EP1737857A1 - Composes pyrazolo[3,4-b] pyridine et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase - Google Patents

Composes pyrazolo[3,4-b] pyridine et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase

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Publication number
EP1737857A1
EP1737857A1 EP04804089A EP04804089A EP1737857A1 EP 1737857 A1 EP1737857 A1 EP 1737857A1 EP 04804089 A EP04804089 A EP 04804089A EP 04804089 A EP04804089 A EP 04804089A EP 1737857 A1 EP1737857 A1 EP 1737857A1
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EP
European Patent Office
Prior art keywords
ethyl
pyrazolo
pyridine
carboxamide
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04804089A
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German (de)
English (en)
Inventor
David George GlaxoSmithKline ALLEN
Diane Mary GlaxoSmithKline COE
Caroline Mary GlaxoSmithKline COOK
Michael Dennis GlaxoSmithKline DOWLE
Christopher David Edlin
Julie Nicole Hamblin
Martin Redpath Johnson
Paul Spencer Jones
Mika Kristian Lindvall
Charlotte Jane Mitchell
Alison Judith Redgrave
John Edward Robinson
Naimisha Trivedi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
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Glaxo Group Ltd
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Publication date
Priority claimed from PCT/EP2003/014867 external-priority patent/WO2004056823A1/fr
Priority claimed from GB0405936A external-priority patent/GB0405936D0/en
Priority claimed from GB0405899A external-priority patent/GB0405899D0/en
Priority claimed from GB0406754A external-priority patent/GB0406754D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to EP04804089A priority Critical patent/EP1737857A1/fr
Priority claimed from PCT/EP2004/014490 external-priority patent/WO2005058892A1/fr
Publication of EP1737857A1 publication Critical patent/EP1737857A1/fr
Withdrawn legal-status Critical Current

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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 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, allergic rhinitis or atopic dermatitis.
  • PDE4 phosphodiesterase type IV
  • COPD chronic obstructive pulmonary disease
  • asthma chronic obstructive pulmonary disease
  • rheumatoid arthritis allergic rhinitis
  • allergic atopic dermatitis atopic dermatitis.
  • NR3R4 can alternatively be a 5-6- membered heterocyclic group in which an additional nitrogen is present such as 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.
  • CA 1003419, C ⁇ 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.
  • 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 denotes 1) a hydrogen atom or 2) a Cl-8 alkoxy group.
  • R 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.
  • a hydrogen atom is prefened.
  • group ⁇ methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are prefened.
  • 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 heterocyclic 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)-NR 6 group as the 5-substituent and optionally substituted at the 1-, 3-, 4-, and/or 6-positions.
  • Bicyclic heterocyclic 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)-NR 4 -C(O)-NR 5 R 6 substituted compounds.
  • WO 00/15222 discloses inter alia pyrazolo[3,4-b]pyridines having ter alia a C(O)-X ⁇ group at the 5-position and a group E at the 4-position of the ring system.
  • Xi can for example be -OR9, -N(R9)(R ⁇ 0) or
  • E can for example be -NH-A1 -cycloalkyl, -NH-A1 -substituted cycloalkyl, or -NH-A1 -heterocyclo; wherein Ai 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.
  • PCT/EP2003/014867 also discloses the use of these compounds as PDE4 inhibitors and for the treatment and/or prophylaxis of inter alia COPD, asthma or allergic rhinitis.
  • Process F on page 58 line 14 to page 59 line 18 of PCT/EP2003/014867 (this passage, plus all definitions elsewhere therein of all compounds, groups and/or substituents mentioned in this passage, being specifically incorporated herein by reference), a compound of general Formula XXNIII:
  • Rl is C ⁇ _ 4 alkyl, C ⁇ _ fluoroalkyl, -CH 2 CH 2 OH or -CH2CH 2 CO 2 C ⁇ _ 2 alkyl;
  • R2 is a hydrogen atom (H), methyl or Ci fluoroalkyl
  • R 3 is optionally substituted C3_gcycloalkyl or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyclic 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 NR 1 ⁇ ;
  • R 3 is a bicyclic group (dd) or (ee): (dd) (ee)
  • R 4 is a hydrogen atom (H); C ⁇ _ 6 alkyl; C ⁇ _ 3fluoroalkyl; or C2-6 a lkyl substituted by one substituent R x .
  • R 5 can be: a hydrogen atom (H); Ci .galkyl; C ⁇ _g fluoroalkyl; C3_gcycloalkyl optionally substituted by a C1 _2alkyl group; -(CH2) n Z ''-C3.8cycloalkyl optionally substituted, in the -(C ⁇ .2)- ⁇ - moiety or in the C3_8cycloalkyl moiety, by a C ⁇ _2 alkyl group, wherein n 4 is 1, 2 or 3; C2-6 a lkyl substituted by one or two independent substituents R.11; -(CH2) n l l-C(O)Rl°; -(CH 2 ) n 12 -C(O)NR 12 R 13 ; -CHR ⁇ -C ⁇ NR ⁇ R 13 ; -(CH 2 ) n 12 -C(O)OR 16 ; -(CH2) n l -C(O)OR 16 ; -
  • R 5 can have the sub-formula (x), (y), (yl) or (z):
  • each R 6 independently of any other R 6 present, is: a halogen atom; C ⁇ alkyl; C ⁇ fluoroalkyl; C ⁇ _4alkoxy; C ⁇ _2fluoroalkoxy;
  • R 7 R 8 N-S(O) 2 S Ci _ 2 alkyl-C(O)-R 15 N-S(O) -; C ⁇ _ 4 alkyl-S(O)-; Ph-S(O)-;
  • n 14 is 1 or 2.
  • G is O or S or NR 9 wherein R 9 is a hydrogen atom (H), Ci _4alkyl or Cifluoroalkyl; 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 fonnula (I) and salts thereof disclosed in PCT/EP03/11814 are disclosed as being inhibitors of phosphodiesterase type IV (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
  • 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 phannaceutically acceptable salt thereof):
  • Ar has the sub-formula (x) or (z):
  • R 1 is C ⁇ _ 3 alkyl, Cifluoroalkyl, or -CH 2 CH 2 OH;
  • R 2 is a hydrogen atom (H), methyl or Cifluoroalkyl
  • R 3 is optionally substituted C3_gcycloalkyl or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyclic 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 N 1 ⁇ ;
  • RlO is a hydrogen atom (H), Ci _2alkyl, C ⁇ _2fluoroalkyl, C(O)NE ⁇ 2, C(O)-C ⁇ _ 2 alkyl, C(O)-C ⁇ fluoroalkyl or -C(O)-CH2 ⁇ -C ⁇ alkyl;
  • R 3 when R 3 is optionally substituted mono-unsaturated-Cs. cycloalkenyl, then the cycloalkenyl is optionally substituted with one substituent being fluoro or C ⁇ _2 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 Y , Y 2 and Y 3 independently are CH2 or oxygen (O) provided that no more than one of Y 1 , Y 2 and Y 3 is oxygen (O);
  • R 4 is ahydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, C ⁇ _2fluoro alkyl, cyclopropyl, -CH2OR 4a , -CH(Me)OR 4a , or -CH 2 CH 2 OR 4a ; wherein R 4a is a hydrogen atom (H), methyl (Me), or Cifluoroalkyl such as CF3 or CHF2; and R5 is a hydrogen atom (H); C ⁇ _galkyl (e.g.
  • C ⁇ _6alkyl or C ⁇ _4alkyl C ⁇ _3fluoroalkyl; C3_8cycloalkyl optionally substituted by a C ⁇ _2 alkyl group; or -(CH2) n 4 -C3_8cycloalkyl optionally substituted, in the -(CH2) n ⁇ - moiety or in the C3_ cycloalkyl moiety, by a C ⁇ _2 a lkyl group, wherein n 4 is 1 or 2;
  • R5 is C ⁇ _4alkyl substituted by one substituent R ⁇ 1 ; wherein R! 1 is: hydroxy (OH); C ⁇ _6alkoxy; C ⁇ _2fluoro alkoxy; phenyloxy; (monofluoro- or difluoro-phenyl)oxy;
  • R ⁇ is C2-4alkyl substituted on different carbon atoms by two hydroxy (OH) substituents
  • R 5 is -(CH2)n U -C(O)R 16 ; -(CH 2 ) n n -C(O)NR 12 R 13 ; -CHR19-C(0)NR 12 R 13 ; -(C ⁇ 2 )n 1 C(O)OR 16 ; -(CH 2 ) n 1 1 -C(O)OH; -CHR19-C(0)0R 16 ; -CHR 19 -C(O)OH;
  • n ⁇ is 0, 1, 2 or 3 (wherein for each R ⁇ group n ⁇ 1 is independent of the value of n ⁇ 1 in other R ⁇ groups); and wherein R 9 is C _2 a lkyl;
  • R5 is -(CH2) n ⁇ -Het, wherein n i3 is 0, 1 or 2 and Het is a 4-, 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring, other than -NR ⁇ R ⁇ 3 , containing one or two ring-hetero-atoms independently selected from O, S, and N; wherein any ring-hetero-atoms present are not bound to the -(CH2) n ⁇ 3 - moiety when n ⁇ 3 is 0; wherein any ring-nitrogens which are present and which are not unsaturated (i.e. which do not partake in a double bond) and which are not connecting nitrogens (i.e.
  • R 5 is phenyl (Ph), -CH 2 -Ph, -CHMe-Ph, -CHEt-Ph, CMe 2 Ph, or -CH 2 CH 2 -Ph, wherein the phenyl ring Ph is optionally substituted with one or two substituents independently being: a halogen atom; C ⁇ _4alkyl (e.g. C ⁇ _2 lkyl); C ⁇ _2fluoroalkyl (e.g. trifluoromethyl); C ⁇ _4 alkoxy (e.g. C ⁇ _2alkoxy); C ⁇ _2fluoroalkoxy (e.g.
  • R 7a R 8 N-C(O)-; -NR 8 -C(O)-C!.4alkyl; R 7a R 8a N; OH; nitro (-NO 2 ); or cyano (-CN); or R 4 and R 5 taken together are -(CH 2 ) p 1 - or -(CH 2 )p 3 -X 5 -(CH 2 )p 4 -, in which: X 5 is O or NR i7a ; pi 2, 3, 4, 5 or 6, and p 3 and p 4 independently are 1, 2 or 3 provided that if p 3 is 3 then p 4 is 1 or 2 and if p 4 is 3 then p 3 is 1 or 2;
  • R 4 and R ⁇ is not a hydrogen atom (H);
  • 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 (TST ⁇ -O")
  • E is C-R6E 5 nitrogen (N) or nitrogen-oxide (N + -O")
  • F is C-R6F, nitrogen (N) or nitrogen-oxide (N + -O ⁇ )
  • R6D ⁇ R6E an( j R6F independently are: a hydrogen atom (H), a halogen atom; Cx. ⁇ alkyl (e.g. C ⁇ _4alkyl or C ⁇ _2 a lkyl); C ⁇ _4fluoroalkyl (e.g. C ⁇ _2fluoroalkyl); C3_gcycloalkyl; C ⁇ _4alkoxy (e.g. C ⁇ _2alkoxy); C ⁇ _2fluoroalkoxy; C 3 . 6 cycloalkyloxy; -C(O)R 16a ; -C(O)OR 30 ; (e.g. C ⁇ . 2 alkyl-S(O) 2 -);
  • R 16 -S(O) 2 -NR 15 - e.g. Ci. 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, C ⁇ lkyl, Cifluoroalkyl, C ⁇ _2alkoxy or Cifluoroalkoxy;
  • 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-);
  • G is O or S or N 9 wherein R 9 is a hydrogen atom (H), C ⁇ _4alkyl, or Cifluoroalkyl;
  • J is C-R6J, 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 S C-[com ⁇ ection point to formula (I)], or nitrogen (N)
  • Q is C-R6Q, C-[com ⁇ ection point to formula (I)], or nitrogen (N)
  • R ⁇ , R ⁇ L R6M an( ⁇ R6Q independently are: a hydrogen atom (H), a halogen atom; C ⁇ _4alkyl (e.g. C ⁇ alkyl); C ⁇ _3fluoroalkyl (e.g. Cifluoroalkyl); C3_6cycloalkyl; C ⁇ _4alko y (e.g. Ci ⁇ alkoxy); C ⁇ _2fluoroalkoxy; C3_gcycloalkyloxy;
  • OH (including any tautomer thereof); or phenyl optionally substituted by one or two substituents independently being fluoro, chloro, C ⁇ _2al yl, Cifluoroalkyl, C ⁇ _2alkoxy or
  • J, L, M and Q are independently C-H, C-F, C-C ⁇ _2 lkyl (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);
  • R 7 and R 8 are independently a hydrogen atom (H); C ⁇ _4alkyl (e.g. C ⁇ _2 lkyl such as methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two substituents independently being: fluoro, chloro, C ⁇ _2alkyl, Cifluoroalkyl, C ⁇ _2 alkoxy or Cifluoroalkoxy;
  • 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 -(CH2) n 8 -X 7 -(CH 2 )n 9 - or -C(O)-X 7 -(CH 2 ) n 1() - in which: n 6 is 3, 4, 5 or 6, n 7 is 2, 3, 4, or 5, n 8 and n 9 and n ⁇ independently are 2 or 3, and X 7 is O or NR ⁇ 4 ;
  • R 7a is a hydrogen atom (H) or C ⁇ alkyl
  • R 8a is a hydrogen atom (H) or methyl
  • R i2 and R 13 independently are H; C _4alkyl (e.g. C ⁇ _2 a lkyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two substituents independently being: fluoro, chloro, C ⁇ _2 lkyl, Cifluoroalkyl, C ⁇ _2alkoxy or Cifluoroalkoxy;
  • R 12 and R 13 together are -(CH 2 ) n 6a - or -C(O)-(CH 2 ) n 7a - or -C(O)-(CH 2 ) n 10a -C(O)- or -(CH 2 ) n 8a -X 12 -(CH 2 ) n 9a - or -C(O)- ⁇ l 2 -(CH 2 ) n 10a - in which: n 6 is 3, 4, 5 or 6, n 7a is 2, 3, 4, or 5, n 8a and n 9a and n ⁇ a independently are 2 or 3 and X* is O or NR 14a ;
  • R ⁇ , Rl 4a , l 7 and R i7a independently are: a hydrogen atom (H); C ⁇ _4alkyl (e.g. C ⁇ _2alkyl); C ⁇ . 2 fluoroalkyl (e.g. CF3); cyclopropyl; (e.g. -C(O)Me); -C(O)NR 7 R 8a (e.g. -C(O)NH 2 ); or -S(O) 2 -C ⁇ _ 4 alkyl (e.g. -S(O) 2 Me);
  • R1 ⁇ 5 independent of other R ⁇ 9 is a hydrogen atom (H); C ⁇ _4alkyl (e.g. l Bu or C ⁇ _2alkyl e.g. methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _2alkyl, Cifluoroalkyl, C ⁇ _2 a lkoxy or Cifluoroalkoxy;
  • Rl6 is; C ⁇ _4alkyl (e.g. C ⁇ _2alkyl); C3_6cyclo lkyl (e.g. C5_gcycloalkyl);
  • C3_6cycloalkyl-CH2- e.g. C5_6cycloalkyl-CH2-
  • phenyl or benzyl wherein the phenyl and benzyl are independently optionally substituted on their ring by one or two substituents independently being fluoro, chloro, methyl, Cifluoroalkyl, methoxy or
  • Rl 6a is: C ⁇ _6alkyl (e.g. C ⁇ alkyl or C ⁇ alkyl);
  • C3_6cycloalkyl e.g. Cs.gcycloalkyl
  • oxo e.g. OH
  • OH oxo
  • 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, C ⁇ _2alkyl, Cifluoroalkyl, C ⁇ _2 alkoxy or Cifluoroalkoxy;
  • Ar5c phenyl optionally substituted by one or two substituents independently being: a halogen atom, C 1 _2alkyl, C 1 fluoroalkyl, C 1 _2 alkoxy or C 1 fluoroalkoxy; benzyl optionally substituted on its ring by one or two substituents independently being: a halogen atom, C ⁇ alkyl, Cifluoroalkyl, Ci ⁇ alkoxy or Cifluoroalkoxy; or a 4-, 5-, 6- or 7-membered saturated heterocyclic 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 NR 27 where R 27 is H, C ⁇ _2 lkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one
  • R 3 0, independent of other R 3 0, is a hydrogen atom (H), C i _4alkyl or C3. ⁇ cycloalkyl;
  • Ar ⁇ b and Ar ⁇ c independently is/are a 5-membered aromatic heterocyclic ring containing one O, S or NR ⁇ a [ n the 5-membered ring, wherein the 5-membered ring can optionally additionally contain one or two N atoms, and wherein the heterocyclic ring is optionally substituted on a ring carbon atom by one of: a halogen atom, C ⁇ _2alkyl, Cifluoroalkyl,
  • Hefl is a 4-, 5-, 6- or 7-membered saturated heterocyclic 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 NR 1 where R 3 1 is H, C ⁇ _2alkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one
  • R 3 when R 3 is the heterocyclic group of sub-formula (bb), n s 1, and Y is NR ⁇ O, then lO is not C ⁇ _2alkyl or Cifluoroalkyl; and when R 3 is the heterocyclic group of sub-formula (aa) and Y is NR ⁇ O, then RlO i s not C(O)-C ⁇ _2alkyl, C(O)-C ⁇ fluoroalkyl or -C(O)-CH 2 O-C ⁇ alkyl; and when R 3 is the heterocyclic group of sub-formula (cc), then Y is O, S, SO2 or NR ⁇ O wherein RIO is H;
  • any -C(O)OR 23 , -C(O)NHR 24 , -C(O)R 25 , -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 4-position of a R 3 Cgcycloalkyl (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 (wherein, in this connection, the 1 -position of the R 3 cycloalkyl or cycloalkenyl ring is deemed to be the connection
  • R 3 when R 3 is optionally substituted C3_gcycloalkyl, then any OH, alkoxy, fluoroalkoxy,
  • -CH2CH2OH or -CH2NHR 22 substituent is: 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 5- position of a R 3 Cgcycloalkyl (cyclohexyl) ring; or at the 3-, 4-, 5- or 6- position of a R 3 cycloheptyl ring, or at the 3-, 4-, 5-, 6- or 7- position of a R 3 cyclooctyl ring; and
  • any OH substituent is: at the 5-position of a six-membered R 3 heterocyclic group of sub-formula (cc) wherein n 2 is 1 ; or at the 5- or 6- position of a seven-membered R 3 heterocyclic group of sub-formula (cc) wherein n 2 is 2; or at the 6- position of a seven-membered R 3 heterocyclic group of sub-formula (bb) wherein n is 2 (wherein, in this connection, the 1 -position of the R 3 heterocyclic ring is deemed to be the connection point to the -NH- in fonnula (I), that is 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).
  • an "alkyl” group or moiety may be straight-chain or branched.
  • Alkyl groups for example Ci.galkyl or Ci.galkyl or C ⁇ _4alkyl or C ⁇ _3alkyl or
  • C ⁇ _2 alkyl which may be employed include Ci. ⁇ alkyl or C ⁇ alkyl or C 1.3 alkyl or C ⁇ _2 a lkyl 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 conesponding meaning is intended for "alkoxy", "alkylene", and like terms derived from alkyl.
  • alkoxy such as C . ⁇ alkoxy or C ⁇ _4alkoxy or C ⁇ _2 a lkoxy includes methoxy, ethoxy, propyloxy, and oxy derivatives of the alkyls listed above.
  • Alkylsulfonyl such as C ⁇ _4alkylsulfonyl includes methylsulfonyl
  • alkylsulfonyloxy such as C ⁇ _4alkylsulfonyloxy includes methanesulfonyloxy
  • Cycloalkyl for example C3_gcycloalkyl, includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • a C3_gcycloalkyl group can be C3_6cycloaIkyl or C5_6cycloalkyl or C4_7cycloalkyl or C ⁇ _ ⁇ cycloalkyl, that is contains a 3-6 membered or 5-6 membered or 4-7 membered or 6-7 membered carbocyclic ring.
  • “Fluoroalkyl” includes alkyl groups with one, two, three, four, five or more fluorine substituents, for example Cifluoroalkyl or Cifluoroalkyl or Cifluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF 3 CH 2 -), 2,2-difluoroethyl (CHF 2 CH2-), 2-fluoroethyl
  • “Fluoroalkoxy” includes Cifluoroalkoxy or Cifluoroalkoxy such as trifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy, etc.
  • “Fluoroalkylsulfonyl” such as C ⁇ _4fluoroalkylsulfonyl includes frifluoromethanesulfonyl, 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 is C 1.3 alkyl or C 1.3 fluoroalkyl, it can be straight-chained or branched.
  • R! is C ⁇ _3 alkyl then it can be methyl, ethyl, n-propyl, or isopropyl.
  • R! is C ⁇ _3 alkyl then it can be methyl, ethyl, n-propyl, or isopropyl.
  • R! can for example be Cifluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl; or R 1 can be C2fluoroalkyl such as pentafluoroethyl or more preferably C ⁇ fluoroalkyl-CH2- such as 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF 2 CH 2 -), or 2-fluoroefhyl (CH 2 FCH 2 -).
  • Cifluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl
  • R 1 can be C2fluoroalkyl such as pentafluoroethyl or more preferably C ⁇ fluoroalkyl-CH2- such as 2,2,2-trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF 2 CH 2 -), or 2-fluoroefhyl (CH 2 FCH
  • R! is C ⁇ _3alkyl (e.g. methyl, ethyl or n-propyl), Cifluoroalkyl or -CH2CH2OH.
  • R 1 is suitably C ⁇ alkyl, C ⁇ _2 fluoroalkyl, or -CH2CH2OH.
  • R 1 is C2-3 a lkyl (e.g. ethyl or n-propyl), C2fluoroalkyl (e.g. Cifluoroalkyl-CH - such as CF3-CH2-) or -CH2CH2OH; in particular ethyl, n-propyl or -CH2CH2OH.
  • R 1 is C2alkyl (ethyl) or C2fh ⁇ oroalkyl.
  • R 1 is most preferably ethyl.
  • R 2 is a hydrogen atom (H) or methyl, for example a hydrogen atom (H).
  • R 3 there is one substituent or no substituent.
  • R 3 is the optionally substituted C3_gcycloalkyl or the optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc).
  • R 3 when R 3 is optionally substituted C3_gcycloalkyl, it is not unsubstituted Cscycloalkyl, i.e. not unsubstituted cyclopentyl.
  • R 3 is optionally substituted Cg.gcycloalkyl or optionally substituted cyclobutyl.
  • R 3 is optionally substituted C3_gcycloalkyl, it is more suitably optionally substituted Cg. cycloalkyl or optionally substituted cyclobutyl, preferably optionally substituted C6cycloalkyl (i.e. optionally substituted cyclohexyl).
  • C ⁇ _4alkyl such as C ⁇ _2alkyl
  • any OH, alkoxy, fluoroalkoxy or NHR 2 i 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 heterocyclic group (aa), (bb) or (cc).
  • C3_gcycloalkyl e.g. Cg. cycloalkyl or cyclobutyl
  • R 3 is C3
  • R 3 is optionally substituted C3_gcycloalkyl
  • R 3 is C3_gcycloalkyl (e.g. C ⁇ . cycloalkyl or cyclobutyl) optionally substituted with one or two substituents independently being (e.g.
  • R 3 is optionally substituted C3_gcycloalkyl, then R 3 is C3_8cycloalkyl (e.g.
  • 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 21 ) 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.
  • R 3 and in particular when R 3 is optionally substituted C3_gcycloalkyl or optionally substituted C5_7cycloalkenyl, the one or two optional R 3 substituents if present can comprise a substituent (for example is or are substituent(s)):
  • 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
  • R 3 Cgcycloalkyl (cyclohexyl) ring e.g. at the 3- or 5-position of a R 3 cyclohexyl ring especially for any OH substituent
  • any OH, alkoxy, fluoroalkoxy, -CH2CH2OH or -CH2NHR 22 substituent is at the 3- or 4- position of a R 3 C5cycloalkyl
  • any -C(O)OR 23 , -C(O)NHR 24 , -C(O)R 25 , -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 4-position of a R 3
  • any -C(O)NHR 24 substituent is particularly preferable for any -C(O)NHR 24 substituent to be at the 4-position of a R 3 cyclohexyl ring.
  • any NHR i substituent is at any position other than the 1 -position (the ring atom connecting to the -NH- in formula (I)), e.g. at the 2-, 3-, 4-, 5-, 6-, 7- or 8- position.
  • any NHR 2 1 substituent is at the 2-, 3-, 4-, 5- or 6- position, for example 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 1 -position, of the R 3 ring.
  • 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. Cg.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. C ⁇ cycloalkyl)
  • Cifluoroalkyl, -C(O)OR 23 , -C(O)NHR 24 , fluoro, hydroxyimino ( N-OH), or
  • the optional substituent can for example be at the 3- or 4- position of the
  • R 3 is cyclobutyl optionally substituted by one -C(O)NHR 24 substituent wherein R 24 is H or methyl (preferably H).
  • R 3 can for example be cyclobutyl (i.e. unsubstituted) or 3-(aminocarbonyl)cyclobutyl (i.e. 3-(aminocarbonyl)cyclobutan-l-yl) (e.g. in a cis or trans configuration, preferably cis).
  • R 3 can for example be 4-hydroxy- cyclohexyl (i.e. 4-hydroxycyclohexan-l-yl), 4-methylcyclohexyl, 2-aminocyclohexyl, 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. in a cis or trans configuration, preferably cis), 4-oxo-cyclohexyl (i.e.
  • R 3 can preferably be 4-acetylcyclohexyl (e.g. in a cis or trans configuration, preferably cis).
  • R 3 is most preferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl) (preferably 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) (preferably in a cis configuration).
  • cyclohexyl i.e. unsubstituted
  • 3-hydroxy-cyclohexyl i.e. 3-hydroxycyclohexan-l-yl
  • 4-oxo-cyclohexyl i.e. 4-oxocyclohex
  • R 3 is optionally substituted C5cycloalkyl (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.
  • substituents independently being fluoro or methyl.
  • there are two substituents then they are not both methyl.
  • the R 3 cycloalkenyl (e.g. cyclohexenyl) is optionally substituted with one substituent being fluoro or C ⁇ _2alkyl (preferably fluoro or methyl); suitably the R 3 cycloalkenyl (e.g. cyclohexenyl) can be 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.
  • R 3 cycloalkenyl the optional substituent(s) can for example be at the 1-, 2-, 3-, 4-, 5- or 6- position(s) of the cycloalkenyl ring.
  • R 3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is suitably O or NRIO.
  • Y is preferably O or N-C(0)-NH2-
  • R 10 is a hydrogen atom (H), methyl, ethyl, C(O)NH2, C(O)-C ⁇ _2alkyl or C(O)-C ⁇ fluoroalkyl.
  • RlO is not C ⁇ _2 lkyl or Cifluoroalkyl.
  • 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)NH 2 or C(O)methyl; for example C(O)NH 2 .
  • R 3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then it is preferable that R 3 is the heterocyclic 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 prefened in the R 3 heterocyclic group.
  • the heterocyclic group of sub-formula (aa), (bb) or (cc) can be unsubstituted on a ring carbon. (In this com ection, where Y is NR 1 ⁇ , RlO is not a substituent on a ring carbon).
  • the one or two optional substituents i.e. the one or two optional ring-carbon substituents
  • 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 heterocyclic ring, for example at the 1-, 3- or 5- position of a six-membered R 3 heterocyclic ring.
  • any OH substituent is: at the 5-position of a six-membered R 3 heterocyclic group of sub-formula (cc) wherein n 2 is 1; at the 5- or 6- position of a seven-membered R 3 heterocyclic group of sub- formula (cc) wherein n 2 is 2; or at the 6- position of a seven-membered R 3 heterocyclic group of sub-formula (bb) wherein n* is 2.
  • any other optional ring-carbon substituents of the R 3 heterocyclic group can optionally be positioned on the R 3 heterocyclic 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 heterocyclic group of sub-formula (aa) and Y is NR ⁇ O, then RlO is not C(O)-C ⁇ _ 2 alkyl, C(O)-C ⁇ fluoroalkyl or -C(O)-CH 2 O-C ⁇ alkyl.
  • R 3 is the heterocyclic group of sub-formula (aa) then Y is O, S, SO 2 , NH or NC(O)NH 2 (e.g. O, S, SO 2 or NH).
  • R 3 is the heterocyclic group of sub-formula (bb), n is 1, and Y is R ⁇ O (e.g.
  • R 3 is the heterocyclic group of sub-formula (bb) wherein n* is 1 or 2 and Y is RlO, then preferably RlO is not C ⁇ _2 lkyl or C ⁇ _2fluoroalkyl.
  • R 3 when R 3 is the heterocyclic group of sub-formula (bb), then preferably Y is O, S, SO 2 or NR 10 wherein R 10 is H, C(O)NH 2 , C(O)-C ⁇ _ 2 alkyl (e.g. C(O)methyl) or C(O)-C ⁇ fluoroalkyl (e.g. C(O)-CF3), or more preferably R 10 is H, C(O)NH2 or C(O)Me, for example C(O)NH 2 or C(O)Me, most preferably C(O)NH 2 .
  • R 10 is H, C(O)NH2 or C(O)Me, for example C(O)NH 2 or C(O)Me, most preferably C(O)NH 2 .
  • R 3 is the heterocyclic group of sub-formula (cc)
  • Y is O, S, SO2 or NR ⁇ O wherein R 1 0 is H.
  • Y is O or NR ⁇ O.
  • R 3 is optionally substituted C3_gcycloalkyl (e.g. Cg ⁇ cycloalkyl) or optionally substituted mono-unsaturated-C5_7cycloalkenyl or an optionally substituted heterocyclic 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 wherein the stated configuration is the major component.
  • 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
  • C ⁇ 5_7cycloalkyl can for example be in the cis or trans configuration, with respect to the
  • R 3 is a bicyclic group of sub-formula (ee), then preferably Y 1 , Y 2 and Y 3 are all CH 2 .
  • 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), (n), (o), (ol), (o2), (o3), (p), (pi), (p2), (p3), (p4), (p5), (p6), (p9), (plO), (pl l) or (q): (a) (a1) (b) (c) (c1) (c2)
  • NHR 3 is of sub-formula (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), (ml), (m3), (n), (o), (ol), (o2), (o3), (p), (p2), (p5), (p6), (p9), (plO), (pl l) or (q); or preferably NHR 3 is of sub-formula (al), (c), (cl), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (gl), (g4), (h), (i), (j), (k), (k2), (L), (m), (ml), (m3), (n), (o), (ol), (o
  • NHR 3 is of sub-formula (c), (cl), (c 4), (c 5), (h), (i), ), (k), (k2), (ml), (n), (o), (o2), (o3), (p2), (p5), (p6), (p9), (pll) or (q).
  • NHR 3 can for example be of sub- formula (c), (h), (k), (k2), (n), (o), (o2), (p9) or (pll); or still more preferably (c), (h), (k2), (n), (o), (o2), (p9) or (pll).
  • 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.
  • NHR 3 When NHR 3 is of sub-formula (n), then it can be in the trans configuration; but preferably it is in the cis configuration, i.e. preferably it is a c ⁇ -(3-hydroxycyclohexan-l- yl)amino group (including mixtures of configurations wherein the cis configuration is the major component), e.g. in any enantiomeric form or mixture of forms such as a racemic mixture.
  • NHR 3 When NHR 3 is of sub-formula (p9), then it can be in the trans configuration; but preferably it is in the cis configuration, i.e. preferably it is a ct5-[4-(aminocarbonyl)cyclohexan-l-yl]amino group (including mixtures of configurations wherein the cis configuration is the major component).
  • NHR 3 is of sub-formula (pi 2) or (pi 3):
  • NHR 3 When NHR 3 is of sub-formula (pi 2) or (pi 3), then it can be in the trans configuration; but preferably it is in the cis configuration, i.e. preferably NHR 3 is a cts-[4-acetylcyclohexan-l-yl] amino group or a ct5 , -[3-(aminocarbonyl)cyclobutan-l- yl]amino group respectively (each including mixtures of configurations wherein the cis configuration is the major component).
  • 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 -CH 2 OMe; or preferably a hydrogen atom (H), methyl, ethyl, CF3, -CH 2 OH, or -CH2OMe . More preferably, R 4 is methyl, ethyl, CF 3 , -CH 2 OH, or -CH2OMe; for example methyl, ethyl, CF3 or -CH 2 OH. Still more preferably, R 4 is methyl or ethyl. Most preferably, R 4 is ethyl.
  • R 4 is not a hydrogen atom (H), and more suitably R ⁇ is a hydrogen atom (H).
  • R ⁇ is C ⁇ _4alkyl substituted by one substituent R 1 1 or R ⁇ is C2-4 a l yl (e.g. ethyl or n-propyl) substituted on different carbon atoms by two OH substituents, then suitably R ⁇ is C ⁇ _4alkyl substituted by one substituent R! 1.
  • R5 is C ⁇ _4alkyl substituted by one substituent R 1 1
  • R ⁇ is C ⁇ _3alkyl (e.g. Chalky!) substituted by one substituent R! 1.
  • R ⁇ is C ⁇ _3alkyl (e.g. Chalky!) substituted by one substituent R! 1.
  • R ⁇ is
  • n 5 is 1, 2, 3 or 4 or R 5 is -CH(Me)-R n .
  • n 5 is 1, 2 or 3, more preferably 1 or 2, still more preferably 1.
  • RU is: ⁇ hydroxy (OH); C ⁇ _4alkoxy or C ⁇ _2alkoxy (such as t-butyloxy, ethoxy or preferably methoxy); Cifluoroalkoxy; -NR 12 R 13 ; -NR 15 -C(O)R 16 ; or
  • R 11 is hydroxy (OH), C _4alkoxy (e.g. C ⁇ alkoxy), or -NR 12 R 13 ; still more suitably OH, ethoxy, methoxy, NH2, NHMe, NHEt, NMe2, pynolidin-1-yl or piperidin-1-yl; preferably OH, methoxy, NH2, NHMe or NMe2-
  • R$ is C ⁇ _8alkyl, then suitably it is Ci.galkyl or C ⁇ _5alkyl or C ⁇ _4alkyl or
  • R ⁇ is C 1.3 fluoroalkyl then suitably it is C ⁇ ._2fluoroalkyl or
  • Cifluoroalkyl such as monofluoromethyl, difluoromethyl or trifluoromethyl.
  • R ⁇ is C3_8cycloalkyl optionally substituted by a C ⁇ _2alkyl group, then optionally the C3_8cycloalkyl is not substituted at the connecting ring-carbon.
  • R ⁇ is optionally substituted C3_8cycloalkyl, then suitably it is C3_gcycloalkyl (i.e. unsubstituted) and/or optionally substituted C3_gcycloalkyl such as optionally substituted cyclopropyl or optionally substituted cyclohexyl.
  • n 4 is preferably 1, and/or suitably R ⁇ is optionally substituted -(CH2) ⁇ -C3-6 c y c lo l yl such as optionally substituted -(C ⁇ ⁇ -cyclopropyl or optionally substituted -(CH2) n ⁇ -C6cycloalkyl.
  • R5 is optionally substituted -(CH2) n ⁇ -C3_8cycloal yl, preferably it is not substituted.
  • R ⁇ can be (cyclohexyl)methyl-, that is -CH2-cyclohexyl, or -CH2-cyclopropyl.
  • Rl9 is C ⁇ _2 lkyl, then optionally it can be methyl.
  • R* can suitably be -(CH 2 )n n -C(O)NR 12 R 13 ; -(CH 2 ) n 1 1 -C(O)OR 1 6; -(CH 2 ) n n -C(O)
  • n ⁇ 1 is 0, 1 or 2.
  • n 1 1 is 0 or 1, for example 0.
  • n 1 1 is 2.
  • n ⁇ 3 can for example be 0 or 1.
  • Het is a 5- or 6-membered saturated or unsaturated heterocyclic ring, and/or preferably Het is a 4-, 5-, 6- or 7-membered saturated heterocyclic ring.
  • the heterocyclic ring Het contains one ring-hetero-atom selected from O, S and N.
  • the carbon ring-atoms in Het are not substituted.
  • Het can for example be:
  • R 5 is phenyl (Ph), -CH 2 -Ph, -CHMe-Ph, -CHEt-Ph, CMe 2 Ph, or -CH 2 CH 2 -Ph, wherein the phenyl ring Ph is optionally substituted, then suitably Ph is optionally substituted with one of the substituents defined herein.
  • R ⁇ is phenyl (Ph) or -CH2-Ph wherein the phenyl ring Ph is optionally substituted with one or two substituents as defined herein.
  • R 5 is phenyl (Ph), -CH 2 -Ph, -CHMe-Ph, -CHEt-Ph, CMe 2 Ph, or -CH 2 CH 2 -Ph, wherein the phenyl ring Ph is optionally substituted with one or two substituents, then preferably the phenyl ring Ph is optionally substituted with one or two (e.g. one) substituents independently being: fluoro; chloro; C ⁇ _2alkyl (e.g. methyl); Cifluoroalkyl
  • C ⁇ _2alkoxy e.g. methoxy
  • Cifluoroalkoxy e.g. trifluoromethoxy or difluoromethoxy
  • Ph can be unsubstituted.
  • R 4 and R 5 taken together are -(CH 2 ) p 1 - or -(CH 2 ) p 3 -X 5 -(CH2) p 4 -, in which X 5 is O or NR i7a ; then preferably R 4 and R ⁇ taken together are -(CH2)pl- In one embodiment of the invention, R 4 and R ⁇ are not taken together to be either -(CH2)pl- or -(CH 2 )p 3 -X 5 -(CH 2 )p 4 -.
  • p 1 can for example be 2, 4, 5 or 6.
  • pi is preferably 2, 4 or 5, more preferably 2 or 4.
  • R 4 and R 5 taken together are -(CH 2 ) p 3 -X 5 -(CH2)p 4 -, in which X 5 is O or NRl 7a ; then suitably: p 3 is 2, and/or p 4 is 2, and/or one of p 3 and p 4 is 1 and the other of p 3 and p 4 is 2, and/or p 3 and p 4 are both 1.
  • X 5 is O.
  • -(CH 2 ) p 3 -X 5 -(CH2)p 4 - can for example be -(CH 2 )2-0-(CH 2 )2-.
  • R 4 and R ⁇ are not taken together as -(CH2)pl- or -(CH 2 ) p 3 -X 5 -(CH 2 )p 4 -.
  • 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).
  • 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 ⁇ ).
  • 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).
  • 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), (xl2a), (xl3), (xl4), (xl5) or (xl6):
  • Ar has the sub-fonnula (x) which is sub-formula (xl), (x2), (x3), (x4), (x5), (x6), (x7), (x8), (x9), (xlO), (xll), (xl2), (xl3), (xl4), (xl5) or (xl6).
  • Ar has the sub-formula (x) which is sub-fonnula (xl), (x2), (x3), (x8), ( l3), 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).
  • sub-formula (x) preferably, 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, Cifluoroalkoxy (e.g.
  • 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, Cifluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy), nitro (-NO2), OH, Ci _ 3 alkylS(O) 2 - such as MeS(O) 2 -, C ⁇ .
  • H hydrogen atom
  • a fluorine chlorine, bromine or iodine atom
  • methyl ethyl
  • n-propyl isopropyl
  • isobutyl trifluoromethyl
  • -CH2OH methoxy
  • lkylS(O) 2 -NH- such as Me-S(O) 2 -NH-, -CONH 2 , cyano (-CN), or C 1 _ 2 alkylS(O)2-CH 2 - such as Me-S(O) 2 -CH 2 .
  • 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-.
  • R ⁇ A and R ⁇ F are independently a hydrogen atom (H), a fluorine atom (F), or methyl.
  • R6A and R ⁇ F can be a hydrogen atom (H).
  • sub-formula (x) e.g. in sub-formula (xl)
  • the ring or ring system is unsubstituted, monosubstituted, disubstituted or trisubstituted; or preferably the ring or ring system is unsubstituted, monosubstituted or disubstituted; more preferably monosubstituted or disubstituted.
  • sub-fonnula (xl) for monosubstitution of the ring or ring system, then the one substituent selected from R6B, R6D 5 R6E and R&F is suitably present at the 3- or 4-position with respect to the - (CR 4 R5)- side-chain (i.e., for a 4-position substituent, D is CR ⁇ D where R ⁇ is other than H), or is a 2-methyl, 2-ethyl, 2-fluoro or 2-chloro substituent.
  • sub-formula (x) e.g.
  • sub-formula (xl) for disubstitution of the ring or ring system, then 3,4- disubstitution, 2,4-disubstitution, 2,3-disubstitution or 3,5-disubstitution is suitable, hi sub-formula (x), 2,5-disubstitution is also 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-S ⁇ 2-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: - monoC ⁇ _4alkyl-phenyl- or monoC ⁇ _3alkyl-phenyl- such as 4-C ⁇ _4alkyl-phenyl- (e.g.
  • - mono(C ⁇ fluoroalkoxy)-phenyl- such as 4-C ⁇ fluoroalkoxy-phenyl-
  • - 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 i .3 alkyl-monochloro-phenyl- or monoC 1.3 alkyl-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 (xl) and is triC ⁇ _2alkyl-phenyl- such as trimethylphenyl-, e.g. 2,4,6-trimethylphenyl-. In an alternative embodiment, 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 fonnula (I)].
  • R 9 is a hydrogen atom (H) or methyl.
  • R ⁇ J, R6L ? 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 ⁇ _2 lko y (methoxy); Cifluoroalkoxy (e.g. CF2HO-); OH (including any tautomer thereof); or phenyl optionally substituted by one substituent being fluoro, methyl, Cifluoroalkyl, methoxy or
  • Cifluoroalkoxy More suitably, R°J, R ⁇ L, RoM and/or R°Q independently is or are H, OH (including any keto tautomer thereof), or more preferably C ⁇ _2alkyl (e.g. methyl) or Cifluoroalkyl.
  • sub-fonnula (z) can suitably be one of the following:
  • R 7a is H or C ⁇ _2alkyl, more suitably H or methyl.
  • R 8a is H.
  • R 7 and/or R 8 are independently a hydrogen atom (H); C ⁇ _2alkyl such as methyl; C3_6cycloalkyl; or phenyl optionally substituted by one or two (e.g. one) substituents independently being: fluoro, chloro, C ⁇ _2 alkyl, Cifluoroalkyl, Ci ⁇ alkoxy or Cxfluoroalkoxy; or R 7 and R 8 together are -(CH 2 ) n 6 - or -(CH 2 ) n 8 -X 7 -(CH2) n 9 - wherein X 7 is NR.I 4 or preferably O.
  • R 8 is neither cycloalkyl nor optionally substituted phenyl.
  • R 8 can for example be H.
  • R 7 and/or R 8 independently are a hydrogen atom (H) or C ⁇ alkyl. It is preferable that R 8 is a hydrogen atom (H).
  • n is 4 or 5.
  • n 7 is 3 or 4.
  • n 8 , n 9 and/or n*-® independently is/are 2.
  • R! 2 and/or RI 3 independently are H; C ⁇ _2 alkyl such as methyl; C3_6cycloalkyl; or phenyl optionally substituted by one or two (e.g. one) substituents independently being: fluoro, chloro, C 1 alkyl, C 1 fluoroalkyl, C 1 _2 alkoxy or
  • Cifluoroalkoxy or R 12 and R 13 together are -(CH 2 ) n 6a - or -(CH 2 ) n 8a -Xl 2 -(CH2) n 9a - in which ⁇ 2 is NRl 4a or preferably O.
  • R 3 is neither cycloalkyl nor optionally substituted phenyl.
  • RI 3 can for example be H.
  • R and/or R 3 independently are a hydrogen atom (H) or C ⁇ alkyl. It is preferable that RI 3 is a hydrogen atom (H).
  • n ⁇ a is 4 or 5.
  • n 7a is 3 or 4.
  • n a , n a and/or nl ⁇ a independently is/are 2.
  • R 7 and R 8 together are -(CH2)2-O-(CH2)2-)» or NMe 2 .
  • Rl 4 , Rl 4a , Rl 7 and/or Rl 7a independently are: a hydrogen atom (H); C ⁇ _2alkyl; Cifluoroalkyl (e.g. CF3); -C(O)Me; -C(O)NH 2 ; or -S(O) 2 Me. More suitably, R 14 Rl4a R 17 ⁇ d/or Rl 7a independently is/are: H, C ⁇ alkyl, or -C(O)Me; or for example H or C i _2 a lkyl.
  • Rl5 is a hydrogen atom (H) or C ⁇ _4alkyl (e.g. l Bu or C ⁇ _2 alkyl e.g. methyl); more suitably, Rl5 is a hydrogen atom (H).
  • R 5 a independent of other Rl a ? i s a hydrogen atom (H) or C ⁇ _4alkyl, it can for example be H, l Bu or C ⁇ _2alkyl such as methyl.
  • Rl5a ? independent of other Rl5a j is H or C ⁇ alkyl, more preferably H.
  • Rl5 b is H.
  • Rl6 is C ⁇ _4alkyl (e.g. C ⁇ alkyl) or C3_6cycloalkyl (e.g. Cs.gcycloalkyl); more suitably Rl° " is C _4alkyl (e.g. C ⁇ _2alkyl).
  • Rl 6a is: C ⁇ _4alkyl (e.g. Ci ⁇ alkyl);
  • 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, C ⁇ _2 alkyl, Cifluoroalkyl, C ⁇ _2 alkoxy or Cifluoroalkoxy;
  • Ar5c phenyl optionally substituted by one or two substituents independently being: a halogen atom, C ⁇ _2alkyl, Cifluoroalkyl, C ⁇ _2 alkoxy or Cifluoroalkoxy; benzyl optionally substituted on its ring by one or two substituents independently being: a halogen atom, C ⁇ alkyl, Cifluoroalkyl, C ⁇ _2 l oxy or Cifluoroalkoxy; or a 5- or 6-membered saturated heterocyclic 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 NR 27 where R 27 is H, C ⁇ _2alkyl or -C(O)Me (preferably H or C ⁇ _2 lkyl); and wherein the ring is not substituted at carbon.
  • Rl6a is: C ⁇ _4alkyl (e.g. C ⁇ ancyl); unsubstituted C3_6cycloalkyl (e.g. unsubstituted Cs.gcycloalkyl); phenyl optionally substituted by one or two substituents independently being: a halogen atom, C ⁇ _2 alkyl, Cifluoroalkyl, C ⁇ _2 lkoxy or Cifluoroalkoxy; or benzyl optionally substituted on its ring by one or two substituents independently being: a halogen atom, C ⁇ alkyl, Cifluoroalkyl, C ⁇ _2 alkoxy or Cifluoroalkoxy.
  • Rl6a s f ⁇ alkyl e.g. C ⁇ alkyl
  • R 3 ⁇ independent of other R 3 ⁇ , is a hydrogen atom (H) or C ⁇ _4alkyl, for example H, t-butyl or C ⁇ _2 alkyl.
  • the compound of formula (I) or the salt thereof is racemic at the carbon atom bearing the R 4 and R5 groups, or (more preferably) the compound of formula (I) or the salt thereof is a compound of formula (LA) 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 R5 groups.
  • Formula (IA) on a molarity basis, preferably 70% or more, more preferably 75% or more, still more preferably 85% or more, yet more preferably 90% or more, for example 95%) or more such as 98% or more, of the compound or salt present has the stereochemistry shown at the carbon atom bearing the R 4 and R5 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 R5 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 R5 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 is methyl, ethyl, Cifluoroalkyl (such as CF3), -CH2OH, or
  • R 4 is methyl, ethyl, CF3 or -CH2OH; yet more preferably R 4 is methyl or ethyl; and most preferably R 4 is ethyl.
  • R is particularly preferable that R is a hydrogen atom (H) and R 4 is not a hydrogen atom (H).
  • R5 is a hydrogen atom (H); and R 4 is methyl, ethyl, Cifluoroalkyl (such as CF 3 ), -CH 2 OH, or -CH 2 OMe (e.g. methyl, ethyl, CF3 or -CH2OH).
  • Ln formula (LA) it is most preferable that R is a hydrogen atom (H); and R 4 is methyl or ethyl (preferably ethyl).
  • HN-CR 4 R5-AT is the HN-CR 4 R5-AT group as defined in any one of Examples 1 to 314 and/or as defined in any one of Examples 315 to 382.
  • the compound of fonnula (I) or the salt thereof is one of Examples 1 to 314 or Example 314A, as a compound or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
  • the structures of these specific compounds, or embodiments thereof, are given in Examples 1 to 314 hereinafter, and their names are given in the Examples section.
  • the compound of fonnula (I) or the salt thereof is a compound of Example 73, 98, 283, 304, 306, 307, 310 or 311 (or is a compound of Example 75), as defined by the structures and/or names described herein, or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
  • These Examples can for example be for inhaled administration e.g. to a mammal such as a human, and/or can be contained in a pharmaceutical composition suitable and/or adapted for inhaled administration, and/or can be in a particle-size-reduced form (e.g. in a size-reduced form obtained or obtainable by micronisation, e.g. see "Particle size reduction” section below).
  • the compound of formula (I) or the salt thereof is:
  • the compound of fonnula (I) or the salt thereof is a compound of Example 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 341, 342, 343, 344, 345, 351, 352, or 353, as defined by the structures and/or names described herein, or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
  • Examples 316-333, 335, 338-345, and 351-353 are believed to consist essentially of an enantiomer which is believed to have the (R)-stereochemistry at the benzylic carbon atom.
  • the compound of formula (I) or the salt thereof is a compound of Example 316, 321, 324, 326, 327, 328, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 343, 344 or 345, as defined by the structures and/or names described herein, or a salt thereof, e.g. a phannaceutically acceptable salt thereof.
  • the structures and names of these Examples are described in the Examples section.
  • the compound of fonnula (I) or the salt thereof is:
  • Example 333 is believed to consist essentially of an enantiomer which is believed to have the (R)-stereochemistry at the benzylic carbon atom. See Example 333 below for the believed structure.
  • Example 333 or a salt thereof can for example be for inhaled administration e.g. to a mammal such as human, and/or can be contained in a pharmaceutical composition suitable and/or adapted for inhaled administration, and/or can be in a particle-size-reduced form (e.g. in a size-reduced form obtained or obtainable by micronisation, e.g. see "Particle size reduction” section below).
  • the compound of formula (I) or salt thereof can be a compound of Formula (XXNIII) or a salt thereof:
  • RXI is a hydrogen atom (H), C ⁇ _2alkyl or Cifluoroalkyl (preferably H);
  • RY is a hydrogen atom (H) or C ⁇ _2alkyl
  • R ⁇ 2 is a hydrogen atom (H); C ⁇ alkyl (e.g. C ⁇ alkyl or methyl); or -(CH2) n 7aa -OH; wherein n 7aa is 1, 2 or 3; and
  • RX 2 is ArA wherein: (i) ArA is phenyl optionally substituted by one or two substituents independently being: fluoro, chloro, bromo, C ⁇ _2alkyl, C ⁇ _2fluoroalkyl, C ⁇ _2alkoxy,
  • Cifluoroalkoxy OH; - ⁇ R l aa Rl l bb (wherein Rl l aa is H or C ⁇ _ 2 alkyl and R 1 l b is
  • heterocyclic aromatic ring ArA contains 2, 3 or 4 heteroatoms (e.g. 2 or 3 heteroatoms), one is selected from O, N and S and the remaining heteroatom(s) are
  • heterocyclic aromatic ring Ar ⁇ - is optionally substituted by one or two groups independently being C ⁇ _4alkyl (e.g. C ⁇ _2alkyl) or OH (including any keto tautomer of an OH-substituted aromatic ring).
  • a compound of formula (XXNIII) can suitably be:
  • the compounds of Formula (XXNIII) are also disclosed in PCT/EP2003/014867 (e.g. see page 59 thereof) and are incorporated herein by reference. According to an alternative optional embodiment of the invention, the compound of formula (I) or salt thereof is not a compound of Formula (XXNIII) or a salt thereof.
  • a further aspect of the present invention provides a compound of formula (IB) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
  • R l is C 2 _3alkyl, C 2 fluoroalkyl or -CH 2 CH 2 OH;
  • R 2a is a hydrogen atom (H) or methyl
  • ⁇ HR 3a is of sub-formula ( ⁇ l4), in which the -NH- connection point of the NHR 3a group to the 4-position of the pyrazolopyridine of formula (LB) is underlined:
  • R 6Aa , R 6Ba , R 6Da R 6Ea and R 6Fa independently of each other, 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,
  • Cifluoroalkoxy e.g. trifluoromethoxy or difluoromethoxy
  • nitro (-NO2) OH
  • C ⁇ _3alkylS(O) 2 - such as MeS(O) 2 -
  • C ⁇ _ 2 alkylS(O) 2 -NH- such as Me-S(O) -NH-, -CONH 2 , cyano (-CN)
  • C 1 _ 2 alkylS(O) 2 -CH 2 - such as Me-S(O) -CH 2 ;
  • R ⁇ Aa , R ⁇ a , R ⁇ Da ⁇ R6Ea a d R6Fa ar e a hydrogen atom (H);
  • C2.3a.lkyl can for example be ethyl or n-propyl.
  • C2fluoroalkyl can for example be C ⁇ fluoroalkyl-CH2- such as CF3-CH2-.
  • Rl a is ethyl, n-propyl or -CH2CH2OH.
  • Rl a is most preferably ethyl.
  • R 2a can for example be H.
  • the NHR a group of sub-formula (pi 4) is preferably in the cis configuration, i.e. is a [cz5 , -4-(l-hydroxyethyl)cyclohexyl]amino group (including mixtures of configurations wherein the cis configuration is the major component).
  • R4aa s methyl, ethyl, CF3 or -CH2OH; more preferably R 4a a i s methyl or ethyl; most preferably R4aa i s ethyl.
  • R 6Aa , R 6Ba , R 6Da , ROEa and/or R 6Fa 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 orMeS(O) 2 -.
  • R ⁇ Aa ? R6Ba ? RODa ⁇ R6Ea a nd R6Fa ar e a hydrogen atom (H).
  • the phenyl ring attached to -(CHR aa )- is suitably unsubstituted, monosubstituted, disubstituted or trisubstituted; or preferably the phenyl ring is unsubstituted, monosubstituted or disubstituted; more preferably monosubstituted or disubstituted.
  • R6Ba or R6Da i a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, n-propoxy, difluoromethoxy, OH or MeS(O)2 ⁇ (preferably a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy or difluoromethoxy) and the remainder of R6Aa R6Ba R6Da R6Ea ⁇ d ROFa are H.
  • R6Aa can ⁇ , e a fluorine or chlorine atom, methyl, ethyl, trifluoromethyl, methoxy or difluoromethoxy, and R ⁇ Ba . , R ⁇ Da, R6Ea an d R 6Fa ar e H.
  • the phenyl ring can be 3,4-dimethylphenyl (R 6B and R 6Da are methyl, and R 6Aa , R 6Ea and R 6E a are H) or 2,4-dimethylphenyl (R 6Aa and R 6Da are methyl, and R 6Ba , R 6Ea and R 6pa are H) or 2,5-dimethylphenyl (R 6A and R6Ea are methyl, and R 6Ba R 6Da and R 6E are H) or 3,5-dimethylphenyl (R 6Ba and R ⁇ Ea are methyl, and R 6Aa R 6Da and R 6Ea are H) or 2-fluoro-4-chlorophenyl (R6Aa i s a fluorine atom, R ⁇ Da i s a chlorine atom, and R ⁇ Sa, R6Ea and R6Fa are H) or 3-chloro-4-methylphenyl (
  • hi Formula (LB) on a molarity basis, preferably 70% or more, more preferably 75%> or more, still more preferably 85%> or more, yet more preferably 90% or more, for example 95%> or more such as 98% or more, of the compound or salt present has the stereochemistry shown at the carbon atom bearing the R 4aa group.
  • the stereochemistry at the carbon atom bearing the R 4a a group is such that there is an enantiomeric excess (e.e.) of 50% or more at the carbon atom bearing the R 4 a group (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 4a a group (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%.
  • the compound formula (LB) or the salt thereof is preferably
  • Suitable phannaceutically 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 suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric,
  • 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 phannaceutically acceptable salts include phannaceutically 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.
  • 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%o 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. IH NMR) spectroscopy in the presence of chiral agent.
  • NMR e.g. IH NMR
  • 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- ⁇ i- 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 fonns, 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.
  • a carboxylic acid of formula (II) can be converted into an activated compound of formula (III) wherein ⁇ l is a leaving group substitutable by an amine (as defined below), and subsequently the activated compound can be reacted with an amine of formula ArCR 4 R5NH2:
  • the activated compound (the compound of formula (III)) can be an activated ester wherein the leaving group ⁇ l is
  • the latter activated compound of formula (III) can be formed from the carboxylic acid of formula (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
  • This process preferably involves reaction of compound of formula (IN) with either:
  • a base such as sodium hydroxide or potassium hydroxide
  • a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane or
  • an acid such as hydrochloric acid
  • a solvent e.g. an aqueous solvent such as aqueous dioxane.
  • 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 fonnula R ⁇ 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 or acetonitrile.
  • the reaction may require heating e.g. to ca. 60-100°C, for example ca. 80-90°C:
  • preparation of the amino pyrazole (VI) can be achieved, for example, using methods described by Dorgan et. al. inJ. Chem. Soc, Perkin Trans. 1, (4), 938-42; 1980, by reaction of cyanoethyl hydrazine with a suitable aldehyde of fonnula R 4 ⁇ CHO in a solvent such as ethanol, with heating, followed by reduction, for example reduction with sodium in a solvent such as t-butanol.
  • 4-alkoxy e.g. C ⁇ _4alkoxy such as ethoxy
  • X 4 1 is a group displaceable by the N-1 nitrogen of the pyrazolopyridine, in order to re- insert the desired R group [i.e. to prepare the 4-amino 5-ester compound of Formula (IN)].
  • X 4 1 can for example be a halogen, e.g. Cl, Br or I; or X 4 1 can be -O-S(O)2-R l where R 4 1 is C ⁇ _4alkyl, Cifluoroalkyl, or phenyl optionally substituted by C ⁇ _2alkyl.
  • the ⁇ -l alkylation reation with R!-X 1 is preferably carried out in the presence of base
  • 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 NH2-
  • the leaving group displaceable by the amine can for example be R EA , in a compound of formula (Na), wherein R EA is an alkoxy group OR 3 5 such as OC ⁇ _4alkyl (in particular
  • R 37 is Ci.galkyl (e.g. C ⁇ alkyl or C ⁇ _ 2 alkyl such as methyl), Ci. ⁇ fluoroalkyl (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 C ⁇ _2alkyl, halogen or C _2alkoxy (such as phenyl or 4-methyl-phenyl).
  • Ci.galkyl e.g. C ⁇ alkyl or C ⁇ _ 2 alkyl such as methyl
  • Ci. ⁇ fluoroalkyl e.g. Cifluoroalkyl or C ⁇ _2fluoroalkyl such as CF3 or C4F9
  • phenyl wherein the phenyl is optionally substituted by one or two of independently C ⁇ _2alkyl, halogen or C _2alkoxy (such as phenyl
  • reaction of the compound of formula (Na) with the amine of formula R ⁇ H2 may be carried out with or without solvent and may require heating: (Va) (IV)
  • the compound of formula (IN), described herein can be prepared by reaction of a compound of formula (IX) with an alkylating agent of formula Rl-X 3 , where X 3 is a leaving group displaceable by the 1- position pyrazolopyridine nitrogen atom of the compound of formula (IX):
  • a suitable alkylating agent of formula Rl-X 3 can be used.
  • X 3 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 ⁇ alkyl or C ⁇ _2alkyl such as methyl), Ci. ⁇ fluoro alkyl (e.g.
  • Cifluoroalkyl or Cifluoroalkyl such as CF3 or C4F9), or phenyl wherein the phenyl is optionally substituted by one or two of independently C _2alkyl, halogen or C ⁇ _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.
  • the 4-chloro can be replaced by 4-C ⁇ _4alkoxy such as 4- ethoxy; these modified compounds, of formula (Xa), can optionally be made as described above, e.g. see the Intermediate 170 scheme shown and described above or Intermediate 1 A below.
  • Compounds of fonnula (I) can be prepared by reaction of a compound of formula (Nil) with an amine of formula R 3 ⁇ H2- Ln the compound of formula (Nil), R EB is a leaving group which is displaceable by the amine of formula R 3 ⁇ H2- R EB can be a bromine atom (Br) or more particularly a chlorine atom (Cl), or alternatively R EB can be an alkoxy group OR 3 5 such as OC ⁇ _4alkyl (in particular OEt) or a group -O-S(O)2-R 37 .
  • R 37 is Ci.galkyl (e.g. C ⁇ alkyl or C ⁇ _2 a 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 C _2alkyl, halogen or C ⁇ _2 a lkoxy (such as phenyl or 4-methyl-phenyl).
  • Ci.galkyl e.g. C ⁇ alkyl or C ⁇ _2 a lkyl such as methyl
  • Ci.gfluoroalkyl e.g. Cifluoroalkyl or Cifluoroalkyl such as CF3 or C4F9
  • phenyl wherein the phenyl is optionally substituted by one or two of independently C _2alkyl, halogen or C ⁇ _2 a lkoxy (
  • the reaction of (Nil) to (I) is preferably carried out in the presence of a base, such as triethylamine or ⁇ , ⁇ - diisopropylethylamine, and/or in an organic solvent such as ethanol, THF, dioxane or acetonitrile.
  • a base such as triethylamine or ⁇ , ⁇ - 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 (VIII) can be prepared by hydrolysis of an ester of formula (N) 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 compounds of formula (I) can be prepared by reaction of a compound of formula (LXa) with an alkylating agent of formula Rl-X 3 , where X 3 is a leaving group displaceable by the 1 -position pyrazolopyridine nitrogen atom of the compound of formula (LXa) :
  • a suitable alkylating agent of formula Rl-X 3 can be used.
  • X 3 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 C ⁇ _galkyl (e.g. C ⁇ _4alkyl or Ci ⁇ alkyl 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.
  • ester (IX) by hydrolysis of the ester and conversion of the resulting carboxylic acid to the amide of formula (LXa) by activation of the acid and reaction with an amine of formula AXCR 4 R NH2-
  • the ester (IX) to acid to amide (IXa) conversion can suitably use the reagents and reaction conditions mentioned in Process A above for conversion of (IN) to (II) to (III) to (I).
  • the ester compound of formula (IX) can be prepared using the method described in the alternative embodiment of Process A, above.
  • Process D Conversion of one compound of formula (I), (II) or (IV) or salt thereof into another compound of formula (I), (II) or (IV) or salt thereof
  • One compound of formula (I), (II) or (IN) or salt thereof can be converted into a or another compound of formula (I), (II) or (IN) or salt thereof.
  • This conversion preferably comprises or is one or more of the following processes DI to D7:
  • 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.
  • the oxidation process can e.g. comprise or be conversion of a nitrogen-containing compound of formula (I) or salt thereof to the conesponding ⁇ -oxide (e.g. using r ⁇ et ⁇ -chloroperoxybenzoic acid), for example conversion of a pyridine-containing compound to the conesponding pyridine ⁇ -oxide (e.g. see Examples 210-212 of PCT/EP03/11814 (WO 2004/024728 A2), filed on 12 September 2003 and incorporated herein by reference, for suitable process details).
  • 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.
  • D7 Deprotection, e.g. deprotection of (e.g. deacylation of or t-butyloxycarbonyl (BOC) removal from) an amine group.
  • BOC deprotection can be carried out under acidic conditions e.g. using hydrogen chloride in an organic solvent such as dioxan - Examples 381 and 382 herein are examples of such a BOC deprotection process.
  • the Beckmann reanangement can for example comprise conversion of a compound of formula (I) wherein NHR 3 is of sub-formula (o2)
  • the present invention therefore also provides a method of preparing a compound of fonnula (I) or a salt thereof:
  • Rl, R 2 , R 3 , R 4 , R5 and Ar are as defined herein, the method comprising
  • R EB is a leaving group which is displaceable by an amine of formula R 3 NH2, with an amine of fonnula R 3 NH2;
  • the present invention also provides: (e) a method of preparing a pharmaceutically acceptable salt of a compound of formula (I) comprising conversion of the compound of formula (I) or a salt thereof into the desired pharmaceutically acceptable salt thereof. (See for example Example 307 herein).
  • the present invention also provides a compound of formula (I) or a salt thereof, prepared by a method as defined herein.
  • the present invention also provides a compound of formula (I) or a phannaceutically 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 such as a human; or e.g. for use in the treatment and/or prophylaxis of cognitive impairment or depression in a mammal such as a human) 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, or e.g. for the treatment and/or prophylaxis of cognitive impairment or depression in a mammal.
  • a medicament e.g. pharmaceutical composition
  • 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, cognitive impairment or depression 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 (e.g. inflammatory pain). Ulcerative colitis and/or Crohn's disease are collectively often refened to as inflammatory bowel disease.
  • the inflammatory and/or allergic disease can suitably be chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, allergic rhinitis or atopic dermatitis in a mammal (e.g. human).
  • COPD chronic obstructive pulmonary disease
  • the inflammatory and/or allergic disease is suitably 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.Bumouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466- 473; P.J. Barnes, Naure Reviews - Drug Discovery, October 2004, 831-844; and references cited in the aforementioned publications).
  • PDE4 inhibitors for example cilomilast and roflumilast, are thought to be effective in the treatment of COPD.
  • PDE4 inhibitors for example cilomilast and roflumilast.
  • 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.Bumouf et al. Current Pharmaceutical Design, 2002, 8(14), 1255-1296
  • A.M.Doherty Current Opinion Chem. Biol, 1999, 3(4), 466-473; A.M.
  • 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.Bumouf 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).
  • topical administration e.g. topical administration to the skin e,g. to affected skin
  • topical administration e.g. topical administration to the skin e,g. to affected skin
  • 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, E pert Opinion on Investigational Drugs, 2000, 9(3), 621-625; H.T. Zhang et al., Neuropsychopharmacology, October 2002, 27(4), 587-595; J. M. O'Donnell and H.-T. Zhang, Trends Pharmacol. Sci, March 2004, 25(3), 158-163; and T. ⁇ .Renau, Curr. Opinion Invest. Drugs, 2004, 5(1), 34-39).
  • PD ⁇ 4 inhibition has been suggested for the treatment of inflammatory bowel disease (e.g. ulcerative colitis and/or Crohn's disease), see K.H.Banner and M.A.Trevethick, Trends Pharmacol. Sci., August 2004, 25(8), 430-436.
  • inflammatory bowel disease e.g. ulcerative colitis and/or Crohn's disease
  • K.H.Banner and M.A.Trevethick Trends Pharmacol. Sci., August 2004, 25(8), 430-436.
  • 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 earners 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 pharmaceutical 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, topical (e.g. skin topical), or nasal administration.
  • the pharmaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled, topical (e.g. skin topical), 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.
  • 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 e.g. oral
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • the pharmaceutical composition is in unit dose form, such as a tablet or capsule for oral administration, e.g. for oral administration to a human.
  • 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 (polyvinylpynolidone), a lubricant e.g.
  • the pharmaceutical 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 phannaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures.
  • pellets or powder containing the active ingredient can be prepared using a suitable phannaceutically 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.
  • a parenteral composition can comprise a solution or suspension of the compound or phannaceutically 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.
  • a topical pharmaceutical composition e.g. skin topical pharmaceutical composition
  • can for example be an ointment, a cream (i.e. an oil-in-water pharmaceutical composition), an aqueous gel, or a DMSO-containing solution such as a DMSO/acetone solution (DMSO dimethyl sulphoxide).
  • a topical pharmaceutical composition e.g. an oil-in-water composition
  • a skin-penetration enhancer such as propylene glycol
  • an emulsifier e.g. surfactant
  • SDS sodium dodecyl sulphate
  • a topical ointment can for example comprise polyethylene glycol and/or propylene glycol.
  • the compound of formula (I) or the salt thereof can optionally be present at 0.25 to 5%, for example 0.5 to 2.5%, by weight of the total composition, hi a topical pharmaceutical composition, the compound of formula (I) or the salt thereof can optionally be Example 73, 75, 98, 283, 304, 306, 307, 310, 311, 316, 321, 324, 326, 327, 328, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 343, 344 or 345, as the compound or a phannaceutically acceptable salt thereof.
  • a topical pharmaceutical composition e.g. skin topical pharmaceutical composition
  • Compositions for nasal or inhaled administration may conveniently be fonnulated 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.
  • 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.
  • 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 fonn, 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 or about 1 to about 5 microns (e.g.
  • 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 or (e.g. about 1 to about 5 microns or 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 2 to about 15 microns or about 3 to about 15 microns (e.g. about 5 to about 15 microns or about 5 to about 10 microns or about 2 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), and/or a D50 of about 0.5 to about 10 microns or 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.
  • Example 73 To micronise Example 73, 75, 98, 283, 304, 306, 307, 308, 309, 310, 311, 312, 313, 314 or 314A or 333 (described hereinafter), usually in an amount of approximately 600-1000 mg thereof, using a Jetpharma MCI micronizer.
  • the parent (unmicronised) and micronised materials are analyzed for particle size by laser diffraction and crystallinity by PXRD.
  • Jetpharma MCI Micronizer Nitrogen supply Air tank with 275psi rate tubing
  • Example 73 Materials to be micronised Example 73, Example 75, Example 283 or
  • the Jetpharma MCI Micronizer comprises a horizontal disc-shaped milling housing having: a tubular compound inlet (e.g. angled at ca. 30 degrees to the horizontal) for entry of a suspension of unmicronised compound of formula (I) or salt in a gasflow, a separate gas inlet for entry of gases, a gas outlet for exit of gases, and a collection vessel (micronizer container) for collecting micronised material.
  • the milling housing has two chambers: (a) an outer annular chamber in gaseous connection with the gas inlet, the chamber being for receiving pressurised gas (e.g.
  • the annular wall (ring R) has a plurality of nanow-bored holes connecting the inner and outer chambers and circumferentially-spaced-apart around the annular wall.
  • the holes opening into the inner chamber are directed at an angle (directed part-way between radially and tangentially), and in use act as nozzles directing pressurised gas at high velocity from the outer chamber into the inner chamber and in an inwardly-spiral path (vortex) around the inner chamber (cyclone).
  • the compound inlet is in gaseous communication with the inner chamber via a nozzle directed tangentially to the inner chamber, within and near to the annular wall / ring R.
  • Upper and lower broad-diameter exit vents in the central axis of the inner milling chamber connect to (a) (lower exit) the collection vessel which has no air outlet, and (b) (upper exit) the gas outlet.
  • a venturi inlet (N) Inside and coaxial with the tubular compound inlet and longitudinally-movable within it is positioned a venturi inlet (N) for entry of gases.
  • the compound inlet also has a bifurcation connecting to an upwardly- directed material inlet port for inputting material.
  • the nanow head of the venturi inlet (N) is preferably positioned below and slightly forward of the material inlet port, so that when the venturi delivers pressurised gas (e.g. air or nitrogen) the feed material is sucked from the material inlet port into the gas stream through the compoxmd inlet and is accelerated into the inner milling chamber tangentially at a subsonic speed. Inside the milling chamber the material is further accelerated to a supersonic speed by the hole/nozzle system around the ring (R ) (annular wall) of the milling chamber. The nozzles are slightly angled so that the acceleration pattern of the material is in the form of an inwardly-directed vortex or cyclone.
  • pressurised gas e.g. air or nitrogen
  • the material inside the milling chamber circulates rapidly and particle collisions occur during the process, causing larger particles to fracture into smaller ones.
  • "Centrifugal" acceleration in the vortex causes the larger particles to remain at the periphery of the inner chamber while progressively smaller particles move closer to the centre until they exit the milling chamber, generally through the lower exit, at low pressure and low velocity.
  • the particles that exit the milling chamber are heavier than air and settle downward thorugh the lower exit into the collection vessel (micronizer container), while the exhaust gas rises (together with a minority of small particles of micronised material) and escapes into the atmosphere at low pressure and low velocity.
  • the micronizer is assembled.
  • the nanow head of the venturi inlet is positioned below and slightly forward of the material inlet port and is measured with a micro-caliper to make sure that it is inserted conectly.
  • the ring (R ) and venturi (N) pressures are adjusted according to the values specified in the experimental design (refer to experimental section below) by adjusting the valves on the pressure gauges on the micronizer.
  • the setup is checked for leakage by observing if there is any fluctuation in the reading of the pressure gauges.
  • the venturi (V) pressure is kept at least 2 bars greater than the ring (R ) pressure to prevent regurgitation of material, e.g. outwardly from the material inlet port.
  • Balance performance is checked with calibration weights.
  • Specified amount of the parent material is fed into the input container of the micronizer using a spatula.
  • the input container plus material is weighed.
  • the equipment pressure is monitored during the micronization process.
  • the nitrogen supply is shut off and the micronised material is allowed to settle into the micronizer container.
  • the micronised powder in the micronizer container (collection vessel) and the cyclone (above the recovery vessel) are collected together into a pre-weighed and labelled collection vial.
  • the weight of the micronised material is recorded.
  • the input container is re-weighed in order to calculate the amount of input material by difference.
  • the micronizer is disassembled and residual PDE4 compound on the micronizer inner surface is rinsed with 70/30 isopropyl alcohol / water and collected into a flask. The micronizer is then thoroughly cleaned in a Lancer washing machine and dried before subsequent runs are performed.
  • Procedure 1 In alternative embodiments of Procedure 1, Procedure 1 or variations thereof generally using generally similar conditions, have also been carried out for the following Examples: Example 73 Example 75 Example 283 Example 333.
  • Parent (unmicronised) material (Procedure 2): Example 73, 98, 283, 304, 306, 307, 308,
  • Procedure 2 includes possible parameters and conditions, and micronisation of possible Examples, and has not been carried out.
  • Dry powder inhalable compositions For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is prefened that 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%o 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.
  • 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 (e.g. as prepared in the Micronisation Example above), 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 compound/salt e.g. 10 mg, 1% w/w
  • inhalation-grade lactose containing 10% fines e.g. 990 mg, 99% w/w
  • TeflonTM polytetraflu
  • Mikro-dismembrator (available from B. Braun Biotech International, Schwarzenberger Weg 73-79, D-34212 Melsungen, Germany; www.bbraunbiotech.com) comprises abase with an upwardly-projecting and sidewardly-vibratable arm to which is attached the Teflon TM p 0l ⁇ ⁇ e vibration of the arm achieves blending.
  • Other blends can include: 10% w/w compound/salt (50 mg) + 90%> w/w lactose
  • 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 pharmaceutical composition in powder form from the opened container.
  • Unit dose form and dosing regimens 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 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 pharmaceutically 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 phannaceutically 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 formula (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.
  • a ⁇ 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.
  • ⁇ -adrenoreceptor agonists are prefened, especially those having a therapeutic effect over a 12-24 hour period such as salmeterol or formoterol.
  • the ⁇ -adrenoreceptor agonist is for inhaled administration, e.g. once per day and/or for simultaneous inlialed 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.
  • Prefened long acting ⁇ -adrenoreceptor agonists include those described in WO 02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933.
  • Especially prefened long-acting ⁇ 2 -adrenoreceptor agonists include compounds of
  • R 11X is -XSO 2 NR 16X R 17X wherein X is -(CH 2 ) p ⁇ - or C 2-6 alkenylene;
  • R 16x and R 17x are independently selected from hydrogen, C 1-6 alkyl, C 3- cycloalkyl,
  • R 16x and R 17X are each optionally substituted by one or two groups selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy- substituted C 1-6 alkoxy, -CO 2 R 18X , -SO 2 NR 18X R 19X , -CONR 18X R 19x , -NR 18X C(O)R 19X , or a 5-, 6- or 7-membered heterocylic ring;
  • R 18 and R 19x are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, and phenyl (C 1- alkyl)-; and p x is an integer of from 0 to 6, preferably from 0 to 4; R 12X and R 13X are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, phenyl, and C 1-6 haloalkyl; and
  • R 14X and R 15X are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 14x and R 15X is not more than 4.
  • Prefened ⁇ 2 -adrenoreceptor agonists disclosed in WO 02/066422 include:
  • a prefened ⁇ 2 -adrenoreceptor agonist disclosed in WO 03/024439 is:
  • 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 TM)
  • 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, M ⁇ /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 Mi and/or M2 receptor.
  • an anticholinergic compound e.g. a muscarinic (M) receptor antagonist in particular an M , M2, M ⁇ /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 Mi and/or M2 receptor.
  • 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
  • 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 pharmaceutically 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 drug (NSALD) 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 inhibitors 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 ⁇ which is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-l 1 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester ⁇ or Example 41 therein ⁇ which is 6 ⁇ ,9 ⁇ -difluoro-l l ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-l,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 prefened 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.
  • Prefened 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
  • PDE4D3A Human recombinant PDE4D
  • 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 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 as described by: P. Catty and P. Detene,
  • 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.
  • PDE4B or PDE4D inhibition can be measured in the following Fluorescence Polarisation (FP) assay:
  • the ability of compounds to inhibit catalytic activity at PDE4B (human recombinant) or PDE4D (human recombinant) can optionally be determined by LMAP Fluorescence Polarisation (FP) assay (LMAP Explorer kit, available from Molecular Devices Corporation, Sunnydale, CA, USA; Molecular Devices code: R8062) in 384-well format.
  • FP LMAP Fluorescence Polarisation
  • 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. LMAP 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 Analyst ⁇ M i 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 (LD Business Solutions Limited, 2 Ocean Court, Suney Research Park, Guildford, Suney GU2 7QB, United Kingdom). Results are expressed as pICso values. In the FP assay, reagents are usually dispensed using MultidropTM (available from Thermo Labsystems Oy, Ratastie 2, PO Box 100, Nantaa 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 about 0.5 log units, for each of PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R.Mobbs et al., "Comparison of the LMAP 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 generally as follows, based on measurements only, generally using SPA and/or FP assays generally as described above or generally similar to those described above, hi each of the SPA and FP assays, absolute accuracy of measurement is not possible, and the readings given are thought to be accurate only up to about ⁇ 0.5 of a log unit, depending on the number of readings made and averaged:
  • a large majority or substantially all of the Examples have been tested for PDE4B inliibition, normally using the radioactive SPA assay and/or the FP assay generally as described above or generally similar to those described above.
  • Emesis Some known PDE4 inhibitors can cause emesis and/or nausea to greater or lesser extents, especially after systemic exposure e.g. after oral administration (e.g. see Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438, see especially pages 433-434 and refs cited therein). Therefore, it would be preferable, but not essential, if a PDE4 inhibitory compound or salt of the invention were to cause only limited or manageable emetic side-effects, e.g. after oral or parenteral administration.
  • Emetic side-effects can for example be measured by the emeto genie potential of the compound or salt when administered to fenets; for example one can measure the time to onset, extent, frequency and/or duration of vomiting, retching and/or writhing in fenets after oral or parenteral administration of the compound or salt. See for example In vivo Assay 4 hereinafter for one optional measurement method for anti-inflammatory effect, emetic side-effects and therapeutic index (TF) in the fenet. See also for example A.
  • emetic side-effects and therapeutic index (TI) in rats can be conveniently measured by monitoring the pica feeding behaviour of rats after administration of the compound or salt of the invention (see In Nivo Assay 2 below).
  • Ot ⁇ er side effects Some known PDE4 inhibitors can cause other side effects such as headache and other central nervous sytem (C ⁇ S-) mediated side effects; and/or gastrointestinal (Gl) tract disturbances. Therefore, it would be preferable but not essential if a particular PDE4 inhibitory compound or salt of the invention were to cause only limited or manageable side-effects in one or more of these side-effect categories.
  • C ⁇ S- central nervous sytem
  • Gl gastrointestinal tract disturbances. Therefore, it would be preferable but not essential if a particular PDE4 inhibitory compound or salt of the invention were to cause only limited or manageable side-effects in one or more of these side-effect categories.
  • Test compounds are prepared as a ca. lOmM stock solution in DMSO and a dilution series prepared in DMSO with 8 successive 3-fold dilutions, either directly from the lOmM stock solution or from a more dilute solution in DMSO.
  • the compound is added to assay plates using a Biomek Fx liquid handling robot.
  • ca. 1 hr incubation at ca. 37 °C, 5%> CO2 ca. 25 ⁇ l (ca. 25ul) of LPS (lipopolysacchari.de) solution (S. typhosa) in RPMI 1640 (containing 1%> L- glutamine and 1% Penicillin/ streptomycin) is added (ca. 50ng/ml final).
  • LPS lipopolysacchari.de
  • S. typhosa lipopolysacchari.de solution
  • RPMI 1640 containing 1%> L- glutamine and 1% Penicillin/ streptomycin
  • Plasma TNF content is determined by electrochemiluminescence assay using the IGEN technology (see below) or by enzyme linked immunosorbant assay (ELISA) (see below).
  • Test compounds are prepared as a ca. lOmM stock solution in DMSO and a dilution series prepared in DMSO with 8 successive 3-fold dilutions, either directly from the lOmM stock solution or from a more dilute solution in DMSO.
  • the compound is added to assay plates using a Biomek Fx liquid handling robot.
  • PBMC cells (monocytes) are prepared from heparinised human blood from normal volunteers by centrifugation on histopaque at ca. lOOOg for ca. 30 minutes. The cells are collected from the interface, washed by centrifugation (ca. 1300g, ca. 10 minutes) and resuspended in assay buffer (RPMI1640 containing 10%> foetal calf serum, 1% L- glutamine and 1%> penicillin/streptomycin) at 1x10 cells/ml.
  • Ca. 50 ⁇ l (ca. 50ul) cells are added to microtitre wells containing ca. 0.5 or ca/ 1.0 ⁇ l (ul) of an appropriately diluted compound solution.
  • Ca. 75 ⁇ l (ul) LPS (ca.
  • Ca. 50 ⁇ l supernatant from either whole blood or PBMC assay plates is transfened to a 96 well polypropylene plate. Each plate also contains a TNF ⁇ standard curve (ca. 0 to 30000 pg/ml: R+D Systems, 210-TA).
  • Ca. 50 ⁇ l (ul) of streptavidin/biotinylated anti-TNF ⁇ antibody mix, ca. 25 ⁇ l ruthenium tagged anti-TNF ⁇ monoclonal and ca. lOO ⁇ l PBS containing 0.1 %> bovine serum albumin are added to each well and the plates are sealed and shaken for ca. 2 hours before being read on an IGEN instrument.
  • Human TNF ⁇ can be assayed using a commercial assay kit (AMS Biotechnology, 211- 90-164-40) according to the manufacturers' instructions but with TNF ⁇ calibration curves prepared using Pharmingen TNF ⁇ (cat No. 555212). In Vivo Biological Assays
  • LPS-induced pulmonary neutrophilia in rats effect of orally administered PDE4 inhibitors Pulmonary neutrophil influx has been shown to be a significant component to the family of pulmonary diseases like chronic obstructive pulmonary disease (COPD) which can involve chronic bronchitis and/or emphysema (G.F. Filley, Chest. 2000; 117(5); 251s-260s).
  • COPD chronic obstructive pulmonary disease
  • the purpose of this neutrophilia model is to study the potentially anti- inflammatory effects in vivo of orally administered PDE4 inhibitors on neutrophilia induced by inhalation of aerosolized lipopolysaccharide (LPS), modelling the neutrophil inflammatory component(s) of COPD. See the literature section below for scientific background.
  • test compound for example suspended in ca. 0.5%) methylcellulose (obtainable from Sigma- Aldrich, St Louis, MO, USA) in water or (b) vehicle only, delivered orally in a dose volume of ca. 10 ml/kg.
  • dose response curves can for example be generated using the following approx. doses of PDE4 inhibitors: 2.0, 0.4, 0.08, 0.016 and 0.0032 mg/kg.
  • the rats are exposed to aerosolized LPS (Serotype E.
  • Coli 026:B6 prepared by trichloroacetic acid extraction, obtainable from Sigma- Aldrich, St Louis, MO, USA), generated from a nebulizer containing a ca. 100 ⁇ g/ml LPS solution (ca. 100 ug/ml). Rats are exposed to the LPS aerosol at a rate of ca. 4 L/min for ca. 20 minutes. LPS exposure is carried out in a closed chamber with internal dimensions of roughly 45 cm length x 24 cm width x 20 cm height. The nebulizer and exposure chamber are contained in a certified fume hood. At about 4 hours-post LPS exposure the rats are euthanized by overdose with pentobarbital at ca. 90 mg/kg, administered intraperitoneally.
  • Bronchoalveolar lavage (BAL) is performed through a 14 gauge blunt needle into the exposed trachea. Five, 5 ml washes are performed to collect a total of 25 ml of BAL fluid. Total cell counts and leukocyte differentials are performed on BAL fluid in order to calculate neutrophil influx into the lung. Percent neutrophil inhibition at each dose (cf. vehicle) is calculated and a variable slope, sigmoidal dose-response curve is generated, usually using Prism Graph-Pad. The dose-response curve is used to calculate an ED50 value (in mg per kg of body weight) for inhibition by the PDE4 inhibitor of the LPS- induced neutrophilia.
  • ED50 value in mg per kg of body weight
  • a single oral dose of 10 mg/kg, or more usually 1.0 mg/kg or 0.3 mg/kg, of the PDE4 inhibitor (or vehicle) is administered to the rats, and percent neutrophil inhibition is calculated and reported for that specific dose.
  • Rat Pica Model of emesis Background Selective PDE4 inhibitors have been shown to inhibit inflammation in various in vitro and in vivo models by increasing intracellular levels of cAMP of many immune cells (e.g. lymphocytes, monocytes). However, a side effect of some PDE4 inhibitors in some species is emesis. Because many rat models of inflammation are well characterized, they can be used in procedures (see e.g. In Nivo Assay 1 above) to show beneficial anti-inflammatory effects of PDE 4 inhibitors. However rats have no emetic response (they have no vomit reflex), so that the relationship between beneficial anti- inflammatory effects of PDE 4 inhibitors and emesis is difficult to study directly in rats.
  • Pica feeding is a behavioural response to illness in rats wherein rats eat non-nutritive substances such as earth or in particular clay (e.g. kaolin) which may help to absorb toxins.
  • Pica feeding can be induced by motion and chemicals (especially chemicals which are emetic in humans), and can be inhibited pharmacologically with drugs that inhibit emesis in humans.
  • the Rat Pica Model, In Nivo Assay 2 can determine the level of pica response of rats to PDE 4 inhibition at pharmacologically relevant doses in parallel to in vivo anti-inflammatory Assays in (a separate set of) rats (e.g.
  • Rat TI can for example be calculated as the ratio of a) the potentially-emetic Pica Response ED50 dose from Assay 2 to b) the rat anti-inflammatory ED50 dose (e.g. measured by rat neutrophilia-inhibition in eg In Nivo Assay 1), with larger TI ratios possibly indicating lower emesis at many anti-inflammatory doses. This might allow a choice of a non-emetic or low-emetic pharmaceutical dose of the compounds or salts of the invention which has an anti-inflammatory effect.
  • the rats By the end of the 72 hour acclimation period the rats generally show no interest in the clay pellets. At the end of 72 hours the rats are placed in clean cages and the food cups weighed. Rats that are still consuming clay regularly are removed from the study. Immediately prior to the dark cycle (the time when the animals are active and should be eating) the animals are split into treatment groups and dosed orally with a dose of the compound/salt of the invention (different doses for different treatment groups) or with vehicle alone, at a dose volume of ca. 2 ml/kg. hi this oral dosing, the compound/salt can for example be in the form of a suspension in ca. 0.5% methylcellulose (obtainable Sigma- Aldrich, St. Louis, MO, USA) in water.
  • a dose response is calculated by first converting the data into quantal response, where animals are either positive or negative for the pica response.
  • a rat is "pica positive” if it consumes greater than or equal to 0.3 grams of clay over the mean of its control group.
  • the D50 value is usually calculated using logistic regression performed by the Statistica software statistical package.
  • a Pica Response ED50 value in mg per kg of body weight can then be calculated.
  • the Pica Response ED50 value can be compared to the neutrophilia-inhibition ED50 values for the same compound administered orally to the rat (measurable by In Nivo Assay 1 above), so that a Therapeutic Index (TI) in rats can be calculated thus:
  • Rat Therapeutic index (TI) (50/50) Pica Response ED50 value rat neutrophilia-inhibition ED 50 value
  • the Therapeutic Index (TI) calculated this way is often substantially different to, and for example can often be substantially higher than, the TI (D20/D50) calculated in the fenet (see In vivo Assay 4 below).
  • TI Therapeutic Index
  • the In Nivo Assay 2 (pica) can use only a single oral dose of the test compound (e.g. 10 mg/kg orally).
  • Literature Beavo JA, Contini, M., Heaslip, R.J. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol. 1994; 46:399-405. Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT, Minnicozzi M. Comparison of PDE 4 inhibitors, Rolipram and SB 207499 (ArifloTM), in a rat model of pulmonary neutrophilia. Pulmonary Pharmacology and Therapeudtics. 2001; 14:157- 164.
  • LPS induced pulmonary neutrophilia in rats effect of intratracheally administered PDE4 inhibitors
  • This assay is an animal model of inflammation in the lung - specifically neutrophilia induced by lipopolysaccharide (LPS) - and allows the study of putative inhibition of such neutrophilia (anti-inflammatory effect) by intratracheally (i.t.) administered PDE4 inhibitors.
  • the PDE4 inhibitors are preferably in dry powder or wet suspension form. It. administration is one model of inhaled administration, allowing topical delivery to the lung.
  • Animals Male CD (Sprague Dawley Derived) rats supplied by Charles River,
  • the intratracheal dosing device (a 3-way sterile tap, Nycon 876.00; or Perm Century dry powder insufflator, DP-4) is weighed, the drug blend or inhalation grade lactose (vehicle control) is then added to the tap, the tap is closed to prevent loss of drug, and the tap is re-weighed to determine the weight of drug in the tap. After dosing, the tap is weighed again to determine the weight of drug that had left the tap.
  • the needle a Sigma Z21934-7 syringe needle 19-gauge 152 mm (6 inches) long with luer hub, is cut by engineering to approximately 132 mm (5.2 inches), a blunt end is made to prevent them damaging the rat's trachea, and the needle is weighed prior to and after drug delivery to confinn that no drag is retained in the needles after dosing.
  • Device for wet suspension administration This is the similar to the above but a blunt dosing needle, whose forward end was slightly angled to the needle axis, is used, with a flexible plastic portex canula inserted into the needle.
  • Drugs and Materials Lipopolysaccharide (LPS) (Serotype:0127:B8) (e.g.
  • PBS phosphate-buffered saline
  • PDE4 inhibitors are preferably used in size-reduced (e.g. micronised) form, for example according to the Micronisation Example(s) given above.
  • the Dry Powder Formulation Example given above comprising drag and inhalation-grade lactose, can optionally be used.
  • One suitable inhalation-grade lactose that can be used e.g. Lot E98L4675 Batch 845120
  • wet suspensions of the drug can be prepared by adding the required volume of vehicle to the drug; the vehicle used can for example be saline alone or a mixture of saline/tween (e.g. 0.2%> tween 80). The wet suspension is usually sonicated for ca. 10 minutes prior to use.
  • Preparation, and dosing with PDE 4 inhibitor Rats are anaesthetised by placing the animals in a sealed Perspex chamber and exposing them to a gaseous mixture of isoflourane (4.5 %>), nitrous oxide (3 litres.minute "1 ) and oxygen (1 lifre.minute "1 ).
  • the animals are placed onto a stainless steel i.t. dosing support table. They are positioned on their back at approximately a 35° angle. A light is angled against the outside of the throat to highlight the trachea. The mouth is opened and the opening of the upper airway visualised.
  • the procedure varies for wet suspension and dry powder administration of PDE4 inhibitors as follows: Dosing with a Wet suspension: A portex cannula is introduced via a blunt metal dosing needle that has been carefully inserted into the rat trachea. The animals are intratracheally dosed with vehicle or PDE4 inhibitor via the dosing needle with a new internal canula used for each different drag group. The formulation is slowly (ca.
  • the intratracheal dosing device (a three-way sterile tap device, Nycon 876.00; or Perm Century dry powder insufflator, DP-4) and needle are inserted into the rat trachea up to a pre-determined point established to be located approximately 1 cm above the primary bifurcation. Another operator holds the needle at the specified position whilst 2 x 4ml of air (using 3-way tap device) is delivered through the three-way tap by depressing the syringes (ideally coinciding with the animal inspiring), aiming to expel the entire drug quantity from the tap.
  • the rats can be exposed to LPS less than 2 hours (e.g. about 30 minutes) after i.t. dosing. In another alternative embodiment, the rats can be exposed to LPS more than 2 hours (e.g. ca. 4 to ca. 24 hours) after i.t.
  • Bronchoalveolar lavage About 4 hours after LPS exposure the animals are killed by overdose of sodium pentobarbitone (i.p.). The trachea is cannulated with polypropylene tubing and the lungs are lavaged (washed out) with 3 x 5 mis of heparinised (25 units.ml "1 ) phosphate buffered saline (PBS). Neutrophil cell counts: The Bronchoalveolar lavage (BAL) samples are centrifuged at ca. 1300 rpm for ca. 7 minutes.
  • a cell slide of the resuspension fluid is prepared by placing ca. lOO ⁇ l (ca. lOOul) of resuspended BAL fluid into cytospin holders and then is spun at ca. 5000 rpm for ca. 5 minutes. The slides are allowed to air dry and then stained with Leishmans stain (ca. 20 minutes) to allow differential cell counting. The total cells are also counted from the resuspension. From these two counts, the total numbers of neutrophils in the BAL are determined.
  • a comparison of the neutrophil count in rats treated with vehicle and rats treated with PDE4 inhibitors is conducted.
  • a dose-response curve can be generated.
  • PDE4 inhibitors are prepared for oral (p.o.) administration by dissolving in a fixed volume (ca. 1 ml) of acetone and then adding cremophor to ca. 20% of the final volume. Acetone is evaporated by directing a flow of nitrogen gas onto the solution. Once the acetone is removed, the solution is made up to final volume with distilled water. LPS is dissolved in phosphate buffered saline.
  • the diet comprises SDS diet C pelleted food given ad lib with WhiskersT ca t food given 3 times per week.
  • the animals are supplied with pasteurised animal grade drinking water changed daily.
  • Fenet Therapeutic index (TI) D20 incidence of emesis in fenet D50 inhibition of neutrophilia in fenet
  • the Fenet Therapeutic index (TI) (D20/D50) calculated using this in vivo Assay 4 is often substantially different to, and for example is often substantially lower than, the Rat TI (50/50) calculated using the rat oral inflammation and pica feeding Assays 1+2.
  • Intermediates can represent syntheses of intermediate compounds intended for use in the synthesis of one or more of the “Examples”, or “Intermediates” can represent syntheses of intermediate compounds which can be used in the synthesis of compounds of formula (I) or salts thereof.
  • “Examples” are generally exemplary compounds or salts of the invention, for example compounds of formula (I) or (LB) or salts thereof.
  • HATU O-(7- Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • TRET retention time (from LCMS) Room temperature this is usually in the range of about 20 to about 25 °C.
  • Solvent A 95%> acetonitrile + 0.05%> formic acid
  • Solvent B 0.1 %> formic acid + lOmMolar ammonium acetate
  • T RET retention times
  • the prep column used was a Supelcosil ABZplus (10cm x 2.12cm)
  • Injection Volume 1ml; or more preferably 0.5 ml
  • Solvent B 95%> acetonitrile + 5% formic acid; or more usually 99.95% acetonitrile +
  • ChiralPak AD, ChiralCel OD and ChiralCel OJ columns can be obtained from:

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un composé représenté par la formule (I) ou à un sel de ce composé. Dans la formule (I), Ar est représenté par la sous-formule (x) ou (z), et R3 est cycloalkyle C3-8 éventuellement substitué, cycloalcényle C5-7 éventuellement substitué, un groupe hétérocyclique éventuellement substitué (aa), (bb) ou (cc), ou un groupe bicyclique (ee); et R4 est H, alkyle C1-3, fluoroalkyle C1-2, cyclopropyle, -CH2OR4a, -CH(Me)OR4a, ou -CH2CH2OR4a; et R5 est entre autres H, alkyle C1-8, fluoroalkyle C1-8, cycloalkyle C3-8, certains groupes alkyle substitués, -(CH2)n13-Het, ou phényle éventuellement substitué ou -CH2-Ph; ou R4 et R5 pris conjointement sont -(CH2)p1- ou (CH2)p3 X5 (CH2)p4- ; à condition qu'au moins un des groupes que sont R4 et R5 ne soit pas un atome d'hydrogène (H). L'invention se rapporte également à l'utilisation de ces composés en tant qu'inhibiteurs de la phosphodiestérase de type IV (PDE4) et/ou pour le traitement et/ou la prophylaxie de maladies inflammatoires et/ou allergiques telles que la broncho-pneumopathie chronique obstructive (COPD), l'asthme, la polyarthrite rhumatoïde, la rhinite allergique ou la dermatite atopique.
EP04804089A 2003-12-19 2004-12-17 Composes pyrazolo[3,4-b] pyridine et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase Withdrawn EP1737857A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04804089A EP1737857A1 (fr) 2003-12-19 2004-12-17 Composes pyrazolo[3,4-b] pyridine et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
PCT/EP2003/014867 WO2004056823A1 (fr) 2002-12-23 2003-12-19 Composes de pyrazolo[3,4-b]pyridine et leur utilisation en tant qu'inhibiteurs de phosphodiesterase
GB0405936A GB0405936D0 (en) 2004-03-16 2004-03-16 Compounds
GB0405899A GB0405899D0 (en) 2004-03-16 2004-03-16 Compounds
GB0406754A GB0406754D0 (en) 2004-03-25 2004-03-25 Compounds
EP04804089A EP1737857A1 (fr) 2003-12-19 2004-12-17 Composes pyrazolo[3,4-b] pyridine et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase
PCT/EP2004/014490 WO2005058892A1 (fr) 2003-12-19 2004-12-17 Composes pyrazolo [3,4-b] pyridine et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase

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EP1737857A1 true EP1737857A1 (fr) 2007-01-03

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005058892A1 *

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