2899191A1 (en) 2009-04-30 2015-07-29 Glaxo Group Limited Oxazole substituted indazoles as pi3-kinase inhibitors
WO2015173701A2 (en) 2014-05-12 2015-11-19 Glaxosmithkline Intellectual Property (No. 2) Limited Pharmaceutical compositions for treating infectious diseases
WO2017137535A1 (en) 2016-02-12 2017-08-17 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as inhibitors of kinase activity
WO2018029126A1 (en) 2016-08-08 2018-02-15 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
WO2018192864A1 (en) 2017-04-18 2018-10-25 Glaxosmithkline Intellectual Property Development Limited Oxepinopyrazole derivatives as inhibitors of pi3-kinase activity
WO2019020657A1 (en) 2017-07-27 2019-01-31 Glaxosmithkline Intellectual Property Development Limited Pyridine-3-sulfonamide compounds as pi3-kinase inhibitors
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103819339A (en) * 2014-03-25 2014-05-28 杜承贤 Preparation method of organic intermediate diethyl butyryl-propanedioate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227099A1 (en) * 2001-01-24 2002-07-31 Yung Shin Pharmeutical Ind. Co., Ltd. Fused Pyrazolyl compounds
WO2004024728A2 (en) * 2002-09-16 2004-03-25 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors
WO2004056823A1 (en) * 2002-12-23 2004-07-08 Glaxo Group Limited PYRAZOLO[3,4-b]PYRIDINE COMPOUNDS, AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227099A1 (en) * 2001-01-24 2002-07-31 Yung Shin Pharmeutical Ind. Co., Ltd. Fused Pyrazolyl compounds
WO2004024728A2 (en) * 2002-09-16 2004-03-25 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors
WO2004056823A1 (en) * 2002-12-23 2004-07-08 Glaxo Group Limited PYRAZOLO[3,4-b]PYRIDINE COMPOUNDS, AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS

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US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US7709497B2 (en) 2004-03-16 2010-05-04 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compound, and its use as a PDE4 inhibitor
WO2007122165A1 (en) 2006-04-20 2007-11-01 Glaxo Group Limited Novel compounds
WO2007150016A2 (en) 2006-06-23 2007-12-27 Smithkline Beecham Corporation Il-8 receptor antagonist
WO2008009735A1 (en) * 2006-07-21 2008-01-24 Glaxo Group Limited Pyrazolo (3, 4-b) pyridine derivatives as pde4 inhibitors
US8003663B2 (en) 2006-08-01 2011-08-23 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as PDE4 inhibitors
WO2008015416A1 (en) 2006-08-01 2008-02-07 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as pde4 inhibitors
JP2009545579A (en) * 2006-08-01 2009-12-24 グラクソ グループ リミテッド Pyrazolo [3,4-B] pyridine compounds and their use as PDE4 inhibitors
WO2008015437A1 (en) * 2006-08-01 2008-02-07 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as pde4 inhibitors
WO2008118724A1 (en) 2007-03-23 2008-10-02 Smithkline Beecham Corporation Indole carboxamides as ikk2 inhibitors
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
WO2009147187A1 (en) 2008-06-05 2009-12-10 Glaxo Group Limited 4-carboxamide indazole derivatives useful as inhibitors of p13-kinases
WO2010016846A1 (en) * 2008-08-08 2010-02-11 Kalypsys, Inc. Heterocyclic modulators of tgr5 for treatment of disease
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WO2015055691A1 (en) 2013-10-17 2015-04-23 Glaxosmithkline Intellectual Property Development Limited Pi3k inhibitor for treatment of respiratory disease
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WO2015173701A2 (en) 2014-05-12 2015-11-19 Glaxosmithkline Intellectual Property (No. 2) Limited Pharmaceutical compositions for treating infectious diseases
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
WO2017137535A1 (en) 2016-02-12 2017-08-17 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as inhibitors of kinase activity
WO2018029126A1 (en) 2016-08-08 2018-02-15 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
WO2018192864A1 (en) 2017-04-18 2018-10-25 Glaxosmithkline Intellectual Property Development Limited Oxepinopyrazole derivatives as inhibitors of pi3-kinase activity
WO2019020657A1 (en) 2017-07-27 2019-01-31 Glaxosmithkline Intellectual Property Development Limited Pyridine-3-sulfonamide compounds as pi3-kinase inhibitors

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