WO2004024728A2 - Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors - Google Patents

Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors Download PDF

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Publication number
WO2004024728A2
WO2004024728A2 PCT/EP2003/011814 EP0311814W WO2004024728A2 WO 2004024728 A2 WO2004024728 A2 WO 2004024728A2 EP 0311814 W EP0311814 W EP 0311814W WO 2004024728 A2 WO2004024728 A2 WO 2004024728A2
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Prior art keywords
ethyl
pyrazolo
pyridine
carboxamide
methyl
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PCT/EP2003/011814
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French (fr)
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WO2004024728A3 (en
Inventor
David George Allen
Diane Mary Coe
Caroline Mary Cook
Michael Dennis Dowle
Christopher David Edlin
Julie Nicole Hamblin
Martin Redpath Johnson
Paul Spencer Jones
Richard Graham Knowles
Mika Kristian Lindvall
Charlotte Jane Mitchell
Alison Judith Redgrave
Peter Ward
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Glaxo Group Limited
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Priority claimed from GB0221455A external-priority patent/GB0221455D0/en
Priority claimed from GBGB0230045.7A external-priority patent/GB0230045D0/en
Priority claimed from GB0306595A external-priority patent/GB0306595D0/en
Priority claimed from GB0308017A external-priority patent/GB0308017D0/en
Priority claimed from GB0319708A external-priority patent/GB0319708D0/en
Priority claimed from GB0321074A external-priority patent/GB0321074D0/en
Priority to SI200331680T priority Critical patent/SI1539753T1/en
Priority to DK03778283T priority patent/DK1539753T3/en
Priority to MXPA05002887A priority patent/MXPA05002887A/en
Priority to DE60329193T priority patent/DE60329193D1/en
Priority to CNB038250438A priority patent/CN100387598C/en
Priority to BR0314392-9A priority patent/BR0314392A/en
Priority to NZ538515A priority patent/NZ538515A/en
Priority to US10/527,866 priority patent/US20060089375A1/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to EP03778283A priority patent/EP1539753B1/en
Priority to CA002497550A priority patent/CA2497550A1/en
Priority to AU2003285300A priority patent/AU2003285300B2/en
Priority to JP2004571743A priority patent/JP2006503108A/en
Priority to AT03778283T priority patent/ATE442367T1/en
Priority to ES03778283T priority patent/ES2331119T3/en
Publication of WO2004024728A2 publication Critical patent/WO2004024728A2/en
Publication of WO2004024728A3 publication Critical patent/WO2004024728A3/en
Priority to IL166898A priority patent/IL166898A/en
Priority to NO20050841A priority patent/NO20050841L/en
Priority to IS7709A priority patent/IS7709A/en
Priority to US12/013,529 priority patent/US20080175914A1/en
Priority to AU2010201417A priority patent/AU2010201417A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to pyrazolopyridine 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 pyrazolopyridine compounds in therapy, for example as inhibitors of phosphodiesterases and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.
  • COPD chronic obstructive pulmonary disease
  • 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, 191 A, 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 2 denotes 1) a hydrogen atom or 2) a Cl-8 alkoxy group.
  • R 3 denotes 1) a hydrogen atom or 2) a Cl-8 alkyl group.
  • R 4 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group, 5) a phenyl group which may be substituted by 1-3 halogen atoms or 6) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms.
  • R 5 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3- 7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group or 5) a phenyl group which may be substituted by 1-3 substituents.
  • group R 3 a hydrogen atom is preferred.
  • group R ⁇ methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are preferred.
  • the compounds of JP-2002-20386-A are stated as having PDE4 inhibitory activity and as being useful in the prevention and/or treatment of inflammatory diseases and many other diseases.
  • EP 0 076 035 Al discloses pyrazolo[3,4-b]pyridine derivatives as central nervous system depressants useful as tranquilisers or ataractic agents for the relief of anxiety and tension states.
  • WO 02/060900 A2 appears to disclose, as MCP-1 antagonists for treatment of allergic, inflammatory or autoimmune disorders or diseases, a series of bicyclic 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)-NR 4 -C(O)-NR 5 R 6 group as the 5-substituent and optionally substituted at the 1-, 3-, 4-, and/or 6-positions.
  • Bicyclic 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.
  • PDE4 phosphodiesterase type IN
  • the present invention provides a compound of formula (I) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
  • R 1 is C ⁇ _ 4 alkyl, C ⁇ fluoroalkyl, -CH 2 CH 2 OH or -CH 2 CH2CO 2 C 1 .2alkyl;
  • R2 is a hydrogen atom (H), methyl or Ci fluoroalkyl
  • R3 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, SO 2 , or N lO;
  • RlO is a hydrogen atom (H), C ⁇ alkyl (e.g. methyl or ethyl), C ⁇ _ 2 fluoroalkyl, CH 2 C(O)NH 2 , C(O)NH 2 , C(O)-C!. alkyl, C(O)-C ⁇ fluoroalkyl or -C(O)-CH 2 O-C ⁇ _ 2 alkyl;
  • NHR 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); and wherein, when R 3 is optionally substituted mono-unsaturated-Cs. cycloalkenyl, then the cycloalkenyl is optionally substituted with one or two substituents being fluoro or C ⁇ _ 2 alkyl provided that if there are two substituents then they are not both C 2 alkyl, 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 (dd): ⁇ ' or of sub-formula (ee):
  • ⁇ l, Y 2 and Y 3 independently are CH 2 or oxygen (O) provided that no more than one of ⁇ l, Y 2 and Y 3 is oxygen (O); and
  • X is NR 4 R 5 or OR 5a , in which:
  • R 4 is a hydrogen atom (H); Ci.galkyl; C ⁇ -.3 fluoroalkyl; or C 2 _6alkyl substituted by one substituent R! 1 ; and
  • R5 is a hydrogen atom (H); Ci .galkyl; C ⁇ .g fluoroalkyl; C3_gcycloalkyl optionally substituted by a C ⁇ _ alkyl group; or -(CH 2 ) n 4 -C3_gcycloalkyl optionally substituted, in the -(CH 2 ) n 4 - moiety or in the C3_gcycloalkyl moiety, by a C ⁇ _ 2 alkyl group, wherein n 4 is 1, 2 or 3;
  • R5 is C 2 _6alkyl substituted by one or two independent substituents R 1 1 ;
  • each substituent R! 1, independently of any other R! substituent present, is: hydroxy (OH); Ci.galkoxy; phenyloxy; benzyloxy; -NR 12 R 13 ; -NR 15 -C(O)R 16 ;
  • R 5 is -(CH2)n 1 1 -C(O)R 16 ; -(CH 2 ) n 12 -C(O)NR 12 R 13 ; -CHR19-C(0)NR 1 R 13 ; -(CH 2 ) n 12 -C(O)OR 16 ; -(CH 2 ) n l 2 -C(O)OH; -CHR19_C(0)0R 16 ; -CHR 19 -C(O)OH; -(CH 2 ) n 12 -SO 2 -NR 12 R 13 ; -(CH 2 ) n 12 -SO 2 R 16 ; or -(CH 2 ) n l 2 -CN; wherein nl 1 is 0, 1, 2, 3 or 4 and n 12 is 1, 2, 3 or 4;
  • R ⁇ is -(CH 2 ) n i3 -Het wherein n 3 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or
  • R5 is phenyl optionally substituted with, independently, one, two or three of: a halogen atom; C ⁇ .galkyl (e.g. Ci _4alkyl or Ch lky!); Ci ⁇ fluoroalkyl (e.g. trifluoromethyl);
  • C ⁇ _4alkoxy e.g. C ⁇ _2 lko y
  • C ⁇ fluoro alkoxy e.g. trifluoromethoxy
  • C 3 . 6 cycloalkyloxy e.g. C ⁇ _2 alkylsulphonyl or Rl6a_ S (0) 2 -NR 15a - (e.g. C ⁇ _ 2 alkyl-SO 2 -NH-);
  • C _ 2 alkyl such as methyl
  • C3_gcycloalkyl or phenyl optionally substituted by one or two of: fluoro, chloro, C ⁇ . 2 alkyl, C ⁇ fluoroalkyl, C _ 2 alkoxy or C ⁇ fluoroalkoxy; or R 7 and R 8 together are -(CH 2 ) n 6- or -C(O)-(CH 2 ) n 7 - or -C(O)-(CH 2 ) n -C(O)- or
  • n 6 is 3, 4, 5 or 6, n 7 is 2, 3,
  • n 7 is 2, 3 or 4
  • n 8 and n 9 and n ⁇ O independently are 2 or 3 (preferably independently 2)
  • X 7 is O or NR i4 wherein R i4 is H, C ⁇ . 2 alkyl or C(O)Me (preferably H or C ⁇ . 2 alkyl);
  • R ⁇ has the sub-formula (x), (y), (yl) or (z):
  • sub-formula (x) and (y) and (yl) wherein in sub-formula (x) and (y) and (yl), none, one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N + -O") provided that no more than one of A, B, D, E and F is nitrogen-oxide; and the remaining of A, B, D, E and F are independently CH or CR 6 ; provided that when n is 0 in sub-formula (x) then one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N + -O ⁇ ) and no more than one of A, B, D, E and F is nitrogen-oxide;
  • each R 6 independently of any other R 6 present, is: a halogen atom; C ⁇ _6alkyl (e.g. C ⁇ _4alkyl or Chalky!); C ⁇ fluoroalkyl (e.g. C ⁇ _2fluoroalkyl); C ⁇ _4alkoxy (e.g.
  • n* 4 is 0 or 1; cyano (CN); Ar5b ; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C ⁇ _2 alkyl,
  • R! 8 is: C ⁇ _4alkyl (e.g. C ⁇ _ 2 alkyl); C ⁇ _ 2 fluoroalkyl; C3_6cycloalkyl; C ⁇ _2alkoxy (not substituted at a ring-carbon bonded to the NR 4 R5 ring-nitrogen); C ⁇ fluoroalkoxy (not substituted at a ring-carbon bonded to the N 4 R ⁇ ring-nitrogen); OH (not substituted at a ring-carbon bonded to the NR 4 R 5 ring-nitrogen); -(CH2) p 7 -C(O)R! 6 wherein p 7 is 0, 1 , 2 or 3
  • phenyl optionally substituted by one or two of: a halogen atom, C ⁇ . 2 alkyl, C ⁇ fluoro alkyl, C ⁇ _2alkoxy or C ⁇ fluoroalkoxy;
  • R 4 and R 5 taken together are -(CH 2 ) p - or -C(O)-(CH2) p 2 - or
  • R 4 R5 heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, C ⁇ _ 2 alkyl, Ci fluoroalkyl, C ⁇ . 2 alkoxy or C ⁇ fluoroalkoxy; and
  • R ⁇ a is Ci .galkyl; C ⁇ _g fluoroalkyl; C3_gcycloalkyl; -(CH 2 ) n 4a -C3_6cycloalkyl wherein n a is 1 or 2; phenyl optionally substituted with one or two of: a halogen atom, C- ⁇ _ 2 alkyl, trifluoromethyl, Ci _ alkoxy or trifluoromethoxy; or R ⁇ a has the sub-formula (x), (y) or (z) as defined herein
  • R! and R 3 independently are H; C ⁇ _5alkyl (e.g. Chalky!); C3_ 0 xycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _ 2 alkyl, C fluoroalkyl, C ⁇ _ 2 alkoxy or C ⁇ fluoroalkoxy;
  • R 2 and R 3 together are -(CH 2 ) n 6 - or -C(O)-(CH 2 ) n 7 - or -C(O)-(CH 2 ) n 7 -C(O)- or -(CH 2 ) n 8 -Xl 2 -(CH 2 ) n 9 - or -C(O)- ⁇ l 2 -(CH 2 ) n 10- in which: n 6 is 3, 4, 5 or 6 (preferably n 6 is 4 or 5), n 7 is 2, 3, 4, or 5 (preferably n 7 is 2, 3 or 4), n 8 and n 9 and ⁇ )-® independently are 2 or 3 (independently preferably 2) and X 12 is O or NR 14a wherein R 14a is H, C ⁇ _ 2 alkyl or C(O)Me (preferably H or C ⁇ _ 2 alkyl);
  • Rl5 is a hydrogen atom (H); C ⁇ _4alkyl (e.g. t ⁇ u or Ci ⁇ alkyl e.g. methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _ 2 alkyl, C ⁇ fluoroalkyl, C ⁇ . 2 alkoxy or C ⁇ fmoroalkoxy;
  • Rl5a 9 independent of other R ⁇ a , ls a hydrogen atom (H) or C ⁇ _4alkyl (e.g. H, *Bu or
  • C ⁇ _ 2 alkyl such as methyl; preferably R ⁇ a i s JJ 0 r C ⁇ . 2 alkyl, more preferably H);
  • Rl 6 and R i6a independently are:
  • Ci. ⁇ alkyl e.g. Ci _4alkyl or C ⁇ . 2 alkyl
  • C3_6cycloalkyl e.g. C5_ fj Cycloalkyl
  • C3_6cycloalkyl-CH 2 - e.g. C5_6cycloalkyl-CH 2 -
  • pyridinyl e.g.
  • pyridin-2-yl optionally substituted on a ring carbon atom by one of: a halogen atom, C ⁇ _ 2 alkyl, C fluoroalkyl, C ⁇ _ 2 alkoxy or Ci fluoroalkoxy;
  • Ar 5c phenyl optionally substituted by one or two of: a halogen atom, C _ 2 alkyl,
  • Ar ⁇ a ⁇ Ar ⁇ b an ⁇ ⁇ 5c independently is/are a 5-membered aromatic heterocyclic ring containing one O, S or ⁇ a in 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 ⁇ . alkyl, O ⁇ fluoroalkyl, -CH 2 OH, -CH 2 -OC ⁇ _ 2 alkyl, OH (including the keto tautomer thereof) or -CH 2 -NR 28 R 29 wherein R 28 and R 29 independently are H or methyl;
  • Rl 7 is a hydrogen atom (H); C ⁇ _4alkyl (e.g. C ⁇ . 2 alkyl); C ⁇ _ 2 fluoroalkyl; C3_6cycloalkyl; -(CH 2 ) p 6 -C(O)R 16 wherein p 6 is 0, 1, 2 or 3 (preferably p 6 is 0); -(CH 2 )p 6 -C(O)NRl 2 Rl 3 ; -(CH 2 ) p 6 -C(O)ORl6; -(CH 2 ) p 6 -C(O)OH; -SO 2 R 16 ;
  • phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, C ⁇ _2alkyl, C fluoroalkyl, C ⁇ _2alkoxy or
  • R 19 is C ⁇ _4alkyl; -(CH2) n 20 -OR 20 wherein n 20 is 1, 2, 3 or 4 and R 20 is a hydrogen atom (H) or -CH(Me)-OH; -CH 2 -SH; -CH 2 -CH 2 -S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyl); and
  • R 0, independent of other ⁇ is a hydrogen atom (H), C ⁇ _4alkyl or C3_6cycloalkyl;
  • R 3 when R 3 is the heterocyclic group of sub-formula (bb), n* is 1, and Y is NR ⁇ O, then: either (a) R 10 is not Ci ⁇ alkyl, C ⁇ fluoroalkyl or CH2C(O)NH 2 ; or (b) R 10 is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide or l-ethyl-N-(4- fluorophenyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide.
  • the compound is other than the compound wherein Rl is methyl, X is OEt, and R 3 is cyclopentyl.
  • R* is C ⁇ _4alkyl or C ⁇ _2 fluoroalkyl.
  • R 2 is a hydrogen atom (H).
  • R 3 is
  • C3_gcycloalkyl or a heterocyclic group being " in which Y is O, S, SO2, or NR 10 ; where R 10 is hydrogen, Ci ⁇ alkyl, Ci ⁇ fluoroalkyl, C(O)-C ⁇ _ 2alkyl, or C(O)-CF 3 ; and wherein in R 3 the C3_gcycloalkyl or heterocyclic group is optionally substituted with one or two substituents being OH, C ⁇ _ 2 alkoxy, trimethoxy, or C ⁇ _ 2 alkyl; and wherein any OH, alkoxy or trimethoxy 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.
  • R 4 is hydrogen, C ⁇ _2alkyl or C ⁇ _2 fluoroalkyl.
  • HX> is hydrogen, C ⁇ _galkyl, C ⁇ _g fluoroalkyl, or C3_gcycloalkyl; or phenyl optionally substituted with one or two of: a halogen atom, C ⁇ _ 2 alkyl, trifluoromethyl, C ⁇ _2 alkoxy or trifluoromethoxy; or ⁇ Rp has the sub-formula (x), (y) or (z):
  • R 3 is optionally substituted C3_gcycloalkyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);
  • nl and n 2 independently are 1 or 2; and in which Y is O, S, SO 2 , or NRIO;
  • RlO is a hydrogen atom (H), C ⁇ _4alkyl (e.g. methyl or ethyl), C . 2 fluoroalkyl, CH 2 C(O)NH 2 , C(O)NH 2 , C(O)-C ⁇ _ 2 alkyl, or C(O)-C ⁇ fluoroalkyl; and wherein in R 3 the C3_gcycloalkyl or the heterocyclic group of sub-formula
  • any OH, alkoxy or fluoroalkoxy substituent is not substituted at the R 3 ring carbon attached (bonded) to the -NH- group of
  • X is NR 4 R ⁇ or OR ⁇ ; in which:
  • R 4 is a hydrogen atom (H); Ci _galkyl; C ⁇ _3fluoroalkyl; or C 2 _6alkyl substituted by one substituent Rl ; and
  • R5 is a hydrogen atom (H); C ⁇ _galkyl; C ⁇ _g fluoroalkyl; C3_gcycloalkyl optionally substituted by a C ⁇ _ 2 alkyl group; or -(CH 2 ) n 4 -C3_gcycloalkyl optionally substituted, in the -(CH 2 ) n 4 - moiety or in the C3_gcycloalkyl moiety, by a C ⁇ _ 2 alkyl group, wherein n 4 is 1, 2 or 3;
  • R5 is C 2 .galkyl substituted by one or two independent substituents R 1;
  • each substituent R 1 independently of any other Rl substituent present, is: hydroxy (OH); Ci ⁇ alkoxy; phenyloxy; benzyloxy; -NR1 2 R1 3 ; -NRl 5 -C(O)Rl 6 ;
  • any RU substituent which is OH, alkoxy or -N 1 2 R1 is not substituted at any carbon atom, of any R 4 or R$ substituted alkyl, which is bonded to the nitrogen of R 4 R5; or R 5 is -(CH 2 ) n ll-C(O)Rl 6 ; -(CH 2 ) n l 2 -C(O)NRl 2 Rl 3 ; -CHR1 9 -C(O)NR1 2 R1 3 ; -(CH 2 ) n l 2 -C(O)ORl 6 ; -CHR1 9 -C(0)0R1 6 ; -(CH 2 ) n l 2 -SO 2 -NRl 2 Rl 3 ; -(CH 2 ) n l 2 -SO
  • R 5 is -(CH 2 ) n l 3 -Het wherein n i3 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or
  • R5 is phenyl optionally substituted with one or two of: a halogen atom; C ⁇ _4alkyl (e.g. C ⁇ . 2 alkyl); C ⁇ . 2 fluoro alkyl (e.g. trifluoromethyl); C ⁇ _4alkoxy (e.g. C ⁇ . 2 alkoxy); C ⁇ _ 2 fluoroalkoxy (e.g. trifluoromethoxy); C ⁇ _ 2 alkylsulphonyl (C ⁇ . 2 alkyl-SO 2 -);
  • C ⁇ _4alkyl e.g. C ⁇ . 2 alkyl
  • C ⁇ . 2 fluoro alkyl e.g. trifluoromethyl
  • C ⁇ _4alkoxy e.g. C ⁇ . 2 alkoxy
  • C ⁇ _ 2 fluoroalkoxy e.g. trifluoromethoxy
  • C ⁇ _ 2 alkylsulphonyl C ⁇ . 2 alkyl-SO 2 -
  • R 7 and R 8 together are -(CH 2 ) n 6 - or -C(O)-(CH 2 ) n 7 - or -C(O)-(CH 2 ) n 7 -C(O)- or
  • n 6 is 3, 4, 5 or 6, n 7 is 2, 3,
  • n 7 is 2, 3 or 4
  • n 8 and n 9 and n*0 independently are 2 or 3
  • X 7 is O or N I 4 wherein R 14 is H or C ⁇ _ 2 alkyl
  • R5 has the sub-formula (x), (y) or (z):
  • sub-formula (x) and (y) wherein in sub-formula (x) and (y), none, one or two of A, B, D, E and F are nitrogen; and the remaining of A, B, D, E and F are independently CH or CR 6 ;
  • R 6 is a halogen atom; C ⁇ _4alkyl (e.g. Chalky!); C ⁇ _4fluoroalkyl (e.g.
  • C i-2 fluoroalkyl C ⁇ _4alkoxy (e.g. C ⁇ _ 2 alkoxy); C ⁇ _ 2 fluoroalkoxy; C ⁇ . 2 alkylsulphonyl
  • G is O or S or NR 9 wherein R 9 is a hydrogen atom (H), C ⁇ _ 4al yl or C ⁇ ⁇ fluoroalkyl; 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 6 where R 6 is as defined herein;
  • R 4 and R 5 taken together are -(CH ) p l- or -C(O)-(CH 2 ) p 2 - or
  • C3_6cycloalkyl -(CH 2 ) p 6 -C(O)Rl 6 wherein p 6 is 0, 1, 2 or 3 (preferably p 6 is 0);
  • phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, C ⁇ _ 2 alkyl, C fluoroalkyl, C ⁇ _ 2 alkoxy or C ⁇ fluoroalkoxy; and wherein, when R 4 and R ⁇ taken together are -(CH 2 )pl- or -C(O)-(CH 2 )p 2 -, the NR 4 R5 heterocycle is optionally substituted by one Rl 8 substituent wherein Rl is: C ⁇ _4alkyl (e.g.
  • R 4 and R 5 taken together are -(CH 2 ) p l- or -C(O)-(CH2) p 2 - or -(CH 2 )p 3 -X 5 -(CH 2 )p 4 - or -C(O)- ⁇ 5-(CH 2 ) p 5 - as defined herein, and wherein the
  • NR 4 R heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, C ⁇ _ 2 alkyl, C fluoroalkyl, C ⁇ _ 2 alkoxy or C ⁇ fluoroalkoxy; and
  • R ⁇ a is C ⁇ .galkyl; C ⁇ _g fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, C ⁇ _2 alkyl, trifluoromethyl, Ci ⁇ alkoxy or trifluoromethoxy; or R ⁇ a has the sub-formula (x), (y) or (z) as defined herein
  • Rl 2 and Rl 3 independently are H; C ⁇ _5alkyl (e.g. C ⁇ alkyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _2 alkyl, C fluoroalkyl, C ⁇ _2 alkoxy or C ⁇ fluoroalkoxy;
  • Rl 2 and Rl 3 together are -(CH 2 ) n 6 - or -C(O)-(CH 2 ) n 7 - or -C(O)-(CH 2 ) n 7 -C(O)- or -(CH 2 ) n 8 -X 12 -(CH 2 ) n 9 - or -C(O)- ⁇ l 2 -(CH 2 ) n 1() - in which: n 6 is 3, 4, 5 or 6
  • n 6 is 4 or 5
  • n 7 is 2, 3, 4, or 5
  • n 8 and n 9 and nlO independently are 2 or 3 (independently preferably 2) and ⁇ l 2 is O or NRI 4 wherein Rl is H or C ⁇ _2alkyl;
  • Rl5 is a hydrogen atom (H); C ⁇ _4alkyl (e.g. t ⁇ u or C ⁇ _2alkyl e.g. methyl);
  • C3_gcycloalkyl or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _2alkyl, C ⁇ fluoroalkyl, C ⁇ _2alkoxy or C fluoroalkoxy;
  • Rl6 is C ⁇ _4alkyl (e.g. C ⁇ _2alkyl); C3_6cycloalkyl; pyridinyl (e.g. pyridin-2-yl); or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _2alkyl, C fluoroalkyl, C ⁇ _2 alkoxy or C ⁇ fluoroalkoxy; and
  • R 19 is C ⁇ _4alkyl; -(CH2) n 20 -OR 20 wherein n 20 is 1, 2, 3 or 4 and R 20 is a hydrogen atom (H) or C ⁇ _4alkyl; -CH(Me)-OH; -CH 2 -SH; -CH 2 -CH2-S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyl).
  • an "alkyl" group or moiety may be straight-chain or branched.
  • Alkyl groups for example C ⁇ _galkyl or C ⁇ _6alkyl or C ⁇ _4alkyl or C ⁇ _3alkyl or C ⁇ _ 2 alkyl, which may be employed include Cj.galkyl or C ⁇ alkyl or C ⁇ _3alkyl or C ⁇ __2 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.
  • Cj.galkyl or C ⁇ alkyl or C ⁇ _3alkyl or C ⁇ __2 lkyl such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hex
  • alkoxy such as C ⁇ .galkoxy or C ⁇ alkoxy or
  • C ⁇ _ 2 alkoxy 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 (methylsulfonyloxy), ethanesulfonyloxy, et al.
  • C3_gcycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • a C3_gcycloalkyl group is C3_6cycloalkyl or Cs.gcycloalkyl , that is contains a 3-6 membered or 5-6 membered carbocyclic ring.
  • “Fluoroalkyl” includes alkyl groups with one, two, three, four, five or more fluorine substituents, for example C ⁇ _4fluoroalkyl or C ⁇ .3 fluoroalkyl or C ⁇ _ 2 fluoro alkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF CH 2 -), 2,2-difluoroethyl (CHF 2 CH 2 -), 2-fluoroethyl (CH2FCH 2 -), etc.
  • “Fluoroalkoxy” includes C _4fluoroalkoxy or C ⁇ .
  • fluoroaikoxy such as trifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy, etc.
  • fluoroalkylsulfonyl such as C ⁇ .4fluoroalkylsulfonyl includes trifluoromethanesulfonyl, pentafluoroethylsulfonyl, etc.
  • halogen atom present in compounds, for example in the compounds of formula (I), can be a fluorine, chlorine, bromine or iodine atom ("fluoro", “chloro”, “bromo” or “iodo").
  • Rl is C ⁇ _4alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl),
  • Rl is more preferably C ⁇ _3alkyl (e.g. methyl, ethyl or n-propyl), C ⁇ _ 2 fluoroalkyl, or -CH 2 CH 2 OH; still more preferably C ⁇ .3 alkyl, C2fluoroalkyl or -CH2CH2OH such as methyl, ethyl, n-propyl or -CH2CH2OH. Yet more preferably, Rl is C2-3alkyl (e.g. ethyl or n-propyl), C2fluoroalkyl (e.g.
  • C ⁇ fluoroalkyl-CH 2 - such as CF3-CH 2 -) or -CH 2 CH 2 OH; in particular ethyl, n-propyl or -CH 2 CH 2 OH.
  • Rl is most preferably ethyl.
  • R 2 is a hydrogen atom (H) or methyl, more preferably 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 is optionally substituted C3_gcycloalkyl, it is not optionally substituted C5cycloalkyl, i.e. not optionally substituted cyclopentyl. In this case, more preferably, R 3 is optionally substituted Cg.gcycloalkyl.
  • R 3 is optionally substituted C3_gcycloalkyl
  • any OH, alkoxy, fluoroalkoxy or HR 2 1 substituent is not substituted at the R 3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R 3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc). More preferably, where R 3 is optionally substituted C3_gcycloalkyl, the one or two optional substituents comprise (e.g. is or independently are (e.g.
  • R 3 is optionally substituted C3_gcycloalkyl
  • R 3 is optionally substituted C3_gcycloalkyl
  • the C3_gcycloalkyl can be unsubstituted.
  • R 3 is optionally substituted C3_gcycloalkyl, e.g. optionally substituted
  • C5_gcycloalkyl such as optionally substituted Cgcycloalkyl (optionally substituted cyclohexyl), the one or two optional substituents if present preferably comprise a substituent (for example is or are substituent(s)) at the 3-, 4- or 5- position(s) of the R 3 cycloalkyl ring.
  • the 1 -position of the R 3 cycloalkyl ring is deemed to be the connection point to the -NH- in formula (I)).
  • R 3 is optionally substituted C3_gcycloalkyl
  • any OH, alkoxy, fluoroalkoxy, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHR 22 , -C(O)OR 23 , -C(O)NHR 24 , -C(O)R 25 or fluoro substituent (particularly any OH substituent) is more preferably at the the 3-, 4- or 5- position, e.g. 3- or 5-position, of the R 3 cycloalkyl (e.g. Cg-gcycloalkyl) ring.
  • any OH, alkoxy, fluoroalkoxy, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHR 22 e.g. Cg-gcycloalkyl
  • -C(O)OR 23 , -C(O)NHR 24 , -C(O)R 25 or fluoro substituent (particularly any OH substituent) can be at the 3-position of a R 3 Cscycloalkyl (cyclopentyl) ring or at the 3-, 4- or 5- position, e.g. 3- or 5-position, of a R 3 Cgcycloalkyl (cyclohexyl) ring. (In this connection, and also below, the 1-position of the R 3 cycloalkyl ring is deemed to be the connection point to the -NH- in formula (I)).
  • any NHR 2 1 substituent is preferably at the 2-, 3-, 4- or 5- position, preferably the 2- or 3-position or more preferably the 3-position, of the R 3 cycloalkyl (e.g. Cg.gcycloalkyl e.g. cyclohexyl) ring.
  • R 3 cycloalkyl e.g. Cg.gcycloalkyl e.g. cyclohexyl
  • any alkyl or fluoroalkyl substituent is preferably at the 1-, 2-, 3-, 4- or 5- position, more preferably the 1-, 2-, 3- or 5-position, still more preferably the 1- or 3-position, of the R 3 cycloalkyl (e.g. Cg.gcycloalkyl e.g. cyclohexyl) ring.
  • R 3 cycloalkyl e.g. Cg.gcycloalkyl e.g. cyclohexyl
  • R 3 cycloalkyl e.g. Cg.gcycloalkyl e.g. cyclohexyl
  • R 3 is optionally substituted C3_gcycloalkyl
  • oxo oxo
  • hydroxyimino N-OH
  • the optional substituent can be at the 3- or 4- position, e.g.
  • R 3 can for example be 4-hydroxy- cyclohexyl (i.e. 4-hydroxycyclohexan-l-yl), but R 3 is more preferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-l-yl), 4-(hydroxyimino)cyclohexyl (i.e.
  • R 3 is optionally substituted Cg yclo alkyl
  • R3 1S most preferably cyclohexyl (i.e. unsubstituted), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-l-yl) or 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-l-yl).
  • R 3 is optionally substituted Cscycloalkyl (optionally substituted cyclopentyl)
  • R 3 can for example be cyclopentyl (i.e. unsubstituted) or 3-hydroxy-cyclopentyl.
  • R 3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl
  • the R 3 cycloalkenyl is optionally substituted with one or two substituents being fluoro or methyl provided that if there are two substituents then they are not both methyl.
  • the R 3 cycloalkenyl is optionally substituted with one substituent being fluoro or C ⁇ _ 2 alkyl (e.g. methyl); more preferably the R 3 cycloalkenyl is substituted with one fluoro substituent or is unsubstituted.
  • the optional substituent(s) can be at the 1-, 2-, 3-, 4- or 5- position(s) of the cycloalkenyl ring.
  • R 3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is preferably O, S, SO , NH or N-C(O)methyl, more preferably O, NH or N-C(O)methyl, still more preferably O or N-C(O)methyl, most preferably O. (When Y is NH or N-C(O)methyl, then Rl° is H or C(O)methyl).
  • RlO is a hydrogen atom (H), methyl, ethyl, C(O)NH 2 , C(O)methyl or
  • RlO can be a hydrogen atom (H), methyl, ethyl, C(O)methyl or C(O)-CF3, more preferably H, C(O)methyl or C(O)-CF3, still more preferably H or C(O)methyl.
  • 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).
  • nl is preferably 1.
  • n 2 is preferably 1. That is, six-membered rings are preferred in the R 3 heterocyclic group.
  • the heterocyclic group of sub-formula (aa), (bb) or (cc) is unsubstituted (h this connection, where Y is NRlO, R!0 is not classified as a substituent).
  • the 1- position of the R 3 heterocyclic ring is deemed to be the connection point to the -NH- in formula (I)).
  • Preferably, only Ci _2alkyl, C ⁇ _2fluoroalkyl, fluoro or oxo ( O) substitution or no substitution is allowed at each of the 2- and 6-positions of the R 3 heterocyclic ring.
  • R 3 is the heterocyclic group of sub-formula (aa) and Y is NRlO, then preferably
  • RIO is not C(O)-Me. More preferably, when R 3 is the heterocyclic group of sub-formula
  • RlO is preferably not C(O)R, i.e. or e.g. RlO is preferably not C(O)NH2, C(O)-C ⁇ _2alkyl or C(O)-C ⁇ fluoroalkyl.
  • Y is O, S, SO 2 or NH when R 3 is the heterocyclic group of sub-formula (aa).
  • NHR 3 is not
  • R 3 is the heterocyclic group of sub-formula (bb) and Y is NRlO, and optionally when nl is 1, then preferably RlO is not methyl. More preferably, when
  • R 3 is the heterocyclic group of sub-formula (bb) and Y is NRlO, and optionally when nl is 1, then RlO is preferably not alkyl or substituted alkyl, i.e. or e.g. RlO is preferably not C ⁇ _4alkyl (e.g. methyl or ethyl), C ⁇ _2fluoroalkyl or CH2C(O)NH2- In one embodiment, when R 3 is the heterocyclic group of sub-formula (bb), Y is preferably O, S, SO 2 or
  • RlO is H, C(O)NH 2 , C(O)-C ⁇ _ 2 alkyl or C(O)-C 1 fluoroalkyl, or more preferably Y is H or C(O)Me. More preferably, for sub-formula (bb), Y is O or NRlO.
  • R 3 is a bicyclic group of sub-formula (dd) or (ee), preferably it is of sub-formula (ee).
  • sub-formula (ee) preferably ⁇ l
  • Y 2 and Y 3 are all CH2.
  • 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), (L), (m), (ml), (m2),
  • 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), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (o4), (o5), (p), (p2), (p3), (p5), (p6), (p7) or (q).
  • NHR 3 is of sub- formula (c), (cl), (c 4), (c 5), (h), (i), (j), (k), (ml), (m2), (n), (o), (o2), (o3), (p2), (p5), (p6) or (q). Still more preferably, NHR 3 is of sub-formula (c), (h), (k), (n), (o) or (o2); for example (c), (h), (o) or (o2). Most preferably, R 3 is tetrahydro-2H-pyran-4-yl; that is NHR 3 is most preferably of sub-formula (h), as shown above.
  • NHR 3 is of sub-formula (a), (b), (c), (d), (e), (f), (g), (gl), (g2), (g3), (h), (i), (j), (k), (L), (m), (ml), (n), (o), (ol), (p) or (q).
  • NHR 3 is of sub-formula (c), (d), (e), (f), (gl), (h), (i), (j), (k), (m), (ml), (n), (o), (ol), (p), or (q); and more preferably in this embodiment, NHR 3 is of sub-formula (c), (h), (i), (j), (k), (ml), (n), (o) or (q). Still more preferably in this embodiment, NHR 3 is of sub-formula (c), (h), (k), (n) or (o). Most preferably, R 3 is tetrahydro-2H-pyran-4- yl; that is NHR 3 is most preferably of sub-formula (h), as shown above.
  • NHR 3 is of sub-formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j) or (k).
  • NHR 3 is of sub-formula (c), (d), (e), (f), (h), (i), (j) or (k); and more preferably in this embodiment, NHR 3 is of sub-formula (c), (h), (i), (j) or (k).
  • R 3 is tetrahydro-2H-pyran-4-yl; that is NHR 3 is most preferably of sub-formula (h), as shown above.
  • NHR 3 is of sub-formula (n), then preferably it is a ct5-(3-hydroxycyclohex-l- yl)amino group, eg in any enantiomeric form or mixture of forms but preferably racemic.
  • X is NR 4 R 5 .
  • R 4 is Cx.galkyl, then preferably it is C ⁇ _4alkyl or C ⁇ _ 2 alkyl. Where R 4 is C ⁇ _3 fluoroalkyl then preferably it is C ⁇ _ 2 fluoroalkyl.
  • R 4 is a hydrogen atom (H).
  • R 4 is C ⁇ galkyl substituted by one substituent Rl 1, then preferably R 4 is
  • R 4 is -(CH 2 ) n 3 -Rl 1 wherein n 3 is 2, 3 or 4. Still more preferably, n 3 is 2 and/or R 4 is -(CH 2 ) n 3 -OH.
  • R ⁇ is C 2 .galkyl substituted by one or two independent substituents Rl 1
  • R ⁇ is C 2 _4alkyl (e.g. C 2 _3alkyl) substituted by one or two independent substituents Rl 1.
  • R ⁇ is C 2 _galkyl (e.g. C 2 _4alkyl or C _3 alkyl) substituted by one or two independent substituents RU
  • R ⁇ is C 2 _6alkyl (e.g. C 2 _4alkyl or C 2 _3 alkyl) substituted by one substituent Rl 1.
  • R ⁇ is -(CH 2 ) n ⁇ -Rl 1 wherein n$ is 2, 3 or 4.
  • n ⁇ is 2 or 3, more preferably 2.
  • each substituent Rl 1, independently of any other Rl 1 substituent present, is: hydroxy (OH); C ⁇ . ⁇ alkoxy (e.g. C ⁇ _4alkoxy such as t-butyloxy, ethoxy or methoxy); phenyloxy; benzyloxy; -NR1 2 R1 3 ; -NR1 5 -C(O)R1 6 ; -NR1 5 -C(0)-N ⁇ -R15; or -NRl 5 -SO 2 Rl6 (more preferably Ci.galkoxy, -NR1 5 -C(0)-NH-R1 5 , or -NRl 5 -SO 2 Rl 6 ; most preferably -NR1 5 -SO 2 R1 6 ).
  • any Rl 1 substituent which is OH, alkoxy or -N 2 R1 3 is not substituted at any carbon atom, of any R 4 or R ⁇ substituted alkyl, which is bonded to the nitrogen of NR 4 R4
  • R ⁇ is C ⁇ _galkyl, then preferably it is C ⁇ _5alkyl or C _3alkyl.
  • R ⁇ is C ⁇ _ gfluoroalkyl then preferably it is C ⁇ .3 fluoroalkyl or C ⁇ _ 2 fluoroalkyl.
  • R ⁇ is C3_gcycloalkyl optionally substituted by a C ⁇ _ 2 alkyl group, then preferably the
  • C3_gcycloalkyl is not substituted at the ring-carbon bonded to the nitrogen of NR 4 R- ⁇
  • R ⁇ is optionally substituted C3_gcycloalkyl, then more preferably it is C3_gcycloalkyl (i.e. unsubstituted).
  • R5 is optionally substituted -(CH 2 ) n 4 -C3_gcycloalkyl wherein n 4 is 1, 2 or 3, then n 4 is preferably 1 or 2 or more preferably 1, and/or preferably R ⁇ is optionally substituted -(CH 2 ) n -C5_6cycloalkyl or optionally substituted -(CH 2 ) n 4 -C6cycloalkyl.
  • R ⁇ is optionally substituted -(CH 2 ) n 4 -C3_gcycloalkyl, preferably it is not substituted. Most preferably R ⁇ is (cyclohexyl)methyl-, that is -CH 2 -cyclohexyl.
  • Rl 9 is C ⁇ _4alkyl, then preferably it is isobutyl, sec-butyl, or C .3 alkyl such as methyl or isopropyl.
  • Rl 9 is -(CH 2 ) n 0-OR 0, then preferably n 2 ⁇ is 1 and/or preferably R 2 ⁇ is a hydrogen atom (H).
  • R5 is -(CH 2 ) n l l-C(O)Rl 6 ; -(CH 2 ) n l 2 -C(O)NRl 2 Rl 3 ; -CHR1 9 -C(0)NR1 2 R1 3 ; -(CH 2 ) n l 2 -C(O)ORl 6 ; -CHR1 -C(0)0R16; -(CH 2 ) n l 2 -SO 2 -NRl 2 Rl 3 ; -(CH 2 ) n l 2 -SO Rl 6 ; or -(CH 2 ) n l -CN; then in one embodiment of the invention R5 can be: -(CH 2 ) n l l-C(O)Rl6; -(CH 2 ) n l 2 -C(O)NRl 2 Rl 3 ; -(CH 2 ) n l 2 -C(O)ORl6; -(CH
  • R 5 is -(CH 2 ) n ll-C(O)Rl6 ; -(CH 2 ) n l 2 -C(O)NRl 2 Rl 3 ; -(CH 2 ) n l 2 -C(O)ORl6; -(CH ) n l 2 -SO 2 -NRl 2 Rl 3 ; -(CH 2 ) n l 2 -SO 2 Rl 6 ; or -(CH 2 ) n l 2 -CN; then R5 can for example be -(C ⁇ .
  • nl 1 is 1, 2, 3 or 4; more preferably nl 1 is 1 or 2.
  • nl 2 is 1 or 2.
  • nl 3 is 0, 1 or 2, more preferably 0 or 1.
  • Het is a 5- or 6-membered saturated or partly-saturated heterocyclic ring and/or preferably 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 is most preferably one
  • R5 is optionally substituted phenyl, then preferably it is phenyl optionally substituted with one or two of the substituents defined herein.
  • R ⁇ is phenyl optionally substituted with, independently, one, two or three (preferably one or two; or one) of: a halogen atom (preferably fluoro and/or chloro); C ⁇ _ 2 alkyl; C ⁇ _ 2 fluoroalkyl (e.g. trifluoromethyl); C ⁇ _ 2 alkoxy (e.g. methoxy); trifluoromethoxy; C ⁇ _ 2 alkylsulphonyl
  • R 7 R 8 N OH; C ⁇ _ 2 alkoxymethyl; C ⁇ _ 2 alkyl-SO 2 -CH 2 -; cyano (CN); or phenyl optionally substituted by one of fluoro, C _ 2 alkyl, Cj fluoroalkyl, C ⁇ _ 2 alkoxy or
  • Ci fluoroalkoxy More preferably R ⁇ is phenyl optionally substituted with one or two (preferably one) of: a halogen atom, C ⁇ _ 2 alkyl, trifluoromethyl, C ⁇ _ 2 alkoxy, trifluoromethoxy, R 7 R 8 N-SO 2 -, R 7 R 8 N-CO-, or C ⁇ _ 2 alkyl-SO 2 -CH 2 -.
  • R 5 is optionally substituted phenyl
  • R 5 is optionally substituted phenyl
  • one or all of the one or two optional substituents are substituted at the meta- (3- and/or 5-) and/or para- (4-) position(s) of the phenyl ring with respect to the phenyl ring-carbon bonded to the nitrogen of NR 4 R ⁇ .
  • R 7 and/or R 8 are independently a hydrogen atom (H); C ⁇ _ 2 alkyl such as methyl; C3_gcycloalkyl; or phenyl optionally substituted by one of: fluoro, chloro,
  • X 7 is R.I 4 or preferably O.
  • R 7 is cycloalkyl or optionally substituted phenyl
  • R 8 is neither cycloalkyl nor optionally substituted phenyl.
  • R 7 and/or R 8 independently are a hydrogen atom (H) or C _ 2 alkyl. It is preferable that R 7 is a hydrogen atom (H).
  • n 6 is 4 or 5.
  • n 7 is 2, 3 or 4.
  • n 8 , n 9 and/or nlO is/are independently 2.
  • R ⁇ has the sub-formula (x) or (y) or (yl) or (z).
  • R ⁇ has the sub-formula (x) or (y) or (yl) or (z). More preferably R ⁇ has the sub-formula (x) or (y), most preferably (x). In one embodiment, R ⁇ has the sub- formula (z).
  • m 1.
  • r 1 or 2, more preferably 1.
  • none, one or two of A, B, D, E and F are nitrogen; none, one, two or three of A, B, D, E and F are CR 6 ; and the remaining of A, B, D, E and F are CH. More preferably, none, one or two of A, B, D, E and F are nitrogen; none, one or two of A, B, D, E and F are CR 6 ; and the remaining of A, B, D, E and F are CH.
  • sub-formula (x) is: benzyl; phenethyl (Ph-C 2 H4-); benzyl substituted on the phenyl ring with one or two R 6 substituents; phenethyl (Ph-C 2 H4-) substituted on the phenyl ring with one or two R 6 substituents; or one of the following:
  • R 6a is either R 6 as defined herein or (preferably) hydrogen.
  • sub-formula (x) is benzyl or pyridinylmethyl
  • sub-formula (y) is: or
  • sub-formula (yl) is:
  • R 6a is or independently are either R 6 as defined herein or preferably hydrogen.
  • none, one or two of J, L, M and Q are nitrogen.
  • each R 6 independently of any other R 6 present, is a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, C4alkyl, trifluoromethyl, -CH 2 OH, methoxy, ethoxy, C ⁇ fluoroalkoxy (e.g.
  • C ⁇ _3alkylS(O) 2 - such as methylsulphonyl which is MeS(O) 2 -
  • C ⁇ _3alkylS(O) 2 -NH- such as methyl-SO -NH-, Me 2 N-S(O) 2 -, H 2 N-S(O) 2 -, -CONH 2 , -CONHMe, -CO 2 H, cyano (CN), NMe 2 , t-butoxymethyl, or
  • each R 6 independently of any other R 6 present, is a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, isobutyl, trifluoromethyl, -CH 2 OH, methoxy, ethoxy,
  • Ci fluoroalkoxy e.g. trifluoromethoxy or difluoromethoxy
  • C ⁇ _3alkylS(O) 2 - such as methylsulphonyl
  • C ⁇ _3alkylS(O) 2 -NH- such as methyl-SO 2 -NH-, Me 2 N-S(O) 2 -,
  • each R 6 independently of any other R 6 present, is a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH 2 OH, methoxy, difluoromethoxy, methylsulphonyl, methyl-SO 2 -NH- or methyl-SO 2 -CH 2 -.
  • R 6 substituents are also, independently, the preferred phenyl optional and independent substituents for where R$ is optionally substituted phenyl.
  • sub-fonnula (x) and/or (y) preferably, one, two or three R 6 substituents are present in B, D and/or E; so that for example in sub-formula (x), one, two or three R 6 substituents are present in the meta- (3- and/or 5-) and/or para- (4-) positions with respect to the - (CH 2 ) n - side-chain.
  • R ⁇ has the sub-formula (x), n is 1 and none of A, B, D, E and F are nitrogen or nitrogen-oxide (N ⁇ -O"); and all of A, B, D, E and F are independently CH or CR 6 ; that is R5 has the sub-formula (x) and is optionally substituted benzyl.
  • a R 6 substituent is present at the 4-position with respect to the -(CH 2 ) n - side- chain (that is D is CR 6 : i.e.
  • a R 6 substituent is present in D); and/or preferably a R 6 substituent is present at the 3- and/or 5- position with respect to the -(CH 2 ) n ⁇ side-chain (that is B and/or E is CR 6 : i.e. one or two R 6 substituents are present in B and/or E).
  • the one R 6 substituent is preferably present at the 4-position with respect to the -(CH 2 ) n - side-chain
  • D is CR 6
  • disubstitution that is where two of A, B, D, E and F are independently CR 6
  • 3,4-disubstitution that is where two of A, B, D, E and F are independently CR 6
  • 3,4-disubstitution B+D or D+E are independently CR 6
  • 2,4- disubstitution A+D or D+F are independently CR 6
  • 2,3-disubstitution A+B or E+F are independently CR 6
  • any optional R 6 substituent can optionally be present only in B, D and/or E, so that in sub-formula (x) any optional R 6 substituent is present only in the meta- (3- and/or 5-) and/or para- (4-) positions with respect to the -(CH ) n - side- chain.
  • any optional R 6 substituent can be present in the ortho- (2- and/or 6-) position with respect to the -(CH ) n - side-chain, either alone or in combination with one or more other optional R 6 substituents.
  • R ⁇ is a hydrogen atom (H); C ⁇ _galkyl (e.g.
  • Ci 2or3 a lky or C3_6 lkyl Ci 2or3 a lky or C3_6 lkyl); C gfluoroalkyl, C3_6cycloalkyl (e.g. C5_6cycloalkyl), (C5 _ cycloalkyl)methyl-, phenyl optionally substituted with one or two of: a fluorine or chlorine atom, methyl, trifluoromethyl, methoxy or trifluoromethoxy; or R ⁇ has the sub- formula (x), (y) or (z), for example as described above.
  • R ⁇ is a hydrogen atom (H), methyl, ethyl, n-propyl, iso-propyl, 2-ethylbutan-l-yl, cyclopentyl, cyclohexyl, (cyclohexyl)methyl-, optionally substituted phenyl e.g. fluorophenyl e.g. 4-fluorophenyl, optionally substituted benzyl, or optionally substituted pyridinylmethyl, or R ⁇ has the sub-formula (z).
  • R ⁇ can be benzyl, pyridinylmethyl (e.g. pyridin-4-ylmethyl, pyridin-3- ylmethyl, or preferably pyridin-2-ylmethyl), or 4-fluorophenyl.
  • pyridinylmethyl e.g. pyridin-4-ylmethyl, pyridin-3- ylmethyl, or preferably pyridin-2-ylmethyl
  • 4-fluorophenyl e.g. pyridin-4-ylmethyl, pyridin-3- ylmethyl, or preferably pyridin-2-ylmethyl
  • R ⁇ has the sub-formula (x) and is: benzyl, (monoalkyl- phenyl)methyl, [mono(fluoroa ⁇ kyl)-phenyl]methyl, (monohalo-phenyl)methyl, (monoalkoxy-phenyl)methyl, [mono(fluoroalkoxy)-phenyl]methyl, [mono(N,N- dimethylamino)-phenyljmethyl, [mono(methyl-SO 2 -NH-)-phenyl]methyl,
  • R ⁇ is of sub-formula (x) and is: (monoalkyl- phenyl)methyl, [mono(fluoroalkyl)-phenyl]methyl, (monohalo-phenyl)methyl, (monoalkoxy-phenyl)methyl, [mono(fluoroalkoxy)-phenyl]methyl, [mono(N,N- dimethylamino)-phenyl]methyl, (dialkyl-phenyl)methyl, (monoalkyl-monohalo- phenyl)methyl, (dihalo-phenyl)methyl or (dihalo-monoalkyl-phenyl)methyl or [dihalo- mono(hydroxymethyl)-phenyl]methyl. More preferably, in this embodiment, R ⁇ is: - (monoC ⁇ _3alkyl-phenyl)methyl such as (4-C ⁇ _3alkyl-phenyl)methyl;
  • (diC ⁇ _2alkyl-phenyl)methyl or (dimethyl-phenyl)methyl such as (3,4-dimethyl- phenyl)methyl, (2,4-dimethyl-phenyl)methyl, (3,5-dimethyl-phenyl)methyl, (2,3- dimethyl-phenyl)methyl or (2,5-dimethyl-phenyl)methyl; more preferably (3,4-dimethyl- phenyl)methyl or (2,4-dimethyl-phenyl)methyl;
  • - (dihalo-phenyl)methyl such as (2-chloro-4-fluorophenyl)methyl or (2,4-difluoro- phenyl)methyl or (4-bromo-2-fluorophenyl)methyl or preferably (4-chloro- 2-fluorophenyl)methyl;
  • (dichloro-phenyl)methyl such as (3,4-dichloro- phenyl)methyl or (2,4-dichloro-phenyl)methyl or (2,6-dichloro-phenyl)methyl or preferably (2,3-dichloro-phenyl)methyl;
  • R ⁇ has the sub-formula (z), and one or preferably none of J, L, M or Q is CR 6 , and/or R 9 is a hydrogen atom (H) or methyl.
  • R 6 is independently OH (including any keto tautomer thereof), or more preferably C ⁇ _ 2 alkyl (e.g. methyl) or Cifluoroalkyl.
  • NR R ⁇ is not NH 2 .
  • R ⁇ is preferably not a hydrogen atom (H).
  • R 4 and R ⁇ taken together are optionally substituted -(CH 2 )pl- or optionally substituted -C(O)-(CH 2 ) p 2 - or -(CH 2 ) p 3 -X 5 -(CH 2 ) p 4 - or -C(O)-X 5 -(CH 2 ) p 5 - or a partially unsaturated derivative of any of the foregoing, preferably R 4 and R ⁇ taken together are optionally substituted -(CH2)pl- or optionally substituted -C(O)-(CH2)p 2 - or -(CH 2 )p 3 -X 5 -(CH 2 ) p 4 - or -C(O)-X 5 -(CH 2 ) p 5 - (i.e. not a partially unsaturated derivative of any of these).
  • R 4 and R$ taken together are -(CH )pl- optionally substituted by Rl 8 , or -C(O)-(CH 2 ) p 2 - optionally substituted by R i8 , or -(CH 2 ) p 3 - ⁇ 5-(CH ) p 4 -, NR 4 R 5 can
  • Rl is a hydrogen atom (H); C ⁇ _4alkyl (e.g. C ⁇ _ 2 alkyl); C3_6cycloalkyl; -(CH 2 )p -C(O)Rl 6 , or the optionally substituted phenyl or benzyl. More preferably, Rl 7 is H; C ⁇ _ 2 alkyl; -(CH 2 )p 6 -C(O)Rl 6 or the optionally substituted phenyl.
  • R 4 and R 5 taken together are -(CH 2 ) p 1- or -C(O)-(CH 2 ) p 2 -, the NR 4 R 5 heterocycle is preferably not substituted by Rl 8 .
  • R 4 and R 5 taken together are -(CH 2 ) p l- or -C(O)-(CH 2 ) p 2 -, and if the NR 4 R 5 heterocycle is substituted by Rl 8 , then optionally Rl 8 is not substituted at a ring-carbon bonded to the R 4 R5 ring-nitrogen.
  • R 4 and R 5 taken together are -(CH 2 ) p l- or -C(O)-(CH 2 ) p 2 - or
  • NR 4 R5 heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, C ⁇ _ 2 alkyl, Ci fluoroalkyl,
  • phenyl is optionally substituted by one or two of: a halogen atom, C ⁇ _ 2 alkyl, Ci fluoroalkyl, C ⁇ _2alkoxy or Ci fluoroalkoxy.
  • NR 7 R 8 and/or N 1 2 R1 can for example
  • Rl 2 and Rl 3 together or R 7 and R 8 together are -(CH2)2-N(R1 4 )-(CH2)2-), or j — N O
  • R!5 is a hydrogen atom (H) or C ⁇ _4alkyl (e.g. *Bu or C ⁇ _2alkyl e.g. methyl); more preferably, Rl ⁇ is a hydrogen atom (H).
  • R 4 and R$ are not taken together , i.e. are not taken together to form the NR 4 R5 ring systems described herein.
  • R ⁇ a is ethyl.
  • NR 4 R ⁇ is the N 4 R ⁇ group as defined in any one of: Examples 21-98, 100-182, 187-188, 191-200, 201-203, 210-353, 355-651, 653-658, 660-664 and 665-686.
  • the compound of formula (I) or the salt thereof is:
  • the compound of formula (I) or the salt thereof can be: l-Ethyl-N-(2-hydroxy-l-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, or
  • the compound of formula (I) or the salt thereof is one of Examples 204 to 664 or one of Examples 665 to 686, as a compound or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
  • the structures of these specific compounds are given in Examples 204 to 664 and Examples 665 to 686 hereinafter, and their names are given in the Examples section.
  • the compound of formula (I) or the salt thereof is a compound of Example 260, 261, 263, 266, 431, 493, 494, 518, 528, 584, 626, 643, 653, 679, 680, 681, 682, 683, 684, 685 or 686 (more preferably Example 260, 518, 653, 679, 680, 681 or 684), as defined by the structures and/or names described herein, or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
  • the structures and names of these Examples are described in the Examples section. These Examples are thought to be suitable for inhaled administration.
  • the compound of formula (I) or the salt thereof is a compound of Example 21, 22, 83, 100, 109, 167, 172, 178 or 600, as defined by the structures and/or names described herein, or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
  • the structures and names of these Examples are described in the Examples section. These Examples are thought to be suitable for oral administration.
  • a second aspect of the present invention provides a compound of formula (IA) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
  • X is NR 4 R 5 or OR 5a , in which:
  • R 4 is hydrogen, C _ 2 alkyl or C ⁇ _ 2 fluoroalkyl
  • R5 is hydrogen, Ci.galkyl, C ⁇ _g fluoroalkyl, or C3_gcycloalkyl, phenyl optionally substituted with one or two of: a halogen atom, C ⁇ _ 2 alkyl, trifluoromethyl, C ⁇ _ 2 alkoxy or trifluoromethoxy; or R ⁇ has the sub-formula (x), (y) or (z):
  • L, M and Q are CH or CR 6 where R 6 is as defined herein;
  • R ⁇ is Ci.galkyl; C ⁇ _g fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, C ⁇ _ 2 alkyl, trifluoromethyl, C ⁇ _ 2 alkoxy or trifluoromethoxy; or R ⁇ a has the sub-formula (x), (y) or (z) as defined herein;
  • R 3 is C3_gcycloalkyl or a heterocyclic group being " in which Y is O, S, SO 2 , or NR.10; where R O is hydrogen, C ⁇ alkyl, C ⁇ _ 2 fluoroalkyl, C(O)-C ⁇ _ 2 alkyl, or C(O)-CF 3 ; and wherein in R 3 the C3_gcycloalkyl or heterocyclic group is optionally substituted with one or two substituents being OH, C ⁇ _ 2 alkoxy, trimethoxy, or C ⁇ _ 2 alkyl group; and wherein any OH, alkoxy or trimethoxy substituent is not substituted at the ring carbon attached to the -NH- group of formula (IA) and is not substituted at either ring carbon bonded to the Y group of the heterocyclic group; and
  • Rl C ⁇ _4alkyl or C ⁇ _ 2 fluoroalkyl.
  • R 3 is the heterocyclic group being ' and Y is Rl°, then: either (a) RlO i s hydrogen, C(O)-C ⁇ _ 2 alkyl, or C(O)-CF 3 ; or (b) RlO is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide or l-ethyl-N-(4- fluorophenyl)-4-[(l-methylpiperidin-4-yl)a ⁇ nino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide.
  • formula (LA) preferably, where X is OR ⁇ a , the compound is other than the compound wherein Rl is methyl, X is OEt, and R 3 is cyclopentyl.
  • Ln formula (IA), preferably, sub-formula (x) is: benzyl; phenethyl (Ph-C 2 H4-); benzyl or phenethyl being substituted on the phenyl ring with a single R 6 substituent, or one of the following:
  • R 6a is either R 6 as defined herein or (preferably) hydrogen.
  • sub-formula (y) is: wherein R 6a is either R 6 as defined herein or preferably hydrogen.
  • Examples 1-99 are examples of compounds or salts of the second aspect of the invention (Formula (LA)).
  • a third aspect of the present invention provides a compound of formula (LB) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
  • Rl is C ⁇ _ 4 a ⁇ kyl, C ⁇ _ 3 fluoroalkyl, -CH CH 2 OH or -CH 2 CH 2 CO 2 C ⁇ _ 2 alkyl;
  • R 2 is a hydrogen atom (H), methyl or Ci fluoroalkyl
  • R 3 is optionally substituted C3_gcycloalkyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);
  • nl and n 2 independently are 1 or 2; and in which Y is O, S, SO 2 , or N O;
  • RlO is a hydrogen atom (H), C ⁇ _4alkyl (e.g. methyl or ethyl), C ⁇ _ 2 fluoroalkyl, CH 2 C(O)NH 2 , C(O)NH 2 , C(O)-C ⁇ _ 2 alkyl, or C(O)-C ⁇ fluoroalkyl;
  • X is NR 4 R 5 or OR 5a , in which:
  • R 4 is a hydrogen atom (H); Ci.galkyl; C gfluoroalkyl; or C 2 _galkyl substituted by one substituent R 1; and
  • R5 is a hydrogen atom (H); Ci.galkyl; C ⁇ _g fluoroalkyl; C3_gcycloalkyl optionally substituted by a C ⁇ _ 2 alkyl group; or -(CH 2 ) n 4 -C3_gcycloalkyl optionally substituted, in the -(CH 2 ) n 4 - moiety or in the C3_gcycloalkyl moiety, by a C ⁇ _ 2 alkyl group, wherein n 4 is 1, 2 or 3;
  • R5 is C 2 -6alkyl substituted by one or two independent substituents Rl
  • each substituent Rl independently of any other Rl 1 substituent present, is: hydroxy (OH); C ⁇ galkoxy; phenyloxy; benzyloxy; -NR1 2 R1 3 ; -NR1 5 -C(O)R1 6 ;
  • R5 is -(CH 2 )n n -C(O)Rl 6 ; -(CH2) n n -C(O)NRl 2 Rl 3 ; -CHR1 -C(O)N 1 2 R 3 ; -(CH 2 ) n l 2 -C(O)ORl 6 ; -CHR1 9 -C(0)0R1 6 ; -(CH 2 )n 12 -S02-N l Rl 3 ; -(CH 2 )n 12 -SO 2 Rl 6 ; or -(CH 2 ) n 12 -CN; wherein nl 1 is 0, 1, 2, 3 or 4 and n 12 is 1, 2, 3 or 4;
  • R 5 is -(CH2) n l -Het wherein n i3 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or 7-membered saturated or partly-saturated heterocyclic ring 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 -(CH 2 ) n l 3 - moiety when nl 3 is 1 and are not bound to the nitrogen of N 4 R5 when n - is 0; wherein any ring-nitrogens which are present and which are not unsaturated (i.e. which do not partake in a double bond) are present as .1 7 where Rl 7 is as defined herein; and wherein one or two of the carbon ring-atoms independently are optionally substituted by C ⁇ _2alkyl;
  • R5 is phenyl optionally substituted with one or two of: a halogen atom; C ⁇ _4alkyl (e.g. Chalky!); Ci ⁇ fluoroalkyl (e.g. trifluoromethyl); C ⁇ _4alkoxy (e.g. C ⁇ alkoxy); C ⁇ _ 2f uoroa l o ⁇ y ( e -S- trifluoromethoxy); C ⁇ _2alkylsu ⁇ phonyl (C ⁇ _2alkyl-S ⁇ 2-);
  • C _2alkyl such as methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: fluoro, chloro, C ⁇ alkyl, Ci fluoroalkyl, C ⁇ _2 alkoxy or Ci fluoroalkoxy; or R 7 and R 8 together are -(CH 2 ) n 6 - or -C(O)-(CH 2 ) n 7 - or -C(O)-(CH 2 ) n 7 -C(O)- or -(CH 2 )n 8 -X 7 -(CH 2 )n 9 - or -C(O)-X 7 -(CH 2 )n 10 - in which: n 6 is 3, 4, 5 or 6, n 7 is 2, 3, 4, or 5 (preferably n 7 is 2, 3 or 4), n 8 and n 9 and nlO independently are 2 or 3, and X 7 is O or N I 4 wherein R !4 is H or C _ alky
  • R5 has the sub-formula (x), (y) or (z):
  • R 6 is a halogen atom; C ⁇ _4alkyl (e.g. Ci- ⁇ alkyl); C gfluoroalkyl (e.g.
  • Ci ⁇ alkoxy e.g. C ⁇ _2alkoxy
  • Ci ⁇ fluoroalkoxy e.g. C ⁇ _2alkylsulphonyl
  • R 7 R 8 N OH; C ⁇ alkoxymethyl; Ci ⁇ alkoxyethyl; C ⁇ _ 2 alkyl-SO 2 -CH 2 -; cyano (CN); or phenyl optionally substituted by one or two of fluoro, chloro, C ⁇ _ 2 alkyl,
  • Ci fluoroalkyl C ⁇ _ 2 alkoxy or Ci fluoroalkoxy; wherein R 7 and R 8 are as herein defined;
  • G is O or S or NR 9 wherein R 9 is a hydrogen atom (H), C ⁇ _ 4alkyl or C ⁇ _4fluoroalkyl; none, one, two or three of J, L, M and Q are nitrogen; and the remaining of J, L, M and Q are independently CH or CR 6 where R 6 is as defined herein;
  • R 4 and R 5 taken together are -(CH 2 ) p l- or -C(O)-(CH 2 ) p 2 - or
  • Rl 7 is a hydrogen atom (H); C ⁇ _4alkyl (e.g. C ⁇ _ 2 alkyl); C ⁇ _ 2 fluoroalkyl; C3_6cycloalkyl; -(CH 2 ) p 6 -C(O)Rl 6 wherein p 6 is 0, 1 , 2 or 3 (preferably p 6 is 0);
  • NR 4 R5 heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, C ⁇ _2 alkyl, Ci fluoroalkyl, C ⁇ _2 alkoxy or Ci fluoroalkoxy; and
  • R ⁇ is Ci.galkyl; C ⁇ _g fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, C ⁇ _2alkyl, trifluoromethyl, C ⁇ _2alkoxy or trifluoromethoxy; or R ⁇ has the sub-formula (x), (y) or (z) as defined herein
  • Rl 2 and Rl 3 independently are H; C ⁇ _5alkyl (e.g. Chalky!); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _2 alkyl, Ci fluoroalkyl, C ⁇ _2alkoxy or Ci fluoroalkoxy;
  • R 12 and Rl 3 together are -(CH 2 ) n 6 - or -C(O)-(CH 2 ) n 7 - or -C(O)-(CH 2 ) n 7 -C(O)- or -(CH 2 )n 8 -X 12 -(CH2) n 9 - or -C(O)-Xl 2 -(CH 2 ) n l°- in which: n 6 is 3, 4, 5 or 6 (preferably n 6 is 4 or 5), n 7 is 2, 3, 4, or 5 (preferably n 7 is 2, 3 or 4), n 8 and n 9 and nlO independently are 2 or 3 (independently preferably 2) and ⁇ l is O or RI 4 wherein Rl 4 is H or C ⁇ _ 2 alkyl;
  • R1 ⁇ is a hydrogen atom (H); C ⁇ _4alkyl (e.g. *Bu or C _ 2 alkyl e.g. methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, C ⁇ _ 2 alkyl, Ci fluoroalkyl, C ⁇ _ alkoxy or C fluoroalkoxy;
  • Rl 6 is C ⁇ _4alkyl (e.g. C ⁇ _2alkyl); C3_6cycloalkyl; pyridinyl (e.g. pyridin-2-yl); or phenyl optionally substituted by one or two of: a halogen atom, Chalky!, Ci fluoroalkyl, C ⁇ _2alkoxy or Ci fluoroalkoxy; and
  • Rl is a hydrogen atom (H); C ⁇ _4alkyl (e.g. isobutyl, sec-butyl, or C ⁇ _3alkyl such as methyl or isopropyl); -(CH 2 ) n 0-OR 2 0 wherein n 2 ⁇ is 1, 2, 3 or 4 (preferably 1) and R ⁇ is a hydrogen atom (H) or C ⁇ alkyl (preferably R 20 is H); -CH(Me)-OH; -CH2-SH; -CH2-CH2-S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyI).
  • C ⁇ _4alkyl e.g. isobutyl, sec-butyl, or C ⁇ _3alkyl such as methyl or isopropyl
  • R 3 is the heterocyclic group of sub-formula (bb)
  • nl is 1, and Y is NRlO
  • Rl° is not Ci ⁇ alkyl, C ⁇ _ 2 fluoroalkyl or CH 2 C(O)NH 2
  • R! ⁇ is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide or l-ethyl-N-(4- fluorophenyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide.
  • the one or two optional substituents in the R 3 heterocyclic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents preferably comprise (e.g. is or are) OH and/or oxo.
  • Examples 1-203 are examples of compounds or salts of the third aspect of the invention (Formula (LB)).
  • the preferred or optional features for the compound or salt of fonnula (IA) and for the compound or salt of formula (LB) are the same as or similar to the preferred or optional features for the compound or salt of formula (I), with all necessary changes (for example to the formula, to the R groups and/or to substituents) having been made.
  • formula (I) is mentioned herein, then in alternative embodiments the statement mentioning formula (I) applies to formula (IA) or formula ( B), with all necessary changes having been made.
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic 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, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt.
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, 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.
  • compositions include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of formula (I).
  • pharmaceutically acceptable metal salts for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the 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).
  • Certain of the groups, e.g. hetero aromatic ring systems, included in compounds of formula (I) or their salts may exist in one or more tautomeric forms.
  • the present invention includes within its scope all such tautomeric forms, including mixtures.
  • the compound of formula (I) can optionally have a molecular weight of 1000 or less, for example 800 or less, in particular 650 or less or 600 or less.
  • Molecular weight here refers to that of the unsolvated "free base” compound, that is excluding any molecular weight contributed by any addition salts, solvent (e.g. water) molecules, etc.
  • the 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:
  • the 4-chloro substituent in the compound of formula (II) can be replaced by a halogen atom, such as a bromine atom or preferably a chlorine atom, in a compound of formula (IIA) as defined below.
  • a halogen atom such as a bromine atom or preferably a chlorine atom
  • the compound of formula (IIA) is reacted with the amine of formula R 3 NH 2 .
  • the reaction is preferably carried out in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, THF, dioxane or acetonitrile.
  • 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 (IN) can be prepared in a two step procedure as described by Bare et. al. inJ. Med. Chem. 1989, 32, 2561-2573. This process involves, first, reaction of a compound of formula (N) with thionyl chloride (or another agent suitable for forming an acid chloride from a carboxylic acid), either in an organic solvent such as chloroform or THF, or as a neat solution. This reaction may require heating and the thus-formed intermediate may or may not be isolated.
  • Step two involves reaction with an amine of formula R 4 R ⁇ H, in an organic solvent such as THF or chloroform and may also involve the use of a base such as triethylamine or diisopropylethyl amine:
  • Compounds of formula (V) can be prepared by hydrolysis of an ester of formula (II) according to the method described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027. This procedure preferably involves reaction with a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:
  • a base such as sodium hydroxide or potassium hydroxide
  • a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:
  • the 4-chloro substituent in the compound of formula (TV) can be replaced by a halogen atom, such as a bromine atom or preferably a chlorine atom, in a compound of formula (IN A) as defined below.
  • a halogen atom such as a bromine atom or preferably a chlorine atom
  • the compound of formula (IN A) is reacted with the amine of formula R 3 ⁇ H 2 .
  • Compounds of formula (I) can also be prepared according to a method, for example as described by Bare et. al. in J. Med. Chem. 1989, 32, 2561-2573, which involves reaction of a compound of formula (VI), in which -O-R 3 ⁇ is a leaving group displaceable by an amine, with an amine of formula R 3 NH 2 .
  • the -O-R 3 ⁇ leaving group can be -O-C ⁇ _4alkyl (in particular -O-Et) or -O-S(O) 2 -R 37 , wherein R 37 is Ci.galkyl (e.g.
  • C ⁇ _4alkyl or C _ 2 alkyl such as methyl
  • Ci .gfluoroalkyl e.g. C gfluoroalkyl or C _ 2 fluoroalkyl such as CF3 or C4F9
  • phenyl wherein the phenyl is optionally substituted by one or two of independently C ⁇ _ 2 alkyl, halogen or C ⁇ _ 2 alkoxy (such as phenyl or 4-methyl-phenyl).
  • the reaction may be carried out with or without solvent and may require heating:
  • the compound of fonnula (VI) can be replaced by a compound of formula (VIA), wherein X is ⁇ R 4 R ⁇ or OR ⁇ a as defined herein:
  • the activated compound (the compound of formula (X)) can be an activated ester wherein the leaving group ⁇ l is
  • the latter activated compound of formula (X) can be formed from the carboxylic acid (X
  • the compound of formula (IX)) either: (a) by reaction of the carboxylic acid with a carbodiimide such as EDC, which is 1-ethyl- 3-(3'-dimethylaminopropyl)carbodiimide and is also l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, or a salt thereof e.g.
  • EDC 1-ethyl- 3-(3'-dimethylaminopropyl)carbodiimide and is also l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, or a salt thereof e.g.
  • hydrochloride salt preferably followed by reaction of the resulting product with 1-hydroxybenzotriazole (HOBT); reaction (a) usually being carried out in the presence of a solvent (preferably anhydrous) such as dimethyl formamide (DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25 °C); or
  • 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
  • DMF dimethyl methacrylate
  • acetonitrile preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25 °C).
  • This ester can itself be prepared by any of Processes A, C, E or F as described herein.
  • Compounds of formula (I) can be prepared by reaction of a compound of formula (XI) with an alkylating agent of formula R!-X 3 , where X 3 is a leaving group displaceable by the 1 -position pyrazolopyridine nitrogen atom of the compound of formula (XL):
  • a suitable alkylating agent of formula R!-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 36 wherein R 36 is Ci.galkyl (e.g. C ⁇ _4alkyl or C ⁇ _ 2 alkyl such as methyl), Ci .gfluoroalkyl (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.
  • a solvent e.g. an organic solvent such as DMF; the solvent is preferably anhydrous.
  • alkylation Process E include Examples 183, 185, 186 and 354.
  • Process F Conversion of one compound of formula (I) or salt thereof into another compound of formula (I) or salt thereof
  • One compound of fonnula (I) or salt thereof can be converted into another compound of formula (I) or salt thereof.
  • This conversion preferably comprises or is one or more of the following processes Fl to F10:
  • the oxidation process can comprise or be oxidation of an alcohol to a ketone (e.g. using Jones reagent, e.g. see Example 205) 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 corresponding N-oxide (e.g. using 7wet ⁇ -chloroperoxybenzoic acid), for example conversion of a pyridine-containing compound to the corresponding pyridine N-oxide (e.g. Examples 210-212).
  • 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.
  • Hydrolysis e.g. hydrolysis of an ester to the corresponding carboxylic acid or salt thereof (e.g. Examples 351, 488, 489, 650, 651).
  • F6 Deprotection, e.g. deprotection (e.g. deacylation or t-butyloxycarbonyl (BOC) removal) of an amine group (e.g. Examples 320, (321), and (352)).
  • deprotection e.g. deacylation or t-butyloxycarbonyl (BOC) removal
  • BOC t-butyloxycarbonyl
  • F7 Formation of an ester or amide, for example from the corresponding carboxylic acid.
  • F8 Conversion of a ketone into the corresponding oxime (e.g. Examples 652, 653, 654 and 680-686).
  • the Beckmann rearrangement 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 formula (I) or a salt thereof:
  • Rl, R 2 and R 3 are as defined herein and X is NR 4 R ⁇ or OR ⁇ a as defined herein, the method comprising :
  • Hal is a halogen atom (such as a bromine atom or preferably a chlorine atom), with an amine of formula R 3 NH 2 , or
  • Hal is a halogen atom (such as a bromine atom or preferably a chlorine atom), with an amine of formula R 3 NH 2 , or
  • VIA in which -O-R 3 ⁇ is a leaving group displaceable by an amine (such as -O-C ⁇ _4alkyl or -O-S(O) 2 -R 37 ), with an amine of formula R 3 ⁇ H 2 ; or
  • the activated compound of formula (X) can be an activated ester wherein the leaving group ⁇ l is
  • the present invention also provides: (g) 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 Examples 490, 491, 518A, 593).
  • 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 fonnula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal such as a human.
  • the compound or salt can be for use in the treatment and/or prophylaxis of any of the diseases / conditions described herein (e.g. for use in the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal) and/or for use as a phosphodiesterase inhibitor e.g. for use as a phosphodiesterase 4 (PDE4) inhibitor.
  • “Therapy” may include treatment and/or prophylaxis.
  • a compoxmd of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal such as a human, e.g. for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.
  • a method of treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal (e.g. human) in need thereof e.g. a method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal (e.g. human) in need thereof, which method comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt thereof.
  • Phosphodiesterase 4 inhibitors are thought to be useful in the treatment and/or prophylaxis of a variety of diseases / conditions, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: asthma, chronic obstructive pulmonary disease (COPD) (e.g.
  • COPD chronic obstructive pulmonary disease
  • chronic bronchitis and/or emphysema chronic bronchitis and/or emphysema
  • atopic dermatitis urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple sclerosis, cognitive impairment (e.g. in a neurological disorder such as Alzheimer's disease), depression, or pain. Ulcerative colitis and/or Crohn's disease are collectively often referred to as inflammatory bowel disease.
  • the inflammatory and/or allergic disease is preferably chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD or asthma in a mammal (e.g. human).
  • COPD chronic obstructive pulmonary disease
  • asthma rheumatoid arthritis
  • allergic rhinitis in a mammal
  • the treatment and/or prophylaxis is of COPD or asthma in a mammal (e.g. human).
  • PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M.A.Giembycz, Drugs, Feb. 2000, 59(2), 193-212; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466- 473; and refs cited therein).
  • COPD COPD
  • S.L. Wolda Emerging Drugs, 2000, 5(3), 309-319
  • Z. Huang et al. Current Opinion in Chemical Biology, 2001, 5: 432-438
  • H.J.Dyke et al. Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13
  • C.Burnouf et al. Current Pharmaceutical Design, 2002, 8(14), 1255-1296
  • A.M.Doherty Current Opinion Chem. Biol, 1999, 3(4), 466- 473; and refs cited therein
  • COPD is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (S.L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).
  • PDE4 inhibitors are thought to be effective in the treatment of allergic rhinitis (e.g. see B.M. Schmidt et al., J. Allergy & Clinical Immunology, 108(4), 2001, 530-536).
  • PDE4 inhibitors are thought to be effective in the treatment of rheumatoid arthritis and multiple sclerosis (e.g. see H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002,
  • the treatment and/or prophylaxis can be of cognitive impairment e.g. cognitive impairment in a neurological disorder such as Alzheimer's disease.
  • the treatment and/or prophylaxis can comprise cognitive enhancement e.g. in a neurological disorder. See for example: H.T.Zhang et al. in: Psychopharmacology, June 2000, 150(3), 311-316 and Neuropsychopharmacology, 2000, 23(2), 198-204; and T. Egawa et al., Japanese J. Pharmacol, 1997, 75(3), 275-81.
  • PDE4 inhibitors such as rolipram have been suggested as having antidepressant properties (e.g. J. Zhu et al., CNS Drug Reviews, 2001, 7(4), 387-398; O'Donnell, Expert Opinion on Investigational Drugs, 2000, 9(3), 621-625; and H.T. Zhang et al., Neuropsychopharmacology, October 2002, 27(4), 587-595).
  • the compounds of the present invention are usually administered as a pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein.
  • the invention also provides a method of preparing a pharmaceutical composition
  • 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 compoxmd 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 phannaceutical composition may be administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration.
  • the phannaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration.
  • the pharmaceutical composition is suitable for inhaled or oral administration, e.g. to a mammal such as a human.
  • Inhaled administration involves topical administration to the lung e.g. by aerosol or dry powder composition.
  • Oral administration to a human is most preferred.
  • a pharmaceutical composition suitable for oral administration can be liquid or solid; for example it can be a syrup, suspension or emulsion, a tablet, a capsule or a lozenge.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable pharmaceutically acceptable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations.
  • examples of such carriers include lactose and cellulose.
  • the tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example binding agents, lubricants such as magnesium stearate, and/or tablet disintegrants.
  • a pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures. For example, pellets containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule. Alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutically acceptable carrier, for example an aqueous gum or an oil and the dispersion or suspension then filled into a soft gelatin capsule.
  • the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human.
  • a parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil.
  • the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal or inhaled administration may conveniently be formulated as aerosols, drops, gels or dry powders.
  • Aerosol formulations 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 form, and more preferably the size-reduced form is obtained or obtainable by micronisation.
  • Micronisation usually involves subjecting the compound/salt to collisional and abrasional forces in a fast-flowing circular or spiral vortex-shaped airstream often including a cyclone component.
  • the preferable particle size (e.g. D50 value) of the size-reduced (e.g. micronised) compound or salt is about 0.5 to about 10 microns, e.g. about 1 to about 5 microns (e.g. as measured using laser diffraction).
  • the compound or salt of formula (I) it is preferable for the compound or salt of formula (I) to have a particle size defined by: a D10 of about 0.3 to about 3 microns (e.g. about 1 micron), and/or a D50 of about 1 to about 5 microns (e.g. about 2-5 or about 2-3 microns), and/or a D90 of about 2 to about 20 microns or about 3 to about 10 microns (e.g. about 5-8 or about 5-6 microns); for example as measured using laser diffraction.
  • a D10 of about 0.3 to about 3 microns e.g. about 1 micron
  • a D50 of about 1 to about 5 microns e.g. about 2-5 or about 2-3 microns
  • a D90 of about 2 to about 20 microns or about 3 to about 10 microns e.g. about 5-8 or about 5-6 microns
  • the laser diffraction measurement can use a dry method (suspension of compound/salt in airflow crosses laser beam) or a wet method [suspension of compound/salt in liquid dispersing medium, such as isooctane or (e.g. if compound soluble in isooctane) 0.1% Tween 80 in water, crosses laser beam].
  • particle size is preferably calculated using the Fraunhofer calculation; and/or preferably a Malvern Mastersizer or Sympatec apparatus is used for measurement.
  • Micronisation Example Micronisation of Example 518 or 518A
  • Example 518 or 518A (described hereinafter) using a Jetpharma MCI micronizer.
  • the parent (unmicronised) and micronised materials are analyzed for particle size by laser diffraction and crystallinity by PXRD.
  • the Jetpharma MCI Micronizer comprises a horizontal disc-shaped milling housing having: a tubular compound inlet (e.g. angled at ca. 30degrees to the horizontal) for entry of a suspension of unmicronised compound of formula (I) or salt in an gasflow, a separate gas inlet for entry of gases, a gas outlet for exit of gases, and a collection vessel for collecting micronised material.
  • a tubular compound inlet e.g. angled at ca. 30degrees to the horizontal
  • a separate gas inlet for entry of gases
  • a gas outlet for exit of gases
  • a collection vessel for collecting micronised material.
  • the milling housing has two chambers: an outer annular chamber in gaseous connection with the gas inlet the chamber being for receiving pressurised gas (e.g. air or nitrogen), an disc-shaped inner milling chamber within and coaxial with the outer chamber for micronising the input compound / salt, the two chambers being separated by an annular wall.
  • the annular wall (ring R) has a plurality of narrow-bored holes connecting the inner and outer chambers and circumferentially- spaced-apart around the annular wall.
  • the compound inlet is is gaseous communication with the inner chamber via a nozzle directed tangentially to the inner chamber, within and near to the annular wall.
  • Upper and lower broad-diameter exit vents in the central axis of the the inner milling chamber connect to (a) (lower exit) the collection vessel which has no air outlet, and (b) (upper exit) the gas outlet which leads to a collection bag, filter and a gas exhaust.
  • a venturi inlet N
  • the compound inlet also has a bifurcation connecting to an upwardly- directed material inlet port for inputting material.
  • the narrow 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 (eg air or nitrogen) the feed material is sucked into the gasstream thorough the compound inlet and accelerates it 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 eg 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 center 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, while the exhaust gas rises (together with a miinority of small particles of micronised material) and escapes into the atmosphere at low pressure and low velocity.
  • the micronizer is assembled.
  • the venturi protrusion distance from input port is adjusted to 1.0cm respectively (e.g. so that the narrow 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 correctly.
  • 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.
  • 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 (see section on experimental run) is weighed into a plastic weigh boat.
  • the material is then fed into the micronizer using a vibrational spatula (e.g. N-shaped in cross-section) at a specified feed rate.
  • the material feeding time and equipment pressures are monitored during the micronization process.
  • the nitrogen supply is shut off and the collection bag is tapped to allow particles to settle into the recovery / collection vessel at the bottom of the micronizer.
  • the collection bag is removed and set aside.
  • the micronised powder in the recovery vessel (collection vessel) and the cyclone (above the recovery vessel) are collected separately into different weighed+labelled collection vials.
  • the weight of the micronised material is recorded.
  • 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 by rinsing and wiping with suitable solvent and dried before subsequent runs are perfonned.
  • % yield [(Material from vessel + Material from cyclone)/Material input amount] xlOO In general, very approximately 50-75% yields are achievable using this method. Procedure 1 has not been completed.
  • Example 518 micronised material was obtained, including material from collection vessel and material from inside walls of cyclone.
  • Example 518 micronised material from Procedure 2 using laser diffraction measurement with Malvern Mastersizer longbed version, dispersing medium 0.1%) Tween 80 in water, stir rate 1500 rpm, 3 mins sonification prior to final dispersion and analysis, 300 RF (Reverse Fourier) lens, Fraunhofer calculation with Malvern software:
  • D10 0.97 microns
  • D50 3.86 microns
  • D90 12.64 microns.
  • D10 0.95 microns
  • D50 3.42 microns
  • D90 9.42 microns.
  • Examples of the compounds/salts of the invention other than Examples 518 or 518A can be micronised.
  • the pharmaceutical composition is a dry powder inhalable composition.
  • a dry powder inhalable composition can comprise a powder base such as lactose or starch, the compound of formula (I) or salt thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine, mannitol, trehalose and/or magnesium stearate.
  • the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof.
  • the lactose is preferably lactose hydrate e.g.
  • the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90%) or more of the lactose particles being less than 300 microns (e.g. 10-300 microns e.g.
  • the particle size of the lactose is defined by 90%) or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter.
  • a suitable inhalation-grade lactose is E9334 lactose (10% 0 fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).
  • the dry powder inhalable composition preferably, the compound of formula (I) or salt thereof is present in about 0.1% to about 70%> (e.g. about 1% to about 50%o, e.g. about 5% to about 40%, e.g. about 20 to about 30%>) by weight of the composition.
  • the dry powder blend is prepared by mixing the required amount of the compound/salt (e.g. 10 mg, 1% w/w) with inhalation-grade lactose containing 10% fines (e.g. 990 mg, 99% w/w) in a TeflonTM (polytetrafluoroethene) pot in a Mikro-dismembrator ball-mill (but without a ball bearing) at % speed (ca. 2000-2500 rpm) for about 4 hours at each blend concentration.
  • the Mikro-dismembrator available from B.
  • a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel-openable on demand and the dose, e.g. of the dry powder composition, can be administered by inhalation via a device such as the DISKUS TM device, marketed by GlaxoSmitliKline.
  • 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.
  • 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. human) in a daily oral or parenteral dose of 0.001 mg to 50 mg per kg body weight per day (mg/kg/day), for example 0.01 to 20 mg/kg/day or 0.03 to 10 mg/kg/day or 0.1 to 2 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • a mammal e.g. human
  • a daily oral or parenteral dose of 0.001 mg to 50 mg per kg body weight per day (mg/kg/day), for example 0.01 to 20 mg/kg/day or 0.03 to 10 mg/kg/day or 0.1 to 2 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • a pharmaceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g. human) in a daily nasal or inhaled dose of: 0.0001 to 5 mg/kg/day or 0.0001 to 1 mg/kg/day, e.g. 0.001 to 1 mg/kg/day or 0.001 to 0.3 mg/kg/day or 0.001 to 0.1 mg/kg/day or 0.005 to 0.3 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the pharmaceutically acceptable compounds or salts of the invention is preferably administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day e.g. 2 to 500 mg per day, or a nasal or inhaled dose of 0.001 to 300 mg per day or 0.001 to 50 mg per day or 0.01 to 30 mg per day or 0.01 to 5 mg per day or 0.02 to 2 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • a daily dose for an adult patient
  • an oral or parenteral dose 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day e.g. 2 to 500 mg per day
  • a nasal or inhaled dose of 0.001 to 300 mg per day or 0.001 to 50 mg per day or 0.01 to 30 mg per day or 0.01 to 5 mg per day or 0.02 to 2 mg per day, of the compound of the formula (I) or
  • the compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a ⁇ 2 adrenoreceptor agonist, an anti-histamine, an anti-allergic or an anti-inflammatory agent.
  • a ⁇ 2 adrenoreceptor agonist for example, an anti-histamine, an anti-allergic or an anti-inflammatory agent.
  • the invention thus provides, in a further aspect, a combination comprising a compound of fonnula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent, for example, a ⁇ 2 -adrenoreceptor agonist, an anti-histamine, an anti-allergic, an anti-inflammatory agent or an antiinfective agent.
  • another therapeutically active agent for example, a ⁇ 2 -adrenoreceptor agonist, an anti-histamine, an anti-allergic, an anti-inflammatory agent or an antiinfective agent.
  • the ⁇ 2 -adrenoreceptor agonist is salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline, or a salt thereof (e.g. pharmaceutically acceptable salt thereof), for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • Long-acting ⁇ 2 -adrenoreceptor agonists are prefereed, especially those having a therapeutic effect over a 12-24 hour period such as salmeterol or formoterol.
  • the ⁇ 2 -adrenoreceptor agonist is for inhaled administration, e.g. once per day and/or for simultaneous inhaled administration; and more preferably the ⁇ 2 -adrenoreceptor agonist is in particle-size-reduced form e.g. as defined herein.
  • the ⁇ 2 -adrenoreceptor agonist combination is for treatment and/or prophylaxis of COPD or asthma.
  • Salmeterol or a pharmaceutically acceptable salt thereof, e.g. salmeterol xinofoate, is preferably administered to humans at an inhaled dose of 25 to 50 micrograms twice per day (measured as the free base).
  • the combination with a ⁇ -adrenoreceptor agonist can be as described in WO 00/12078.
  • Preferred long acting ⁇ 2 -adrenoreceptor agonists include those described in WO
  • 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 ⁇ - 6 alkyl, C 3 - 7 cycloalkyl,
  • R and R are each optionally substituted by one or two groups selected from halo, C ⁇ - 6 alkyl, -ehaloalkyl, hydroxy- substituted C,- 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 18X and R 19X are independently selected from hydrogen, C ⁇ - 6 alkyl, C 3 - 6 cycloalkyl, phenyl, and phenyl (C h alky!)-; 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, Cj . -ealkyl, C ⁇ - 6 alkoxy, halo, phenyl, and C ⁇ - 6 haloalkyl;
  • R 14X and R 15 are independently selected from hydrogen and C 1 - 4 alkyl with the proviso that the total number of carbon atoms in R and R is not more than 4.
  • Preferred ⁇ 2 -adrenoreceptor agonists disclosed in WO 02/066422 include:
  • a prefened ⁇ -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) s 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 ⁇ , M 2 , M ⁇ /M 2 , or
  • an anticholinergic compound e.g. a muscarinic (M) receptor antagonist in particular an M ⁇ , M 2 , M ⁇ /M 2 , 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 M 2 receptor.
  • anticholinergic compounds / muscarinic (M) receptor antagonist with PDE4 inhibitors see for example WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 Al and US 2002/052312 Al, and some or all of these publications give examples of anticholinergic compounds / muscarinic (M) receptor antagonists which may be used with the compounds of formula (I) or salts, and/or suitable pharmaceutical compositions.
  • the muscarinic receptor antagonist can comprise or be an ipratropium salt (e.g. ipratropium bromide), an oxitropium salt (e.g. oxitropium bromide), or more preferably a tiotropium salt (e.g. tiotropium bromide); see e.g. EP 418 716 Al for tiotropium.
  • an ipratropium salt e.g. ipratropium bromide
  • an oxitropium salt e.g. oxitropium bromide
  • tiotropium salt e.g. tiotropium bromide
  • the anticholinergic compound or muscarinic (M) receptor antagonist e.g. M3 receptor antagonist
  • M3 receptor antagonist is preferably for inhaled administration, more preferably in particle-size- reduced form e.g. as defined herein. More preferably, both the muscarinic (M) receptor antagonist and the compound of formula (I) or the 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 (NSAID) such as a leukotriene antagonist (e.g. montelukast), an iNOS inhibitor, a tryptase inhibitor, a elastase inhibitor, a beta-2 integrin antagonist, a adenosine 2a agonist, a CCR3 antagonist, or a 5-lipoxogenase inhibitor); or an antiinfective agent (e.g. an antibiotic or antiviral).
  • a leukotriene antagonist e.g. montelukast
  • an iNOS inhibitor e.g. montelukast
  • iNOS inhibitor e.g. montelukast
  • tryptase inhibitor e.g. a tryptas
  • 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 1 ⁇ -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 (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 phannaceutical composition for admimstration of the individual compounds of the combination either sequentially or simultaneously, or
  • the invention also provides a combination as defined herein, prepared by a method as defined herein.
  • Prefereed 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 PDE5 A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase", Gene, 1998, 216, 139-147.
  • PDE3 was 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 was purified from bovine retina as described by: P. Catty and P. Detene,
  • PDE4B or PDE4D inhibition can be measured in the following Fluorescence Polarisation (FP) assay:
  • LMAP Fluorescence Polarisation (FP) assay LMAP Explorer kit, available from Molecular Devices Corporation, Sunnydale, CA, USA; Molecular Devices code: R8062
  • the LMAP FP assay is able to measure PDE activity in an homogenous, non-radioactive assay format.
  • the FP assay uses the ability of immobilised trivalent metal cations, coated onto nanoparticles (tiny beads), to bind the phosphate group of Fl-AMP that is produced on the hydrolysis of fluorescein-labelled (Fl) 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. 0.5 to 1 ul, of solution in DMSO
  • ambient temperature room temperature, e.g. 19-23°C
  • PDE enzyme 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 was set by experimentation so that reaction was linear throughout the incubation.
  • Fluorescein adenosine 3 ',5 '-cyclic phosphate (from Molecular Devices Corporation, Molecular Devices code: R7091) was added to give about 40nM final concentration (final assay volume usually ca. 25-40 ul). Plates were 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) was added (60ul of a 1 in 400 dilution in binding buffer of the kit stock solution) to terminate the assay. Plates were allowed to stand at ambient temperature for 1 hour.
  • FP Fluorescence Polarisation
  • the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly.
  • the PIC50 inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units, for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R.Mobbs et al, "Comparison of the LMAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity", poster to be presented at 2003 Molecular Devices UK & Europe User Meeting, 2nd October 2003, Down Hall, Harlow, Essex, United Kingdom).
  • Biological Data obtained for some of the Examples are as follows, based on current measurements only. In each of the SPA and FP assays, absolute accuracy of measurement is not possible, and the readings given are accurate only up to about ⁇ 0.5 of a log unit, depending on the number of readings made and averaged:
  • Emesis Some known PDE4 inhibitors can cause emesis and/or nausea to greater or lesser extents (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.
  • Emetic side-effects can for example be measured by the emetogenic potential of the compound or salt when administered to ferrets; for example one can measure the time to onset, extent, frequency and/or duration of vomiting, retching and/or writhing in fercets after oral or parenteral administration of the compound or salt. See for example In vivo Assay 4 hereinafter for a measurement method for anti-inflammatory effect, emetic side-effects and therapeutic index (TI) in the ferret. 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 Vivo Assay 2 below).
  • PDE4 inhibitors can cause other side effects such as headache and other central nervous sytem (CNS-) 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.
  • CNS- central nervous sytem
  • Gl gastrointestinal tract disturbances
  • Pulmonary neutropliil 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 suspended in 0.5%> methylcellulose (obtainable from Sigma- Aldrich, St Louis, MO, USA) in water or (b) vehicle only, delivered orally in a dose volume of 10 ml/kg.
  • dose response curves are generated using the following doses of PDE4 inhibitors: 10.0, 2.0, 0.4, 0.08 and 0.016 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 100 ⁇ g/ml LPS solution. Rats are exposed to the LPS aerosol at a rate of 4 L/min for 20 minutes. LPS exposure is carried out in a closed chamber with internal dimensions of 45 cm length x 24 cm width x 20 cm height. The nebulizer and exposure chamber are contained in a certified fume hood. At 4 hours-post LPS exposure the rats are euthanized by overdose with pentobarbital at 90 mg/kg, administered intraperitoneally.
  • Bronchoalveolar lavage (BAL) is preformed through'a 14 gauge blxmt 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 perfonned on BAL fluid in order to calculate neutropliil 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
  • 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 Vivo 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.
  • TI therapeutic index
  • the 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 Vivo Assay 1), with larger TI ratios possibly indicating lower emesis at many anti-inflammatory doses.
  • the rats are housed individually in cages without bedding or "enrichment".
  • the rats are kept off of the cage floor by a wire screen.
  • Pre-weighed food cups containing standard rat chow and clay pellets are placed in the cage.
  • the clay pellets obtainable from Languna Clay Co, City of Industry, CA, USA, are the same size and shape as the food pellets.
  • the rats are acclimated to the clay for 72 hours, during which time the cups and food and clay debris from the cage are weighed daily on an electronic balance capable of measuring to the nearest 0.1 grams. By the end of the 72 hour acclimation period the rats generally show no interest in the clay pellets.
  • the rats are placed in clean cages and the food cups weighed. Rats that are still consuming clay regularly are removed from the study.
  • the animals are split into treatment groups and dosed orally with a dose of the compoxmd/salt of the invention (different doses for different treatment groups) or with vehicle alone, at a dose volume of 2 ml/kg.
  • the compound/salt is in the form of a suspension in 0.5% methylcellulose (obtainable Sigma- Aldrich, St. Louis, MO, USA) in water.
  • 0.5% methylcellulose obtainable Sigma- Aldrich, St. Louis, MO, USA
  • 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 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 Therapeutic Index (TI) calculated this way is often significantly different to, and often higher than, the TI calculated in the fenet (see hi vivo Assay 4 below).
  • 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.) admimstered PDE4 inhibitors.
  • the PDE4 inhibitors are preferably in dry powder or wet suspension form.
  • I.t. administration is one model of inhaled administration, allowing topical delivery to the lung.
  • mice Male CD (Sprague Dawley Derived) rats supplied by Charles River, Raleigh, NC, USA were housed in groups of 5 rats per cage, acclimatised after delivery for at least 7 days with bedding/nesting material regularly changed, fed on SDS diet Rl pelleted food given ad lib, and supplied with daily-changed pasteurised animal grade drinking water.
  • Male CD Sprague Dawley Derived rats supplied by Charles River, Raleigh, NC, USA were housed in groups of 5 rats per cage, acclimatised after delivery for at least 7 days with bedding/nesting material regularly changed, fed on SDS diet Rl pelleted food given ad lib, and supplied with daily-changed pasteurised animal grade drinking water.
  • Device for dry powder administration Disposable 3-way tap between dosing needle and syringe.
  • a 3-way sterile tap (Vycon Ref 876.00) was weighed, the drug blend or inhalation grade lactose (vehicle control) was then added to the tap, the tap closed to prevent loss of drug, and the tap was re-weighed to determine the weight of drug in the tap. After dosing, the tap was 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, was cut by engineering to approximately 132 mm (5.2 inches), a blunt end was made to prevent them damaging the rat's trachea, and the needle weighed prior to and after drug delivery to confirm that no drug was retained in the needles after dosing.
  • Lipopolysaccharide (LPS) (Serotype:0127:B8) (L3129 Lot 61K4075) was dissolved in phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • PDE4 inhibitors are used in size-reduced (e.g. micronised) form, for example according to the Micronisation Example given above.
  • the Dry Powder Formulation Example given above comprising drug and inhalation-grade lactose, can be used.
  • the inhalation-grade lactose usually used (Lot E98L4675 Batch 845120) has 10% fines (10% of material under 15um particle size measured by Malvern particle size).
  • Wet suspensions of the drug can be prepared by adding the required volume of vehicle to the drug; the vehicle used being a mixture of saline/tween (0.2%> tween 80). The wet suspension was sonicated for 10 minutes prior to use.
  • Preparation, and dosing with PDE 4 inhibitor Rats were' 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 litre.minute "1 ). Once anaesthetised, the animals were placed onto a stainless steel i.t. dosing support table. They were positioned on their back at approximately a 35° angle. A light was angled against the outside of the throat to highlight the trachea. The mouth was opened and the opening of the upper airway visualised. The procedure varies for wet suspension and dry powder administration of PDE4 inhibitors as follows:
  • a portex cannula was introduced via a blunt metal dosing needle that had been carefully inserted into the rat trachea.
  • the animals were intratracheally dosed with vehicle or PDE4 inhibitor via the dosing needle with a new internal canula used for each different drug group.
  • the formulation was slowly (10 seconds) dosed into the trachea using a syringe attached to the dosing needle.
  • Dosing with a Dry Powder The three-way tap device and needle were 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 2x 4ml of air 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. After dosing, the needle and tap are removed from the airway and the tap closed off to prevent any retained drug leaving the tap.
  • Exposure to LPS About 2 hours after i.t. dosing with vehicle control or the PDE4 inhibitor, the rats were placed into sealed Perspex containers and exposed to an aerosol of LPS (nebuliser concentration 150 ⁇ g.ml "1 ) for 15 minutes. Aerosols of LPS were generated by a nebuliser (DeVilbiss, USA) and this was directed into the Perspex exposure chamber. Following the 15-minute LPS-exposure period, the animals were returned to the holding cages and allowed free access to both food and water.
  • the rats can exposed to LPS less than 2 hours after i.t. dosing.
  • the rats can exposed to LPS more than 2 hours (e.g. ca. 4 or ca. 6 hours) after i.t. dosing by vehicle or PDE4 inhibitor, to test whether or not the PDE4 inhibitor has a long duration of action (which is not essential).
  • Bronchoalveolar lavage A hours after LPS exposure the animals were killed by overdose of sodium pentobarbitone (i.p.).
  • the trachea was cannulated with polypropylene tubing and the lungs lavaged (washed out) with 3 x 5 mis of heparinised (25 units.mi "1 ) phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • Neutrophil cell counts The Bronchoalveolar lavage (BAL) samples were centrifuged at 1300 rpm for 7 minutes. The supernatant was removed and the resulting cell pellet resuspended in 1 ml PBS. A cell slide of the resuspension fluid was prepared by placing lOO ⁇ l of resuspended BAL fluid into cytospin holders and then spun at 5000 rpm for 5 minutes. The slides were allowed to air dry and then stained with Leishmans stain (20 minutes) to allow differential cell counting. The total cells were also counted from the resuspension. From these two counts, the total numbers of neutrophils in the BAL were determined. For a measure of PDE4-inhibitor-induced inhibition of neutrophilia, 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 (1 ml) of acetone and then adding cremophor to 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. 1.2 Animals
  • the diet comprises SDS diet C pelleted food given ad lib with WhiskersTM ca ⁇ f 00 d g 1V en 3 times per week.
  • the animals are supplied with pasteurised animal grade drinking water changed daily.
  • PDE4 inhibitors are administered orally (p.o.), using a dose volume of lml/kg. Ferrets are fasted overnight but allowed free access to water.
  • the animals are orally dosed with vehicle or PDE 4 inhibitor using a 15cm dosing needle that is passed down the back of the throat into the oesophagus. After dosing, the animals are returned to holding cages fitted with perspex doors to allow observation, and given free access to water. The animals are constantly observed and any emetic episodes (retching and vomiting) or behavioural changes are recorded. The animals are allowed access to food 60 - 90 minutes after p.o. dosing. 1.3.2 Exposure to LPS
  • the fereets are placed into sealed perspex containers and exposed to an aerosol of LPS (30 ⁇ g/ml) for 10 minutes. Aerosols of LPS are generated by a nebuliser (DeVilbiss, USA) and this is directed into the perspex exposure chamber. Following a 10-minute exposure period, the animals are returned to the holding cages and allowed free access to water, and at a later stage, food. General observation of the animals continues for a period of at least 2.5 hours post oral dosing. All emetic episodes and behavioural changes are recorded. 1.3.3 Bronchoalveolar lavage and cell counts
  • the animals are killed by overdose of sodium pentobarbitone administered intraperitoneally.
  • the trachea is then cannulated with polypropylene tubing and the lungs lavaged twice with 20 ml heparinised (10 units/ml) phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the bronchoalveolar lavage (BAL) samples are centrifuged at 1300 m for 7 minutes. The supernatant is removed and the resulting cell pellet re-suspended in 1 ml PBS.
  • a cell smear of re-suspended fluid is prepared and stained with Leishmans stain to allow differential cell counting. A total cell count is made using the remaining re-suspended sample. From this, the total number of neutrophils in the BAL sample is determined.
  • Therapeutic index (TI) D20 incidence of emesis
  • Therapeutic index (TI) calculated using this in vivo Assay 4 is often significantly different to, and often lower than, that calculated using the rat oral inflammation and pica feeding Assays 1+2.
  • Solvent A 95% acetonitrile + 0.05% formic acid
  • Solvent B 0.1% formic acid + lOmMolar ammonium acetate
  • the prep column used was a Supelcosil ABZplus (10cm x 2.12cm)
  • UV wavelength 200-320nM
  • Injection Volume 1ml; or more preferably 0.5 ml
  • Solvent B 95%» acetonitrile + 5% formic acid; or more usually 99.95%) acetonitrile + 0.05% formic acid
  • Step 1 N,N-dibenzyltetrahydro-2H-pyran-4-amine
  • Dibenzylamine (34.5g) and acetic acid (6.7ml) were added to a stined solution of tetrahydro-4H-pyran-4-one (16.4g, commercially available from e.g. Aldrich) in dichloromethane (260ml) at 0 °C to 5 °C. After 2.5h at 0 °C to 5 °C, sodium triacetoxyborohydride (38.9g) was added portionwise, and the mixture was allowed to warm to room temperature.
  • Step 2 Tetrahydro-2H-pyran-4-amine hydrochloride N,N-dibenzyltetrahydro-2H-pyran-4-amine (20.5g) was dissolved in ethanol (210ml) and hydrogenated over 10%> palladium on carbon catalyst (4g) at 100 psi for 72h at room temperature. The reaction mixture was filtered and the filtrate was adjusted to p ⁇ 1 with 2M-hydrogen chloride in diethyl ether. Evaporation of solvents gave a solid which was triturated with diethyl ether to give the product as a white solid (9.23g). ⁇ ⁇ MR (400MHz in d 6 -DMSO, 27°C, ⁇ ppm) 8.24 (br. s, 3H), 3.86 (dd, 12, 4Hz, 2H), 3.31 (dt, 2, 12Hz, 2H), 3.20 (m, IH), 1.84 (m, 2H), 1.55 (dq, 4, 12Hz, 2H).
  • DCM dichloromethane
  • Acid chloride hitermediate 16 was syntliesised from Intermediate 15 using the method shown above for Intermediate 17.
  • Intermediate 16 (0.473 g) was dissolved in THF (4ml) and treated with diisopropylethylamine (DLPEA) (0.509ml), then with 4- (aminomethyl)pyridine (0.21 lg) and the mixture stined under nitrogen for 0.5h. The mixture was concentrated in vacuo, then partitioned between DCM and water.
  • DLPEA diisopropylethylamine
  • Intermediate 33 l-EthyI-4-(tetrahydro-2H-pyran-4-yIamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxylic acid
  • the resultant white solid precipitate was removed by filtration and dried under vacuum.
  • Example 190 2M-Sodium hydroxide solution (0.39ml, 0.78mmol) was added to Example 190 (0.128g, 0.39mmol, described hereinafter) in ethanol (1.5ml), and the mixture was heated at 50 °C for 16 hours. The reaction mixture was concentrated, and the resulting aqueous solution was neutralised with 2M-hydrochloric acid to precipitate a solid which was collected by filtration. The filtrate was applied to an OASIS ® hydrophilic-lipophilic balance (HLB) Extraction cartridge * (lg) which was eluted with water followed by methanol.
  • HLB hydrophilic-lipophilic balance
  • OASIS ® HLB Extraction cartridges are available from Waters Co ⁇ oration, 34 Maple Street, Milford, MA 01757, USA.
  • the cartridges include a column containing a copolymer sorbent having a HLB such that when an aqueous solution is eluted through the column, the solute is absorbed or adsorbed into or onto the sorbent, and such that when organic solvent (e.g. methanol) is eluted the solute is released as an organic (e.g. methanol) solution. This is a way to separate the solute from aqueous solvent.
  • organic solvent e.g. methanol
  • Benzylamine (0.16ml) was added to a stined mixture of Intermediate 49 (0.13g), DLPEA (0.26ml) and HATU (0.285g) in DMF (3ml). The resultant mixture was heated with stirring at 85 °C for 16 hours. Further portions of HATU (0.14g), DLPEA (0.13ml) and benzylamine (0.082ml) were added and the mixture heated for 16 hours at 88 °C. The resultant solution was concentrated, diluted with dichloromethane (20ml) and washed with saturated sodium bicarbonate solution (20ml), separated by hydrophobic frit and the organic layer concentrated.
  • intermediate 55 is: Where NR 4 R 5 ⁇ ⁇
  • Intermediate 15 (1.04g) was treated with thionyl chloride (13.22g). The mixture was stirred and heated at 75 °C for 2h. Excess thionyl chloride was removed in vacuo and the residual oil azeotroped with toluene to afford Intermediate 16, presumed to be the acid chloride derivative of intermediate 15, as a cream solid (1.12g).
  • Aqueous sodium hydroxide solution (8.55ml, 2M) was added to a solution of Example 207 (1.55g) in EtOH (13ml). The mixture was heated at 50 °C for 18h then neutralised using aqueous hydrochloric acid and evaporated in vacuo to afford a mixture of 1-ethyl- 4-(4-piperidinylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid and 4-[(l-acetyl-4- piperidinyl)amino]-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid
  • Acetic acid (0.36ml) was added to a stined mixture of ⁇ ATU (2.41g) and N,N- diisopropylethylamine (2.21ml) in N,N-dimethylfonnamide (65ml). After stirring for 15 min the mixture was added to the mixture of l-ethyl-4-(4-piperidinylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxylic acid and 4-[(l-acetyl-4-piperidinyl)amino]-l-ethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid and the reaction stined for 15h.

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Abstract

The invention relates to a compound of formula (I) or a salt thereof: wherein:R1 is C1-4alkyl, C1-3fluoroalkyl, -CH2CH2OH or -CH2CH2CO2C1-2alkyl;R2 is a hydrogen atom (H), methyl or C1fluoroalkyl;R3 is optionally substituted C3-8cycloalkyl or optionally substituted mono-unsaturated-C5-7cycloalkenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc); in which n1 and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NR10; or R3 is a bicyclic group (dd) or (ee): ; and wherein X is NR4R5 or OR5a. The compounds are phosphodiesterase (PDE) inhibitors, in particular PDE4 inhibitors. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human, for example chronic obstructive pulmonary disease (COPD), asthma, or allergic rhinitis.

Description

Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors
The present invention relates to pyrazolopyridine 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 pyrazolopyridine compounds in therapy, for example as inhibitors of phosphodiesterases and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.
US 3,979,399, US 3,840,546, and US 3,966,746 (E.R.Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxamides wherein the 4-amino group NR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR3R4 can alternatively be a 3-6-membered heterocyclic group such as pyrrolidino, piperidino and piperazino. The compounds are disclosed as central nervous system depressants useful as ataractic, analgesic and hypotensive agents.
US 3,925,388, US 3,856,799, US 3,833,594 and US 3,755,340 (E.R.Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxylic acids and esters. The 4-amino group NR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR3R4 can alternatively be a 5-6- membered 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.
H. Hoehn et al., J. Heterocycl. Chem., 1972, 9(2), 235-253 discloses a series of 1H- pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives with 4-hydroxy, 4-chloro, 4-alkoxy, 4-hydrazino, and 4-amino substituents.
CA 1003419, CΗ 553 799 and T.Denzel, Archiv der Pharmazie, 191 A, 307(3), 177-186 disclose 4,5-disubstituted lH-pyrazolo[3,4-b]pyridines unsubstituted at the 1-position.
Japanese laid-open patent application JP -2002 -20386- A (Ono Yakuhin Kogyo KK) published on 23 January 2002 discloses pyrazolopyridine compounds of the following formula:
Figure imgf000004_0001
wherein R1 denotes 1) a group -OR6, 2) a group -SR7, 3) a C2-8 alkynyl group, 4) a nitro group, 5) a cyano group, 6) a Cl-8 alkyl group substituted by a hydroxy group or a Cl-8 alkoxy group, 7) a phenyl group, 8) a group -C(O)R8, 9) a group -SO2NR9R10, 10) a group -NRπSO2R12, 11) a group -NR13C(O)R14 or 12) a group -CH=NR15. R6 and R7 denote i) a hydrogen atom, ii) a Cl-8 alkyl group, iii) a Cl-8 alkyl group substituted by a Cl-8 alkoxy group, iv) a trihalomethyl group, v) a C3-7 cycloalkyl group, vi) a Cl-8 alkyl group substituted by a phenyl group or vii) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R2 denotes 1) a hydrogen atom or 2) a Cl-8 alkoxy group. R3 denotes 1) a hydrogen atom or 2) a Cl-8 alkyl group. R4 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group, 5) a phenyl group which may be substituted by 1-3 halogen atoms or 6) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R5 denotes 1) a hydrogen atom, 2) a Cl-8 alkyl group, 3) a C3- 7 cycloalkyl group, 4) a Cl-8 alkyl group substituted by a C3-7 cycloalkyl group or 5) a phenyl group which may be substituted by 1-3 substituents. In group R3, a hydrogen atom is preferred. In group R^ , methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are preferred. The compounds of JP-2002-20386-A are stated as having PDE4 inhibitory activity and as being useful in the prevention and/or treatment of inflammatory diseases and many other diseases.
EP 0 076 035 Al (ICI Americas) discloses pyrazolo[3,4-b]pyridine derivatives as central nervous system depressants useful as tranquilisers or ataractic agents for the relief of anxiety and tension states.
The compound cartazolate, ethyl 4-(n-butylamino)-l-ethyl-lH-pyrazolo[3,4-b]-pyridine- 5-carboxylate, is known. J.W. Daly et al., Med. Chem. Res., 1994, 4, 293-306 and D. Shi et al., Drug Development Research, 1997, 42, 41-56 disclose a series of 4- (amino)substituted lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives, including ethyl 4-cyclopentylamino-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate, and their affinities and antagonist activities at Ai - and A2A_adenosine receptors, and the latter paper discloses their affinities at various binding sites of the GABA^-receptor channel. S. Schenone et al., Bioorg. Med. Chem. Lett., 2001, 11, 2529-2531 and F. Bondavalli et al., J. Med. Chem., 2002, vol. 45 (Issue 22, 24 October 2002, allegedly published on Web 09/24/2002), pp. 4875-4887 disclose a series of 4-amino-l-(2-chloro-2-ρhenylethyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters as Ai -adenosine receptor ligands.
WO 02/060900 A2 appears to disclose, as MCP-1 antagonists for treatment of allergic, inflammatory or autoimmune disorders or diseases, a series of bicyclic 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)-NR5R6 group as the 5-substituent and optionally substituted at the 1-, 3-, 4-, and/or 6-positions. Bicyclic heterocyclic compounds with a -C(O)NΗ2 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)-NR4-C(O)-NR5R6 substituted compounds.
It is desirable to find new compounds which bind to, and preferably inhibit, phosphodiesterase type IN (PDE4).
The present invention provides a compound of formula (I) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
Figure imgf000005_0001
wherein:
R1 is Cι_4alkyl, C^fluoroalkyl, -CH2CH2OH or -CH2CH2CO2C1.2alkyl;
R2 is a hydrogen atom (H), methyl or Ci fluoroalkyl;
R3 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);
Figure imgf000006_0001
(aa) (bb) (cc) in which n and n2 independently are 1 or 2; and in which Y is O, S, SO2, or N lO; where RlO is a hydrogen atom (H), C^alkyl (e.g. methyl or ethyl), Cι_2fluoroalkyl, CH2C(O)NH2, C(O)NH2, C(O)-C!. alkyl, C(O)-Cι fluoroalkyl or -C(O)-CH2O-Cι_2alkyl;
and wherein in R3 the C3_gcycloalkyl or the heterocyclic group of sub-formula (aa), (bb) or (cc) is optionally substituted with one or two substituents independently being (e.g. being) oxo (=O); OH; Cι_2alkoxy; Ci_2fluoroalkoxy (e.g. trifluoromethoxy); NHR^l wherein R is a hydrogen atom (H) or C\_ζ straight-chain alkyl (e.g. H or C1.4 straight- chain alkyl); Cι_2alkyl; Cι_2fluoroalkyl (e.g. Ci fluoroalkyl such as -CH2F or -CHF2);
-CH OH; -CH2CH2OH; -CH2NHR22 wherein R22 is H or Cι_2alkyl; -C(O)OR23 wherein R23 is H or
Figure imgf000006_0002
-C(O)NHR24 wherein R24 is H or Cι_2alkyl; -C(O)R25 wherein R2^ is Cι_2alkyl; fluoro; hydroxyimino (=N-OH); or (Ci _4alkoxy)imino (=N-OR2(> where R ^ is Chalky!); and wherein any OH, alkoxy, fluoroalkoxy or
NHR i substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc); and wherein, when R3 is optionally substituted mono-unsaturated-Cs. cycloalkenyl, then the cycloalkenyl is optionally substituted with one or two substituents being fluoro or Cι_2alkyl provided that if there are two substituents then they are not both C2alkyl, and the R3 ring carbon bonded to the -NH- group of formula (I) does not partake in the cycloalkenyl double bond;
Figure imgf000006_0003
or R3 is a bicyclic group of sub-formula (dd): ^ ' or of sub-formula (ee):
Figure imgf000006_0004
ee) wherein γl, Y2 and Y3 independently are CH2 or oxygen (O) provided that no more than one of γl, Y2 and Y3 is oxygen (O); and X is NR4R5 or OR5a, in which:
R4 is a hydrogen atom (H); Ci.galkyl; C\ -.3 fluoroalkyl; or C2_6alkyl substituted by one substituent R! 1 ; and
R5 is a hydrogen atom (H); Ci .galkyl; C^.g fluoroalkyl; C3_gcycloalkyl optionally substituted by a Cι_ alkyl group; or -(CH2)n 4-C3_gcycloalkyl optionally substituted, in the -(CH2)n 4- moiety or in the C3_gcycloalkyl moiety, by a Cι_2alkyl group, wherein n4 is 1, 2 or 3;
or R5 is C2_6alkyl substituted by one or two independent substituents R11 ;
wherein each substituent R! 1, independently of any other R! substituent present, is: hydroxy (OH); Ci.galkoxy; phenyloxy; benzyloxy; -NR12R13; -NR15-C(O)R16;
-NR15-C(O)-O-R16; -NR15-C(O)-NH-R15; or -NR15-SO R16; and wherein any R1 1 substituent which is OH, alkoxy or -N i Rl3 is not substituted at any carbon atom, of any R4 or R^ substituted alkyl, which is bonded to the nitrogen of N 4R5;
or R5 is -(CH2)n1 1-C(O)R16; -(CH2)n 12-C(O)NR12R13; -CHR19-C(0)NR1 R13; -(CH2)n 12-C(O)OR16; -(CH2)nl2-C(O)OH; -CHR19_C(0)0R16; -CHR19-C(O)OH; -(CH2)n 12-SO2-NR12R13; -(CH2)n 12-SO2R16; or -(CH2)nl2-CN; wherein nl 1 is 0, 1, 2, 3 or 4 and n12 is 1, 2, 3 or 4;
or R^ is -(CH2)n i3-Het wherein n 3 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or
7-membered saturated or partly-saturated heterocyclic ring 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- nioiety when n^3 is 1 and are not bound to the nitrogen of N 4R5 when ni3 is 0; wherein any ring-nitrogens which are present and which are not unsaturated (i.e. which do not partake in a double bond) are present as NR17' where R1^ is as defined herein; and wherein one or two of the carbon ring-atoms independently are optionally substituted by Ci _ 2 alkyl;
or R5 is phenyl optionally substituted with, independently, one, two or three of: a halogen atom; C^.galkyl (e.g. Ci _4alkyl or Ch lky!); Ci^fluoroalkyl (e.g. trifluoromethyl);
Cι_4alkoxy (e.g. Cι_2 lko y); C^fluoro alkoxy (e.g. trifluoromethoxy); C3.6cycloalkyloxy; -C(O)Rl6a; -C(O)OR30; -S(O)2-R16a (e.g. Cι_2alkylsulphonyl or
Figure imgf000008_0001
Rl6a_S(0)2-NR15a- (e.g. Cι_2alkyl-SO2-NH-); R7R8N-S(O)2-;
C1_2alkyl-C(O)-R15aN-S(O)2-;
Figure imgf000008_0002
Ph-S(O)-, R7R8N-CO-;
-NR15-C(O)R16; R7R8N; OH;
Figure imgf000008_0003
C1.2alkyl-S(O)2-CH2-; R7R8N-S(O)2-CH2-; Cι_2alkyl-S(O)2-NRl5a.cH2-;
-CH2-OH; -CH2CH2-OH; -CH2-NR7R8; -CH2-CH2-NR7R8; -CH2-C(O)OR30;
-CH2-C(O)-NR7R8; -CH -NR15a-C(O)-Ci_3alkyl; -(CH2)nl4-Hefl where n14 is 0 or 1; cyano (CN); Ar^a- or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C _2alkyl, C\ fluoroalkyl, Cχ_2 alkoxy or C fluoroalkoxy; or where two adjacent substituents taken together are -O-(CMe2)-O- or -O-(CH )nl4-O- where n^4 is 1 or 2; wherein R7 and R8 are independently a hydrogen atom (H); Cχ_4alkyl (e.g. C _2alkyl such as methyl); C3_gcycloalkyl; or phenyl optionally substituted by one or two of: fluoro, chloro, Cχ.2alkyl, C\ fluoroalkyl, C _2 alkoxy or Cχfluoroalkoxy; or R7 and R8 together are -(CH2)n6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n -C(O)- or
-(CH2)n 8-X7-(CH2)n 9- or -C(O)-X7-(CH2)n 10- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3,
4, or 5 (preferably n7 is 2, 3 or 4), n8 and n9 and n^O independently are 2 or 3 (preferably independently 2), and X7 is O or NRi4 wherein Ri4 is H, Cχ.2alkyl or C(O)Me (preferably H or Cχ.2alkyl);
or R^ has the sub-formula (x), (y), (yl) or (z):
Figure imgf000008_0004
wherein in sub-formula (x), n = 0, 1 or 2; in sub-formula (y) and (yl), m = 1 or 2; and in sub-formula (z), r = 0, 1 or 2;
wherein in sub-formula (x) and (y) and (yl), none, one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+-O") provided that no more than one of A, B, D, E and F is nitrogen-oxide; and the remaining of A, B, D, E and F are independently CH or CR6; provided that when n is 0 in sub-formula (x) then one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+-O~) and no more than one of A, B, D, E and F is nitrogen-oxide;
wherein, each R6, independently of any other R6 present, is: a halogen atom; Cχ_6alkyl (e.g. Cχ_4alkyl or Chalky!); C^fluoroalkyl (e.g. Cχ_2fluoroalkyl); Cι_4alkoxy (e.g.
Cι_2alkoxy); Cι_2fluoroalkoxy; C3_6cycloalkyloxy; -C(O)R16a; -C(O)OR30;
-S(O)2-R16a (e.g. Cι. alkylsulphonyl, that is Cι.2alkyl-SO2-); R16a-S(O)2-NR15a-
(e.g. Cι_2alkyl-SO2-NH-); R7R8N-S(O)2-; C1_2alkyl-C(O)-R15aN-S(O)2-;
Cι. alkyl-S(O)-, Ph-S(O)-, R7R8N-CO-; -NR15-C(O)R16; R7R8N; OH;
Cι.4alkoxymethyl; Cι_4alkoxyethyl; C1.2alkyl-S(O)2-CH2-; R7R8N-S(O)2-CH2-;
Cι.2alkyl-S(O)2-NR15a-CH2-; -CH2-OH; -CH2CH2-OH; -CH2-NR7R8;
-CH2-CH2-NR7R8; -CH2-C(O)OR30; -CH2-C(O)-NR7R8;
-CH2-NR15a-C(O)-Cι_3alkyl; -(CH2)n 14-Het1 where n*4 is 0 or 1; cyano (CN); Ar5b; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, Cχ_2 alkyl,
Cx fluoroalkyl, Cχ_2alkoxy or Cχfluoroalkoxy; or where two adjacent R6 taken together are -O-(CMe2)-O- or -O-(CH2)n 14-O- where n*4 is 1 or 2; wherein R7 and R8 are as herein defined;
wherein sub-formula (y) and (yl), independently, are optionally substituted by oxo (=O) at a ring carbon adjacent the 6-membered aromatic ring (for example, sub-formula (y) can
or sub-formula (yl) can optionally
Figure imgf000009_0001
wherein in sub-formula (z), G is O or S or N 9 wherein R9 is a hydrogen atom (H), Cχ_4alkyl or Cj ^fluoroalkyl; 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 CR6 where R6, independently of any other R6 present, is as defined herein; or R4 and R5 taken together are -(CH2)p 1- or -C(O)-(CH2)p 2- or -(CH2)p3-X5-(CH2)p4- or -C(O)-X5-(CH2)p 5-, in which: pi = 3, 4, 5 or 6 (preferably p = 4 or 5), p2 is 2, 3, 4, or 5 (preferably p2 is 2, 3 or 4), and p3 and p4 and p5 independently are 2 or 3 (independently preferably 2) and X^ is O or NR.I7; and wherein, when R4 and R^ taken together are -(CH2)p - or -C(O)-(CH2)p 2-, the 4R^ heterocycle is optionally substituted by one R! substituent wherein R!8 is: Cι_4alkyl (e.g. Cι_2alkyl); Cι_2fluoroalkyl; C3_6cycloalkyl; Cχ_2alkoxy (not substituted at a ring-carbon bonded to the NR4R5 ring-nitrogen); Cχfluoroalkoxy (not substituted at a ring-carbon bonded to the N 4R^ ring-nitrogen); OH (not substituted at a ring-carbon bonded to the NR4R5 ring-nitrogen); -(CH2)p 7-C(O)R! 6 wherein p7 is 0, 1 , 2 or 3
(preferably p7 is 0 or 1); -(CH2)p 7-C(O)ORl6; -(CH2)p7-OC(O)R!6;
-(CH2)p7-C(O)NRl2R1 ; -(CH2)p7-NRl5C(O)Rl6; -(CH2)p7-NR15C(O)NR12R13;
-(CH2)p7-NRl5c(O)ORl6; -(CH2)p 7-SO2Rl6; -(CH2)P 7-SO2 NR1 R13;
-(CH2)p 7-NR15SO2R16; -(CH )p 7-OH; -(CH2)p7-OR!6; or phenyl optionally substituted by one or two of: a halogen atom, Cχ.2alkyl, C\ fluoro alkyl, Cχ_2alkoxy or Cχfluoroalkoxy;
or R4 and R5 taken together are -(CH2)p - or -C(O)-(CH2)p 2- or
-(CH2)p3-X5-(CH2)p4- or -C(O)-X5-(CH2)p 5- as defined herein, and wherein the R4R5 heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, Cχ_2 alkyl, Ci fluoroalkyl, Cχ.2alkoxy or Cχfluoroalkoxy; and
R^a is Ci .galkyl; Cχ_g fluoroalkyl; C3_gcycloalkyl; -(CH2)n 4a-C3_6cycloalkyl wherein n a is 1 or 2; phenyl optionally substituted with one or two of: a halogen atom, C- χ_2alkyl, trifluoromethyl, Ci _ alkoxy or trifluoromethoxy; or R^a has the sub-formula (x), (y) or (z) as defined herein
and wherein:
R! and R 3 independently are H; Cχ_5alkyl (e.g. Chalky!); C3_0xycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, C fluoroalkyl, Cχ_2alkoxy or Cχfluoroalkoxy;
or R 2 and R 3 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n 8-Xl2-(CH2)n 9- or -C(O)-χl2-(CH2)n10- in which: n6 is 3, 4, 5 or 6 (preferably n6 is 4 or 5), n7 is 2, 3, 4, or 5 (preferably n7 is 2, 3 or 4), n8 and n9 and Ώ)-® independently are 2 or 3 (independently preferably 2) and X12 is O or NR14a wherein R14a is H, Cι_2alkyl or C(O)Me (preferably H or Cι_2alkyl);
Rl5 is a hydrogen atom (H); Cχ_4alkyl (e.g. tβu or Ci^alkyl e.g. methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, C\ fluoroalkyl, Cχ.2alkoxy or Cχfmoroalkoxy;
Rl5a 9 independent of other R^a, ls a hydrogen atom (H) or Cχ_4alkyl (e.g. H, *Bu or
Cχ_2 alkyl such as methyl; preferably R^a is JJ 0r Cχ.2alkyl, more preferably H);
Rl6 and Ri6a independently are:
Ci.βalkyl (e.g. Ci _4alkyl or Cχ.2alkyl);
C3_6cycloalkyl (e.g. C5_fjCycloalkyl) optionally substituted by one oxo (=O), OH or Cχ.2alkyl substituent (e.g. optionally substituted at the 3- or 4-position of a C5_6cycloalkyl ring; and/or preferably unsubstituted C3_6cycloalkyl); C3_6cycloalkyl-CH2- (e.g. C5_6cycloalkyl-CH2-); pyridinyl (e.g. pyridin-2-yl) optionally substituted on a ring carbon atom by one of: a halogen atom, Cχ_2alkyl, C fluoroalkyl, Cχ_2 alkoxy or Ci fluoroalkoxy;
Ar5c; phenyl optionally substituted by one or two of: a halogen atom, C _2 alkyl,
Oχ fluoroalkyl, Cχ. alkoxy or Cχfluoroalkoxy; benzyl optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, Cχ_2 alkyl, C\ fluoroalkyl, C _2alkoxy or Cχfluoroalkoxy; 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 NR27 where R27 is H, Cχ.2alkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one
Cχ_2 alkyl or oxo (=O) substituent, provided that any oxo (=0) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
wherein Ar^a } Ar^b an^ β^5c independently is/are a 5-membered aromatic heterocyclic ring containing one O, S or ^a in 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, Cχ. alkyl, Oχ fluoroalkyl, -CH2OH, -CH2-OCχ_2 alkyl, OH (including the keto tautomer thereof) or -CH2-NR28R29 wherein R28 and R29 independently are H or methyl;
and Rl7 is a hydrogen atom (H); Cχ_4alkyl (e.g. Cχ.2alkyl); Cι_2fluoroalkyl; C3_6cycloalkyl; -(CH2)p 6-C(O)R16 wherein p6 is 0, 1, 2 or 3 (preferably p6 is 0); -(CH2)p6-C(O)NRl2Rl3; -(CH2)p 6-C(O)ORl6; -(CH2)p 6-C(O)OH; -SO2R16;
-C(O)-CH2-NR12R13; -C(O)-CH2-NR15a-C(O)-C1.3alkyl; -C(O)-CH2-O-C1_3 alkyl; or phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, Cχ_2alkyl, C fluoroalkyl, Cχ_2alkoxy or
Cχfluoroalkoxy;
R19is Cι_4alkyl; -(CH2)n 20-OR20 wherein n20 is 1, 2, 3 or 4 and R20 is a hydrogen atom (H) or
Figure imgf000012_0001
-CH(Me)-OH; -CH2-SH; -CH2-CH2-S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyl); and
R 0, independent of other ^, is a hydrogen atom (H), Cχ_4alkyl or C3_6cycloalkyl; and
Hefl , independent of other 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 NR31 where R3^ is H, Cχ_2alkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one Cχ_2 alkyl or oxo (=O) substituent, provided that any oxo
(=O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
provided that: when R3 is the heterocyclic group of sub-formula (bb), n* is 1, and Y is NR^O, then: either (a) R10 is not Ci^alkyl, C ^fluoroalkyl or CH2C(O)NH2; or (b) R10 is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide or l-ethyl-N-(4- fluorophenyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide.
Preferably, where X is OR^a, the compound is other than the compound wherein Rl is methyl, X is OEt, and R3 is cyclopentyl.
In one optional embodiment of the invention, R* is Cχ_4alkyl or Cχ_2 fluoroalkyl.
Alternatively or additionally, in one optional embodiment of the invention, R2 is a hydrogen atom (H). Alternatively or additionally, in one optional embodiment of the invention, R3 is
Figure imgf000013_0001
C3_gcycloalkyl or a heterocyclic group being " in which Y is O, S, SO2, or NR10; where R10 is hydrogen, Ci^alkyl, Ci^fluoroalkyl, C(O)-Cι_ 2alkyl, or C(O)-CF3; and wherein in R3 the C3_gcycloalkyl or heterocyclic group is optionally substituted with one or two substituents being OH, Cχ_2alkoxy, trimethoxy, or Cχ_2 alkyl; and wherein any OH, alkoxy or trimethoxy substituent is not substituted at the (R3) ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either (R3) ring carbon bonded to the Y group of the heterocyclic group. Alternatively or additionally, in one optional embodiment of the invention, R4 is hydrogen, Cχ_2alkyl or Cχ_2 fluoroalkyl.
Alternatively or additionally, in one optional embodiment of the invention, HX> is hydrogen, Cχ_galkyl, Cχ_g fluoroalkyl, or C3_gcycloalkyl; or phenyl optionally substituted with one or two of: a halogen atom, Cχ_2alkyl, trifluoromethyl, Cχ_2 alkoxy or trifluoromethoxy; or ~Rp has the sub-formula (x), (y) or (z):
Figure imgf000013_0002
(x) (y) (z)
wherein in sub-formula (x), n = 1 or 2; in sub-formula (y), m = 1 or 2; and in sub- formula (z), r = 1 or 2; wherein in sub-formula (x) and (y), none, one or two of A, B, D, E and F are nitrogen; and the remaining of A, B, D, E and F are CH or CR6 where Rβ is a halogen atom, Cχ.4alkyl, C^fluoroalkyl, Cι__2 alkoxy, Cχ_2fluoroalkoxy, Cχ_2alkylsulphonyl
(C!.2alkyl-SO2-), C1.2alkyl-SO2-NH-, R7R8N-SO2-, R7R8N-CO-, R7R8N, OH, Cχ_4alkoxymethyl, or Cχ_2alkyl-SO2-CH2-, wherein R7 and R8 are independently hydrogen or Cχ_2 alkyl; wherein in sub-formula (z), G is O or S or NR9 wherein R9 is Cχ_4alkyl or Cι_4fluoroalkyl; none, one or two of J, L, M and Q are nitrogen; and the remaining of J,
L, M and Q are CH or CR6 where Rβ is as defined herein. In the alternative to the above R4 and/or R^ optional embodiments, in one optional embodiment of the invention, R4 and R^ taken together can be -(CH2)pl- where i = 3, 4 or 5 (preferably p = 4 or 5). In one optional embodiment of the invention, R3 is optionally substituted C3_gcycloalkyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);
Figure imgf000014_0001
(aa) (bb) (cc) in which nl and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NRIO; where RlO is a hydrogen atom (H), Cχ_4alkyl (e.g. methyl or ethyl), C .2fluoroalkyl, CH2C(O)NH2, C(O)NH2, C(O)-Cι_2alkyl, or C(O)-Cχ fluoroalkyl; and wherein in R3 the C3_gcycloalkyl or the heterocyclic group of sub-formula
(aa), (bb) or (cc) is optionally substituted with one or two substituents being oxo (=O), OH, Cχ_2alkoxy, Cχ_ fluoroalkoxy (e.g. trifluoromethoxy), or Cχ.2alkyl; and wherein any OH, alkoxy or fluoroalkoxy substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc).
Alternatively or additionally to the above optional R3 definition, in one optional embodiment of the invention, X is NR4R^ or OR^ ; in which:
R4 is a hydrogen atom (H); Ci _galkyl; Cχ_3fluoroalkyl; or C2_6alkyl substituted by one substituent Rl ; and
R5 is a hydrogen atom (H); Cχ_galkyl; Cχ_g fluoroalkyl; C3_gcycloalkyl optionally substituted by a Cχ_2alkyl group; or -(CH2)n 4-C3_gcycloalkyl optionally substituted, in the -(CH2)n 4- moiety or in the C3_gcycloalkyl moiety, by a Cχ_2alkyl group, wherein n4 is 1, 2 or 3;
or R5 is C2.galkyl substituted by one or two independent substituents R 1;
wherein each substituent R 1, independently of any other Rl substituent present, is: hydroxy (OH); Ci^alkoxy; phenyloxy; benzyloxy; -NR12R13; -NRl5-C(O)Rl6;
-NR15-C(0)-0-R16; -NR15-C(0)-NH-R15; or -NR15-SO2R16; and wherein any RU substituent which is OH, alkoxy or -N 12R1 is not substituted at any carbon atom, of any R4 or R$ substituted alkyl, which is bonded to the nitrogen of R4R5; or R5 is -(CH2)nll-C(O)Rl6; -(CH2)nl2-C(O)NRl2Rl3; -CHR19-C(O)NR12R13; -(CH2)nl2-C(O)ORl6; -CHR19-C(0)0R16; -(CH2)nl2-SO2-NRl2Rl3; -(CH2)nl2-SO2Rl6; or -(CH2)nl2-CN; wherein nl 1 is 0, 1, 2, 3 or 4 and n12 is 1, 2, 3 or 4;
or R5 is -(CH2)nl3-Het wherein ni3 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or
7-membered saturated or partly-saturated heterocyclic ring 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)nl3- moiety when 11I is 1 and are not bound to the nitrogen of 4R5 when nl is 0; wherein any ring-nitrogens which are present and which are not unsaturated (i.e. which do not partake in a double bond) are present as NR.I7 where Rl is as defined herein; and wherein one or two of the carbon ring- atoms independently are optionally substituted by Cχ_2 alkyl;
or R5 is phenyl optionally substituted with one or two of: a halogen atom; Cχ_4alkyl (e.g. Cχ.2alkyl); Cχ.2fluoro alkyl (e.g. trifluoromethyl); Cχ_4alkoxy (e.g. Cχ.2alkoxy); Cχ_ 2fluoroalkoxy (e.g. trifluoromethoxy); Cχ_2alkylsulphonyl (Cχ.2alkyl-SO2-);
Cι_2alkyl-SO2-NH-; R7R8N-SO2-; R7R8N-CO-; -NR15-C(0)R16; R7R8N; OH; Cι_4alkoxymethyl; Cχ_4alkoxyethyl; Cχ_2alkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one or two of fluoro, chloro, Cχ_2alkyl, C fluoroalkyl, Cχ_2alkoxy or Cχfluoroalkoxy; wherein R7 and R8 are independently a hydrogen atom (H); Cχ_4alkyl (e.g. Cχ.2alkyl such as methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: fluoro, chloro, Cχ_2alkyl, C\ fluoroalkyl, Cχ_2alkoxy or Cχfluoroalkoxy; or R7 and R8 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or
-(CH2)n 8-X7-(CH2)n 9- or -C(O)-X7-(CH2)nl°- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3,
4, or 5 (preferably n7 is 2, 3 or 4), n8 and n9 and n*0 independently are 2 or 3, and X7 is O or N I4 wherein R14 is H or Cι_2alkyl;
or R5 has the sub-formula (x), (y) or (z):
Figure imgf000015_0001
(x) (y) (z) wherein in sub-formula (x), n = 1 or 2; in sub-formula (y), m = 1 or 2; and in sub-formula (z), r = 0, 1 or 2;
wherein in sub-formula (x) and (y), none, one or two of A, B, D, E and F are nitrogen; and the remaining of A, B, D, E and F are independently CH or CR6;
where R6 is a halogen atom; Cχ_4alkyl (e.g. Chalky!); Cχ_4fluoroalkyl (e.g.
C i-2 fluoroalkyl); Cχ_4alkoxy (e.g. Cι_2alkoxy); Cχ_2fluoroalkoxy; Cχ.2alkylsulphonyl
(Cι_2alkyl-SO2-); C1.2alkyl-SO2-NH-; R7R8N-SO2-; R7R8N-CO-; -NR15-C(O)R16; R7R8N; OH; C^alkoxymethyl; Ci^alkoxyethyl; Cι_2alkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one or two of fluoro, chloro, Cχ_2 alkyl,
Ci fluoroalkyl, Cχ_2alkoxy or C fluoroalkoxy; wherein R7 and R8 are as herein defined;
wherein in sub-formula (z), G is O or S or NR9 wherein R9 is a hydrogen atom (H), Cχ_ 4al yl or C^ ^fluoroalkyl; 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 CR6 where R6 is as defined herein;
or R4 and R5 taken together are -(CH )pl- or -C(O)-(CH2)p 2- or
-(CH2)p 3-χ5-(CH2)p4- or -C(O)-X5-(CH2)p 5-, in which: pi = 3, 4, 5 or 6 (preferably p = 4 or 5), p2 is 2, 3, 4, or 5 (preferably p2 is 2, 3 or 4), and p3 and p4 and p^ independently are 2 or 3 (independently preferably 2) and X^ is O or NRI7; wherein Rl7 is a hydrogen atom (H); Cχ_4alkyl (e.g. Cχ_2alkyl); Cχ. fluoroalkyl;
C3_6cycloalkyl; -(CH2)p 6-C(O)Rl6 wherein p6 is 0, 1, 2 or 3 (preferably p6 is 0);
-(CH2)p6-C(O)NRl2Rl3; -(CH )p 6-C(O)ORl6; -SO R16; or phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, Cχ_2 alkyl, C fluoroalkyl, Cχ_2alkoxy or C\ fluoroalkoxy; and wherein, when R4 and R^ taken together are -(CH2)pl- or -C(O)-(CH2)p2-, the NR4R5 heterocycle is optionally substituted by one Rl8 substituent wherein Rl is: Cχ_4alkyl (e.g. Cχ_2alkyl); Cχ.2fluoroalkyl; C3_6cycloalkyl; Cχ_2alkoxy (not substituted at a ring-carbon bonded to the N 4R5 ring-nitrogen); C\ fluoroalkoxy (not substituted at a ring-carbon bonded to the NR4R5 ring-nitrogen); OH (not substituted at a ring-carbon bonded to the NR4R5 ring-nitrogen); -(CH )p 7-C(O)Rl6 wherein p7 is 0, 1, 2 or 3 (preferably p7 is 0 or 1); -(CH2)p 7-C(O)ORl6; -(CH2)p 7-OC(O)Rl6; -(CH2)p7-C(O)NRl2Rl 3; -(CH2)p 7-NRl 5c(O)Rl 6; -(CH2)p 7-NRl 5C(O)NRl2Rl 3 ; -(CH2)p7-NRl5c(O)ORl6; -(CH2)p 7-SO2Rl6; -(CH2)p 7-SO2 NRl2Rl ;
-(CH2)P 7-NR15SO R16; -(CH2)p 7-OH; -(CH2)p 7-ORl6; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, C fluoroalkyl, Cχ_2alkoxy or Cx fluoroalkoxy;
or R4 and R5 taken together are -(CH2)pl- or -C(O)-(CH2)p 2- or -(CH2)p3-X5-(CH2)p4- or -C(O)-χ5-(CH2)p 5- as defined herein, and wherein the
NR4R heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, Cχ_2alkyl, C fluoroalkyl, Cι_2alkoxy or C\ fluoroalkoxy; and
R^a is Cχ.galkyl; Cχ_g fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, Cχ_2 alkyl, trifluoromethyl, Ci^alkoxy or trifluoromethoxy; or R^a has the sub-formula (x), (y) or (z) as defined herein
and wherein:
Rl2 and Rl3 independently are H; Cχ_5alkyl (e.g. C^alkyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2 alkyl, C fluoroalkyl, Cχ_2 alkoxy or C\ fluoroalkoxy;
or Rl2 and Rl3 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n 8-X12-(CH2)n 9- or -C(O)-χl2-(CH2)n 1()- in which: n6 is 3, 4, 5 or 6
(preferably n6 is 4 or 5), n7 is 2, 3, 4, or 5 (preferably n7 is 2, 3 or 4), n8 and n9 and nlO independently are 2 or 3 (independently preferably 2) and χl2 is O or NRI4 wherein Rl is H or Cι_2alkyl;
Rl5 is a hydrogen atom (H); Cχ_4alkyl (e.g. tβu or Cχ_2alkyl e.g. methyl);
C3_gcycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, C\ fluoroalkyl, Cχ_2alkoxy or C fluoroalkoxy;
Rl6 is Cχ_4alkyl (e.g. Cχ_2alkyl); C3_6cycloalkyl; pyridinyl (e.g. pyridin-2-yl); or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, C fluoroalkyl, Cχ_2 alkoxy or C\ fluoroalkoxy; and
R19is Cι_4alkyl; -(CH2)n 20-OR20 wherein n20 is 1, 2, 3 or 4 and R20 is a hydrogen atom (H) or Cχ_4alkyl; -CH(Me)-OH; -CH2-SH; -CH2-CH2-S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyl). In compounds, for example in the compounds of formula (I) (or formula (LA) or formula (LB), see later), an "alkyl" group or moiety may be straight-chain or branched. Alkyl groups, for example Cχ_galkyl or Cχ_6alkyl or Cχ_4alkyl or Cχ_3alkyl or Cχ_2alkyl, which may be employed include Cj.galkyl or C^alkyl or Cχ_3alkyl or Cι__2 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 corresponding meaning is intended for "alkoxy", "alkylene", and like terms derived from alkyl. For example, "alkoxy" such as Cχ.galkoxy or C^alkoxy or
Cχ_2alkoxy includes methoxy, ethoxy, propyloxy, and oxy derivatives of the alkyls listed above. "Alkylsulfonyl" such as Cχ_4alkylsulfonyl includes methylsulfonyl
(methanesulfonyl), ethylsulfonyl, and others derived from the alkyls listed above. "Alkylsulfonyloxy" such as C _4alkylsulfonyloxy includes methanesulfonyloxy (methylsulfonyloxy), ethanesulfonyloxy, et al.
"Cycloalkyl", for example C3_gcycloalkyl, includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, a C3_gcycloalkyl group is C3_6cycloalkyl or Cs.gcycloalkyl , that is contains a 3-6 membered or 5-6 membered carbocyclic ring. "Fluoroalkyl" includes alkyl groups with one, two, three, four, five or more fluorine substituents, for example Cχ_4fluoroalkyl or C\ .3 fluoroalkyl or Cι_2fluoro alkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF CH2-), 2,2-difluoroethyl (CHF2CH2-), 2-fluoroethyl (CH2FCH2-), etc. "Fluoroalkoxy" includes C _4fluoroalkoxy or Cχ.2fluoroaikoxy such as trifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy, etc. "Fluoroalkylsulfonyl" such as Cχ.4fluoroalkylsulfonyl includes trifluoromethanesulfonyl, pentafluoroethylsulfonyl, etc.
A halogen atom ("halo") present in compounds, for example in the compounds of formula (I), can be a fluorine, chlorine, bromine or iodine atom ("fluoro", "chloro", "bromo" or "iodo").
When the specification states that atom or moiety A is "bonded" or "attached" to atom or moiety B, it means that atom/moiety A is directly bonded to atom/moiety B usually by means of one or more covalent bonds, 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.
Preferably, Rl is Cχ_4alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl),
Cχ_3 fluoroalkyl or -CH2CH2OH; Rl is more preferably Cχ_3alkyl (e.g. methyl, ethyl or n-propyl), Cχ_2fluoroalkyl, or -CH2CH2OH; still more preferably Cχ.3 alkyl, C2fluoroalkyl or -CH2CH2OH such as methyl, ethyl, n-propyl or -CH2CH2OH. Yet more preferably, Rl is C2-3alkyl (e.g. ethyl or n-propyl), C2fluoroalkyl (e.g. Cχfluoroalkyl-CH2- such as CF3-CH2-) or -CH2CH2OH; in particular ethyl, n-propyl or -CH2CH2OH. Rl is most preferably ethyl.
Preferably, R2 is a hydrogen atom (H) or methyl, more preferably a hydrogen atom (H).
Preferably, in R3 there is one substituent or no substituent.
In one optional embodiment, R3 is the optionally substituted C3_gcycloalkyl or the optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc). In this embodiment, optionally, in R3, the C3_gcycloalkyl or the heterocyclic group of sub- formula (aa), (bb) or (cc) is optionally substituted with one or two substituents independently being (e.g. being) oxo (=O), OH, Cχ_2alkoxy, Cχ.2fluoroalkoxy (e.g. trifluoromethoxy), or Cχ_2 alkyl; and wherein any OH, alkoxy or fluoroalkoxy substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc).
In one optional embodiment, where R3 is optionally substituted C3_gcycloalkyl, it is not optionally substituted C5cycloalkyl, i.e. not optionally substituted cyclopentyl. In this case, more preferably, R3 is optionally substituted Cg.gcycloalkyl.
Where R3 is optionally substituted C3_gcycloalkyl, it is more preferably optionally substituted Cgcycloalkyl (i.e. cyclohexyl); for example Cβcycloalkyl optionally substituted with one or two substituents independently being (e.g. being) oxo (=O), OH, Cχ.2alkoxy, Cχ_2fluoroalkoxy (e.g. trifluoromethoxy), or Cχ_2alkyl, and wherein any
OH, alkoxy or fluoroalkoxy substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I).
Where R3 is optionally substituted C3_gcycloalkyl, the one or two optional substituents preferably comprise (e.g. is or independently are (e.g. is or are)) oxo (=O); OH;
Cχalkoxy; C\ fluoroalkoxy (e.g. trifluoromethoxy); NHR21 wherein R21 is a hydrogen atom (H) or Cχ_2 straight-chain alkyl; Cχ_2alkyl such as methyl; C\ fluoroalkyl such as
-CH2F or -CHF2; -CH2OH; -CH2NHR22 wherein R22 is H; -C(O)OR23 wherein R23 is
H or methyl; -C(O)NHR24 wherein R24 is H or methyl; -C(O)R25 wherein R25 is methyl; fluoro; hydroxyimino (=N-OH); or (Cχ_2alkoxy)imino (=N-OR26 where R26 is
Cχ.2alkyl); and wherein any OH, alkoxy, fluoroalkoxy or HR21 substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc). More preferably, where R3 is optionally substituted C3_gcycloalkyl, the one or two optional substituents comprise (e.g. is or independently are (e.g. is or are)) oxo (=O); OH; NHR21 wherein R 1 is a hydrogen atom (H); Cχ_2alkyl such as methyl; Cχfluoroalkyl such as -CH2F or -CHF2; -C(O)OR23 wherein R23 is H or methyl; -C(O)NHR24 wherein R24 is H or methyl; fluoro; hydroxyimino (=N-OH); or (Cχ_2alkoxy)immo (=N-OR26 where R26 is Chalky!).
Still more preferably, where R3 is optionally substituted C3_gcycloalkyl, the one or two optional substituents comprise (e.g. is or independently are (e.g. is or are)) oxo 4=0); OH; NHR21 wherein R2i is a hydrogen atom (H); methyl; -CH2F; -CHF2; -C(O)OR23 wherein R23 is H; fluoro; hydroxyimino (=N-OH); or (Cχ_2alkoxy)imino (=N-OR26 where R26 is Cχ.2alkyl). Yet more preferably, where R3 is optionally substituted C3_gcycloalkyl, the one or two optional substituents comprise (e.g. is or independently are (e.g. is or are)) oxo (=O); OH; methyl; fluoro; hydroxyimino (=N-OH); or (Cχ_2alkoxy)immo (=N-OR26 where R26 is Cχ_2alkyl).
Most preferably, where R3 is optionally substituted C3_gcycloalkyl, the one or two optional substituents comprise (e.g. is or independently are (e.g. is or are)) OH, oxo (=O) or oximo (=N-OH). For example, the one or two optional substituents can comprise (e.g. is or are) OH and/or oxo (=O).
Optionally, in R3, the C3_gcycloalkyl can be unsubstituted.
Where R3 is optionally substituted C3_gcycloalkyl, e.g. optionally substituted
C5_gcycloalkyl such as optionally substituted Cgcycloalkyl (optionally substituted cyclohexyl), the one or two optional substituents if present preferably comprise a substituent (for example is or are substituent(s)) at the 3-, 4- or 5- position(s) of the R3 cycloalkyl ring. (In this connection, the 1 -position of the R3 cycloalkyl ring is deemed to be the connection point to the -NH- in formula (I)).
Where R3 is optionally substituted C3_gcycloalkyl, any OH, alkoxy, fluoroalkoxy, -CH2OH, -CH2CH2OH, -CH2NHR22, -C(O)OR23, -C(O)NHR24, -C(O)R25 or fluoro substituent (particularly any OH substituent) is more preferably at the the 3-, 4- or 5- position, e.g. 3- or 5-position, of the R3 cycloalkyl (e.g. Cg-gcycloalkyl) ring. For example, any OH, alkoxy, fluoroalkoxy, -CH2OH, -CH2CH2OH, -CH2NHR22,
-C(O)OR23, -C(O)NHR24, -C(O)R25 or fluoro substituent (particularly any OH substituent) can be at the 3-position of a R3 Cscycloalkyl (cyclopentyl) ring or at the 3-, 4- or 5- position, e.g. 3- or 5-position, of a R3 Cgcycloalkyl (cyclohexyl) ring. (In this connection, and also below, the 1-position of the R3 cycloalkyl ring is deemed to be the connection point to the -NH- in formula (I)).
Where R3 is optionally substituted C3_gcycloalkyl, any NHR21 substituent is preferably at the 2-, 3-, 4- or 5- position, preferably the 2- or 3-position or more preferably the 3-position, of the R3 cycloalkyl (e.g. Cg.gcycloalkyl e.g. cyclohexyl) ring.
Where R3 is optionally substituted C3_gcycloalkyl, any alkyl or fluoroalkyl substituent is preferably at the 1-, 2-, 3-, 4- or 5- position, more preferably the 1-, 2-, 3- or 5-position, still more preferably the 1- or 3-position, of the R3 cycloalkyl (e.g. Cg.gcycloalkyl e.g. cyclohexyl) ring.
Where R3 is optionally substituted C3_gcycloalkyl, any oxo (=O), hydroxyimino (=N-OH); or (Cχ_4alkoxy)imino (=N-OR26) substituent is preferably at the 3- or
4-position, preferably at the 4-position, of the R3 cycloalkyl (e.g. Cg.gcycloalkyl e.g. cyclohexyl) ring.
Where R3 is optionally substituted C3_gcycloalkyl, R3 is preferably cyclohexyl (i.e. unsubstituted), or cyclohexyl substituted by one oxo (=O), OH, NHR21, Cχ. alkyl,
Cι_2fluoroalkyl, -CH2OH, -C(O)OR23, -C(O)NHR24, -C(O)R25, fluoro, hydroxyimino
(=N-OH), (C _4alkoxy)imino (=N-OR26) substituent, or cyclohexyl substituted by two fluoro substituents. More preferably, R3 is cyclohexyl (i.e. unsubstituted), or cyclohexyl substituted by one oxo (=O), OH, NHR21, Cι_2alkyl, Cι_ fluoroalkyl, -C(O)OR23, fluoro, hydroxyimino (=N-OH) or (Cχ_4alkoxy)imino (=N-OR26) substituent, or cyclohexyl substituted by two fluoro substituents. Still more preferably R3 is cyclohexyl
(i.e. unsubstituted) or cyclohexyl substituted by one oxo (=O), hydroxyimino (=N-OH), Cχ_2alkyl or OH substituent. The optional substituent can be at the 3- or 4- position, e.g.
3-position, of the R3 cyclohexyl ring; more preferably any OH substituent is preferably at the 3-position of the R3 cyclohexyl ring, and/or any oxo (=O), hydroxyimino (=N-OH) or
(Cχ_4alkoxy)imino (=N-OR26) substituent is preferably at the 4-position of the R3 cyclohexyl ring.
Where R3 is optionally substituted Cgcycloalkyl, R3 can for example be 4-hydroxy- cyclohexyl (i.e. 4-hydroxycyclohexan-l-yl), but R3 is more preferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-l-yl), 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan- 1 -yl), 4-(C _2alkoxyimino)cyclohexyl, 1 -methylcyclohexyl or 3-methylcyclohexyl. Where R3 is optionally substituted Cg yclo alkyl, R3 1S most preferably cyclohexyl (i.e. unsubstituted), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-l-yl) or 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-l-yl).
Where R3 is optionally substituted Cscycloalkyl (optionally substituted cyclopentyl), R3 can for example be cyclopentyl (i.e. unsubstituted) or 3-hydroxy-cyclopentyl.
Where R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, preferably it is optionally substituted mono-unsaturated-Cs.gcycloalkenyl, more preferably optionally substituted mono-unsaturated-Cgcycloalkenyl (i.e. optionally substituted mono-unsaturated-cyclohexenyl = optionally substituted cyclohexenyl). Still more preferably, the R3 cyclohexenyl is optionally substituted cyclohex-3-en-l-yl.
Where R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, preferably the R3 cycloalkenyl is optionally substituted with one or two substituents being fluoro or methyl provided that if there are two substituents then they are not both methyl. Preferably, the R3 cycloalkenyl is optionally substituted with one substituent being fluoro or Cχ_2 alkyl (e.g. methyl); more preferably the R3 cycloalkenyl is substituted with one fluoro substituent or is unsubstituted. For R3 cycloalkenyl, the optional substituent(s) can be at the 1-, 2-, 3-, 4- or 5- position(s) of the cycloalkenyl ring.
Where R3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is preferably O, S, SO , NH or N-C(O)methyl, more preferably O, NH or N-C(O)methyl, still more preferably O or N-C(O)methyl, most preferably O. (When Y is NH or N-C(O)methyl, then Rl° is H or C(O)methyl).
Preferably, RlO is a hydrogen atom (H), methyl, ethyl, C(O)NH2, C(O)methyl or
C(O)-CF3. Optionally, RlO can be a hydrogen atom (H), methyl, ethyl, C(O)methyl or C(O)-CF3, more preferably H, C(O)methyl or C(O)-CF3, still more preferably H or C(O)methyl.
Where R3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then it is preferable that R3 is the heterocyclic group of sub-formula (aa) or (bb), more preferably of sub- formula (bb).
hi sub-formula (bb), nl is preferably 1. In sub-formula (cc), n2 is preferably 1. That is, six-membered rings are preferred in the R3 heterocyclic group.
Suitably, in R3, the heterocyclic group of sub-formula (aa), (bb) or (cc) is unsubstituted (h this connection, where Y is NRlO, R!0 is not classified as a substituent). In the R3 heterocyclic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents preferably comprise (e.g. is or independently are ((e.g. is or are)) OH; oxo (=O); Ci _2alkyl (e.g. methyl) or Cχ.2fluoroalkyl (e.g. Cχfluoroalkyl such as -CH2F or -CHF2). More preferably, in the R3 heterocyclic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents comprise (e.g. is or independently are ((e.g. is or are)) OH and/or oxo; most preferably the one or two optional substituents comprise (e.g. is or are) oxo (=O). In the R3 heterocyclic group of sub-formula (aa), (bb) or (cc), any oxo (=O) substituents are preferably on a carbon atom bonded (adjacent) to X, and/or can be at the 2-, 3-, 4- or 5- position(s) of the R3 heterocyclic ring. (In this connection, the 1- position of the R3 heterocyclic ring is deemed to be the connection point to the -NH- in formula (I)). Preferably, only Ci _2alkyl, Cχ_2fluoroalkyl, fluoro or oxo (=O) substitution or no substitution is allowed at each of the 2- and 6-positions of the R3 heterocyclic ring.
When R3 is the heterocyclic group of sub-formula (aa) and Y is NRlO, then preferably
RIO is not C(O)-Me. More preferably, when R3 is the heterocyclic group of sub-formula
(aa) and Y is NRlO, then RlO is preferably not C(O)R, i.e. or e.g. RlO is preferably not C(O)NH2, C(O)-Cι_2alkyl or C(O)-Cιfluoroalkyl. In one embodiment, Y is O, S, SO2 or NH when R3 is the heterocyclic group of sub-formula (aa).
Optionally, according to one embodiment of the invention, NHR3 is not
Figure imgf000023_0001
More preferably, when R3 is the heterocyclic group of sub-formula (bb) and Y is NRlO, and optionally when nl is 1, then preferably RlO is not methyl. More preferably, when
R3 is the heterocyclic group of sub-formula (bb) and Y is NRlO, and optionally when nl is 1, then RlO is preferably not alkyl or substituted alkyl, i.e. or e.g. RlO is preferably not Cχ_4alkyl (e.g. methyl or ethyl), Cχ_2fluoroalkyl or CH2C(O)NH2- In one embodiment, when R3 is the heterocyclic group of sub-formula (bb), Y is preferably O, S, SO2 or
NRl°, wherein RlO is H, C(O)NH2, C(O)-Cι_2alkyl or C(O)-C1fluoroalkyl, or more preferably Y is H or C(O)Me. More preferably, for sub-formula (bb), Y is O or NRlO.
Where R3 is a bicyclic group of sub-formula (dd) or (ee), preferably it is of sub-formula (ee). In sub-formula (ee), preferably γl, Y2 and Y3 are all CH2.
Preferably, NHR3 is of sub-formula (a), (al), (b), (c), (c 1), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (g), (gl), (g2), (g3), (g4), (h), (i), (j), (k), (kl), (L), (m), (ml), (m2),
(m3), (m4), (m5), (n), (o), (ol), (o2), (o3), (o4), (o5), (p), (pi), (p2), (p3), (p4), (p5), (p6), (P7), (p8) or (q):
Figure imgf000024_0001
(a) (aD (b) (c) (d) (c2)
Figure imgf000024_0002
(c3) (c4) (c5) (06) (C7)
Figure imgf000024_0003
(P5) (P6) (P7) (p8) (q) (°)
Figure imgf000024_0004
In the sub-formulae (a) to (q) etc above, the -NH- com ection point of the NHR3 group to the 4-position of the pyrazolopyridine of formula (I) is underlined.
Preferably, NHR3 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), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (o4), (o5), (p), (p2), (p3), (p5), (p6), (p7) or (q). More preferably, NHR3 is of sub- formula (c), (cl), (c 4), (c 5), (h), (i), (j), (k), (ml), (m2), (n), (o), (o2), (o3), (p2), (p5), (p6) or (q). Still more preferably, NHR3 is of sub-formula (c), (h), (k), (n), (o) or (o2); for example (c), (h), (o) or (o2). Most preferably, R3 is tetrahydro-2H-pyran-4-yl; that is NHR3 is most preferably of sub-formula (h), as shown above.
According to one embodiment, NHR3 is of sub-formula (a), (b), (c), (d), (e), (f), (g), (gl), (g2), (g3), (h), (i), (j), (k), (L), (m), (ml), (n), (o), (ol), (p) or (q). In this embodiment, preferably, NHR3 is of sub-formula (c), (d), (e), (f), (gl), (h), (i), (j), (k), (m), (ml), (n), (o), (ol), (p), or (q); and more preferably in this embodiment, NHR3 is of sub-formula (c), (h), (i), (j), (k), (ml), (n), (o) or (q). Still more preferably in this embodiment, NHR3 is of sub-formula (c), (h), (k), (n) or (o). Most preferably, R3 is tetrahydro-2H-pyran-4- yl; that is NHR3 is most preferably of sub-formula (h), as shown above.
According to another embodiment, NHR3 is of sub-formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j) or (k). In this embodiment, preferably, NHR3 is of sub-formula (c), (d), (e), (f), (h), (i), (j) or (k); and more preferably in this embodiment, NHR3 is of sub-formula (c), (h), (i), (j) or (k). Most preferably, R3 is tetrahydro-2H-pyran-4-yl; that is NHR3 is most preferably of sub-formula (h), as shown above.
When NHR3 is of sub-formula (n), then preferably it is a ct5-(3-hydroxycyclohex-l- yl)amino group, eg in any enantiomeric form or mixture of forms but preferably racemic.
Preferably, X is NR4R5.
Where R4 is Cx.galkyl, then preferably it is Cχ_4alkyl or Cχ_2 alkyl. Where R4 is Cχ_3 fluoroalkyl then preferably it is Cχ_2fluoroalkyl.
Most preferably, R4 is a hydrogen atom (H).
Where R4 is C^galkyl substituted by one substituent Rl 1, then preferably R4 is
C2_4alkyl (e.g. Chalky!) substituted by one substituent Rl 4 More preferably, R4 is -(CH2)n 3-Rl 1 wherein n3 is 2, 3 or 4. Still more preferably, n3 is 2 and/or R4 is -(CH2)n 3-OH.
When R^ is C2.galkyl substituted by one or two independent substituents Rl 1, it is preferable that R^ is C2_4alkyl (e.g. C2_3alkyl) substituted by one or two independent substituents Rl 1. When R^ is C2_galkyl (e.g. C2_4alkyl or C _3 alkyl) substituted by one or two independent substituents RU, it is preferable that R^ is C2_6alkyl (e.g. C2_4alkyl or C2_3 alkyl) substituted by one substituent Rl 1. It is more preferable that R^ is -(CH2)n^-Rl 1 wherein n$ is 2, 3 or 4. Preferably n^ is 2 or 3, more preferably 2.
Preferably, each substituent Rl 1, independently of any other Rl 1 substituent present, is: hydroxy (OH); C^.^alkoxy (e.g. Cχ_4alkoxy such as t-butyloxy, ethoxy or methoxy); phenyloxy; benzyloxy; -NR12R13; -NR15-C(O)R16; -NR15-C(0)-NΗ-R15; or -NRl5-SO2Rl6 (more preferably Ci.galkoxy, -NR15-C(0)-NH-R15, or -NRl5-SO2Rl6; most preferably -NR15-SO2R16). In all cases, any Rl 1 substituent which is OH, alkoxy or -N 2R13 is not substituted at any carbon atom, of any R4 or R^ substituted alkyl, which is bonded to the nitrogen of NR4R4
Where R^ is Cχ_galkyl, then preferably it is Cχ_5alkyl or C _3alkyl. Where R^ is Cχ_ gfluoroalkyl then preferably it is C\ .3 fluoroalkyl or Cχ_2fluoroalkyl. Where R^ is C3_gcycloalkyl optionally substituted by a Cχ_2alkyl group, then preferably the
C3_gcycloalkyl is not substituted at the ring-carbon bonded to the nitrogen of NR4R-\
Where R^ is optionally substituted C3_gcycloalkyl, then more preferably it is C3_gcycloalkyl (i.e. unsubstituted).
When R5 is optionally substituted -(CH2)n 4-C3_gcycloalkyl wherein n4 is 1, 2 or 3, then n4 is preferably 1 or 2 or more preferably 1, and/or preferably R^ is optionally substituted -(CH2)n -C5_6cycloalkyl or optionally substituted -(CH2)n 4-C6cycloalkyl. When R^ is optionally substituted -(CH2)n 4-C3_gcycloalkyl, preferably it is not substituted. Most preferably R^ is (cyclohexyl)methyl-, that is -CH2-cyclohexyl.
When Rl9 is Cχ_4alkyl, then preferably it is isobutyl, sec-butyl, or C .3 alkyl such as methyl or isopropyl. When Rl9 is -(CH2)n 0-OR 0, then preferably n2^ is 1 and/or preferably R2^ is a hydrogen atom (H). When R5 is -(CH2)nl l-C(O)Rl6; -(CH2)nl2-C(O)NRl2Rl3; -CHR19-C(0)NR12R13; -(CH2)nl2-C(O)ORl6; -CHR1 -C(0)0R16; -(CH2)nl2-SO2-NRl2Rl3; -(CH2)nl2-SO Rl6; or -(CH2)nl -CN; then in one embodiment of the invention R5 can be: -(CH2)nl l-C(O)Rl6; -(CH2)nl2-C(O)NRl2Rl3; -(CH2)nl2-C(O)ORl6; -(CH2)nl2-SO2-NRl2Rl3; -(CH2)nl2-SO2Rl6; or -(CH2)nl2-CN.
When R5 is -(CH2)nll-C(O)Rl6; -(CH2)nl2-C(O)NRl2Rl3; -(CH2)nl2-C(O)ORl6; -(CH )nl2-SO2-NRl2Rl3; -(CH2)nl2-SO2Rl6; or -(CH2)nl2-CN; then R5 can for example be -(CΗ.2)nU-C(0)R16; -(CH2)nl2-C(O)NRl2Rl3; or -(CH2)nl2-CN; preferably -(CH2)nl 1 -C(O)Rl 6.
Preferably, nl 1 is 1, 2, 3 or 4; more preferably nl 1 is 1 or 2. Advantageously, nl2 is 1 or 2.
When R^ is -(CH2)nl3-Het, it is preferable that nl3 is 0, 1 or 2, more preferably 0 or 1.
Preferably, Het is a 5- or 6-membered saturated or partly-saturated heterocyclic ring and/or preferably is a 4-, 5-, 6- or 7-membered saturated heterocyclic ring. Preferably, the heterocyclic ring Het contains one ring-hetero-atom selected from O, S and N. Preferably, the carbon ring-atoms in Het are not substituted. Het is most preferably one
Figure imgf000027_0001
When R5 is optionally substituted phenyl, then preferably it is phenyl optionally substituted with one or two of the substituents defined herein.
When R5 is optionally substituted phenyl, then preferably R^ is phenyl optionally substituted with, independently, one, two or three (preferably one or two; or one) of: a halogen atom (preferably fluoro and/or chloro); Cχ_2alkyl; Cχ_2fluoroalkyl (e.g. trifluoromethyl); Cχ_2alkoxy (e.g. methoxy); trifluoromethoxy; Cχ_2alkylsulphonyl
(Cχ.2alkyl-SO2-); Cι_2alkyl-SO -NH-; R7R8N-SO2-; R7R8N-CO-; -NR15-C(O)R16;
R7R8N; OH; Cι_2alkoxymethyl; Cι_2alkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one of fluoro, C _2alkyl, Cj fluoroalkyl, Cχ_2alkoxy or
Ci fluoroalkoxy. More preferably R^ is phenyl optionally substituted with one or two (preferably one) of: a halogen atom, Cχ_2alkyl, trifluoromethyl, Cχ_2 alkoxy, trifluoromethoxy, R7R8N-SO2-, R7R8N-CO-, or Cι_2alkyl-SO2-CH2-. When R5 is optionally substituted phenyl, then preferably one or all of the one or two optional substituents are substituted at the meta- (3- and/or 5-) and/or para- (4-) position(s) of the phenyl ring with respect to the phenyl ring-carbon bonded to the nitrogen of NR4R^.
Preferably, R7 and/or R8 are independently a hydrogen atom (H); Cχ_2alkyl such as methyl; C3_gcycloalkyl; or phenyl optionally substituted by one of: fluoro, chloro,
Cχ_2 alkyl, C\ fluoroalkyl, Cχ_2alkoxy or C\ fluoroalkoxy; or R7 and R8 together are
-(CH2)n 6- or -(CH2)n 8-X7-(CH2)n 9- wherein X7 is R.I4 or preferably O.
When R7 is cycloalkyl or optionally substituted phenyl, then preferably R8 is neither cycloalkyl nor optionally substituted phenyl.
Most preferably, R7 and/or R8 independently are a hydrogen atom (H) or C _2 alkyl. It is preferable that R7 is a hydrogen atom (H).
Preferably n6 is 4 or 5. Preferably n7 is 2, 3 or 4. Preferably, n8, n9 and/or nlO is/are independently 2.
In general, it is preferable that R^ has the sub-formula (x) or (y) or (yl) or (z).
When R5 has the sub-formula (x) or (y) or (yl) or (z), then preferably R^ has the sub- formula (x) or (y) or (yl) or has the sub-formula (x) or (y) or (z). More preferably R^ has the sub-formula (x) or (y), most preferably (x). In one embodiment, R^ has the sub- formula (z).
Preferably, n is 1 or 2. More preferably, n = 1. Preferably, m = 1. Preferably, r = 1 or 2, more preferably 1.
In sub-formula (x), (y) and/or (yl), it is preferred that none, one or two of A, B, D, E and F are nitrogen; none, one, two or three of A, B, D, E and F are CR6; and the remaining of A, B, D, E and F are CH. More preferably, none, one or two of A, B, D, E and F are nitrogen; none, one or two of A, B, D, E and F are CR6; and the remaining of A, B, D, E and F are CH.
n sub-formula (x), (y) and/or (yl), preferably, none or one of A, B, D, E and F are nitrogen, and/or preferably none, one or two of A, B, D, E and F are CR6. Preferably, sub-formula (x) is: benzyl; phenethyl (Ph-C2H4-); benzyl substituted on the phenyl ring with one or two R6 substituents; phenethyl (Ph-C2H4-) substituted on the phenyl ring with one or two R6 substituents; or one of the following:
Figure imgf000029_0001
Figure imgf000029_0002
wherein R6a is either R6 as defined herein or (preferably) hydrogen.
Most preferably, sub-formula (x) is benzyl or pyridinylmethyl
[e.g. pyridin-4-ylmethyl (i.e.
Figure imgf000029_0003
or preferably
pyridin-2-ylmethyl (i.e. )]•
Preferably, sub-formula (y) is:
Figure imgf000029_0004
or
Figure imgf000029_0005
, wherein Roa is or independently are either R° as defined herein or preferably hydrogen. Preferably, sub-formula (y) is not substituted by oxo (=O) at the carbon between the 6-membered aromatic ring and the carbon bonded to the nitrogen of NR4R5. Preferably, sub-formula (yl) is:
Figure imgf000030_0001
Figure imgf000030_0002
, wherein R6a is or independently are either R6 as defined herein or preferably hydrogen.
Preferably, in sub-formula (z), none, one or two of J, L, M and Q are nitrogen.
In sub-formula (x), (y) and/or (z), preferably, each R6, independently of any other R6 present, is a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, C4alkyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, C\ fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy), OH, Cχ_3alkylS(O)2- (such as methylsulphonyl which is MeS(O)2-), Cι_3alkylS(O)2-NH- such as methyl-SO -NH-, Me2N-S(O)2-, H2N-S(O)2-, -CONH2, -CONHMe, -CO2H, cyano (CN), NMe2, t-butoxymethyl, or
Cι_3alkylS(O)2-CH2- such as methyl-SO2-CH2-. More preferably, each R6, independently of any other R6 present, is a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, isobutyl, trifluoromethyl, -CH2OH, methoxy, ethoxy,
Ci fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy), Cχ_3alkylS(O)2- such as methylsulphonyl, Cι_3alkylS(O)2-NH- such as methyl-SO2-NH-, Me2N-S(O)2-,
H2N-S(O)2-, -CONH2, or Cι_3alkylS(O)2-CH2- such as methyl-SO2-CH2. Still more preferably, each R6, independently of any other R6 present, is a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH2OH, methoxy, difluoromethoxy, methylsulphonyl, methyl-SO2-NH- or methyl-SO2-CH2-.
The above preferred R6 substituents are also, independently, the preferred phenyl optional and independent substituents for where R$ is optionally substituted phenyl.
In sub-fonnula (x) and/or (y), preferably, one, two or three R6 substituents are present in B, D and/or E; so that for example in sub-formula (x), one, two or three R6 substituents are present in the meta- (3- and/or 5-) and/or para- (4-) positions with respect to the - (CH2)n- side-chain.
Preferably, R^ has the sub-formula (x), n is 1 and none of A, B, D, E and F are nitrogen or nitrogen-oxide (N^-O"); and all of A, B, D, E and F are independently CH or CR6; that is R5 has the sub-formula (x) and is optionally substituted benzyl. In this embodiment, preferably, a R6 substituent is present at the 4-position with respect to the -(CH2)n- side- chain (that is D is CR6: i.e. a R6 substituent is present in D); and/or preferably a R6 substituent is present at the 3- and/or 5- position with respect to the -(CH2)n~ side-chain (that is B and/or E is CR6: i.e. one or two R6 substituents are present in B and/or E).
For monosubstitution, i.e. where one of A, B, D, E and F is CR6, then the one R6 substituent is preferably present at the 4-position with respect to the -(CH2)n- side-chain
(i.e. D is CR6). Where there is disubstitution, that is where two of A, B, D, E and F are independently CR6, then 3,4-disubstitution (B+D or D+E are independently CR6), 2,4- disubstitution (A+D or D+F are independently CR6) or 2,3-disubstitution (A+B or E+F are independently CR6) is preferred.
n sub-fonnula (x) and/or (y), any optional R6 substituent can optionally be present only in B, D and/or E, so that in sub-formula (x) any optional R6 substituent is present only in the meta- (3- and/or 5-) and/or para- (4-) positions with respect to the -(CH )n- side- chain. Alternatively, in sub-formula (x), any optional R6 substituent can be present in the ortho- (2- and/or 6-) position with respect to the -(CH )n- side-chain, either alone or in combination with one or more other optional R6 substituents.
Overall for R^, it is preferable that R^ is a hydrogen atom (H); Cι_galkyl (e.g.
Ci 2or3alky or C3_6 lkyl); C gfluoroalkyl, C3_6cycloalkyl (e.g. C5_6cycloalkyl), (C5 _ cycloalkyl)methyl-, phenyl optionally substituted with one or two of: a fluorine or chlorine atom, methyl, trifluoromethyl, methoxy or trifluoromethoxy; or R^ has the sub- formula (x), (y) or (z), for example as described above.
Still more preferably, R^ is a hydrogen atom (H), methyl, ethyl, n-propyl, iso-propyl, 2-ethylbutan-l-yl, cyclopentyl, cyclohexyl, (cyclohexyl)methyl-, optionally substituted phenyl e.g. fluorophenyl e.g. 4-fluorophenyl, optionally substituted benzyl, or optionally substituted pyridinylmethyl, or R^ has the sub-formula (z).
Optionally, R^ can be benzyl, pyridinylmethyl (e.g. pyridin-4-ylmethyl, pyridin-3- ylmethyl, or preferably pyridin-2-ylmethyl), or 4-fluorophenyl.
In one preferable embodiment, R^ has the sub-formula (x) and is: benzyl, (monoalkyl- phenyl)methyl, [mono(fluoroaιkyl)-phenyl]methyl, (monohalo-phenyl)methyl, (monoalkoxy-phenyl)methyl, [mono(fluoroalkoxy)-phenyl]methyl, [mono(N,N- dimethylamino)-phenyljmethyl, [mono(methyl-SO2-NH-)-phenyl]methyl,
[mono(methyl-SO2-)-phenyl]methyl, (dialkyl-phenyl)methyl, (monoalkyl-monohalo- phenyl)methyl, [mono(fluoroaιkyl)-monohalo-phenyl]methyl, (dihalo-phenyl)methyl, (dihalo-monoalkyl-phenyl)methyl, [dihalo-mono(hydroxymethyl)-phenyl]methyl, or (dialkoxy-phenyl)methyl such as (3,4-dimethoxy-phenyl)methyl. The substituents can preferably be further defined, as defined in preferable embodiments herein.
In one preferable embodiment, R^ is of sub-formula (x) and is: (monoalkyl- phenyl)methyl, [mono(fluoroalkyl)-phenyl]methyl, (monohalo-phenyl)methyl, (monoalkoxy-phenyl)methyl, [mono(fluoroalkoxy)-phenyl]methyl, [mono(N,N- dimethylamino)-phenyl]methyl, (dialkyl-phenyl)methyl, (monoalkyl-monohalo- phenyl)methyl, (dihalo-phenyl)methyl or (dihalo-monoalkyl-phenyl)methyl or [dihalo- mono(hydroxymethyl)-phenyl]methyl. More preferably, in this embodiment, R^ is: - (monoCι_3alkyl-phenyl)methyl such as (4-Cι_3alkyl-phenyl)methyl;
- (monoCιfluoroalkyl-phenyl)methyl such as (4-Cιfluoroalkyl-phenyl)methyl;
- (monoCι_2alkoxy-phenyl)methyl such as (4-Cι_2alkoxy-phenyl)methyl;
- [mono(C fluoroalkoxy)-phenyl]methyl such as (4-Cιfluoroalkoxy-phenyl)methyl;
- (diCχ_2alkyl-phenyl)methyl or (dimethyl-phenyl)methyl such as (3,4-dimethyl- phenyl)methyl, (2,4-dimethyl-phenyl)methyl, (3,5-dimethyl-phenyl)methyl, (2,3- dimethyl-phenyl)methyl or (2,5-dimethyl-phenyl)methyl; more preferably (3,4-dimethyl- phenyl)methyl or (2,4-dimethyl-phenyl)methyl;
- (monoCι_2alkyl-monohalo-phenyl)methyl or (monoCι_2 alkyl -monochloro- phenyl)methyl such as (4-methyl-3-chloro-phenyl)methyl, (3-methyl-4-chloro-phenyl)methyl, (2-methyl-4-chloro-phenyl)methyl;
- (dihalo-phenyl)methyl such as (2-chloro-4-fluorophenyl)methyl or (2,4-difluoro- phenyl)methyl or (4-bromo-2-fluorophenyl)methyl or preferably (4-chloro- 2-fluorophenyl)methyl; for example (dichloro-phenyl)methyl such as (3,4-dichloro- phenyl)methyl or (2,4-dichloro-phenyl)methyl or (2,6-dichloro-phenyl)methyl or preferably (2,3-dichloro-phenyl)methyl;
- (dihalo-monoC _2alkyl-phenyl)methyl e.g. (2,4-dichloro-6-methyl-phenyl)methyl; or
- [dihalo-mono(hydroxymethyl)-phenyl]methyl such as [2,3-dichloro-6-(hydroxymethyl)- phenyl]methyl.
In an alternative preferable embodiment, R^ has the sub-formula (z), and one or preferably none of J, L, M or Q is CR6, and/or R9 is a hydrogen atom (H) or methyl.
Preferably r is 1. Preferably, for (z), R6 is independently OH (including any keto tautomer thereof), or more preferably Cι_2alkyl (e.g. methyl) or Cifluoroalkyl.
Preferably NR R^ is not NH2. R^ is preferably not a hydrogen atom (H).
When R4 and R^ taken together are optionally substituted -(CH2)pl- or optionally substituted -C(O)-(CH2)p 2- or -(CH2)p 3-X5-(CH2)p 4- or -C(O)-X5-(CH2)p 5- or a partially unsaturated derivative of any of the foregoing, preferably R4 and R^ taken together are optionally substituted -(CH2)pl- or optionally substituted -C(O)-(CH2)p2- or -(CH2)p3-X5-(CH2)p 4- or -C(O)-X5-(CH2)p 5- (i.e. not a partially unsaturated derivative of any of these).
When R4 and R$ taken together are -(CH )pl- optionally substituted by Rl8, or -C(O)-(CH2)p 2- optionally substituted by Ri8, or -(CH2)p 3-χ5-(CH )p 4-, NR4R5 can
for example be ^ — ' optionally substituted by Rl , or ^^ optionally
: — N NR' substituted by Rl8, or ' optionally substituted by Rl8, or ^ — (i.e. R4 j — N O and R5 taken together are -(CH2)2-N(Rl 7)-(CH2)2-), or ^ — ^ (i.e. R4 and R5 taken together are -(CH2)2-O-(CH2)2-).
Preferably, Rl is a hydrogen atom (H); Cι_4alkyl (e.g. Cι_2alkyl); C3_6cycloalkyl; -(CH2)p -C(O)Rl6, or the optionally substituted phenyl or benzyl. More preferably, Rl7 is H; Cι_2alkyl; -(CH2)p6-C(O)Rl6 or the optionally substituted phenyl.
When R4 and R5 taken together are -(CH2)p 1- or -C(O)-(CH2)p 2-, the NR4R5 heterocycle is preferably not substituted by Rl8.
When R4 and R5 taken together are -(CH2)pl- or -C(O)-(CH2)p 2-, and if the NR4R5 heterocycle is substituted by Rl8, then optionally Rl8 is not substituted at a ring-carbon bonded to the R4R5 ring-nitrogen.
When R4 and R5 taken together are -(CH2)pl- or -C(O)-(CH2)p 2- or
-(CH2)p3-X5-(CH2)p 4- or -C(O)-X5-(CH )p5- or a partially unsaturated derivative of any of these, and wherein the NR4R5 heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, Cι_2 alkyl, Ci fluoroalkyl,
Cι_2alkoxy or Ci fluoro alkoxy; then in one embodiment of the invention NR4R^ is
Figure imgf000033_0001
wherein the phenyl is optionally substituted by one or two of: a halogen atom, Cι_2 alkyl, Ci fluoroalkyl, Cι_2alkoxy or Ci fluoroalkoxy.
In one embodiment of the invention, NR7R8 and/or N 12R1 can for example
Figure imgf000033_0002
(i.e. Rl2 and Rl3 together or R7 and R8 together are -(CH2)2-N(R14)-(CH2)2-), or j — N O
^ — / (i.e. Rl2 and Rl3 together or R7 and R8 together are -(CH2)2-O-(CH2)2-)> or NMe2-
Preferably, R!5 is a hydrogen atom (H) or Cχ_4alkyl (e.g. *Bu or Cι_2alkyl e.g. methyl); more preferably, Rl^ is a hydrogen atom (H).
Preferably, however, R4 and R$ are not taken together , i.e. are not taken together to form the NR4R5 ring systems described herein.
(Similar preferances apply for R^a as for R$, except that R^a cannot be a hydrogen atom. Most preferably, R^a is ethyl.)
hi an especially preferable embodiment, NR4R^ is the N 4R^ group as defined in any one of: Examples 21-98, 100-182, 187-188, 191-200, 201-203, 210-353, 355-651, 653-658, 660-664 and 665-686.
It is particularly preferred that the compound of formula (I) or the salt thereof is:
Ethyl 4-(cyclopentylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate, Ethyl 4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate, Ethyl l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylate, Ethyl 4-[( 1 -acetylpiperidin-4-yl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate, Ethyl 4-(cyclopentylamino)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate (not this compound per se, and for the use or method of treatment preferably not this compound),
Ethyl 1 -methyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate, Ethyl l-ethyl-4-[(3S)-te1xahydroιuran-3-ylamino]-lH-pyrazolo[3,4-b]pyridine-5-carboxylate, Ethyl l-ethyl-4-[(3R)-te1xahydrofuran-3-ylamino]-lH-pyrazolo[3,4-b]p3τidine-5-carboxylate, Ethyl 1 -ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate, Ethyl 1 -ethyl-4-(tetrahydrothien-3 -ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5-carboxylate, Ethyl 4-(cyclopropylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate, Ethyl 4-[( 1 , 1 -dioxidotetrahydrothien-3 -yl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxylate, Ethyl 4-[( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxylate,
N-Benzyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, N-Cyclopentyl-4-(cyclopentylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, 4-(Cyclohexylamino)-N-cyclopentyl-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, N-Cyclopentyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]p)τidine-5- carboxamide,
4-[( 1 -Acetylpiperidin-4-yl)amino] -N-cyclopentyl- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-Cyclopentyl- 1 -ethyl-5 -(pyrrolidin- 1 -ylcarbonyl)- lH-pyrazolo [3 ,4-b]pyridin-4-amine, N-Cyclohexyl- 1 -ethyl-5 -(pyrrolidin- 1 -ylcarbonyl)- 1 H-pyrazolo [3 ,4-b]pyridin-4-amine, l-Ethyl-5-(pyrrolidin-l-ylcarbonyl)-N-tetτahydro-2H-pyran-4-yl-lH-pyrazolo[3,4-b]pyridin-4- amine, 4-(Cyclopentylamino)-l-ethyl-N-(pyridin-4-ylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-(pyridin-4-ylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, 1 -Ethyl-N-(pyridin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine- 5 -carboxamide,
4-(Cyclopentylamino)- 1 -ethyl- 1 H-pyrazolo[3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5-carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Benzyl-4-(cyclopentylaιmno)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, N-Benzyl-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-[(l-Acetylpiperidin-4-yl)amino]-N-benzyl-l-ethyl-lH-p3τazolo[3,4-b]pyridine-5-carboxamide, 4-(Cyclopentylamino)-l-ethyl-N-(2-ethylbutyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, 4-(Cyclohexylamino)-l-ethyl-N-(2-ethylbutyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(2-ethylbutyl)-4-(tetrahydro-2H-p3τan-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-N-(2-ethylbutyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-[( 1 -Acety lpiperidin-4-yl)amino] - 1 -ethyl-N-(2-ethylbutyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, 4-(Cyclopentylamino)- 1 -ethyl-N-(4-fluorophenyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, 4-(Cyclohexylamino)-l-ethyl-N-(4-fluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, 1 -Ethyl-N-(4-fluorophenyl)-4-[( 1 -methylpiperidin-4-yl)amino] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, 4-[( 1 -Acetylpiperidin-4-yl)amino] - 1 -ethyl-N-(4-fluorophenyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclopentylamino)- 1 -ethyl-N-n-propyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, 4-(Cyclohexylamino)- 1 -ethyl-N-n-propyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, 1 -Ethyl-N-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide, 4-[( 1 -Acetylpiperidin-4-yl)amino] - 1 -ethyl-N-n-propyl- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide, 4-[(l-Acetylpiperidin-4-yl)amino]-l-ethyl-N-(pyridin-4-ylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-4-(cyclopentylamino)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-Benzyl-4-(cyclohexylamino)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, N-Benzyl- 1 -methyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclopentylamino)-N-(2-ethylbutyl)- 1 -methyl- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N-(2-ethylbutyl)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2-Ethylbutyl)- 1 -memyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclopentylamino)-N-(4-fluorophenyl)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cyclohexylamino)-N-(4-fluorophenyl)-l-methyl-lH-pjτazolo[3,4-b]pyridine-5-carboxamide,
N-(4-Fluorophenyl)- 1 -methyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, 4-(Cyclopentylamino)-l -methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cyclohexylamino)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetylpiperidin-4-yl)amino] -N-benzyl- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
1 -Ethyl-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, l-Ethyl-N,N-dimethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-N-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl- 1 -ethyl-4-[(3 S)-tetrahydrofuran-3 -ylamino] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-Benzyl-l-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, N-Benzyl-l-ethyl-4-(tetrahydrothien-3-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-Benzyl-4-(cyclopropylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Benzyl-4-[( 1 , 1 -dioxidotetrahydrothien-3 -yl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridme-5- carboxamide,
N-Benzyl-4- [(1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino] - 1 -ethyl- 1 H-pyrazolo[3 ,4- b]pyridine-5 -carboxamide,
N-Benzyl-l-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
1 -Ethyl-N-(4-fluorophenyl)-4-[(3 S)-tetrahydrofuran-3 -ylamino] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, 1 -Ethyl-N-(4-fluorophenyl)-4-[(3R)-tetrahydrofuran-3 -ylamino] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, l-Ethyl-N-(4-fluorophenyl)-4-(terrahydro-2H-thiopyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5 -carboxamide, l-Ethyl-N-(4-fluorophenyl)-4-(tetrahydrothien-3-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclopropylamino)- 1 -ethyl-N-(4-fluorophenyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5-carboxamide,
4-[( 1 , 1 -Dioxidotetrahydrothien-3 -yl)amino]- 1 -ethyl-N-(4-fluorophenyl)- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide, or
4-[( 1 , 1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino] - 1 -ethyl-N-(4-fluorophenyl)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide;
or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.
The structures of these specific compounds are given in Examples 1-98 hereinafter.
Alternatively, it is particularly preferred that the compound of formula (I) or the salt thereof is:
l-Ethyl-N-[4-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[3-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-5- {[5-methoxy-6-(trifluoromethyl)-2,3-dihydro- lH-indol- 1 -yljcarbonyl} -N- tetrahydro-2H-pyran-4-yl-lH-pyrazolo[3,4-b]pyridin-4-amine, N-[(5-Chloropyridin-2-yl)methyl]- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-bjpyridine-5-carboxamide,
N-(4-Chlorobenzyl)- 1 -ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(3-Chlorobenzyl)-l-ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2-tert-Butoxyethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-4-(tetrahydro-2H-ρyran-4-ylamino)-N-(l,3-thiazol-2-ylmethyl)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-N-(pyrimidin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-N-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[3-(tert-Butoxymethyl)benzyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, 1 -Ethyl-N- {2-[methyl(methylsulfonyl)amino]ethyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-ρyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(pyrazin-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, 1 -Ethyl-5- {[4-(pyridin-2-ylcarbonyl)piperazin- 1 -yljcarbonyl} -N-tetrahydro-2H-ρyran-4- yl-lH-pyrazolo[3,4-bjpyridin-4-amine,
N-(2-Chloro-6-fluorobenzyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[(6-oxo-l,6-dihydropyridin-3-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-bjpyridine-5-carboxamide,
N-[3-(Aminocarbonyl)benzyl]- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- {4-[(methylamino)carbonyl]phenyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3, 4-b]pyridine-5 -carboxamide, 1 -Ethyl-N-[2-(l -methyl- lH-imidazol-4-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N- {2-[(Anilinocarbonyl)amino]ethyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(lH-tetraazol-5-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[2-( IH- 1 ,2,4-triazol- 1 -yl)ethyl j- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)phenyl]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, tert-Butyl 4-({[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridin-5- yl]carbonyl}amino)piperidine-l-carboxylate, l-Ethyl-N-{3-[(methylsulfonyl)amino]propyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[2-(Dimethylamino)benzyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(l-ethylpyrrolidin-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(tetiahydrofuran-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-ethyl-N-tetrahydro-2H-pyran-4-yl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N- {4-[(Dimethylamino)sulfonyljbenzyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{3-[(methylsulfonyl)amino]benzyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b jpyridine-5 -carboxamide, l-Ethyl-N-(4-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-N-[3-(2-oxopyrrolidin-l-yl)propyl]-4-(tetiahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[2-(l -methylpyrrolidin-2-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N- yridin-3-ylrnethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- bjpyridine-5-carboxamide,
1 -Ethyl-N-( 1 -methylpiperidin-4-yl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3 ,4- b]pyridine-5-carboxamide, l-Ethyl-N-(l-ethylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-N-(2-piperidin- 1 -ylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3 ,4- b]pyridine-5-carboxamide,
1 -Ethyl-N-(3 -morpholin-4-ylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, N-(3 -Ethoxypropyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3 ,4- b]pyridine-5-carboxamide,
N-(Cyclohexylmethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-[3-(Dimethylamino)propyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-bjpyridine-5-carboxamide, l-Ethyl-N-neopentyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-ethyl-N-(4-methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-N-{2-[(phenylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[2-(Acetylamino)ethyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- b]pyridine-5-carboxamide, l-Ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{2-[(2-methoxyphenyl)(methyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-(2-oxo-2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 Η-pyrazolo[3 ,4- b]pyridine-5-carboxamide, N-(2,5-Difluorobenzyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)benzyl]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N, 1 -Diethyl-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5- carboxamide,
N-Cyclopropyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5 -carboxamide, N-(2-amino-2-oxoethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-N-(3-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, N-(3 ,4-Difluorobenzyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3,4- b]pyridine-5-carboxamide,
Ethyl 3-({[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridin-5- yljcarbonyl} amino)propanoate,
N-(l-Benzylpiperidin-4-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-Butyl-4- { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b jpyridin-5- yl]carbonyl}piperazine-l-carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-( 1 ,3 ,4-thiadiazol-2-yl)- lH-pyrazolo[3 ,4- b]pyridine-5-carboxamide, N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3, 4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- [2-(2-oxoimidazolidin- 1 -yl)ethyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-bjpyridine-5-carboxamide,
N-(3 ,4-Dimethoxybenzyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3 ,4- bjpyridine-5-carboxamide,
N-(3-Chlorobenzyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-5-[(4-methylpiperazin- 1 -yl)carbonyl]-N-tetrahydro-2H-pyran-4-yl- 1H- pyrazolo [3 ,4-b]pyridin-4-amine, 1 -Ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- b]pyridine-5-carboxamide, l-Ethyl-5-{[4-(4-methoxyphenyl)piperazin-l-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl- lH-pyrazolo [3 ,4-b jpyridin-4-amine, l-Ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-bjpyridine-5-carboxamide,
Ν-[3-(dimethylamino)-3-oxopropyl]-l-ethyl-4-(tetrahydro-2Η-pyran-4-ylamino)-lΗ- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(l-methyl-lH-imidazol-5-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{4-[(methylamino)sulfonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2-Cyanoethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- bjpyridine-5-carboxamide, l-Ethyl-N-[(l-methyl-lH-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-methyl-N-[(l -methyl- lH-imidazol-2-yl)methyl]-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-(tetiahydro-2H-pyran-4-ylamino)-N-(2-thien-2-ylethyl)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-[2-(4-Chlorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-bjpyridine-5-carboxamide, l-Ethyl-N-[2-(2-methoxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
Ethyl 4-(cyclohexylamino)-l-(3-ethoxy-3-oxopropyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxylate,
Ethyl l-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxylate,
Ethyl 1 -(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- bjpyridine-5-carboxylate,
Ν-[4-(Methylsulfonyl)benzyl]-l-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, N-(4-Fluorophenyl)- 1 -n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3 ,4- b]pyridine-5-carboxamide,
Ethyl l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5 -carboxylate,
Ethyl 4-(cyclohexylamino)-l-ethyl-6-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate, 4-(Cyclohexylamino)- 1 -ethyl-6-methyl-N- [4-(methylsulfonyl)benzyl] - lH-pyrazolo[3 ,4- bjpyridine-5-carboxamide,
N-Benzyl-4-(cyclohexylamino)-l-ethyl-6-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-(4-fluorophenyl)-6-methyl-lH-pyrazolo[3,4-b]pyridine- 5-carboxamide,
4-(Cyclohexylamino)-l-ethyl-6-methyl-N-[4-(trifluoromethyl)benzylj-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
4-(Cyclohexylamino)-N-(2,3 -dihydro- lH-inden-2-yl)- 1 -ethyl-6-methyl- lH-pyrazolo[3 ,4- b]pyridine-5-carboxamide, N-Benzyl-l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- bjpyridine-5-carboxamide,
N-Benzyl-l-ethyl-4-[(2-oxoazepan-3-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-l-ethyl-4-[(3-hydroxycyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-l-ethyl-4-[(4-hydroxycyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-l-ethyl-4-[(3-hydroxycyclopentyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, or N-B enzyl- 1 -ethyl-4- [(4-oxocyclohexyl) amino] - lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide;
or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. The structures of these specific compounds are given in Examples 100-201 hereinafter.
Alternatively, the compound of formula (I) or the salt thereof can be: l-Ethyl-N-(2-hydroxy-l-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, or
Methyl (2S)-2-({[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridin- 5-yl]carbonyl } amino)-3-hydroxypropanoate; or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. (See for example Examples 202-203).
Alternatively, it is particularly preferred that the compound of formula (I) or the salt thereof is one of Examples 204 to 664 or one of Examples 665 to 686, as a compound or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. The structures of these specific compounds are given in Examples 204 to 664 and Examples 665 to 686 hereinafter, and their names are given in the Examples section.
In one embodiment, is still further preferred that the compound of formula (I) or the salt thereof is a compound of Example 260, 261, 263, 266, 431, 493, 494, 518, 528, 584, 626, 643, 653, 679, 680, 681, 682, 683, 684, 685 or 686 (more preferably Example 260, 518, 653, 679, 680, 681 or 684), as defined by the structures and/or names described herein, or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. The structures and names of these Examples are described in the Examples section. These Examples are thought to be suitable for inhaled administration.
In another embodiment, is still further preferred that the compound of formula (I) or the salt thereof is a compound of Example 21, 22, 83, 100, 109, 167, 172, 178 or 600, as defined by the structures and/or names described herein, or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. The structures and names of these Examples are described in the Examples section. These Examples are thought to be suitable for oral administration.
A second aspect of the present invention provides a compound of formula (IA) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
Figure imgf000042_0001
wherein:
X is NR4R5 or OR5a, in which:
R4 is hydrogen, C _2 alkyl or Cι_2fluoroalkyl, and
R5 is hydrogen, Ci.galkyl, Cι_g fluoroalkyl, or C3_gcycloalkyl, phenyl optionally substituted with one or two of: a halogen atom, Cι_2alkyl, trifluoromethyl, Cι_2alkoxy or trifluoromethoxy; or R^ has the sub-formula (x), (y) or (z):
Figure imgf000043_0001
(x) (y) (z)
wherein in sub-formula (x) and (z), n = 1 or 2; and in sub-formula (y), m = 1 or 2; wherein in sub-formula (x) and (y), none, one or two of A, B, D, E and F are nitrogen; and the remaining of A, B, D, E and F are CH or CR6 where R6 is a halogen atom, Cι_4alkyl, C gfluoroalkyl, Cι_2 alkoxy, Cι_2fluoroalkoxy, Cι_2alkylsulphonyl
(Cι_2alkyl-SO -), Cι_2alkyl-SO2-NH-, R7R8N-SO2-, R7R8N-CO-, R7R8N, OH,
Cι_4alkoxymethyl, or Cι_2alkyl-SO2-CH2-, wherein R7 and R8 are independently hydrogen or Cι_2alkyl; wherein in sub-formula (z), G is O or S or NR9 wherein R9 is Cι_4alkyl or
Cι_4fIuoroalkyl; none, one or two of J, L, M and Q are nitrogen; and the remaining of J,
L, M and Q are CH or CR6 where R6 is as defined herein;
or R4 and R^ taken together are -(CH2)p- where p = 3, 4 or 5 (preferably p = 4);
R^ is Ci.galkyl; Cι_g fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, Cι_2alkyl, trifluoromethyl, Cι_2alkoxy or trifluoromethoxy; or R^a has the sub-formula (x), (y) or (z) as defined herein;
Figure imgf000043_0002
R3 is C3_gcycloalkyl or a heterocyclic group being " in which Y is O, S, SO2, or NR.10; where R O is hydrogen, C^alkyl, Cι_2fluoroalkyl, C(O)-Cι_2alkyl, or C(O)-CF3; and wherein in R3 the C3_gcycloalkyl or heterocyclic group is optionally substituted with one or two substituents being OH, Cι_2alkoxy, trimethoxy, or Cι_2alkyl group; and wherein any OH, alkoxy or trimethoxy substituent is not substituted at the ring carbon attached to the -NH- group of formula (IA) and is not substituted at either ring carbon bonded to the Y group of the heterocyclic group; and
Rl = Cι_4alkyl or Cι_2fluoroalkyl.
Figure imgf000044_0001
In formula (IA), preferably, when R3 is the heterocyclic group being ' and Y is Rl°, then: either (a) RlO is hydrogen, C(O)-Cι_2alkyl, or C(O)-CF3; or (b) RlO is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide or l-ethyl-N-(4- fluorophenyl)-4-[(l-methylpiperidin-4-yl)aιnino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide.
In formula (LA), preferably, where X is OR^a, the compound is other than the compound wherein Rl is methyl, X is OEt, and R3 is cyclopentyl.
In formula (LA), in sub-formula (x) and/or (y), it is preferred that none, one or two of A, B, D, E and F are nitrogen; none, one, two or three of A, B, D, E and F are CR6; and the remaining of A, B, D, E and F are CH. More preferably, none, one or two of A, B, D, E and F are nitrogen; none or one or two of A, B, D, E and F are CR6; and the remaining of A, B, D, E and F are CH. In formula (LA), in sub-formula (x) and/or (y), preferably, none or one of A, B, D, E and F are nitrogen.
Ln formula (IA), preferably, sub-formula (x) is: benzyl; phenethyl (Ph-C2H4-); benzyl or phenethyl being substituted on the phenyl ring with a single R6 substituent, or one of the following:
Figure imgf000045_0001
Figure imgf000045_0002
, wherein R6a is either R6 as defined herein or (preferably) hydrogen.
In formula (LA), preferably, sub-formula (y) is:
Figure imgf000045_0003
wherein R6a is either R6 as defined herein or preferably hydrogen.
Examples 1-99 are examples of compounds or salts of the second aspect of the invention (Formula (LA)).
A third aspect of the present invention provides a compound of formula (LB) or a salt thereof (in particular, a pharmaceutically acceptable salt thereof):
Figure imgf000045_0004
wherein:
Rl is Cι_4aιkyl, Cι_3 fluoroalkyl, -CH CH2OH or -CH2CH2CO2Cι_2alkyl;
R2 is a hydrogen atom (H), methyl or Ci fluoroalkyl;
R3 is optionally substituted C3_gcycloalkyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);
Figure imgf000046_0001
(aa) (bb) (cc) in which nl and n2 independently are 1 or 2; and in which Y is O, S, SO2, or N O; where RlO is a hydrogen atom (H), Cι_4alkyl (e.g. methyl or ethyl), Cι_2fluoroalkyl, CH2C(O)NH2, C(O)NH2, C(O)-Cι_2alkyl, or C(O)-Cχ fluoroalkyl;
and wherein in R3 the C3_gcycloalkyl or the heterocyclic group of sub-formula (aa), (bb) or (cc) is optionally substituted with one or two substituents being oxo (=O), OH, Cι_2alkoxy, Cι_2fluoroalkoxy (e.g. trifluoromethoxy), or Cι_ alkyl; and wherein any OH, aikoxy or fluoroalkoxy substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (LB) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc);
and X is NR4R5 or OR5a, in which:
R4 is a hydrogen atom (H); Ci.galkyl; C gfluoroalkyl; or C2_galkyl substituted by one substituent R 1; and
R5 is a hydrogen atom (H); Ci.galkyl; Cι_g fluoroalkyl; C3_gcycloalkyl optionally substituted by a Cι_2alkyl group; or -(CH2)n 4-C3_gcycloalkyl optionally substituted, in the -(CH2)n 4- moiety or in the C3_gcycloalkyl moiety, by a Cι_2alkyl group, wherein n4 is 1, 2 or 3;
or R5 is C2-6alkyl substituted by one or two independent substituents Rl
wherein each substituent Rl 1, independently of any other Rl 1 substituent present, is: hydroxy (OH); C^galkoxy; phenyloxy; benzyloxy; -NR12R13; -NR15-C(O)R16;
-NR15-C(0)-0-R16; -NR15-C(0)-NH-R15; or -N 15-S02R16; and wherein any Rl 1 substituent which is OH, alkoxy or -N 12R13 is not substituted at any carbon atom, of any R4 or R^ substituted alkyl, which is bonded to the nitrogen of NR4R^;
or R5 is -(CH2)nn-C(O)Rl6; -(CH2)n n-C(O)NRl2Rl3; -CHR1 -C(O)N 12R 3; -(CH2)nl2-C(O)ORl6; -CHR19-C(0)0R16; -(CH2)n12-S02-N l Rl3; -(CH2)n12-SO2Rl6; or -(CH2)n 12-CN; wherein nl 1 is 0, 1, 2, 3 or 4 and n12 is 1, 2, 3 or 4;
or R5 is -(CH2)nl -Het wherein ni3 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or 7-membered saturated or partly-saturated heterocyclic ring 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)nl3- moiety when nl3 is 1 and are not bound to the nitrogen of N 4R5 when n - is 0; wherein any ring-nitrogens which are present and which are not unsaturated (i.e. which do not partake in a double bond) are present as .17 where Rl7 is as defined herein; and wherein one or two of the carbon ring-atoms independently are optionally substituted by Cι_2alkyl;
or R5 is phenyl optionally substituted with one or two of: a halogen atom; Cι_4alkyl (e.g. Chalky!); Ci^fluoroalkyl (e.g. trifluoromethyl); Cι_4alkoxy (e.g. C ^alkoxy); Cι_ 2f uoroa l oχy (e-S- trifluoromethoxy); Cι_2alkylsuιphonyl (Cι_2alkyl-Sθ2-);
Cι.2alkyl-SO2-NH-; R7R8N-SO2S R7R8N-CO-; -NR15-C(0)R16; R7R N; OH; Cι_4alkoxymethyl; Cι_4alkoxyethyl; Ci_2alkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one or two of fluoro, chloro, C^ lkyl, C fluoroalkyl, Cι_2alkoxy or Ci fluoroalkoxy; wherein R7 and R8 are independently a hydrogen atom (H); Cι_4alkyl (e.g.
C _2alkyl such as methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: fluoro, chloro, C^alkyl, Ci fluoroalkyl, Cι_2 alkoxy or Ci fluoroalkoxy; or R7 and R8 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n8-X7-(CH2)n9- or -C(O)-X7-(CH2)n10- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5 (preferably n7 is 2, 3 or 4), n8 and n9 and nlO independently are 2 or 3, and X7 is O or N I4 wherein R!4 is H or C _ alkyl;
or R5 has the sub-formula (x), (y) or (z):
Figure imgf000047_0001
(x) (y) (z)
wherein in sub-formula (x), n = 1 or 2; in sub-formula (y), m = 1 or 2; and in sub-formula (z), r = 0, l or 2; wherein in sub-formula (x) and (y), none, one or two of A, B, D, E and F are nitrogen; and the remaining of A, B, D, E and F are independently CH or CR6;
where R6 is a halogen atom; Cι_4alkyl (e.g. Ci-^alkyl); C gfluoroalkyl (e.g.
C i _2fluoro alkyl) ; Ci^alkoxy (e.g. Cι_2alkoxy); Ci^fluoroalkoxy; Cι_2alkylsulphonyl
(Cι.2alkyl-SO2-); Cι.2alkyl-SO2-NH-; R7R N-SO2-; R7R8N-CO-; -NR15-C(0)R16;
R7R8N; OH; C^alkoxymethyl; Ci^alkoxyethyl; Cι_2alkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one or two of fluoro, chloro, Cι_2alkyl,
Ci fluoroalkyl, Cι_2 alkoxy or Ci fluoroalkoxy; wherein R7 and R8 are as herein defined;
wherein in sub-formula (z), G is O or S or NR9 wherein R9 is a hydrogen atom (H), Cι_ 4alkyl or Cι_4fluoroalkyl; none, one, two or three of J, L, M and Q are nitrogen; and the remaining of J, L, M and Q are independently CH or CR6 where R6 is as defined herein;
or R4 and R5 taken together are -(CH2)pl- or -C(O)-(CH2)p 2- or
-(CH2)p 3-X5-(CH2)p 4- or -C(O)-X5-(CH2)p 5-, in which: pi = 3, 4, 5 or 6 (preferably p
= 4 or 5), p2 is 2, 3, 4, or 5 (preferably p2 is 2, 3 or 4), and p3 and p4 and p^ independently are 2 or 3 (independently preferably 2) and X^ is O or NRI7; wherein Rl7 is a hydrogen atom (H); Cι_4alkyl (e.g. Cι_2alkyl); Cι_2fluoroalkyl; C3_6cycloalkyl; -(CH2)p 6-C(O)Rl 6 wherein p6 is 0, 1 , 2 or 3 (preferably p6 is 0);
-(CH2)p6-C(O)NRl2Rl3; -(CH2)p 6-C(O)ORl6; -SO Rl6; or phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, Cι_2alkyl, Ci fluoroalkyl, Cι_2alkoxy or C fluoroalkoxy; and wherein, when R4 and R^ taken together are -(CH2)pl- or -C(O)-(CH2)p 2-, the NR4R5 heterocycle is optionally substituted by one Rl substituent wherein Rl 8 is: Cι_4alkyl (e.g. Cι_2alkyl); Cι_2fluoroalkyl; C3_6cycloalkyl; C _2alkoxy (not substituted at a ring-carbon bonded to the N 4R^ ring-nitrogen); Ci fluoroalkoxy (not substituted at a ring-carbon bonded to the N 4R^ ring-nitrogen); OH (not substituted at a ring-carbon bonded to the NR R5 ring-nitrogen); -(CH2)p 7-C(O)Rl6 wherein p7 is 0, 1, 2 or 3 (preferably p7 is 0 or 1); -(CH2)p 7-C(O)ORl6; -(CH2)p 7-OC(O)Rl6;
-(CH2)p7-C(O)NRl 2Rl 3 ; -(CH2)p 7-NRl 5c(O)Rl 6; -(CH2)p 7-NRl 5C(O)N 12R13 ;
-(CH2)p 7-NRl5C(O)ORl6; -(CH2)p 7-SO2Rl6; -(CH2)P 7-SO2 NR12R13;
-(CH2)p 7-NRl5SO2Rl6; -(CH2)p 7-OH; -(CH2)p 7-ORl6; or phenyl optionally substituted by one or two of: a halogen atom, C^alkyl, Ci fluoro alkyl, Cι_2alkoxy or C fluoroalkoxy; or R4 and R5 taken together are -(CH2)pl- or -C(O)-(CH2)p 2- or
-(CH2)p3-X5-(CH2)p 4- or -C(O)-X5-(CH2)p 5- as defined herein, and wherein the
NR4R5 heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, Cι_2 alkyl, Ci fluoroalkyl, Cι_2 alkoxy or Ci fluoroalkoxy; and
R^ is Ci.galkyl; Cι_g fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, Cι_2alkyl, trifluoromethyl, Cι_2alkoxy or trifluoromethoxy; or R^ has the sub-formula (x), (y) or (z) as defined herein
and wherein:
Rl2 and Rl3 independently are H; Cι_5alkyl (e.g. Chalky!); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cι_2 alkyl, Ci fluoroalkyl, Cι_2alkoxy or Ci fluoroalkoxy;
or R12 and Rl3 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n8-X12-(CH2)n 9- or -C(O)-Xl2-(CH2)nl°- in which: n6 is 3, 4, 5 or 6 (preferably n6 is 4 or 5), n7 is 2, 3, 4, or 5 (preferably n7 is 2, 3 or 4), n8 and n9 and nlO independently are 2 or 3 (independently preferably 2) and χl is O or RI4 wherein Rl4 is H or Cι_2alkyl;
R1^ is a hydrogen atom (H); Cι_4alkyl (e.g. *Bu or C _2 alkyl e.g. methyl); C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cι_2 alkyl, Ci fluoroalkyl, Cι_ alkoxy or C fluoroalkoxy;
Rl6 is Cι_4alkyl (e.g. Cι_2alkyl); C3_6cycloalkyl; pyridinyl (e.g. pyridin-2-yl); or phenyl optionally substituted by one or two of: a halogen atom, Chalky!, Ci fluoroalkyl, Cι_2alkoxy or Ci fluoroalkoxy; and
Rl is a hydrogen atom (H); Cι_4alkyl (e.g. isobutyl, sec-butyl, or Cι_3alkyl such as methyl or isopropyl); -(CH2)n 0-OR20 wherein n2^ is 1, 2, 3 or 4 (preferably 1) and R ^ is a hydrogen atom (H) or C^alkyl (preferably R20 is H); -CH(Me)-OH; -CH2-SH; -CH2-CH2-S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyI).
In formula (LB), preferably, when R3 is the heterocyclic group of sub-formula (bb), nl is 1, and Y is NRlO, then: either (a) Rl° is not Ci^alkyl, Cι_2fluoroalkyl or CH2C(O)NH2; or (b) R!^ is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide or l-ethyl-N-(4- fluorophenyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide.
In formula (IB), preferably, where X is OR^a, the compound is other than the compound wherein Rl is methyl, X is OEt, and R3 is cyclopentyl.
In formula (LB), where R3 is optionally substituted C3_gcycloalkyl, the one or two optional substituents preferably comprise (e.g. is or are) OH and/or oxo (=O). In formula (LB), in the R3 heterocyclic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents preferably comprise (e.g. is or are) OH and/or oxo.
Examples 1-203 are examples of compounds or salts of the third aspect of the invention (Formula (LB)).
The preferred or optional features for the compound or salt of fonnula (IA) and for the compound or salt of formula (LB) are the same as or similar to the preferred or optional features for the compound or salt of formula (I), with all necessary changes (for example to the formula, to the R groups and/or to substituents) having been made. Generally, whenever formula (I) is mentioned herein, then in alternative embodiments the statement mentioning formula (I) applies to formula (IA) or formula ( B), with all necessary changes having been made.
Salts, solvates, isomers, tautomeric forms, molecular weights, etc.
Because of their potential use in medicine, the salts of the compounds of formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts. A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration. Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the the compound of formula (I).
Other non-pharmaceutically acceptable salts, eg. oxalates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of formula (I).
Also included within the scope of the invention are all solvates, hydrates and complexes of compounds and salts of the invention.
Certain groups, substituents, compounds or salts included in the present invention may be present as isomers. The present invention includes within its scope all such isomers, including racemates, enantiomers and mixtures thereof.
Certain of the groups, e.g. hetero aromatic ring systems, included in compounds of formula (I) or their salts may exist in one or more tautomeric forms. The present invention includes within its scope all such tautomeric forms, including mixtures.
Especially when intended for oral medicinal use, the compound of formula (I) can optionally have a molecular weight of 1000 or less, for example 800 or less, in particular 650 or less or 600 or less. Molecular weight here refers to that of the unsolvated "free base" compound, that is excluding any molecular weight contributed by any addition salts, solvent (e.g. water) molecules, etc.
Synthetic Process Routes
The following processes can be used to make the compounds of the invention:
Figure imgf000051_0001
Most of the following synthetic processes following are exemplified for compounds of Formula (I) wherein R2 is a hydrogen atom (H). However, some or all of these processes can also be used with appropriate modification, e.g. of starting materials and reagents, for making compounds of Formula (I) wherein R2 is other than H.
Process A
Compounds of formula (I) where X = OR->a, 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 (II) with an amine of formula R3NH2. The reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane or acetonitrile. The reaction may require heating e.g. to ca. 60-100 °C , for example ca. 80-90 °C:
Figure imgf000052_0001
(II) (1)
Compounds of formula (II) are also described in the above reference and can be prepared by reaction of a compound of formula (III) with, for example, diethylethoxymethylene malonate (where R^a = Et) with heating, followed by reaction with phosphorous oxychloride, again with heating:
Figure imgf000052_0002
Formula Formula II
Where the desired amino pyrazole of formula (III) is not commercially available, preparation can be achieved using methods described by Dorgan et. al. in J. Chem. Soc, Perkin Trans. 1, (4), 938-42; 1980, by reaction of cyanoethylhydrazine with a suitable aldehyde of formula R4^CHO in a solvent such as ethanol, with heating, followed by reduction with, for example sodium in a solvent such as t-butanol. R4^ should be chosen so as to contain one less carbon atom than Rl, for example R4^ = methyl will afford Rl = ethyl.
Figure imgf000053_0001
Formula
h an alternative embodiment of Process A, the 4-chloro substituent in the compound of formula (II) can be replaced by a halogen atom, such as a bromine atom or preferably a chlorine atom, in a compound of formula (IIA) as defined below. In this embodiment of Process A, the compound of formula (IIA) is reacted with the amine of formula R3NH2.
Process B
Compounds of formula (I) where X = NR4R^, can be prepared by reaction of a compound of formula (IN) with an amine of formula R3ΝH2. The reaction is preferably carried out in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, THF, dioxane or acetonitrile. The reaction may require heating, e.g. to ca. 60-100 °C or ca. 80-90 °C, for example for 8-48 or 12-24 hours:
Figure imgf000053_0002
Formula IV Formula I
Compounds of formula (IN) can be prepared in a two step procedure as described by Bare et. al. inJ. Med. Chem. 1989, 32, 2561-2573. This process involves, first, reaction of a compound of formula (N) with thionyl chloride (or another agent suitable for forming an acid chloride from a carboxylic acid), either in an organic solvent such as chloroform or THF, or as a neat solution. This reaction may require heating and the thus-formed intermediate may or may not be isolated. Step two involves reaction with an amine of formula R4R^ΝH, in an organic solvent such as THF or chloroform and may also involve the use of a base such as triethylamine or diisopropylethyl amine:
Formula V Formula IV
Compounds of formula (V) can be prepared by hydrolysis of an ester of formula (II) according to the method described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027. This procedure preferably involves reaction with a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:
Figure imgf000054_0002
Formula II Formula V
hi an alternative embodiment of Process B, the 4-chloro substituent in the compound of formula (TV) can be replaced by a halogen atom, such as a bromine atom or preferably a chlorine atom, in a compound of formula (IN A) as defined below. In this embodiment of Process B, the compound of formula (IN A) is reacted with the amine of formula R3ΝH2.
Process C
Compounds of formula (I) can also be prepared according to a method, for example as described by Bare et. al. in J. Med. Chem. 1989, 32, 2561-2573, which involves reaction of a compound of formula (VI), in which -O-R3^ is a leaving group displaceable by an amine, with an amine of formula R3NH2. The -O-R3^ leaving group can be -O-Cι_4alkyl (in particular -O-Et) or -O-S(O)2-R37, wherein R37 is Ci.galkyl (e.g. Cι_4alkyl or C _2alkyl such as methyl), Ci .gfluoroalkyl (e.g. C gfluoroalkyl or C _2fluoroalkyl such as CF3 or C4F9), or phenyl wherein the phenyl is optionally substituted by one or two of independently Cι_2alkyl, halogen or Cι_2 alkoxy (such as phenyl or 4-methyl-phenyl). The reaction may be carried out with or without solvent and may require heating:
Figure imgf000055_0001
Formula VI Formula I
Compounds of formula (VI) (also described in the above reference) can be prepared by reaction of a compound of formula (Nil) with a suitable alkylating agent of formula R!-X, where X is a leaving group such as halogen. The reaction is preferably carried out in the presence of a base such as potassium carbonate, in an anhydrous solvent such as DMF:
Figure imgf000055_0002
Formula VII Formula VI
The preparation of compounds of formula Nil, e.g. where OR35 is OEt, by oxidative cleavage of compounds of formula NIII is described by Bare et. al. in J. Med. Chem. 1989, 32, 2561-2573 (further referred to Zuleski et. al. inJ. Drug. Metab. Dispos., 1985, 13,139).
Figure imgf000055_0003
Formula VII
In another embodiment of Process C, the compound of fonnula (VI) can be replaced by a compound of formula (VIA), wherein X is ΝR4R^ or OR^a as defined herein:
Figure imgf000056_0001
(VIA)
Ln this embodiment of Process C, the compound of formula (VIA) is reacted with the amine of formula R3NH2.
Process D:
To form a compound of formula (I) wherein X = 4R5, a compound of formula (I) but wherein X = OH (a carboxylic acid, the compound of formula (IX) as defined below) can be converted into an activated compound of formula (I) but wherein X = a leaving group χl substitutable by an amine (a compound of formula (X) as defined below, wherein χl is a leaving group substitutable by an amine); and subsequently the activated compound can be reacted with an amine of formula R4R^NH:
Figure imgf000056_0002
For example, the activated compound (the compound of formula (X)) can be the acid chloride i.e. an activated compound of formula (I) but wherein the leaving group χl = Cl. This can be formed from the carboxylic acid (X = OH, the compound of formula (IX)) e.g. by reaction with thionyl chloride, either in an organic solvent such as chloroform or without solvent. See for example Examples 81-85. Alternatively, the activated compound (the compound of formula (X)) can be an activated ester wherein the leaving group χl is
Figure imgf000056_0003
The latter activated compound of formula (X) can be formed from the carboxylic acid (X
= OH, the compound of formula (IX)) either: (a) by reaction of the carboxylic acid with a carbodiimide such as EDC, which is 1-ethyl- 3-(3'-dimethylaminopropyl)carbodiimide and is also l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, or a salt thereof e.g. hydrochloride salt, preferably followed by reaction of the resulting product with 1-hydroxybenzotriazole (HOBT); reaction (a) usually being carried out in the presence of a solvent (preferably anhydrous) such as dimethyl formamide (DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25 °C); or
(b) by reaction with 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-Azabenzotriazol- 1 -yl)-N,N,N^N'-tetiamethyluronium hexafluorophosphate (HATU) ,in the presence of a base such as diisopropylethylamine ( pr2NEt = DLPEA), and usually in the presence of a solvent such as dimethyl formamide
(DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25 °C).
The carboxylic acid wherein X = OH (the compound of formula (LX) below) is usually prepared by hydrolysis of the corresponding ester of formula (I) wherein X is OR^a. This ester can itself be prepared by any of Processes A, C, E or F as described herein.
Process DI
This is the same as Process D, but involves reaction of the activated compound of formula (X), wherein χl = a leaving group substitutable by an amine (for example a leaving group as defined herein), with an amine of formula R4R5]SIH.
Process E
Compounds of formula (I) can be prepared by reaction of a compound of formula (XI) with an alkylating agent of formula R!-X3, where X3 is a leaving group displaceable by the 1 -position pyrazolopyridine nitrogen atom of the compound of formula (XL):
Figure imgf000057_0001
A suitable alkylating agent of formula R!-X3 can be used. For example, X3 can be a halogen atom such as a chlorine atom or more preferably a bromine or iodine atom, or X3 can be -O-S(O)2-R36 wherein R36 is Ci.galkyl (e.g. Cι_4alkyl or Cι_2alkyl such as methyl), Ci .gfluoroalkyl (e.g. C gfluoroalkyl or Cι_2 fluoroalkyl such as CF3 or C4F9), or phenyl wherein the phenyl is optionally substituted by one or two of independently Cι_2alkyl, halogen or Cι_2alkoxy (such as phenyl or 4-methyl-phenyl). The reaction is preferably carried out in the presence of a base; the base can for example comprise or be potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, or a basic resin or polymer such as polymer-bound 2-tert-butylimino-2-diethylamino-l,3-dimethyl- perhydro-l,3,2-diazaphosphorine. The reaction is preferably carried out in the presence of a solvent, e.g. an organic solvent such as DMF; the solvent is preferably anhydrous. Examples of alkylation Process E include Examples 183, 185, 186 and 354.
For preferable methods of making compounds of formula (XI), see for example (Reference) Examples 19-20, and Intermediates 48 and 54A.
Process F: Conversion of one compound of formula (I) or salt thereof into another compound of formula (I) or salt thereof
One compound of fonnula (I) or salt thereof can be converted into another compound of formula (I) or salt thereof. This conversion preferably comprises or is one or more of the following processes Fl to F10:
Fl. An oxidation process. For example, the oxidation process can comprise or be oxidation of an alcohol to a ketone (e.g. using Jones reagent, e.g. see Example 205) 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 corresponding N-oxide (e.g. using 7wetα-chloroperoxybenzoic acid), for example conversion of a pyridine-containing compound to the corresponding pyridine N-oxide (e.g. Examples 210-212).
F2. A reduction process, for example reduction of a ketone or a carboxylic acid to an alcohol.
F3. Acylation, for example acylation of an amine (e.g. Examples 329-349, Example 353) or hydroxy group.
F4. Alkylation, for example alkylation of an amine or of a hydroxy group.
F5. Hydrolysis, e.g. hydrolysis of an ester to the corresponding carboxylic acid or salt thereof (e.g. Examples 351, 488, 489, 650, 651).
F6. Deprotection, e.g. deprotection (e.g. deacylation or t-butyloxycarbonyl (BOC) removal) of an amine group (e.g. Examples 320, (321), and (352)).
F7. Formation of an ester or amide, for example from the corresponding carboxylic acid. F8. Conversion of a ketone into the corresponding oxime (e.g. Examples 652, 653, 654 and 680-686).
F9. Sulfonylation, e.g. sulfonamide fonnation by reaction of an amine with a sulfonyl halide e.g. a sulfonyl chloride (e.g. Examples 322-328).
and/or
F10. Beckmann rearrangement of one compound of formula (I) into another compound of formula (I), preferably using cyanuric chloride (2,4,6-trichloro- 1 ,3 ,5-triazine) together with a formamide such as DMF, e.g. at room temperature (see L.D. Luca, J. Org. Chem., 2002, 67, 6212-621 A). The Beckmann rearrangement can for example comprise conversion of a compound of formula (I) wherein NHR3 is of sub-formula (o2)
( ) into a compound of formula (I) wherein NHR3 is of sub-formula
(
Figure imgf000059_0001
e.g. as illustrated in Examples 658 and 659.
The present invention therefore also provides a method of preparing a compound of formula (I) or a salt thereof:
Figure imgf000059_0002
wherein Rl, R2 and R3 are as defined herein and X is NR4R^ or OR^a as defined herein, the method comprising :
(a) for a compound of formula (I) wherein X = OR^a, reaction of a compound of formula (IIA):
Figure imgf000060_0001
(HA) wherein Hal is a halogen atom (such as a bromine atom or preferably a chlorine atom), with an amine of formula R3NH2, or
(b) for a compound of formula (I) wherein X = NR4R4 reaction of a compound of formula (INA) :
Figure imgf000060_0002
(IVA) wherein Hal is a halogen atom (such as a bromine atom or preferably a chlorine atom), with an amine of formula R3NH2, or
(c) reaction of a compound of formula (NLA):
Figure imgf000060_0003
(VIA) , in which -O-R3^ is a leaving group displaceable by an amine (such as -O-Cι_4alkyl or -O-S(O)2-R37), with an amine of formula R3ΝH2; or
(d) to form a compound of formula (I) wherein X = NR4R^, conversion of a compound of formula (IX) into an activated compound of formula (X) wherein χl = a leaving group substitutable by an amine:
Figure imgf000061_0001
, and subsequent reaction of the activated compound of formula (X) with an amine of formula R4R5NH; or
(dl) to fonn a compound of formula (I) wherein X = NR4R^, reaction of an activated compound of fonnula (X) as defined above with an amine of formula R4R5]MH; or
(e) reaction of a compound of formula (XI):
Figure imgf000061_0002
(XI) with an alkylating agent of formula Rl-X2, where X2 is a leaving group displaceable by the 1 -position pyrazolopyridine nitrogen atom of the compound of fonnula (XL); or
(f) conversion of one compound of formula (I) or salt thereof into another compound of formula (I) or salt thereof;
and optionally converting the compound of formula (I) into a salt thereof e.g. a pharmaceutically acceptable salt thereof.
In methods (d) and/or (dl), the activated compound of formula (X) wherein χl = a leaving group substitutable by an amine can be the acid chloride i.e. an activated compound of formula (X) wherein χl = Cl. Alternatively, the activated compound of formula (X) can be an activated ester wherein the leaving group χl is
Figure imgf000061_0003
Preferred features of methods (a), (b), (c), (d), (dl) and (e), independently of each other, are as described above for Processes A, B, C, D, Dl and E, with all necessary changes being made.
The present invention also provides: (g) 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 Examples 490, 491, 518A, 593).
The present invention also provides a compound of formula (I) or a salt thereof, prepared by a method as defined herein.
Medical uses
The present invention also provides a compound of fonnula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal such as a human. The compound or salt can be for use in the treatment and/or prophylaxis of any of the diseases / conditions described herein (e.g. for use in the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal) and/or for use as a phosphodiesterase inhibitor e.g. for use as a phosphodiesterase 4 (PDE4) inhibitor. "Therapy" may include treatment and/or prophylaxis.
Also provided is the use of a compoxmd of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal such as a human, e.g. for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.
Also provided is a method of treatment and/or prophylaxis of any of the diseases / conditions described herein in a mammal (e.g. human) in need thereof, e.g. a method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal (e.g. human) in need thereof, which method comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt thereof.
Phosphodiesterase 4 inhibitors are thought to be useful in the treatment and/or prophylaxis of a variety of diseases / conditions, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: asthma, chronic obstructive pulmonary disease (COPD) (e.g. chronic bronchitis and/or emphysema), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple sclerosis, cognitive impairment (e.g. in a neurological disorder such as Alzheimer's disease), depression, or pain. Ulcerative colitis and/or Crohn's disease are collectively often referred to as inflammatory bowel disease.
In the treatment and/or prophylaxis, the inflammatory and/or allergic disease is preferably chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD or asthma in a mammal (e.g. human).
PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M.A.Giembycz, Drugs, Feb. 2000, 59(2), 193-212; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466- 473; and refs cited therein).
PDE4 inhibitors are thought to be effective in the treatment of COPD (e.g. see S.L. Wolda, Emerging Drugs, 2000, 5(3), 309-319; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466- 473; and refs cited therein). COPD is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (S.L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).
PDE4 inhibitors are thought to be effective in the treatment of allergic rhinitis (e.g. see B.M. Schmidt et al., J. Allergy & Clinical Immunology, 108(4), 2001, 530-536).
PDE4 inhibitors are thought to be effective in the treatment of rheumatoid arthritis and multiple sclerosis (e.g. see H.J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002,
8(14), 1255-1296; and A.M.Doherty, Current Opinion Chem. Biol, 1999, 3(4), 466-473; and refs cited therein). See e.g. A.M.Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473 and refs cited therein for atopic dermatitis use. PDE4 inhibitors have been suggested as having analgesic properties and thus being effective in the treatment of pain (A.Kumar et al., Indian J. Exp. Biol, 2000, 38(1), 26- 30).
In the invention, the treatment and/or prophylaxis can be of cognitive impairment e.g. cognitive impairment in a neurological disorder such as Alzheimer's disease. For example, the treatment and/or prophylaxis can comprise cognitive enhancement e.g. in a neurological disorder. See for example: H.T.Zhang et al. in: Psychopharmacology, June 2000, 150(3), 311-316 and Neuropsychopharmacology, 2000, 23(2), 198-204; and T. Egawa et al., Japanese J. Pharmacol, 1997, 75(3), 275-81.
PDE4 inhibitors such as rolipram have been suggested as having antidepressant properties (e.g. J. Zhu et al., CNS Drug Reviews, 2001, 7(4), 387-398; O'Donnell, Expert Opinion on Investigational Drugs, 2000, 9(3), 621-625; and H.T. Zhang et al., Neuropsychopharmacology, October 2002, 27(4), 587-595).
Pharmaceutical compositions and dosing
For use in medicine, the compounds of the present invention are usually administered as a pharmaceutical composition.
The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients. The pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein.
The invention also provides a method of preparing a 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 compoxmd 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 phannaceutical composition may be administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration. Accordingly , the phannaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled or nasal administration. More preferably, the pharmaceutical composition is suitable for inhaled or oral administration, e.g. to a mammal such as a human. Inhaled administration involves topical administration to the lung e.g. by aerosol or dry powder composition. Oral administration to a human is most preferred. A pharmaceutical composition suitable for oral administration can be liquid or solid; for example it can be a syrup, suspension or emulsion, a tablet, a capsule or a lozenge.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
A pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations. Examples of such carriers include lactose and cellulose. The tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example binding agents, lubricants such as magnesium stearate, and/or tablet disintegrants. A pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures. For example, pellets containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule. Alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutically acceptable carrier, for example an aqueous gum or an oil and the dispersion or suspension then filled into a soft gelatin capsule.
Preferably the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human.
A parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Alternatively, the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.
Compositions for nasal or inhaled administration may conveniently be formulated as aerosols, drops, gels or dry powders. Aerosol formulations, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non- aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide, or an organic propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane. Suitable HFC propellants include 1,1,1,2,3,3,3- heptafluoropropane and 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also take the form of a pump-atomiser.
For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. Micronisation usually involves subjecting the compound/salt to collisional and abrasional forces in a fast-flowing circular or spiral vortex-shaped airstream often including a cyclone component. The preferable particle size (e.g. D50 value) of the size-reduced (e.g. micronised) compound or salt is about 0.5 to about 10 microns, e.g. about 1 to about 5 microns (e.g. as measured using laser diffraction). For example, it is preferable for the compound or salt of formula (I) to have a particle size defined by: a D10 of about 0.3 to about 3 microns (e.g. about 1 micron), and/or a D50 of about 1 to about 5 microns (e.g. about 2-5 or about 2-3 microns), and/or a D90 of about 2 to about 20 microns or about 3 to about 10 microns (e.g. about 5-8 or about 5-6 microns); for example as measured using laser diffraction. The laser diffraction measurement can use a dry method (suspension of compound/salt in airflow crosses laser beam) or a wet method [suspension of compound/salt in liquid dispersing medium, such as isooctane or (e.g. if compound soluble in isooctane) 0.1% Tween 80 in water, crosses laser beam]. With laser diffraction, particle size is preferably calculated using the Fraunhofer calculation; and/or preferably a Malvern Mastersizer or Sympatec apparatus is used for measurement.
An illustrative non-limiting example of a small-scale micronisation process is now given:
Micronisation Example: Micronisation of Example 518 or 518A
• Purpose: To micronize approximately 600-1000 mg of Example 518 or 518A (described hereinafter) using a Jetpharma MCI micronizer.
• The parent (unmicronised) and micronised materials are analyzed for particle size by laser diffraction and crystallinity by PXRD.
Equipment and material
Equipment/material Description and specification Jetpharma MCI Micronizer Nitrogen supply: Air tank with 275psi rate tubing
Analytical balance Sartorius Analytical Top loader balance Mettler PM400 Digital Caliper VWR Electronic caliper Nibrational spatula Auto-spat Dispenser Materials to be micronised Example 518 or 518 A The Jetpharma MCI Micronizer comprises a horizontal disc-shaped milling housing having: a tubular compound inlet (e.g. angled at ca. 30degrees to the horizontal) for entry of a suspension of unmicronised compound of formula (I) or salt in an gasflow, a separate gas inlet for entry of gases, a gas outlet for exit of gases, and a collection vessel for collecting micronised material. The milling housing has two chambers: an outer annular chamber in gaseous connection with the gas inlet the chamber being for receiving pressurised gas (e.g. air or nitrogen), an disc-shaped inner milling chamber within and coaxial with the outer chamber for micronising the input compound / salt, the two chambers being separated by an annular wall. The annular wall (ring R) has a plurality of narrow-bored holes connecting the inner and outer chambers and circumferentially- spaced-apart around the annular wall. The holes open into the inner chamber 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 is gaseous communication with the inner chamber via a nozzle directed tangentially to the inner chamber, within and near to the annular wall. Upper and lower broad-diameter exit vents in the central axis of the the inner milling chamber connect to (a) (lower exit) the collection vessel which has no air outlet, and (b) (upper exit) the gas outlet which leads to a collection bag, filter and a gas exhaust. Inside 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.
In use, the narrow 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 (eg air or nitrogen) the feed material is sucked into the gasstream thorough the compound inlet and accelerates it 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. 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 center 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, while the exhaust gas rises (together with a miinority of small particles of micronised material) and escapes into the atmosphere at low pressure and low velocity.
Procedure:
The micronizer is assembled. The venturi protrusion distance from input port is adjusted to 1.0cm respectively (e.g. so that the narrow 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 correctly. 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.
Note that 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 (see section on experimental run) is weighed into a plastic weigh boat. The material is then fed into the micronizer using a vibrational spatula (e.g. N-shaped in cross-section) at a specified feed rate. The material feeding time and equipment pressures are monitored during the micronization process.
Upon completion of the micronising run, the nitrogen supply is shut off and the collection bag is tapped to allow particles to settle into the recovery / collection vessel at the bottom of the micronizer. The collection bag is removed and set aside. The micronised powder in the recovery vessel (collection vessel) and the cyclone (above the recovery vessel) are collected separately into different weighed+labelled collection vials. The weight of the micronised material is recorded. 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 by rinsing and wiping with suitable solvent and dried before subsequent runs are perfonned.
Preferred Experimental Parameters Parent (unmicronised) material (Procedure 1): Example 518 or 518 A Parent (unmicronised) material (Procedure 2): Example 518 Balance(s) Used: Sartorius analytical Venturi outlet insertion depth: 10.0 mm
Material Venturi (V) Intended Time Actual feed-rate
Procinput / ring (R ) feed-rate needed to (g/min) edure amount (g) Pressure feed no. (bar) material
(min+sec)
1 0.8795g N= 10 bar 200 mg/min 4 min 51 181 mg/min R= 6 bar sec
2 0.9075g V= 8 bar 200 mg/min 4 min 43 192 mg/min R= 5.5 bar sec
The above parameters can be varied using the skilled person's knowledge.
Results and/or observations
% yield = [(Material from vessel + Material from cyclone)/Material input amount] xlOO In general, very approximately 50-75% yields are achievable using this method. Procedure 1 has not been completed.
In Procedure 2, a 70.8% yield (0.6427g) of Example 518 micronised material was obtained, including material from collection vessel and material from inside walls of cyclone.
Particle size analysis of Example 518 micronised material from Procedure 2, using laser diffraction measurement with Malvern Mastersizer longbed version, dispersing medium 0.1%) Tween 80 in water, stir rate 1500 rpm, 3 mins sonification prior to final dispersion and analysis, 300 RF (Reverse Fourier) lens, Fraunhofer calculation with Malvern software:
- material from collection vessel: D10 = 0.97 microns, D50 = 3.86 microns, D90 = 12.64 microns.
- material from inside walls of cyclone: D10 = 0.95 microns, D50 = 3.42 microns, D90 = 9.42 microns.
Alternative embodiment: Examples of the compounds/salts of the invention other than Examples 518 or 518A can be micronised.
For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the pharmaceutical composition is a dry powder inhalable composition. Such a composition can comprise a powder base such as lactose or starch, the compound of formula (I) or salt thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine, mannitol, trehalose and/or magnesium stearate. Preferably, the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof. The lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is preferably inhalation-grade and/or fine-grade lactose. Preferably, the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90%) or more of the lactose particles being less than 300 microns (e.g. 10-300 microns e.g. 50-300 microns) in diameter, and/or 50% or more of the lactose particles being less than 100 microns in diameter. Optionally, the particle size of the lactose is defined by 90%) or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter. Most importantly, it is preferable that about 3 to about 30%> (e.g. about 10%o) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10%0 fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands). Lu the dry powder inhalable composition, preferably, the compound of formula (I) or salt thereof is present in about 0.1% to about 70%> (e.g. about 1% to about 50%o, 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 Teflon™ (polytetrafluoroethene) pot in a Mikro-dismembrator ball-mill (but without a ball bearing) at % speed (ca. 2000-2500 rpm) for about 4 hours at each blend concentration. The Mikro-dismembrator (available from B. Braun Biotech international, Schwarzenberger Weg 73-79, D-34212 Melsungen, Germany; www.bbraunbiotech.com) comprises a base with an upwardly-projecting and sidewardly-vibratable arm to which is attached the Teflon TM p0t jhe vibration of the arm achieves blending.
Other blends: 10% w/w compound/salt (50 mg) + 90% w/w lactose (450 mg, inhalation-grade lactose containing 10% fines). Serial dilution of the 1% w/w blend can achieve e.g. 0.1% and 0.3%> w/w blends.
Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel-openable on demand and the dose, e.g. of the dry powder composition, can be administered by inhalation via a device such as the DISKUS TM device, marketed by GlaxoSmitliKline. The DISKUS ™ inhalation device is usually substantially as described in GB 2,242,134 A. In such device at least one container for the pharmaceutical composition in powder form (the at least one container preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: means defining an opening station for the said at least one container; means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.
In the pharmaceutical composition, a or each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. A or each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
A pharmaceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g. human) in a daily oral or parenteral dose of 0.001 mg to 50 mg per kg body weight per day (mg/kg/day), for example 0.01 to 20 mg/kg/day or 0.03 to 10 mg/kg/day or 0.1 to 2 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
A pharmaceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g. human) in a daily nasal or inhaled dose of: 0.0001 to 5 mg/kg/day or 0.0001 to 1 mg/kg/day, e.g. 0.001 to 1 mg/kg/day or 0.001 to 0.3 mg/kg/day or 0.001 to 0.1 mg/kg/day or 0.005 to 0.3 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
The pharmaceutically acceptable compounds or salts of the invention is preferably administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day e.g. 2 to 500 mg per day, or a nasal or inhaled dose of 0.001 to 300 mg per day or 0.001 to 50 mg per day or 0.01 to 30 mg per day or 0.01 to 5 mg per day or 0.02 to 2 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
Combinations
The compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a β2 adrenoreceptor agonist, an anti-histamine, an anti-allergic or an anti-inflammatory agent.
The invention thus provides, in a further aspect, a combination comprising a compound of fonnula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent, for example, a β2-adrenoreceptor agonist, an anti-histamine, an anti-allergic, an anti-inflammatory agent or an antiinfective agent.
Preferably, the β2-adrenoreceptor agonist is salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline, or a salt thereof (e.g. pharmaceutically acceptable salt thereof), for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β2-adrenoreceptor agonists are prefereed, especially those having a therapeutic effect over a 12-24 hour period such as salmeterol or formoterol. Preferably, the β2-adrenoreceptor agonist is for inhaled administration, e.g. once per day and/or for simultaneous inhaled administration; and more preferably the β2-adrenoreceptor agonist is in particle-size-reduced form e.g. as defined herein.
Preferably, the β2-adrenoreceptor agonist combination is for treatment and/or prophylaxis of COPD or asthma. Salmeterol or a pharmaceutically acceptable salt thereof, e.g. salmeterol xinofoate, is preferably administered to humans at an inhaled dose of 25 to 50 micrograms twice per day (measured as the free base). The combination with a β -adrenoreceptor agonist can be as described in WO 00/12078.
Preferred long acting β2-adrenoreceptor agonists include those described in WO
02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933.
Especially prefened long-acting β2-adrenoreceptor agonists include compounds of
Figure imgf000072_0001
or a salt or solvate thereof, wherein in formula (XX): mx is an integer of from 2 to 8; nx is an integer of from 3 to 11, with the proviso that mx + nx is 5 to 19,
R11X is -XSO2NR16XR17X wherein X is -(CH2)p χ- or C2-6 alkenylene;
R16x and R17X are independently selected from hydrogen, Cι-6alkyl, C3-7cycloalkyl,
C(O)NR18XR19X, phenyl, and phenyl (Cι-4alkyl)-, or R16x and R17X, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring, and R and R are each optionally substituted by one or two groups selected from halo, Cι-6alkyl, -ehaloalkyl,
Figure imgf000072_0002
hydroxy- substituted C,-6alkoxy, -CO2R18X, -SO2NR18XR19X, -CONR18xR19X, -NR18XC(O)R19X, or a 5-, 6- or 7-membered heterocylic ring;
R18X and R19X are independently selected from hydrogen, Cι-6alkyl, C3-6cycloalkyl, phenyl, and phenyl (Chalky!)-; and px is an integer of from 0 to 6, preferably from 0 to 4;
R12X and R13X are independently selected from hydrogen, Cj.-ealkyl, Cι-6alkoxy, halo, phenyl, and Cι-6haloalkyl; and
R14X and R15 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R and R is not more than 4.
Preferred β2-adrenoreceptor agonists disclosed in WO 02/066422 include:
3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl] ethyl} amino)hexyl]oxy}butyl)benzenesulfonamide and 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide. A prefened β -adrenoreceptor agonist disclosed in WO 03/024439 is:
4-{(lR)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-l-hydroxyethyl}-2-
(hydroxymethyι)phenol.
A combination of a compound of formula (I) or salt together with an anti-histamine is preferably for oral administration (e.g. as a combined composition such as a combined tablet), and can be for treatment and/or prophylaxis of allergic rhinitis. Examples of anti- histamines include methapyrilene, or HI antagonists such as cetirizine, loratadine (e.g. Clarityn TM)s 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, Mχ/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. For combinations of anticholinergic compounds / muscarinic (M) receptor antagonist with PDE4 inhibitors, see for example WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 Al and US 2002/052312 Al, and some or all of these publications give examples of anticholinergic compounds / muscarinic (M) receptor antagonists which may be used with the compounds of formula (I) or salts, and/or suitable pharmaceutical compositions. For example, the muscarinic receptor antagonist can comprise or be an ipratropium salt (e.g. ipratropium bromide), an oxitropium salt (e.g. oxitropium bromide), or more preferably a tiotropium salt (e.g. tiotropium bromide); see e.g. EP 418 716 Al for tiotropium.
The anticholinergic compound or muscarinic (M) receptor antagonist, e.g. M3 receptor antagonist, is preferably for inhaled administration, more preferably in particle-size- reduced form e.g. as defined herein. More preferably, both the muscarinic (M) receptor antagonist and the compound of formula (I) or the pharmaceutically acceptable salt thereof are for inhaled administration. Preferably, the anticholinergic compound or muscarinic receptor antagonist and the compound of formula (I) or salt are for simultaneous administration. The muscarinic receptor antagonist combination is preferably for treatment and/or prophylaxis of COPD.
Other suitable combinations include, for example, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another anti- inflammatory agent such as an anti-inflammatory corticosteroid; or a non-steroidal anti- inflammatory drug (NSAID) such as a leukotriene antagonist (e.g. montelukast), an iNOS inhibitor, a tryptase inhibitor, a elastase inhibitor, a beta-2 integrin antagonist, a adenosine 2a agonist, a CCR3 antagonist, or a 5-lipoxogenase inhibitor); or an antiinfective agent (e.g. an antibiotic or antiviral). An iNOS inhibitor is preferably for oral admiriistration. Suitable iNOS inhibitors (inducible nitric oxide synthase inhibitors) include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Suitable CCR3 inhibitors include those disclosed in WO 02/26722.
In a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anti-inflammatory corticosteroid (which is preferably for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis), then preferably the anti-inflammatory corticosteroid is fluticasone, fluticasone propionate (e.g. see US patent 4,335,121), beclomethasone, beclomethasone 17-propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof, ciclesonide, budesonide, flunisolide, or a compound as described in WO 02/12266 Al (e.g. as claimed in any of claims 1 to 22 therein), or a pharmaceutically acceptable salt of any of the above. If the anti-inflammatory corticosteroid is a compound as described in WO 02/12266 Al, then preferably it is Example 1 therein {which is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-l 1 β-hydroxy-16α-methyl-3- oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester} or Example 41 therein {which is 6α,9α-difluoro-l 1 β-hydroxy-16α-methyl-17α-[(4-methyl-l,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester}, or a pharmaceutically acceptable salt thereof. The anti-inflammatory corticosteroid is preferably for intranasal or inhaled administration. Fluticasone propionate is 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.
Also provided is a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with β2-adrenoreceptor agonist and an anti-inflammatory corticosteroid, for example as described in WO 03/030939 Al. Preferably this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis. The β2-adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 Al. Most preferably, in this "triple" combination, the β2-adrenoreceptor agonist is salmeterol or a pharmaceutically acceptable salt thereof (e.g. salmeterol xinafoate) and the anti- inflammatory corticosteroid is fluticasone propionate.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus a pharmaceutical composition comprising a combination as defined above together with one or more pharmaceutically acceptable carriers and/or excipients represent a further aspect of the invention.
The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical composition. In one embodiment, the combination as defined herein can be for simultaneous inhaled administration and is disposed in a combination inhalation device. Such a combination inhalation device is another aspect of the invention. Such a combination inhalation device can comprise a combined pharmaceutical composition for simultaneous inhaled administration (e.g. dry powder composition), the composition comprising all the individual compounds of the combination, and the composition being incorporated into a plurality of sealed dose containers mounted longitudinally in a strip or ribbon inside the inhalation device, the containers being rupturable or peel-openable on demand; for example such inhalation device can be substantially as described in GB 2,242,134 A (DISKUS TM) and/or as described above. Alternatively, the combination inhalation device can be such that the individual compounds of the combination are administrable simultaneously but are stored separately (or wholly or partly stored separately for triple combinations), e.g. in separate pharmaceutical compositions, for example as described in PCT/EP03/00598 filed on 22 January 2003 (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 phannaceutical composition for admimstration of the individual compounds of the combination either sequentially or simultaneously, or
(b) preparing a combined pharmaceutical composition for administration of the individual compounds of the combination simultaneously, wherein the pharmaceutical composition comprises the combination together with one or more pharmaceutically acceptable carriers and/or excipients.
The invention also provides a combination as defined herein, prepared by a method as defined herein.
BIOLOGICAL TEST METHODS
PDE 3, PDE 4B, PDE 4D, PDE 5, PDE 6 Primary assay methods
The activity of the compounds can be measured in the assay methods shown below. Prefereed compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D, preferably PDE4B) more strongly than they inhibit PDE3 and/or more strongly than they inhibit PDE5 and/or more strongly than they inhibit PDE6.
PDE enzyme sources and literature references
Human recombinant PDE4B, in particular the 2B splice variant thereof (HSPDE4B2B), is disclosed in WO 94/20079 and also M.M. McLaughlin et al., "A low Km, rolipram- sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterisation of recombinant protein, and tissue distribution of mRNA", J. Biol. Chem., 1993, 268, 6470-6476. For example, in Example 1 of WO 94/20079, human recombinant PDE4B is described as being expressed in the PDE- deficient yeast Saccharomyces cerevisiae strain GL62, e.g. after induction by addition of 150 uM CUSO4, and 100,000 x g supernatant fractions of yeast cell lysates are described for use in the harvesting of PDE4B enzyme.
Human recombinant PDE4D (HSPDE4D3A) is disclosed in P. A. Baecker et al., "Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phoshodiesterase (PDE LVD)", Gene, 1994, 138, 253-256.
Human recombinant PDE5 is disclosed in K. Loughney et al, "Isolation and characterisation of cDNAs encoding PDE5 A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase", Gene, 1998, 216, 139-147.
PDE3 was 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 was purified from bovine retina as described by: P. Catty and P. Detene,
"Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis", Eur. J. Biochem., 1991, 199, 263-269; A. Tar et al. "Purification of bovine retinal cGMP phosphodiesterase", Methods in Enzymology, 1994, 238, 3-12; and/or D. Srivastava et al. "Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cyclic GMP phosphodiesterase", Biochem. J., 1995, 308, 653-658. Inhibition of PDE 3, PDE 4B, PDE 4D, PDE 5 or PDE 6 activity: radioactive Scintillation Proximity Assay (SPA)
The ability of compounds to inhibit catalytic activity at PDE4B or 4D (human recombinant), PDE3 (from bovine aorta), PDE5 (human recombinant) or PDE6 (from bovine retina) was determined by Scintillation Proximity Assay (SPA) in 96-well format. Test compounds (preferably as a solution in DMSO, e.g. 0.5 to 1 microlitre (ul) volume) were preincubated at ambient temperature (room temperature, e.g. 19-23°C) in Wallac Isoplates (code 1450-514) with PDE enzyme in 50mM Tris-HCl buffer pH 7.5 , 8.3mM MgCl2, 1.7mM EGTA, 0.05% (w/v) bovine serum albumin for 10-30 minutes (usually 30 minutes). The enzyme concentration was adjusted so that no more than 20% hydrolysis of the substrate defined below occurred in control wells without compound, during the incubation. For the PDE3, PDE4B and PDE4D assays, [5',8-3H]Adenosine 3',5'-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.559; or Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, UK) was added to give 0.05uCi per well and ~ lOnM final concentration. For the PDE5 and PDE6 assays, [8-3H]Guanosine 3 ',5 '-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.392) was added to give 0.05uCi per well and ~ 36nM final concentration. Plates, e.g. containing approx. 100 ul volume of assay mixture, were mixed on an orbital shaker for 5 minutes and incubated at ambient temperature for 1 hour. Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ 0150) were added (~lmg per well) to terminate the assay. Plates were sealed and shaken and allowed to stand at ambient temperature for 35 minutes to lhour (preferably 35 minutes) to allow the beads to settle. Bound radioactive product was measured using a WALLAC TRLLUX 1450 Microbeta scintillation counter. For inhibition curves, 10 concentrations (1.5nM - 30uM) of each compound were assayed. Curves were analysed using ActivityBase and XLfit (LD Business Solutions Limited, 2 Ocean Court, Suney Research Park, Guildford, Surrey GU27QB, United Kindgom) Results were expressed as pICso values.
In an alternative to the above radioactive SPA assay, PDE4B or PDE4D inhibition can be measured in the following Fluorescence Polarisation (FP) assay:
Inhibition ofPDE4B or PDE4D activity: Fluorescence Polarisation (FP) assay
The ability of compounds to inhibit catalytic activity at PDE4B (human recombinant) or PDE4D (human recombinant) was 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. The LMAP FP assay is able to measure PDE activity in an homogenous, non-radioactive assay format. The FP assay uses the ability of immobilised trivalent metal cations, coated onto nanoparticles (tiny beads), to bind the phosphate group of Fl-AMP that is produced on the hydrolysis of fluorescein-labelled (Fl) 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. 0.5 to 1 ul, of solution in DMSO) were preincubated at ambient temperature (room temperature, e.g. 19-23°C) in black 384-well microtitre plates (supplier: NUNC, code 262260) with PDE enzyme in lOmM Tris-HCl buffer pH 7.2, lOmM MgCl2, 0.1% (w/v) bovine serum albumin, and 0.05% NaN3 for 10- 30 minutes. The enzyme level was set by experimentation so that reaction was linear throughout the incubation. Fluorescein adenosine 3 ',5 '-cyclic phosphate (from Molecular Devices Corporation, Molecular Devices code: R7091) was added to give about 40nM final concentration (final assay volume usually ca. 25-40 ul). Plates were 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) was added (60ul of a 1 in 400 dilution in binding buffer of the kit stock solution) to terminate the assay. Plates were allowed to stand at ambient temperature for 1 hour. The Fluorescence Polarisation (FP) ratio of parallel to perpendicular light was measured using an AnalystTM plate reader (from Molecular Devices Corporation). For inhibition curves, 10 concentrations (1.5nM - 30uM) of each compound were assayed. Curves were analysed using ActivityBase and XLfit (LD Businesss Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kindgom). Results were expressed as pIC50 values.
In the FP assay, all reagents were dispensed using MultidropTM (available from Thermo Labsystems Oy, Ratastie 2, PO Box 100, Vantaa 01620, Finland).
For a given PDE4 inhibitor, the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly. However, in a regression analysis of 100 test compounds, the PIC50 inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units, for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R.Mobbs et al, "Comparison of the LMAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity", poster to be presented at 2003 Molecular Devices UK & Europe User Meeting, 2nd October 2003, Down Hall, Harlow, Essex, United Kingdom).
Biological Data obtained for some of the Examples (PDE4B inhibitory activity, either as one reading or as an average of ca. 2-6 readings) are as follows, based on current measurements only. In each of the SPA and FP assays, absolute accuracy of measurement is not possible, and the readings given are accurate only up to about ± 0.5 of a log unit, depending on the number of readings made and averaged:
Figure imgf000078_0001
Figure imgf000079_0001
Examples 1-201 were generally tested for PDE4B inhibition using the radioactive SPA assay. Of Examples 207-665, and 677-686, all or almost all (except perhaps for Examples 451, 631-632, 635, 652) were tested for PDE4B inhibition; and of these some were tested by the radioactive SPA assay, some were tested by the FP assay. Examples 1-201, 207-450, 452-630, 633-634, 636-651, 653-665, and 677-686, but excluding reference examples 19-20, have PDE4B inhibitory activities in the range of pIC50 = about 6 (± about 0.5) to about 10.0 (± about 0.5). Examples 666-676 are predicted to have PDE4B inhibitory activities in the range of pIC50 = about 6 (± about 0.5) to about 10.0 (± about 0.5).
The Examples wherein R3 = cyclohexyl (NHR3 = sub-formula (c)), tetrahydro-2H-pyran- 4-yl (NHR3 = group (h)), 4-oxocyclohexyl (NHR3 = sub-formula (o)), or certain other types of substituted cyclohexyl or certain heterocycles, usually or often (especially with Rl = ethyl) have a higher level of selectivity for PDE4B over PDE5, as measured in the above enzyme inhibition assays, compared to the selectivities of comparable Examples wherein R3 = cyclopropyl (NHR3 = sub-formula (b)). For example, based on current measurements only, and subject to cumulative assay inaccuracies: - Examples 21, 40, 90, 198 and 201 (wherein NHR3 = sub-formula (h), (c), (j), (n) and (o) respectively, Rl = ethyl) have selectivities for PDE4B over PDE5 in the range of about 3 to 20 or more times greater than the selectivity achieved for the equivalent Example 39 wherein R3 = cyclopropyl (NHR3 = sub-formula (b)); - Examples 43 and 44 (wherein NHR3 = sub-formula (c) and (h) respectively) have selectivities for PDE4B over PDE5 in the range of about 4 to 8 or more times greater than the selectivity achieved for the equivalent R3 = cyclopropyl Example 42;
- Examples 22 and 48 (wherein NHR3 = sub-formula (h) and (c) respectively) have selectivities for PDE4B over PDE5 in the range of about 2.5 to 10 or more times greater than the selectivity achieved for the equivalent R3 = cyclopropyl Example 47; and
- Examples 2 and 3 (wherein NHR3 = sub-formula (c) and (h) respectively) have selectivities for PDE4B over PDE5 in the range of about 2 to 5 or more times greater than the selectivity achieved for the equivalent R3 = cyclopropyl Example 1.
Emesis: Some known PDE4 inhibitors can cause emesis and/or nausea to greater or lesser extents (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. Emetic side-effects can for example be measured by the emetogenic potential of the compound or salt when administered to ferrets; for example one can measure the time to onset, extent, frequency and/or duration of vomiting, retching and/or writhing in fercets after oral or parenteral administration of the compound or salt. See for example In vivo Assay 4 hereinafter for a measurement method for anti-inflammatory effect, emetic side-effects and therapeutic index (TI) in the ferret. See also for example A. Robichaud et al., "Emesis induced by inhibitors of [PDE TV] in the fercet", Neuropharmacology, 1999, 38, 289-297, enatum Neuropharmacology, 2001, 40, 465-465. However, optionally, 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 Vivo Assay 2 below).
Other side effects: Some known PDE4 inhibitors can cause other side effects such as headache and other central nervous sytem (CNS-) 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.
In Vivo Biological Assays
The in vitro enzymatic PDE4B inhibition assay described above should be regarded as being the primary test of biological activity. However, additional in vivo biological tests, which are optional and which are not an essential measure of efficacy or side-effects, are described below. In Vivo Assay 1. LPS-induced pulmonary neutrophilia in rats: effect of orally administered PDE4 inhibitors
Pulmonary neutropliil 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). 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.
Male Lewis rats (Charles River, Raleigh, NC, USA) weighing approximately 300- 400 grams are pretreated with either (a) test compound suspended in 0.5%> methylcellulose (obtainable from Sigma- Aldrich, St Louis, MO, USA) in water or (b) vehicle only, delivered orally in a dose volume of 10 ml/kg. Generally, dose response curves are generated using the following doses of PDE4 inhibitors: 10.0, 2.0, 0.4, 0.08 and 0.016 mg/kg. Thirty minutes following pretreatment, 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 100 μg/ml LPS solution. Rats are exposed to the LPS aerosol at a rate of 4 L/min for 20 minutes. LPS exposure is carried out in a closed chamber with internal dimensions of 45 cm length x 24 cm width x 20 cm height. The nebulizer and exposure chamber are contained in a certified fume hood. At 4 hours-post LPS exposure the rats are euthanized by overdose with pentobarbital at 90 mg/kg, administered intraperitoneally. Bronchoalveolar lavage (BAL) is preformed through'a 14 gauge blxmt 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 perfonned on BAL fluid in order to calculate neutropliil 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.
Results: Based on current measurements, the compounds of Examples 22, 83 and 155, administered orally in the above procedure, exhibited neutrophilia-inhibition ED50 values in the range of about 0.5 mg/kg to about 2 mg/kg.
Alternative method and results: In an alternative embodiment of the procedure, single oral doses of 10 mg/kg or 1.0 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. In this embodiment, based on cunent measurements, the compounds of Examples 21, 100, 109, 167, 172 and 600, administered orally in the above procedure at a single dose of 1.0 mg/kg, exhibited percent neutrophilia-inhibition in the range of about 19% to about 69%> (or in the range of about 32%) to about 69%> for Examples 21, 100, 109, 167 and 600). Literature: Filley G.F. Comparison of the structural and inflammatory features of COPD and asthma. Chest. 2000; 117(5) 251s-260s.
Howell RE, Jenkins LP, Fielding LE, and Grimes D. Inhibition of antigen- induced pulmonary eosinophilia and neutrophilia by selective inhibitors of phosphodiesterase types 3 and 4 in brown Norway rats. Pulmonary Pharmacology. 1995; 8: 83-89.
Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT, Minnicozzi M. Comparison of PDE 4 inhibitors, Rolipram and SB 207499 (Ariflo™), in a rat model of pulmonary neutrophilia. Pulmonary Pharmacology and Therapeutics. 2001; 14: 157- 164.
Underwood DC, Osborn RR, Bochnowicz S, Webb EF, Rieman DJ, Lee JC, Romanic AM, Adams JL, Hay DWP, and Griswold DE. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am JPhysiolLung Cell Mol Physiol. 2000; 279: L895-L902.
In Vivo Assay 2. 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 many species is emesis. Because many rat models of inflammation are well characterized, they have been used in procedures (see e.g. hi Vivo 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.
However, in 1991, Takeda et al. (see Literature section below) demonstrated that the pica feeding response is analogous to emesis 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 Vivo 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. In Vivo Assay 1 above). Anti-inflammatory and pica assays in the same species together can provide data on the "therapeutic index" (TI) in the rat of the compounds/salts of the invention. The 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 Vivo Assay 1), with larger TI ratios possibly indicating lower emesis at many anti-inflammatory doses. This might allow a choice of anon-emetic or minimal-emetic pharmaceutical dose of the compounds or salts of the invention which has an anti-inflammatory effect. It is recognised however that achieving a low-emetic PDE4 inhibitory compound is not essential.
Procedure: On the first day of the experiment, the rats are housed individually in cages without bedding or "enrichment". The rats are kept off of the cage floor by a wire screen. Pre-weighed food cups containing standard rat chow and clay pellets are placed in the cage. The clay pellets, obtainable from Languna Clay Co, City of Industry, CA, USA, are the same size and shape as the food pellets. The rats are acclimated to the clay for 72 hours, during which time the cups and food and clay debris from the cage are weighed daily on an electronic balance capable of measuring to the nearest 0.1 grams. 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 compoxmd/salt of the invention (different doses for different treatment groups) or with vehicle alone, at a dose volume of 2 ml/kg. In this oral dosing, the compound/salt is in the form of a suspension in 0.5% methylcellulose (obtainable Sigma- Aldrich, St. Louis, MO, USA) in water. The food and clay cups and cage debris are weighed the following day and the total clay and food consumed that night by each individual animal is calculated.
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 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.
Results: Using the above procedure, and according to current measurements, the compounds of Examples 22, 83 and 155 exhibited a Pica Response ED50 in the range of about 4.8 mg/kg to greater than or equal to about 40 mg/kg. It can be seen that these Pica Response ED50 doses are higher than the neutrophilia-inhibition ED50 values for these three Examples (see In Vivo Assay 1 above), so that a Therapeutic Index (TI) in rats of >2, as measured by Assays 1+2 and according to current measurements, appears at first sight to have been achieved for these three Examples.
The Therapeutic Index (TI) calculated this way is often significantly different to, and often higher than, the TI calculated in the fenet (see hi vivo Assay 4 below).
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, Rung TT, Minnicozzi M. Comparison of PDE 4 inhibitors, Rolipram and SB 207499 (Ariflo™), in a rat model of pulmonary neutrophilia. Pulmonary Pharmacology and Therapeudtics. 2001; 14:157- 164. Takeda N, Hasegawa S, Morita M, and Matsunaga T. Pica in rats is analogous to emesis: an animal model in emesis research. Pharmacology, Biochemistry and Behavior. 1991; 45:817-821.
Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and Matsunaga T. Neuropharmacological mechanisms of emesis. I . Effects of antiemetic drugs on motion- and apomorphine-induced pica in rats. Meth Find Exp Clin Pharmacol. 1995; 17(9) 589-596.
Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and Matsunaga T. Neuropharmacological mechanisms of emesis. LI . Effects of antiemetic drugs on cisplatin-induced pica in rats. Meth Find Exp Clin Pharmacol. 1995; 17(9) 647-652. In Vivo Assay 3. 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.) admimstered PDE4 inhibitors. The PDE4 inhibitors are preferably in dry powder or wet suspension form. I.t. administration is one model of inhaled administration, allowing topical delivery to the lung.
Animals: Male CD (Sprague Dawley Derived) rats supplied by Charles River, Raleigh, NC, USA were housed in groups of 5 rats per cage, acclimatised after delivery for at least 7 days with bedding/nesting material regularly changed, fed on SDS diet Rl pelleted food given ad lib, and supplied with daily-changed pasteurised animal grade drinking water.
Device for dry powder administration: Disposable 3-way tap between dosing needle and syringe. A 3-way sterile tap (Vycon Ref 876.00) was weighed, the drug blend or inhalation grade lactose (vehicle control) was then added to the tap, the tap closed to prevent loss of drug, and the tap was re-weighed to determine the weight of drug in the tap. After dosing, the tap was 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, was cut by engineering to approximately 132 mm (5.2 inches), a blunt end was made to prevent them damaging the rat's trachea, and the needle weighed prior to and after drug delivery to confirm that no drug was 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, was used, with a flexible plastic portex canula inserted into the needle.
Drugs and Materials: Lipopolysaccharide (LPS) (Serotype:0127:B8) (L3129 Lot 61K4075) was dissolved in phosphate-buffered saline (PBS). PDE4 inhibitors are used in size-reduced (e.g. micronised) form, for example according to the Micronisation Example given above. For dry powder administration of the drug, the Dry Powder Formulation Example given above, comprising drug and inhalation-grade lactose, can be used. The inhalation-grade lactose usually used (Lot E98L4675 Batch 845120) has 10% fines (10% of material under 15um particle size measured by Malvern particle size). Wet suspensions of the drug can be prepared by adding the required volume of vehicle to the drug; the vehicle used being a mixture of saline/tween (0.2%> tween 80). The wet suspension was sonicated for 10 minutes prior to use. Preparation, and dosing with PDE 4 inhibitor: Rats were' 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 litre.minute"1). Once anaesthetised, the animals were placed onto a stainless steel i.t. dosing support table. They were positioned on their back at approximately a 35° angle. A light was angled against the outside of the throat to highlight the trachea. The mouth was 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 was introduced via a blunt metal dosing needle that had been carefully inserted into the rat trachea. The animals were intratracheally dosed with vehicle or PDE4 inhibitor via the dosing needle with a new internal canula used for each different drug group. The formulation was slowly (10 seconds) dosed into the trachea using a syringe attached to the dosing needle.
Dosing with a Dry Powder: The three-way tap device and needle were 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 2x 4ml of air 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. After dosing, the needle and tap are removed from the airway and the tap closed off to prevent any retained drug leaving the tap.
After dosing with either wet suspension or dry powder, the animals are then removed from the table and observed constantly until they have recovered from the effects of anaesthesia. The animals are returned to the holding cages and given free access to food and water; they are observed and any unusual behavioural changes noted. Exposure to LPS: About 2 hours after i.t. dosing with vehicle control or the PDE4 inhibitor, the rats were placed into sealed Perspex containers and exposed to an aerosol of LPS (nebuliser concentration 150 μg.ml"1) for 15 minutes. Aerosols of LPS were generated by a nebuliser (DeVilbiss, USA) and this was directed into the Perspex exposure chamber. Following the 15-minute LPS-exposure period, the animals were returned to the holding cages and allowed free access to both food and water.
[Ln an alternative embodiment, the rats can exposed to LPS less than 2 hours after i.t. dosing. In another alternative embodiment, the rats can exposed to LPS more than 2 hours (e.g. ca. 4 or ca. 6 hours) after i.t. dosing by vehicle or PDE4 inhibitor, to test whether or not the PDE4 inhibitor has a long duration of action (which is not essential).] Bronchoalveolar lavage: A hours after LPS exposure the animals were killed by overdose of sodium pentobarbitone (i.p.). The trachea was cannulated with polypropylene tubing and the lungs lavaged (washed out) with 3 x 5 mis of heparinised (25 units.mi"1) phosphate buffered saline (PBS).
Neutrophil cell counts: The Bronchoalveolar lavage (BAL) samples were centrifuged at 1300 rpm for 7 minutes. The supernatant was removed and the resulting cell pellet resuspended in 1 ml PBS. A cell slide of the resuspension fluid was prepared by placing lOOμl of resuspended BAL fluid into cytospin holders and then spun at 5000 rpm for 5 minutes. The slides were allowed to air dry and then stained with Leishmans stain (20 minutes) to allow differential cell counting. The total cells were also counted from the resuspension. From these two counts, the total numbers of neutrophils in the BAL were determined. For a measure of PDE4-inhibitor-induced inhibition of neutrophilia, a comparison of the neutrophil count in rats treated with vehicle and rats treated with PDE4 inhibitors is conducted.
By varying the dose of the PDE4 inhibitor used in the dosing step (e.g. 0.2 or 0.1 mg of PDE4 inhibitor per kg of body weight, down to e.g. 0.01 mg/kg), a dose-response curve can be generated.
In Vivo Assay 4. Evaluation of Therapeutic Index of PDE 4 inhibitors in the conscious ferret
1.1 Materials
The following materials are used for these studies: PDE4 inhibitors are prepared for oral (p.o.) administration by dissolving in a fixed volume (1 ml) of acetone and then adding cremophor to 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. 1.2 Animals
Male ferrets (Mustela Pulorius Furo, weighing 1 - 2 kg) are transported and allowed to acclimatise for not less than 7 days. The diet comprises SDS diet C pelleted food given ad lib with WhiskersTM caχ f00d g1Ven 3 times per week. The animals are supplied with pasteurised animal grade drinking water changed daily. 1.3 Experimental Protocol(s)
1.3.1 Dosing with PDE4 inhibitors
PDE4 inhibitors are administered orally (p.o.), using a dose volume of lml/kg. Ferrets are fasted overnight but allowed free access to water. The animals are orally dosed with vehicle or PDE 4 inhibitor using a 15cm dosing needle that is passed down the back of the throat into the oesophagus. After dosing, the animals are returned to holding cages fitted with perspex doors to allow observation, and given free access to water. The animals are constantly observed and any emetic episodes (retching and vomiting) or behavioural changes are recorded. The animals are allowed access to food 60 - 90 minutes after p.o. dosing. 1.3.2 Exposure to LPS
Thirty minutes after oral dosing with compound or vehicle control, the fereets are placed into sealed perspex containers and exposed to an aerosol of LPS (30 μg/ml) for 10 minutes. Aerosols of LPS are generated by a nebuliser (DeVilbiss, USA) and this is directed into the perspex exposure chamber. Following a 10-minute exposure period, the animals are returned to the holding cages and allowed free access to water, and at a later stage, food. General observation of the animals continues for a period of at least 2.5 hours post oral dosing. All emetic episodes and behavioural changes are recorded. 1.3.3 Bronchoalveolar lavage and cell counts
Six hours after LPS exposure the animals are killed by overdose of sodium pentobarbitone administered intraperitoneally. The trachea is then cannulated with polypropylene tubing and the lungs lavaged twice with 20 ml heparinised (10 units/ml) phosphate buffered saline (PBS). The bronchoalveolar lavage (BAL) samples are centrifuged at 1300 m for 7 minutes. The supernatant is removed and the resulting cell pellet re-suspended in 1 ml PBS. A cell smear of re-suspended fluid is prepared and stained with Leishmans stain to allow differential cell counting. A total cell count is made using the remaining re-suspended sample. From this, the total number of neutrophils in the BAL sample is determined.
1.3.4 Pharmacodynamic readouts The following parameters are recorded: a) %o inhibition of LPS-induced pulmonary neutrophilia to determine the dose of PDE4 inhibitor which gives 50% inhibition (D50). b) Emetic episodes - the number of vomits and retches are counted to determine the dose of PDE4 inhibitor that gives a 20% incidence of emesis (D20). c) A therapeutic index (TL), using this assay, is then calculated for each PDE4 inhibitor using the following equation:
Therapeutic index (TI) = D20 incidence of emesis
D50 inhibition of neutrophilia
It is noted that the Therapeutic index (TI) calculated using this in vivo Assay 4 is often significantly different to, and often lower than, that calculated using the rat oral inflammation and pica feeding Assays 1+2.
The calculation of TI using the PDE4 inhibitor roflumilast in this Assay 4 is: D20 for emesis = 0.5mg/kg p.o., D50 for neutroplilia = 0.49mg/kg p.o., TI = 1.02
All publications, including but not limited to patents and patent applications, cited in this specification are herein incoφorated by reference as if each individual publication were specifically and individually indicated to be incoφorated by reference herein as though fully set forth. EXAMPLES
The various aspects of the invention will now be described by reference to the following examples. These examples are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In this section, "Intermediates" represent syntheses of intermediate compounds intended for use in the synthesis of the "Examples".
Abbreviations used herein:
DMSO dimethyl sulfoxide
DCM dichloromethane
EtOAc ethyl acetate
Et2O diethyl ether
DMF dimethyl formamide
MeOH methanol
HPLC high pressure liquid chromatography
SPE solid phase extraction
NMR nuclear magnetic resonance (in which: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, H = no. of protons)
LCMS liquid chromatography/mass spectroscopy
TLC thin layer chromatography
BEMP 2-t-butylimino-2-diethylamino- 1 ,3-dimethylperhydro- 1 ,3 ,2- diazaphosphazine
EDC l-(3-DimethylaminopiOpyl)-3-ethylcarbodiimide hydrochloride
HATU O-(7-Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HBTU O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HOBT hydroxybenzotriazole = 1-hydroxybenzotriazole h hours
DLPEA diisopropylethyl amine ( ^NEt)
TRET retention time
THF Tetrahydrofuran
Lawesson's reagent 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4- disulphide Room temperature this is usually in the range of about 20 to about 25 °C.
Machine Methods used herein:
LCMS (liquid chromatography/mass spectroscopy) Waters ZQ mass spectrometer operating in positive ion electrospray mode, mass range 100-1000 amu. UV wavelength : 215-330nM Column : 3.3cm x 4.6mm LD, 3μm ABZ+PLUS Flow Rate : 3ml/min Injection Volume : 5μl
Solvent A : 95% acetonitrile + 0.05% formic acid Solvent B : 0.1% formic acid + lOmMolar ammonium acetate Gradient : 0% A/0.7min, 0-100% A/3.5min, 100% A/l.lmin, 100-0% A/0.2min
Mass directed autoprep HPLC
The prep column used was a Supelcosil ABZplus (10cm x 2.12cm)
(usually 10cm x 2.12cm x 5 μm). UV wavelength : 200-320nM
Flow : 20ml/min
Injection Volume: 1ml; or more preferably 0.5 ml
Solvent A : 0.1 %> formic acid
Solvent B : 95%» acetonitrile + 5% formic acid; or more usually 99.95%) acetonitrile + 0.05% formic acid
Gradient : 100% A/lmin, 100-80% A/9min, 80-1% A/3.5min, 1% All.Am , 1-
100%A/0.1min
Intermediates and Examples
All reagents not detailed in the text below are commercially available from established suppliers such as Sigma-Aldrich. The addresses of the suppliers for some of the starting materials mentioned in the Intermediates and Examples below or the Assays above are as follows:
- ABCR GmbH & CO. KG, P.O. Box 21 01 35, 76151 Karlsruhe, Germany
- Aceto Color Intermediates (catalogue name), Aceto Corporation, One Hollow Lane, Lake Success, NY, 11042-1215, USA
- Acros Organics, A Division of Fisher Scientific Company, 500 American Road, Morris Plains, NJ 07950, USA
- Apin Chemicals Ltd., 82 C Milton Park, Abingdon, Oxon OX144RY, United Kingdom
- Apollo Scientific Ltd., Unit IA, Bingswood Industrial Estate, Whaley Bridge, Derbyshire SK23 7LY, United Kingdom
- Aldrich (catalogue name), Sigma-Aldrich Company Ltd., Dorset, United Kingdom, telephone: +44 1202 733114; Fax: +44 1202 715460; ukcustsv@eurnotes.sial.com; or
- Aldrich (catalogue name), Sigma-Aldrich Corp., P.O. Box 14508, St. Louis, MO 63178-9916, USA; telephone: 314-771-5765; fax: 314-771-5757; custserv@sial.com; or
- Aldrich (catalogue name), Sigma-Aldrich Chemie Gmbh, Munich, Germany; telephone: +49 89 6513 0; Fax: +49 89 6513 1169; deorders@eurnotes.sial.com. - Alfa Aesar, A Johnson Matthey Company, 30 Bond Street, Ward Hill, MA 01835-8099, USA
- Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP 84SP, United Kingdom
- Array Biopharma Inc., 1885 33rd Street, Boulder, CO 80301, USA - AstaTech, Inc., 8301 Torresdale Ave., 19C, Philadelphia, PA 19136, USA
- Austin Chemical Company, Inc., 1565 Barclay Blvd., Buffalo Grove, IL 60089, USA
- Avocado Research, Shore Road, Port of Heysham Industrial Park, Heysham Lancashire LA3 2XY, United Kingdom - Bayer AG, Business Group Basic and Fine Chemicals, D-51368 Leverkusen, Germany
- Berk Univar pic, Berk House, P.O.Box 56, Basing View, Basingstoke, Hants RG21 2E6, United Kingdom
- Butt Park Ltd., Braysdown Works, Peasedown St. John, Bath BA2 8LL, United Kingdom
- Chemical Building Blocks (catalogue name), Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France
- ChemBridge Europe, 4 Clark's Hill Rise, Hampton Wood, Evesham, Worcestershire WR11 6FW, United Kingdom
- ChemService Inc., P.O.Box 3108, West Chester, PA 19381, USA
- Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA - Dynamit Nobel GmbH, Germany; also available from: Saville Whittle Ltd (UK agents of Dynamit Nobel), Nickers Street, Manchester M40 8EF, United Kingdom
- E. Merck, Germany; or E. Merck (Merck Ltd), Hunter Boulevard, Magna Park, Lutterworth, Leicestershire LEI 7 4XΝ, United Kingdom
- Esprit Chemical Company, Esprit Plaza, 7680 Matoaka Road, Sarasota, FL 34243, USA - Exploratory Library (catalogue name), Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France
- Fluka Chemie AG, Industriestrasse 25, P.O. Box 260, CH-9471 Buchs, Switzerland
- Fluorochem Ltd., Wesley Street, Old Glossop, Derbyshire SKI 3 7RY, United Kingdom
- ICN Biomedicals, Inc., 3300 Hyland Avenue, Costa Mesa, CA 92626, USA
- Lnterchim Intermediates (catalogue name), Interchim, 213 Avenue Kennedy, BP 1140, Montlucon, Cedex, 03103, France
- Key Organics Ltd., 3, Highfield Indusrial Estate, Camelford, Cornwall PL32 9QZ, United Kingdom
- Lancaster Synthesis Ltd., Newgate, White Lund, Morecambe, Lancashire LA3 3DY, United Kingdom - Manchester Organics Ltd., Unit 2, Ashville Industrial Estate, Sutton Weaver, Runcorn, Cheshire WA7 3PF, United Kingdom
- Matrix Scientific, P.O. Box 25067, Columbia, SC 29224-5067, USA
- Maybridge Chemical Company Ltd., Trevillett, Tintagel, Cornwall PL34 0HW, United Kingdom - Maybridge Reactive intermediates (catalogue name), Maybridge Chemical Company Ltd., Trevillett, Tintagel, Cornwall PL34 0HW, United Kingdom
- MicroChemistry Building Blocks (catalogue name), MicroChemistry-RadaPharma, Shosse Entusiastov 56, Moscow, 111123, Russia
- Miteni S.p.A., Via Mecenate 90, Milano, 20138, Italy - Molecular Devices Corporation, Sunnydale, CA, USA
- N.D. Zelinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia
- Optimer Building Block (catalogue name), Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA - Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak SK23 OPG, United Kingdom
- Pfaltz & Bauer, Inc., 172 East Aurora Street, Waterbury, CT 06708, USA
- Rare Chemicals (catalogue name), Rare Chemicals GmbH, Schulstrasse 6, 24214 Gettorf, Germany
- SALOR (catalogue name) (Sigma Aldrich Library of Rare Chemicals), Aldrich Chemical Company Inc, 1001 West Saint Paul Avenue, Milwaukee, WI 53233, USA
- Sigma (catalogue name), Sigma-Aldrich Coφ., P.O. Box 14508, St. Louis, MO 63178-9916, USA; see "Aldrich" above for other non-US addresses and other contact details
- SIGMA-RBI, One Strathmore Road, Natick, MA 01760-1312, USA
- Synchem OHG Heinrich-Plett-Strasse 40, Kassel, D-34132, Germany
- Syngene International Pvt Ltd, Hebbagodi, Hosur Road, Bangalore, India.
- TCI America, 9211 North Harborgate Street, Portland, OR 97203, USA
- TimTec Building Blocks A, TimTec, Inc., P O Box 8941, Newark, DE 19714-8941, USA
- Trans World Chemicals, Inc., 14674 Southlawn Lane, Rockville, MD 20850, USA
- Ubichem PLC, Mayflower Close, Chandlers Ford industrial Estate, Eastleigh, Hampshire S053 4AR, United Kingdom
- Ultrafine (UFC Ltd.), Synergy House, Guildhall Close, Manchester Science Park, Manchester Ml 5 6SY, United Kingdom
Table of Intermediates
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0003
Intermediate 1 ; Ethyl 4-chloro-l-ethyl-lΗ-pyrazolo[3,4-b]pyridine-5-carboxylate
Prepared from commercially available 5-amino-l -ethyl pyrazole as described by G. Yu et. al. inJ. Med Chem., 2001, 44, 1025-1027:
Figure imgf000093_0001
Intermediate 2: Ethyl 4-ethoxy-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
Can be prepared by oxidative cleavage (Seθ2) of 1-furanylmethyl derivative, as described by T. M. Bare et. al. hi J. Med. Chem., 1989, 32, 2561-2573, (further referenced to Zuleski, F. R, Kirkland, K. R., Melgar, M. D.; Malbica, J. Drug. Metab. Dispos., 1985, 13, 139)
Figure imgf000093_0002
Intermediate 3: Ethyl l-methyl-4-ethoxy-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000094_0001
A mixture of Intermediate 2 (0.47g) and anhydrous potassium carbonate (0.83g) (previously dried by heating at 100°C) in anhydrous dimethylformamide (DMF) (4ml) was treated with iodomethane (0.26ml) and stirred vigorously for 3h. The mixture was then filtered and the filtrate concentrated in vacuo to afford a residual oil, which was partitioned between dichloromethane (DCM) (25ml) and water (25ml). The layers were separated and the aqueous phase was extracted with further DCM (2x25ml). The combined organic extracts were dried over anhydrous sodium sulphate and evaporated to an orange solid which was applied to an SPE cartridge (silica, 20g). The cartridge was eluted sequentially with EtOAc : petrol (1:4, 1:2 and 1:1), then chloroform : methanol (49:1, 19:1 and 9:1). Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 3 (0.165g). LCMS showed MH+= 250; TRE = 2.59 min.
Intermediate 4: Ethyl l-benzvl-4-ethoxv-lH-pyrazolof3,4-blpvridine-5-carboxylate
Figure imgf000094_0002
A mixture of Intermediate 2 (0.47g) and anhydrous potassium carbonate (0.83g) (previously dried by heating at 100°C) in anhydrous DMF (4ml) was treated with benzyl bromide (0.72g) then stined vigorously and heated at 55°C for 4.5h. The mixture was allowed to cool, then filtered and the filtrate concentrated in vacuo to afford a residual oil, which was partitioned between DCM (25ml) and water (25ml). The layers were separated and the aqueous phase was extracted with further DCM (2x25ml). The combined organic extracts were dried over anhydrous sodium sulphate and evaporated to a yellow oily solid which was dissolved in DCM and applied to an SPE cartridge (silica, 20g). The cartridge was eluted with a gradient of EtOAc : petrol (1:4, 1:2 and 1:1) then chloroform : methanol (49:1, 19:1 and 9:1). Fractions containing desired material were combined and concentrated in vacuo to afford Lntermediate 4 (0.33g). LCMS showed MH+= 326; TRET = 3.24 min. Intermediate 5: Ethyl 4-chloro-l-phenyl-lH-pyrazolof3,4-blpyridine-5-carboxylate
Figure imgf000095_0001
A mixture of 5-amino-l -phenyl pyrazole (2.0g) and diethylethoxymethylene malonate (2.54ml) was heated under Dean Stark conditions at 120°C for 16h. The solution was cooled, phosphorus oxychloride (16ml) was then added and the mixture heated under reflux for a further 20h. Excess phosphorus oxychloride was removed in vacuo and the residue partitioned between diethyl ether and water, proceeding with extreme caution on addition of water. The ethereal layer was washed with further water, then dried over magnesium sulphate and concentrated in vacuo to afford ethyl 4-chloro- 1 -phenyl- 1H- pyrazolo[3,4-b]pyridine-5-carboxylate (2.09g). LCMS showed MH+= 302; TRET = 3.80 min.
Intermediate 6; l-Acetyl-4-aminopiperidine
Prepared from commercially available Nl-benzyl-4-aminopiperidine as described by Yamada et. al. Ln WO 00/42011 :
Figure imgf000095_0002
Intermediate 7; l-Methyl-4-aminopiperidine
Prepared from commercially available N-methyl-4-piperidone as described by C. M. Andersson et. al. in WO01/66521:
Figure imgf000095_0003
Intermediate 8: 4-Aminotetrahydropyran
Commercially available from Combi-Blocks Lnc, 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA (CAS 38041-19-9)
H2N— { p Intermediate 8A: Tetrahydro-2H-pvran-4-amine hydrochloride 4-Aminotetrahydropyran hydrochloride
Figure imgf000096_0001
Step 1 : N,N-dibenzyltetrahydro-2H-pyran-4-amine
Dibenzylamine (34.5g) and acetic acid (6.7ml) were added to a stined solution of tetrahydro-4H-pyran-4-one (16.4g, commercially available from e.g. Aldrich) in dichloromethane (260ml) at 0 °C to 5 °C. After 2.5h at 0 °C to 5 °C, sodium triacetoxyborohydride (38.9g) was added portionwise, and the mixture was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was washed successively with 2M-sodium hydroxide (200ml and 50ml), water (2 x 50ml) and brine (50ml), then dried and evaporated to give a yellow oil (45g). This oil was stirred with methanol (50ml) at 4 °C for 30min to give the product as a white solid (21.5g). LCMS showed MH+= 282; TRET = 498 min.
Step 2: Tetrahydro-2H-pyran-4-amine hydrochloride N,N-dibenzyltetrahydro-2H-pyran-4-amine (20.5g) was dissolved in ethanol (210ml) and hydrogenated over 10%> palladium on carbon catalyst (4g) at 100 psi for 72h at room temperature. The reaction mixture was filtered and the filtrate was adjusted to pΗ 1 with 2M-hydrogen chloride in diethyl ether. Evaporation of solvents gave a solid which was triturated with diethyl ether to give the product as a white solid (9.23g). Η ΝMR (400MHz in d6-DMSO, 27°C, δppm) 8.24 (br. s, 3H), 3.86 (dd, 12, 4Hz, 2H), 3.31 (dt, 2, 12Hz, 2H), 3.20 (m, IH), 1.84 (m, 2H), 1.55 (dq, 4, 12Hz, 2H).
Intermediate 9: (R)-(+)-3-Amino tetrahydrofuran 4-toluenesulphonate
Commercially available from Fluka Chemie AG, Germany (CAS 111769-27-8)
Figure imgf000096_0002
Intermediate 10: (S)-(-)-3-Amino tetrahydrofuran 4-toluenesulphonate
Commercially available from E. Merck, Germany; or from E. Merck (Merck Ltd), Hunter Boulevard, Magna Park, Lutterworth, Leicestershire LE17 4XΝ, United Kingdom (CAS 104530-80-5)
Figure imgf000096_0003
Intermediate 11: Tetrahydro-2H-thiopyran-4-amine
Prepared from commercially available tetrahydrothiopyran-4-one as described by Subramanian et. al, J. Org. Chem., 1981, 46, 4376-4383. Subsequent preparation of the hydrochloride salt can be achieved by conventional means.
NH2OH LiAIK,
Figure imgf000097_0002
Figure imgf000097_0001
Figure imgf000097_0003
Intermediate 12: Tetrahydro-3-thiopheneamine
Prepared in an analogous manner to Intermediate 11 from commercially available tetrahydrothiophene-4-one. The oxime formation is described by Grigg et.al., Tetrahedron, 1991, Al, AA11-AA9A and the oxime reduction by Unterhalt et. al. , Arch. Pharm., 1990, 317-318.
Figure imgf000097_0004
Intermediate 13: Tetrahydro-3-thiopheneamine 1,1-dioxide hydrochloride
Commercially available from Sigma Aldrich Library of Rare Chemicals (SALOR) (CAS-
6338-70-1). Preparation of the hydrochloride salt of the amine can be achieved by conventional means.
Figure imgf000097_0005
Intermediate 14: Tetrahvdro-2H-thiopyran-4-amine-l.l-dioxide hydrochloride
Prepared in an analogous manner to Intermediate 11 from commercially available tetrahydrothiophene-4-one. Oxidation to l,l-dioxo-tetrahydro-lλ6-thiopyran-4-one is described by Rule et. al., inJ. Org. Chem., 1995, 60, 1665-1673. Oxime formation is described by Truce et.al., in J. Org. Chem., 1957, 617, 620 and oxime reduction by Barkenbus et. al., J. Am. Chem. Soc, 1955, 77, 3866. Subsequent preparation of the hydrochloride salt of the amine can be achieved by conventional means.
AcOOH NH2OH H2/ Raney Ni
Figure imgf000097_0006
Figure imgf000097_0008
Figure imgf000097_0007
Figure imgf000097_0009
ntermediate 15: 4-Chloro-l-ethyl-lH-pyrazoIo[3,4-b]pyridine-5-carboxylic acid
Figure imgf000098_0001
A solution of Intermediate 1 (3.5g) in dioxane (28ml) was treated with potassium hydroxide (6.3g) as a solution in water (20ml). The mixture was stirred for 2h, then concentrated in vacuo, acidified to pH 3 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The layers were separated, the organic layer dried over sodium sulphate, then concentrated in vacuo to afford Intermediate 15 as a white solid (2.4g). LCMS showed MH+ = 226; TRET = 2.62min.
Intermediate 17: N-Benzyl-4-chloro-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
That is, Intermediate 17 is: erein NR R5 = HN
Figure imgf000098_0002
Lntermediate 15 (3.5g) was dried over phosphorus pentoxide for lh, then treated with thionyl cliloride (47g). The mixture was sthred and heated at 75°C for 1.3h. Excess thionyl chloride was removed in vacuo and the residual oil azeotroped with dichloromethane (DCM) to afford Intermediate 16, presumed to be the acid chloride derivative of Intermediate 15, as a white solid (3.3g).
Intermediate 16 (0.473 g) was dissolved in tetrahydrofuran (THF) (4ml) and treated with N,N-diisopropylethylamine (DLPEA) (0.509ml), then with benzylamine (0.209g) and the mixture stirred under nitrogen for 0.5h. The mixture was concentrated in vacuo, then partitioned between dichloromethane and water. The layers were separated and the organics concentrated in vacuo to afford Intermediate 17 (0.574g). LCMS showed MH+ = 315; TRET := 2.90min.
Similarly prepared were the following:
Figure imgf000099_0001
Figure imgf000099_0004
Intermediate 22: 4-Chloro-l -ethyl-N-(pyridin-4-ylmethyl)-lH-pyrazolo [3,4- b] pyridine-5-carboxamide
Figure imgf000099_0002
Acid chloride hitermediate 16 was syntliesised from Intermediate 15 using the method shown above for Intermediate 17. Intermediate 16 (0.473 g) was dissolved in THF (4ml) and treated with diisopropylethylamine (DLPEA) (0.509ml), then with 4- (aminomethyl)pyridine (0.21 lg) and the mixture stined under nitrogen for 0.5h. The mixture was concentrated in vacuo, then partitioned between DCM and water. The layers were separated and the organics concentrated in vacuo, then applied to an SPE cartridge (silica, lOg) which was eluted with a gradient of cyclohexane : EtOAc (2:1 increasing stepwise up to 0:1), followed by MeOH : EtOAc (5:95, then 10:90). Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 22 (0.086g). LCMS showed MH+ = 316; TRET = 1.84min.
Intermediate 23: 4-Chloro-l-ethyl-N-n-propyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
Figure imgf000099_0003
Acid chloride Intermediate 16 was synthesised from Lntermediate 15 using the method shown above for Lntermediate 17. Intermediate 16 (0.473 g) was dissolved in THF (4ml) and treated with DLPEA (0.509ml), then with n-propyl amine (0.115g) and the mixture stirred under nitrogen for 0.5h. A further portion of n-propyl amine (0.023g) was then added and stirring continued for 18h. The mixture was concentrated in vacuo, then partitioned between DCM and water. The layers were separated and the organics concentrated in vacuo to afford Intermediate 23 (0.405g). LCMS showed MH+ = 267; TRET = 2.54min.
Intermediate 24: 4-Chloro-l-ethyI-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000100_0001
Acid chloride Intermediate 16 was synthesised from Intermediate 15 using the method shown above for Intermediate 17. intermediate 16 (0.30g) was dissolved in THF (3ml) and treated with a 0.5M solution of ammonia in dioxane (4.92ml). The mixture was stined under nitrogen for 18h. A further portion of 0.5M ammonia in dioxane (4.92ml) was added and stirring continued for 72h. The mixture was concentrated in vacuo and the residue partitioned between DCM and 2M sodium hydroxide solution. The layers were separated and the organics concentrated to afford hitermediate 24 (0.278g). LCMS showed MH+ = 225; TRET = 2.10min.
Intermediate 25: Ethyl 4-chloro-l olo [3 ,4-b] py ridine-5-carb oxylate
Figure imgf000100_0002
A mixture of 5-amino-l -methyl pyrazole (4.0g) and diethylethoxymethylene malonate (9.16ml) was heated at 150°C under Dean Stark conditions for 5h. Phosphorous oxychloride (55ml) was carefully added to the mixture and the resulting solution heated at 130°C under reflux for 18h. The mixture was concentrated in vacuo, then the residual oil cooled in an ice bath and treated carefully with water (100ml)(caution: exotherm). The resulting mixture was extracted with DCM (3x100ml) and the combined organic extracts were dried over anhydrous sodium sulphate and concentrated in vacuo. The residual solid was purified by Biotage chromatography (silica, 90g), eluting with Et20 : petrol (1:3). Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 25 (4.82g). LCMS showed MH+ = 240; TRET = 2.98min Intermediate 26: 4-Chloro-l-methyI-lH-pyrazolor3,4-blpyridine-5-carboxylic acid
Figure imgf000101_0001
A solution of Intermediate 25 (4.0g) in dioxane (30ml) was treated with potassium hydroxide (7.54g) as a solution in water (20ml). The mixture was stirred for 16h, then diluted with water (150ml) and acidified to pH 3 with 5M aqueous hydrochloric acid. The mixture was stined in an ice bath for 15min, then collected by filtration, washed with ice- cold water and dried in vacuo over phosphorous pentoxide to afford Lntermediate 26 as a white solid (2.83g). LCMS showed MH+ = 212; TRET = 2.26min.
Intermediate 28: N-Benzyl-4-chloro-l-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
Intermediate 28 NR4R5 _ = HN
Figure imgf000101_0002
Intermediate 26 (2.5g) (previously dried over phosphorus pentoxide) was treated with thionyl chloride (25ml) and the mixture heated under reflux for lh. Excess thionyl chloride was removed in vacuo to afford Intermediate 27, presumed to be the acid chloride derivative of Intermediate 26, as a white solid (2.7g).
hitermediate 27 (0.68g) was dissolved in THF (10ml) and treated with DLPEA (0.77ml), then with benzyl amine (0.339g) and the mixture stirred under nitrogen for 3h. The mixture was concentrated in vacuo, then partitioned between DCM (20ml) and water (10ml). The layers were separated and the organics concentrated in vacuo to afford Intermediate 28 (0.90g). LCMS showed MH* = 301; TRET = 2.72min.
Similarly prepared were the following:
Figure imgf000101_0003
Figure imgf000101_0004
Figure imgf000102_0003
Intermediate 31 : 4-ChIoro-l-methyl-lH-pyrazolo[3,4-blpyridine-5-carboxamide
Figure imgf000102_0001
Acid chloride Intermediate 27 was synthesised from Intermediate 26 using the method shown above for Intermediate 28. Intermediate 27 (0.68g) was then treated with a 0.5M solution of ammonia in dioxane (17.7ml). Diisopropylethylamine (0.51ml) was then added and the mixture stirred for 21h. The mixture was then partitioned between DCM (100ml) and water (30ml). An insoluble solid was removed by filtration, washed with water (20ml) and dried in vacuo over phosphorous pentoxide to afford Lntermediate 31 (0.544g). LCMS showed MH+ = 211; TRET = L84min.
Intermediate 32 (= Example 3): Ethyl l-ethyI-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxyIate
Figure imgf000102_0002
Intermediate 1 (0.20g) and triethylamine (0.55ml) were suspended in ethanol (8ml) and 4- aminotetrahydropyran (0.088g) was added. The mixture was stined under nitrogen, heated at 80°C for 16h, then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was loaded directly onto an SPE cartridge (silica, 5g) which was eluted sequentially with; (i) DCM, (ii) DCM : Et2O (2:1), (iii) DCM : Et2O (1:1), (iv) Et2O and (v) EtOAc. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 32 (0.21g). LCMS showed MH+ = 319; TRET = 2.93min.
In an alternative embodiment, Intennediate 32 (= Example 3) can be made as described below under "Example 3", in particular according to "Example 3, Method B" below. Intermediate 33: l-EthyI-4-(tetrahydro-2H-pyran-4-yIamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxylic acid
Figure imgf000103_0001
A solution of hitermediate 32 (Example 3) (0.21g) in ethanol : water (95:5, 10ml) was treated with sodium hydroxide (0.12g). The mixture was heated at 50°C for 8h, then concentrated in vacuo, dissolved in water and acidified to pH 4 with acetic acid. The resultant white solid was removed by filtration and dried under vacuum to afford Intermediate 33 as an off-white solid (0.156g). LCMS showed MH+ = 291; TRET = 2.11min.
An alternative preparation of Intermediate 33 is as follows:
A solution of Intermediate 32 (Example 3) (37.8g) in ethanol : water (4:1, 375ml) was treated with sodium hydroxide (18.9g). The mixture was heated at 50 °C for 5 hours, then concentrated in vacuo, dissolved in water and acidified to pH 2 with aqueous hydrochloric acid (2M). The resultant white solid was removed by filtration and dried under vacuum to afford intermediate 33 as an off-white solid (29.65g). LCMS showed Mϊt = 291; TRET = 2.17 min.
Intermediate 34 (= Example 8): Ethyl l-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]- 1 H-pyrazolo [3 ,4-b] pyridine-5-carb oxylate
Figure imgf000103_0002
Intermediate 1 (0.05g) and (S)-(-)-3-aminotetrahydrofuran 4-toluenesulphonate (0.052g) were suspended in ethanol (1ml) and triethylamine (0.14ml) was added. The mixture was stined under nitrogen and heated at 80°C for 24h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM (2ml) and water (1.5ml). The layers were separated and the organic layer concentrated to dryness. Purification was carried out using an SPE cartridge (silica, 5g), eluting with a gradient of EtOAc : cyclohexane; (1:16 then, 1:8, 1:4, 1:2, 1:1 and 1:0). Fractions containing desired material were combined and concentrated in vacuo to afford intermediate 34 (= Example 8) (0.052g). LCMS showed MH* = 305; TRET = 2.70min. Similarly pre ared were the following:
Figure imgf000104_0001
Figure imgf000104_0003
Intermediate 39 (= Example 13): Ethyl 4-[(l,l-dioxidotetrahydrothien-3-yI)amino]- l-ethyMH-pyrazoIo[3,4-b]pyridine-5-carboxylate
Figure imgf000104_0002
Intermediate 1 (0.05g) and Lntermediate 13 (0.027g) were suspended in ethanol (1ml) and triethylamine (0.14ml) was added. The mixture was stined under nitrogen and heated at 80°C for 24h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM (2ml) and water (1.5ml). The layers were separated and the organic layer concentrated to dryness. Purification was carried out using an SPE cartridge (silica, 5g), eluting with a gradient of EtOAc : cyclohexane; (1:8 then 1:4, 1:2, 1:1 and 1:0). Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 39 (= Example 13) (0.045g) as a mixture of enantiomers. LCMS showed MH+ = 353; TRET = 2.60min. Similarly prepared was the following:
Figure imgf000105_0001
Figure imgf000105_0004
Intermediate 41 : l-Ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-lH-pyrazolo[3,4- b]pyridine-5-c
Figure imgf000105_0002
A solution of Intermediate 34 (0.037g) in ethanol : water (95:5, 3ml) was treated with sodium hydroxide (0.019g). The mixture was heated at 50°C for 16h, then concentrated in vacuo. The residue was dissolved in water (1.5ml) and acidified to pH 4 with acetic acid.
The resultant white solid precipitate was removed by filtration and dried under vacuum.
The filtrate was extracted with ethyl acetate and the organic layer collected and concentrated in vacuo to afford a further portion of white solid. The two solids were combined to afford Intermediate 41 (0.033g). LCMS showed MH+ = 277; TRET = 2.05 min.
Similarly prepared were the following:
Figure imgf000105_0003
Figure imgf000105_0005
Figure imgf000106_0002
Intermediate 48: Ethyl 4-(cyclohexylamino)-lH-pyrazolo[3,4-Z>]pyridine-5- carboxylate
Figure imgf000106_0001
Lntennediate 2 (0.69g) was suspended in cyclohexylamine (1.01ml), and the mixture was heated at 90 °C for 3h. The residual mixture was allowed to cool to room temperature and partitioned between chloroform (25ml) and water (25ml). The phases were separated and the organic phase was evaporated to dryness. The residue was triturated with Et2O (25ml) and the insoluble solid was collected and dried to afford Intermediate 48 as a beige solid (0.58g). LCMS showed MH+=289; TRET = 2.91min.
Intermediate 49: 4-(CyclohexyIamino)-lH-pyrazolo [3,4-Z>]pyridine-5-carboxyIic acid
Figure imgf000107_0001
2M-Sodium hydroxide solution (0.5ml) was added to a stined suspension of Intermediate 48 (0.2g) in dioxan (4ml) and water (0.5ml). After stirring overnight at room temperature, the reaction mixture was heated at 40 °C for 8h. A further quantity of 2M-sodium hydroxide solution (1.5ml) was added, and the reaction mixture was heated at 40 °C for 48h. The reaction solution was concentrated, diluted with water (10ml) and acidified with glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and dried to give Intermediate 49 (0.18g). LCMS showed MH+ = 261; TRET = 2.09min.
Intermediate 50: l-n-Propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-ft]pyridine-5-carboxylic acid
Figure imgf000107_0002
2M-Sodium hydroxide solution (0.7ml) was added to a stined suspension of Example 185 (0.23g, described hereinafter) in ethanol (5ml) and water (1.5ml). After stirring overnight at room temperature, a further quantity of 2M-sodium hydroxide solution (0.7ml) was added, and the reaction mixture was heated at 43 °C for 2.5h. The reaction solution was concentrated, diluted with water (5ml) and acidified with 2M-hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give intermediate 50 as a white solid (0.14g). LCMS showed MH+ = 305; TRET = 2.42min. Intermediate Sl: Ethyl 4-chIoro-l-ethyl-6-methyI-lH-pyrazolo[3,4-6]pyridine-5- carboxylate
Figure imgf000108_0001
A mixture of 5-amino-l-ethylpyrazole (1.614g, 14.5mmol) and diethyl 2-(l- ethoxyethylidene)malonate (3.68g, lδ.Ommol, as described by P.P. T. Sah, J. Amer. Chem. Soc, 1931, 53, 1836) was heated at 150 °C under Dean Stark conditions for 5 hours. Phosphorous oxychloride (25ml) was carefully added to the mixture and the resulting solution was heated at 130 °C under reflux for 18 hours. The mixture was concentrated in vacuo, then the residual oil was carefully added, with cooling, to water (100ml). The resulting mixture was extracted with DCM (3x100ml) and the combined organic extracts were dried over anhydrous sodium sulphate and concentrated in vacuo. The residual oil was purified by Biotage chromatography (silica, 90g) eluting with ethyl acetate-petrol (1:19). Fractions containing the desired product were combined and concentrated in vacuo to afford Intermediate 51 (1.15g). LCMS showed MH+ = 268; TRET = 3.18min.
Intermediate 52: 4-(Cyclohexylamino)-l-ethyl-6-methyl-lH-pyrazoIo[3,4- Z>]pyridine-5-carboxylic acid
Figure imgf000108_0002
2M-Sodium hydroxide solution (0.39ml, 0.78mmol) was added to Example 190 (0.128g, 0.39mmol, described hereinafter) in ethanol (1.5ml), and the mixture was heated at 50 °C for 16 hours. The reaction mixture was concentrated, and the resulting aqueous solution was neutralised with 2M-hydrochloric acid to precipitate a solid which was collected by filtration. The filtrate was applied to an OASIS ® hydrophilic-lipophilic balance (HLB) Extraction cartridge * (lg) which was eluted with water followed by methanol.
Evaporation of the methanol fraction gave a solid which was combined with the initial precipitated solid to afford Intermediate 52 (0.083g) as a white solid, presumed to be the carboxylic acid.
* OASIS ® HLB Extraction cartridges are available from Waters Coφoration, 34 Maple Street, Milford, MA 01757, USA. The cartridges include a column containing a copolymer sorbent having a HLB such that when an aqueous solution is eluted through the column, the solute is absorbed or adsorbed into or onto the sorbent, and such that when organic solvent (e.g. methanol) is eluted the solute is released as an organic (e.g. methanol) solution. This is a way to separate the solute from aqueous solvent.
Intermediate 53: l-Ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-yIamino)-lH- pyrazoIo[3,4-A]pyridine-5-carboxylic acid
Figure imgf000109_0001
2M-Sodium hydroxide solution (0.75ml, 1.5mmol) was added to Example 189 (0.248g, 0.75mmol, described hereinafter) in ethanol (2ml), and the mixture was heated at reflux for 16 hours. The reaction mixture was concentrated, diluted with water (1ml) and acidified with 2M-hydrochloric acid (0.75ml) to precipitate a solid which was collected by filtration to afford Lntermediate 53 (0.168g). LCMS showed MH+ = 305; TRET = 1.86min.
Intermediate 54: 4- Aminocyclohexanone hydrochloride
Figure imgf000109_0002
A solution of hydrogen chloride in dioxan (0.5ml, 2.0mmol, 4M) was added to a stined solution of tert-butyl 4-oxocyclohexylcarbamate (0.043g, 0.20mmol, commercially available from Astatech Inc., Philadelphia, USA) in dioxan (0.5ml) and the mixture was stined at room temperature. After lh, the reaction mixture was evaporated to give Intermediate 54 as a cream solid (34mg). 1H NMR (400MHz in d6-DMSO, 27°C, δppm) 8.09 (br. s, 3H), 3.51 (tt, 11, 3.5Hz, IH), 2.45 (m, 2H, partially obscured), 2.29 (m, 2H), 2.16 (m, 2H), 1.76 (m, 2H). Intermediate 54A: JV-Benzyl-4-(cyclohexylamino)-lH-pyrazolo[3,4- b] pyridine-5-carboxamide
Figure imgf000110_0001
Benzylamine (0.16ml) was added to a stined mixture of Intermediate 49 (0.13g), DLPEA (0.26ml) and HATU (0.285g) in DMF (3ml). The resultant mixture was heated with stirring at 85 °C for 16 hours. Further portions of HATU (0.14g), DLPEA (0.13ml) and benzylamine (0.082ml) were added and the mixture heated for 16 hours at 88 °C. The resultant solution was concentrated, diluted with dichloromethane (20ml) and washed with saturated sodium bicarbonate solution (20ml), separated by hydrophobic frit and the organic layer concentrated. The residue was purified on a SPE cartridge (silica, 20g) eluting with 60-80%> ethyl acetate in cyclohexane. The residue was purified further on a SPE cartridge (Isolute SCX sulphonic acid cartridge, 5g x2), eluting with methanol (2x20ml) and 10% ammonia in methanol (4x20ml); the basic fractions were combined and concentrated to give Intennediate 54 A as a white solid (0.07g). LCMS showed MH+ = 350; TRET = 2.99min.
Intermediate 55: 4-Chloro-l-ethyl-N- {[4-(methyIoxy)phenyl]methyI}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000110_0002
That is, intermediate 55 is: Where NR4R5 ■■
Figure imgf000110_0003
Figure imgf000110_0004
Intermediate 15 (1.04g) was treated with thionyl chloride (13.22g). The mixture was stirred and heated at 75 °C for 2h. Excess thionyl chloride was removed in vacuo and the residual oil azeotroped with toluene to afford Intermediate 16, presumed to be the acid chloride derivative of intermediate 15, as a cream solid (1.12g). Intermediate 16 (0.997g) was dissolved in tetrahydrofuran (THF) (25ml) and treated with N,N-diisopropylethylamine (1.07ml) then with l-[4-(methyloxy)phenyl]methanamine = 4-methoxybenzylamine (0.54ml) (obtainable from e.g. Aldrich, Acros, or Tetrahedron Lett, 2002, 43(48), 8735; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Organic Letters, 2002, 4(12), 2055) and the mixture was stined for 3h. The solution was concentrated in vacuo, then partitioned between DCM and water. The layers were separated and the organics concentrated in vacuo. The solid was then triturated in 1 : 1 ethyl acetate: cyclohexane to give intermediate 55 (1.27g). LCMS showed MH+= 345, TRET^ 2.86 min.
Similarly prepared were the following:
Figure imgf000111_0001
Figure imgf000111_0003
Intermediate 58: l-Ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-#]pyridine-5- carboxylic acid
Figure imgf000111_0002
A solution of sodium hydroxide (0.053g, 1.32mmol) in water (0.41ml) was added to a stined solution of Example 205 (O.lg, 0.303mmol) in ethanol (1ml), and the resulting mixture was heated at 50°C. After lh, the cooled reaction mixture was adjusted to pH3 with 2M hydrochloric acid, and extracted with EtOAc (2 x 6ml). The combined organic extracts were dried (Na2SO4) and evaporated to give Lntermediate 58 (0.072g) as a white solid. LCMS showed MH+ = 303; TRET = 2.13min.
An alternative preparation of Intermediate 58 is as follows:
A solution of sodium hydroxide (0.792g, 19.8mmol) in water (6ml) was added to a stirred solution of Example 205 (1.487g, 4.5mmol) in ethanol (15ml), and the resulting mixture was heated at 50°C. After 1 hour, the cooled reaction mixture was adjusted to pH4 with 2M hydrochloric acid, and extracted with EtOAc (3 x 30ml). The combined organic extracts were dried (Na SO4) and evaporated to give Intermediate 58 (1.188g) as a white solid. LCMS showed MH+ = 303; TRET = 2.12min.
Intermediate 58A: Ethyl l-ethyl-4-(tetrahydro-2H-pyran-3-yIamino)-lH- pyrazolo[3,4-Z>]pyridine-5-carboxylate
Figure imgf000112_0001
Intermediate 1 (0.76g, 3.0mmol)) was dissolved in acetonitrile (10ml). Tetrahydro-2H- pyran-3-amine hydrochloride (0.5g, 3.6mmol, Anales De Quimica, 1988, 84, 148) and NN-diisopropylethylamine (3.14ml, lS.Ommol) were added and the mixture was stined at 85°C for 24h. After 24h a further portion of tetrahydro-2H-pyran-3-amine hydrochloride (0.14g, 1.02mmol) was added and stining was continued at 85°C. After a further 8h, the mixture was concentrated in vacuo. The residue was partitioned between DCM (20ml) and water (12ml). The layers were separated and the aqueous layer was extracted with further DCM (12ml). The combined organic extracts were dried (Νa SO4), and concentrated in vacuo to give a brown solid which was purified on a SPE cartridge (silica, 20g) eluting with a gradient of ethyl acetate :cyclohexane (1:16, 1:8, 1:4, 1:2, 1:1, 1:0). Fractions containing the desired material were combined and evaporated to afford Intermediate 58A (0.89g). LCMS showed MΗ+ = 319; TRET = 2.92 min. Intermediate 59: l-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxylic acid
Figure imgf000113_0001
A solution of Intermediate 58 A (0.89g, 2.79mmol) in ethanol (16.7ml) was treated with sodium hydroxide (0.47g, 11.7mmol) as a solution in water (3.1ml). The mixture was stined at 50 °C. After 12h, the reaction mixture was concentrated in vacuo to give a residual oil which was dissolved in water (16ml), then cooled and acidified to pH 3 with 2M hydrochloric acid. After stirring at 0°C for 30min, the resulting precipitate was collected by filtration, washed with cooled water (2ml) and dried in vacuo to afford Intermediate 59 as a white solid (0.73g). LCMS showed MIL" = 291; TRET = 2.19min.
Intermediate 60: 4- [(1 - Aceryl-4-piperidinyl) amino] -1 -ethyl- lH-py r azolo [3,4- £]pyridine-5-carboxylic acid
Figure imgf000113_0002
Aqueous sodium hydroxide solution (8.55ml, 2M) was added to a solution of Example 207 (1.55g) in EtOH (13ml). The mixture was heated at 50 °C for 18h then neutralised using aqueous hydrochloric acid and evaporated in vacuo to afford a mixture of 1-ethyl- 4-(4-piperidinylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid and 4-[(l-acetyl-4- piperidinyl)amino]-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid
Acetic acid (0.36ml) was added to a stined mixture of ΗATU (2.41g) and N,N- diisopropylethylamine (2.21ml) in N,N-dimethylfonnamide (65ml). After stirring for 15 min the mixture was added to the mixture of l-ethyl-4-(4-piperidinylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxylic acid and 4-[(l-acetyl-4-piperidinyl)amino]-l-ethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid and the reaction stined for 15h. The reaction mixture was evaporated in vacuo and the residue purified by chromatography using Biotage (silica 90g) eluting with DCM : MeOH (0% - 5% MeOH) to afford Intermediate 60 (1.36g) as a white solid. LCMS showed MH+ 334; TRET= 2.06 min.
Intermediate 61: 4-(Cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-6]pyridine-5- carboxylic acid
Figure imgf000114_0001
A solution of Example 2 (5.37g, 17mmol) in ethanol (30ml) was treated with a solution of sodium hydroxide (2.72g, 68mmol) in water (20ml), and the resulting mixture was stined at 50°C for 3h. The reaction mixture was concentrated in vacuo, dissolved in water (250ml) and the cooled solution was acidified to pH 1 with 5M-hydrochloric acid. The resultant solid was collected by filtration and dried in vacuo to afford Intermediate 61 as a white solid (4.7g). LCMS showed MH* = 289; TRET = 2.83min.
Intermediate 62: 1,1-Dimethylethyl (4,4-difhιorocyclohexyl)carbamate
Figure imgf000114_0002
(Diethylamino)sulphur trifluoride (DAST), (0.06ml, 0.47mmol), was added to a stined solution of l,l-dimethylethyl(4-oxocyclohexyl)carbamate, (250mg, 1.17mmol, commercially available from AstaTech Inc., Philadelphia, USA) in anhydrous dichloromethane (5ml) and the mixture was stined under nitrogen at 20°C. After 22h, the reaction mixture was cooled to 0°C, treated with saturated sodium hydrogen carbonate solution (4ml), and then allowed to warm to ambient temperature. The phases were separated by passage through a hydrophobic frit and the aqueous phase was further extracted with DCM (5ml). The combined organic phases were concentrated in vacuo to give an orange solid (369mg) which was further purified by chromatography using a SPE cartridge (silica, lOg), eluting with DCM to afford intermediate 62 (140mg) containing 20% of 1,1-dimethylethyl (4-fluoro-3-cyclohexen-l-yl)carbamate. 1H NMR (400MHz in CDC13, 27°C, δppm)
Minor component: 65.11 (dm, 16Hz, IH), 4.56 (br, IH), 3.80 (br, IH) 2.45-1.45 (m's, 6H excess), 1.43 (s, 9H). Major component: 54.43 (br, IH), 3.58 (br, IH), 2.45-1.45 (m's, 8H excess), 1.45 (s, 9H).
Intermediate 63: (4,4-Difluorocyclohexyl)amine hydrochloride
Figure imgf000115_0001
A solution of hydrogen chloride in dioxane (4M, 1.6ml) was added at 20°C to a stined solution of Intermediate 62 (140mg, 0.6mmol), in dioxane (1.6ml). After 3h, the reaction mixture was concentrated in vacuo to afford intermediate 63 (96.5mg) containing 4- fluoro-3-cyclohexen-l-amine. 1H NMR (400MHz in d6-DMSO, 27°C, δppm) Minor component: 58.22 (br, 3H excess), 5.18 (dm, 16Hz, IH), 3.28-3.13 (m, IH excess), 2.41- 1.53 (m's, 6H excess). Major component: 68.22 (br, 3H excess), 3.28-3.13 (m, IH excess), 2.41-1.53 (m's, 8H excess). Impurities are also present.
Intermediate 64: 4-Chloro-l-ethyl-N-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
Figure imgf000115_0002
Intermediate 15 (0.06g, 0.266mmol) was treated with thionyl chloride (0.48ml). The mixture was stined and heated at 75°C for 2h. Excess thionyl chloride was removed in vacuo and the residual oil azeotroped with dichloromethane (DCM) to afford
Intermediate 16, presumed to be the acid chloride derivative of Intermediate 15, as a white solid. Intermediate 16 was dissolved in anhydrous tetrahydrofuran (THF) (2ml) and treated with N,N-diisopropylethylamine (DLPEA) (0.069ml), then with methylamine (2M in tetraliydrofuran, 0.15ml) and the mixture stined under nitrogen for 16h. A further
0.05ml of methylamine (2M in THF) was added and the solution stined for 2h. The mixture was concentrated in vacuo, then partitioned between dichloromethane (2ml) and aqueous sodium hydroxide solution (2M, 2ml), then the organic layer washed with water
(2ml). The layers were separated and the organics concentrated in vacuo to afford hitermediate 64 (0.052g). LCMS showed MH+ = 239; TRET = 2.17min. Intermediate 65: Ethyl 4-[(l-{[(l,l-dimethylethyl)oxy]carbonyl}-4- piperidinyl)ammo]-l-ethyl-lH-pyrazolo[3,4-6]pyridine-5-carboxylate
Figure imgf000116_0001
A mixture of hitermediate 17 (2.0g, 6.37mmol), 1,1-dimethylethyl 4-amino-l- piperidinecarboxylate (2.04g, 10.2mmol) and N,N,-diisopropylethylamine (5.54ml, 31.9mmol) in MeCN (40ml) was heated at 85 °C for 42h. The reaction was evaporated and the residues partitioned between DCM and water. The organic phase was dried (MgSO4) then evaporated in vacuo. The residue was chromatographed on silica (Biotage, 90g) eluting with cyclohexane : EtOAc (1:1) to give Intermediate 65 as a white solid (2.70g). LCMS showed MH+ = 479; TRET = 3.37min.
Intermediate 67: 3-Amino-N-cyclohexyI-N-methyIbenzamide
Figure imgf000116_0002
A solution of 3-nitrobenzoyl chloride (2.0g, 10.78mmol) in DCM (20ml) was added dropwise to a stined mixture of N-methylcyclohexylamine (1.83ml, 14.01mmol), N,N,- diisopropylethylamine (3.76ml, 21.56mmol) and N,N-dimethylaminopyridine (O.Olg) in DCM at 20 °C. The reaction mixture was stined for 56h then evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with aqueous HC1 then dried (MgSO ) and evaporated in vacuo. The residue was purified by chromatography on silica eluting with cyclohexane : EtOAc (9:1 followed by 2:1) to afford N-cyclohexyl-N-methyl-3-nitrobenzamide (1.40g). MS showed MH+ 263.
A mixture of N-Cyclohexyl-N-methyl-3-nitrobenzamide (1.40g, 5.35mmol) and palladium on carbon (5%o, 0.140g) in ethanol (10ml) was stined under an atmosphere of hydrogen forl hour. The reaction mixture was filtered through Celite and the filtrate evaporated to afford Intermediate 67 as a brown solid (0.107g). LCMS showed MH+ = 233; TRET = 2.56min. Intermediate 68: iV-EthyI-4-oxo-l-piperidinecarboxamide
Figure imgf000117_0001
A solution of ethyl isocyanate (2.3 lg, 32.5mmol) in DCM (40ml) was added, dropwise over 15min, to a vigorously stined solution of 4-piperidone monohydrate hydrochloride (5.0g, 32.5mmol, commercially available from Aldrich) and sodium hydrogen carbonate (8.2g, 97.5mmol) in water (60ml) at 0°C. The reaction mixture was stined at room temperature for 20h. Sodium chloride (7.0g) was added to the reaction mixture and the organic phase was separated. The aqueous phase was extracted with further DCM (3 x 75ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a white solid (4.0g). Recrystallisation from ethyl acetate: cyclohexane (10:1) afforded Intermediate 68 as a white solid (2.3g).
TLC (silica) gave Rf = 0.24 (ethyl acetate). Anal. Found: C, 56.7; H, 8.3; N, 16.35. C8H14N2O2 requires C, 56.5; H, 8.3; N, 16.5.
Intermediate 69: 4-Amino-N-ethyl-l-piperidinecarboxaιτιide
Figure imgf000117_0002
A solution of Lntermediate 68 (1.5g, 8.8mmol) and benzylamine (1.04g, 9.7mmol) in absolute ethanol (60ml) was hydrogenated over pre-reduced 10% palladium on charcoal catalyst (0.6g) in ethanol (20ml) until the uptake of hydrogen had ceased (22h). The reaction mixture was filtered through filter agent (Celite), and then through silica gel (100ml) eluting with ethanol:0.88-ammonia (100:1) to give a black oil. The oil was dissolved in ethanol (30ml) and treated with a solution of hydrogen chloride in ethanol (3M) until the solution was acidic. The solvent was evaporated and the residue was triturated with ethanol to afford Intermediate 69 as a white solid (1.09g). TLC (silica) gave Rf = 0.73 (ethyl acetate:methanol, 10:1). Anal. Found: C, 45.9; H, 8.4; N, 19.8. C8H18ClN3O requires C, 46.3; H, 8.7; N, 20.2.
Intermediate 70: 1,1-DimethylethyI ({4- [(cyclopropylamino)carbonyl]phenyl}methyl)carbamate
Figure imgf000118_0001
Cyclopropylamine (0.136g, 2.39mmol) and diisopropylethylamine (0.68ml, 3.9mmol) were added to a stirred solution of 4-[({[(l,l-dimethylethyl)oxy]carbonyl}amino)- methyljbenzoic acid (0.501g, 2.0mmol), EDC (0.612g, 3.2mmol) and HOBT (0.35g, 2.6mmol) in DMF (2ml). The resulting mixture was stirred at room temperature overnight. Solvents were removed in vacuo, and the residue was dissolved in ethyl acetate (20ml) and washed with 0.5M-hydrochloric acid (3 x 20ml). The organic phase was dried (Na SO4) and evaporated in vacuo to give the crude product which was purified by Biotage chromatography (silica) eluting with ethyl acetate:cyclohexane (1.3 : 1) to afford Intermediate 70 as a white solid (0.512g). LCMS showed MET1" = 291; TRET = 2.75min.
Intermediate 71 : 4-(Aminomethyl)-N-cyclopropylbenzamide hydrochloride
Figure imgf000118_0002
Intennediate 70 (0.506g, 1.74mmol) was dissolved in a solution of hydrogen chloride in dioxan (20ml, 4M) under nitrogen. After lh, methanol (3ml) was added to the mixture and stirring was continued at room temperature overnight. Solvents were removed in vacuo to afford Intermediate 71 as a white solid (0.416g). LCMS showed MH+ = 191; TRET = 0.82min.
Intermediate 72
Figure imgf000119_0001
intermediate 33 (1.36g, 4.7mmol), EDC (1.26g, 6.57mmol) and HOBT (0.76g, 5.62mmol) were suspended in DMF (50ml) and stined vigorously at room temperature for 0.5h, before adding 1,1-dimethylethyl 4-(aminomethyl)-l-piperidinecarboxylate (L g, 6.07mmol, commercially available from Maybridge Chemical Co. Ltd.,). After stirring at room temperature overnight, a further quantity of 1,1-dimethylethyl 4- (aminomethyl)-l-piperidinecarboxylate (l.Olg, 4.7mmol) was added to the reaction mixture which was then heated at 50°C. After 6h, diisopropylethylamine (0.25ml, 1.44mmol) was added, and the mixture was maintained at 50°C for a further 6h. Solvents were removed in vacuo and the residue was partitioned between DCM (100ml) and water (100ml). The phases were separated by passage through a hydrophobic frit, and the organic phase was evaporated in vacuo to give the crude product. Further purification using SPE cartridges (aminopropyl followed by silica) afford Intermediate 72 as a cream solid (1.24g). LCMS showed MH+ = 487; TRET = 2.97min.
Intermediate 73
Intermediate 73 is used in situ in the general procedure for Examples 360-414.
Intermediate 74: 1 J-Dimethvlethvl ({3-
[(acetylamino)methyl]phenyl}methyl)carbamate
Figure imgf000119_0002
Acetic anhydride (0.52ml, 5.5mmol) was added to a mixture of tert-butyl N-[3- aminomethyl)benzyl] carbamate (l.lg, 4.65mmol commercially available from Astatech) and triethylamine (0.7ml, 5mmol) in THF (20ml). The reaction mixture was stined at 20 °C from 16h then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was dried (MgSO4) and evaporated in vacuo. The residue was chromatographed over silica eluting with hexanes : EtOAc (1:1) followed by EtOAc to afford Intermediate 74 (1.2g) as a colourless oil. Anal. Found: C, 64.79; H, 7.93; Ν, 10.10. C15H22Ν2O3 requires C, 64.73; H, 7.97; N, 10.06. MS (M+Na )+ 301.
Intermediate 75: 7N-{[3-(Aminomethyl)phenyI] methyl} acetamide hydrochloride
Figure imgf000120_0001
/Cl H
Hydrogen chloride in dioxane (4ml, 4M) was added to a solution of Intennediate 74
(1.0g, 3.6mmol) in dioxane (10ml) and the resultant mixture stined for 6 hours at 20 °C. The reaction was diluted with Et2O (20ml) and filtered to afford Intermediate 75 (0.7g) as a white solid. MS MH+ 179. 1H NMR (300MHz in d6-DMSO, 27°C, δppm) 6 8.6 - 8.4 (br m, 3H), 7.38 - 7.26 (m, 3H), 7.22 (bm, IH), 4.24 (d, J = 5.7Hz, 2H), 3.95 (dd, I = 11.6, 5.7Hz, 2H), 1.87 (s, 3H).
Intermediate 76 l-Ethyl-4-{[(lSR,3RS)-3-hydroxycycIohexyl] amino}-lH- pyrazolo[3,4-6]pyridine-5-carboxylic acid
Figure imgf000120_0002
(cw-3-hydroxycyclohex-l -ylamino group, racemic)
A solution of Example 665 (0.68 lg, 2.05mmol) in ethanol (7ml) was treated with a solution of sodium hydroxide (0.362g, 9.05mmol) in water (2.9ml). The resulting mixture was stined at 50°C. After 3h, the reaction mixture was concentrated in vacuo to give a residual oil which was dissolved in water (3ml), then cooled and acidified to pH 3 with 2M-hydrochloric acid. After stirring at 0°C for lh, the resulting precipitate was collected by filtration, washed with cooled water (0.5ml) and dried in vacuo to afford Intermediate 76 as a white solid (0.491g). LCMS showed MH+ = 305; TRET = 2.14min. 119
Table of Examples
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000125_0001
004/024
124.
Figure imgf000126_0001
004/024728
125-
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
ExaName mple no. 204 Ethyl l-ethyl-4-[(4-hydroxycyclohexyl)amino]-lΗ-pyrazolo[3,4-b]pyridine-5-carboxylate 205 Ethyl l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxylate 207 Ethyl 4-[(l-acetyl-4-piperidinyl)amino]-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate 209 Ethyl 4-[(4-aminocyclohexyl)amino]-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate 210 Ethyl-N-[(l-oxido-3-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
211 1 -Ethyl-N-[( 1 -oxido-2-pyridinyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
212 l-Ethyl-N-[(l-oxido-4-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
214 4-[(cis-4-Aminocyclohexyl)amino] - 1 -ethyl-N-(phenylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-
5-carboxamide
221 4-(Cyclobutylamino)-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
222 4-(Cycloheptylamino)-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
223 1 -Ethyl-4-[(4-methylcyclohexyl)amino] -N-(phenylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
224 1 -Ethyl-4-[(3 -methylcyclohexyl)amino] -N-(phenylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
225 l-Ethyl-4-[(l-methylcyclohexyl)amino]-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
226 4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
227 4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
228 l-Ethyl-4-{[(3S)-2-oxo-3-pyrrolidinyl]amino}-N-(phenylmethyl)-lH-pyrazolo[3,4- bJpyridine-5 -carboxamide
229 4-[(2,5-Dioxo-3-pyrrolidinyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine- 5 -carboxamide
230 4-(l-Azabicyclo[2.2.2]oct-3-ylamino)-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
231 l-Ethyl-4-[(l-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
233 4-(Cyclobutylamino)- 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl} - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
234 4-(Cycloheptylamino)- 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl} - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
235 4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-{[4-(methyloxy)phenyl]methyl}- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
236 1 -Ethyl-4-[(4-methylcyclohexyl)amino]-N- { [4-(methyloxy)phenyl]methyl } - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
237 l-Ethyl-4-[(3-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
238 4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-{[4-(methyloxy)phenyl]methyl}- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
239 4-[(cis-4-Aminocyclohexyl)amino]-l-ethyl-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
240 4-(Cycloheptylamino)-l-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
241 4-(Cyclobutylamino)- 1 -ethyl-N-( {4- [(methylsulfonyl)amino]phenyl } methyl)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
242 4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-({4- [(methylsulfonyl)amino]phenyl}methyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
243 4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-({4- [(methylsulfonyl)amino]phenyl } methyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
244 l-Ethyl-4-[(4-methylcyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide 245 1 -Ethyl-4-[(3-methylcyclohexyl)amino]-N-( {4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
247 l-Ethyl-4-[(l-methylcyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
248 4-[(cis-4-Aminocyclohexyl)amino]-l-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)- 1 H-pyrazolo[3 ,4-b]pyridine-5 -carboxamide
249 4-(Cyclohexylamino)- 1 -ethyl-N-( {4-[(methylsulfonyl)amino]phenyl} methyl)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide
250 4-(Cyclohept lamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-ρyrazolo[3,4-b]pyridine- 5-carboxamide
251 4-(Cyclobutylamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
253 N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-[(3-methylcyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
254 N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-[(4-methylcyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
255 4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
256 4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
257 N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-[(l-methylcyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
258 4-[(cis-4-Aminocyclohexyl)amino]-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
259 1 -Ethyl-N- {4-[(methylsulfonyl)methyl]phenyl} -4-[(4-oxocyclohexyl)amino]-lH- ρyrazolo[3,4-b]pyridine-5-carboxamide
260 N-[(2,4-Dimethylphenyl)methyl]-l -ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3 ,4- b]pyridine-5 -carboxamide
261 N-[(3,4-Dimethylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
262 N-[(3,4-Dichlorophenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
263 1 -Ethyl-N- {[4-(methyloxy)phenyl]methyl} -4-[(4-oxocyclohexyl)amino]- lH-pyrazolo[3 ,4- b]pyridine-5 -carboxamide
264 l-Ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
265 N-{[4-(Dimethylamino)phenyl]methyl}-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
266 N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
267 l-Ethyl-4-[(4-oxocyclohexyl)amino]-N-{[4-(trifluoromethyl)phenyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
268 l-Ethyl-N-{[4-(methylsulfonyl)ρhenyl]methyl}-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
269 l-Ethyl-N-(4-fluorophenyl)-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
270 l-Ethyl-4-[(4-oxocyclohexyl)amino]-N-(2-pyridinylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide xrifluoroacetate
271 N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
272 N-(l-Acetyl-4-piperidinyl)-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
273 1 -Ethyl-N- [( 1 -methyl- 1 H-pyrazol-4-yl)methyl] -4-[(4-oxocyclohexyl)amino]- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide
274 N, 1 -Diethyl-4-[(4-oxocyclohexyl)amino] - 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
275 1 -Ethyl-4-[(4-oxocyclohexyl)amino] -N-( 1 ,3 -thiazol-2-ylmethyl)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
276 l-Ethyl-N-(phenylmethyl)-4-(tetτahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4-b]pyridine- 5 -carboxamide
277 N-( {4-[(Difluoromethyl)oxy]phenyl } methyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-3 -ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide
278 1 -Ethyl-4-(tetrahydro-2H-pyran-3 -ylamino)-N- { [4-(trifluoromethyl)phenyl]methyl} - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
279 1 -Ethyl-N- { [4-(methylsulfonyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
280 l-Ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-pyran-3-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
281 l-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
282 l-Ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide xrifluoroacetate
283 N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
284 N-( 1 -Acetyl-4-piperidinyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
285 l-Ethyl-N-[(l-methyl-lH-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-3-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
286 N, 1 -Diethyl-4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
287 l-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-N-(l,3-thiazol-2-ylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
288 4-[(4,4-Difluorocyclohexyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine- 5 -carboxamide
289 1 -Ethyl-4-[(4-fluoro-3 -cyclohexen- 1 -yl)amino] -N-(phenylmethyl)- 1 H-pyrazolo [3 ,4- b]pyridine-5-carboxamide.
290 4-[(l-Acetyl-4-piperidinyl)amino]-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide 291 4-[(l-Acetyl-4-piperidinyl)amino]-N-[(3,4-dichlorophenyl)methyl]-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
292 4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl-N- [(3 -fluorophenyl)methyl] - lH-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
293 4-[(l-Acetyl-4-piperidinyl)amino]-N-[(3,4-difluorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
294 4-[(l-Acetyl-4-piperidinyl)amino]-N-[(2,5-difluorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
295 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[3-(trifluoromethyl)phenyl]methyl}-lH- pyrazolo[3 ,4-b]pyridine-5 -carboxamide
296 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[4-(trifluoromethyl)phenyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
297 4-[(l-Acetyl-4-piperidinyl)amino]-N-[(2,6-difluorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
298 4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(3 -chlorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide
299 4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl-N- { [4-(memyloxy)phenyl]methyl } - 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
300 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-[4-(methyloxy)phenyl]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
301 4-[(l-Acetyl-4-piperidinyl)amino]-N-({4-[(dimethylamino)sulfonyl]phenyl}methyl)-l-ethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxamide
302 4-[(l-Aceryl-4-piperidinyl)amino]-l-ethyl-N-(l,2,3,4-tetrahydro-l-naphthalenyl)-lH- pyrazolo[3 ,4-b]pyridine-5 -carboxamide
303 4-[( 1 -Acetyl-4-piperidinyl)amino] -N- { [2-(dimethylamino)phenyl]methyl} - 1 -ethyl- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
304 4-[(l-Acetyl-4-piperidinyl)amino]-N-[(2,4-dichlorophenyl)methyl]-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
305 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-[(2-fluorophenyl)methyl]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
306 4-[(l -Acetyl-4-piperidinyl)amino]-N-[(2-chloro-6-fluorophenyl)methyl]-l -ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
307 4-[(l-Acetyl-4-piperidinyl)amino]-N-({4-[(difluoromethyl)oxy]phenyl}methyl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
308 4-[( 1 -Acetyl-4-piperidinyl)amino] -N- { [3 -chloro-4-(methyloxy)phenyl]methyl } - 1 -ethyl- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
309 4-[(l-Acetyl-4-piperidinyl)amino]-N-[(5-chloro-2-pyridinyl)methyl]-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
310 4-[(l-Acetyl-4-piperidinyl)amino]-N-(5-chloro-2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
311 4-[( 1 -Acetyl-4-piρeridinyl)amino] - 1 -ethyl-N-( 1 ,3 -thiazol-2-ylmethyl)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
312 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
313 4-[(l-Acetyl-4-piperidinyl)amino]-N-(2,2-diphenylethyl)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
314 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
315 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide
316 4-[(l-Acetyl-4-piperidinyl)amino]-N-{[4-(aminosulfonyl)phenyl]methyl}-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
317 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-({3-[(methylamino)carbonyl]phenyl}methyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
318 4-[( 1 -Acetyl-4-piperidinyl)amino] -N- { [4-(aminocarbonyl)phenyl]methyl} - 1 -ethyl- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
319 4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
320 1 -Ethyl-N-4-piperidinyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide
321 l-Ethyl-N-(4-piperidinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- bJpyridine-5-carboxamide
322 l-Ethyl-N-[l-(ethylsulfonyl)-4-piperidinyl]-4-(texrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
323 1-Ethyl-N- { 1 -[(1 -methylethyl)sulfonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
324 N-[ 1 -(Cyclopentylsulfonyl)-4-piperidinylJ- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-bJpyridine-5-carboxamide
325 1 -Ethyl-N-[1 -(methylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
326 1 -Ethyl-N- { 1 -[(phenylmethyl)sulfonyl]-4-piperidinyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide
327 l-Ethyl-N-[l-(phenylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylammo)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
328 l-Ethyl-N-[l-(propylsulfonyl)-4-piperidinylJ-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
329 N-[l-(Cyclopropylcarbonyl)-4-piperidinyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
330 l-Ethyl-N-[l-(3-furanylcarbonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [ ,4-b]pyridine-5 -carboxamide
331 N-[l-(3,3-Dimethylbutanoyl)-4-piperidinyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
332 1 -Ethyl -N-[ 1 -(2-ethylbutanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide
333 N-[l-(Cyclopentylacetyl)-4-piperidinyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide 334 1 -Ethyl-N-[1 -(2-methylpropanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-bJpyridine-5-carboxamide
335 l-Ethyl-4-(texrahydro-2H-pyran-4-ylamino)-N-[l-(tehahydro-2H-pyran-4-ylcarbonyl)-4- piperidinyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5-carboxamide
336 1 -Ethyl-N-(1 -propanoyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-bJpyridine-5 -carboxamide
337 N-[ 1 -(N-Acetylglycyl)-4-piperidinylJ- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
338 l-Ethyl-N-[l-(4-moφholinylacetyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
339 1 -Ethyl-N- { 1 -[(4-oxocyclohexyl)carbonyl]-4-piperidinyl} -4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
340 l-Ethyl-N-[l-(l-piperidinylacet l)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
341 1 -Ethyl-N- { 1 -[(1 -methyl-5-oxo-3-pyrrolidinyl)carbonyl]-4-piperidinyl} -4-(tetrahydro-2H- pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
342 1 -Ethyl-N- { 1 -[(3 -methyl-3 -oxetanyl)carbonyl] -4-piperidinyl } -4-(tetrahydro-2H-pyran-4- ylamino)- lH-pyrazolo[3 ,4-b]pyridine-5 -carboxamide
343 1-Ethyl-N- { 1 -[(4-fluorophenyl)acetyl]-4-piperidinyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide
344 N- { [ 1 -(3 ,3 -Dimethylbutanoyl)-4-piperidinyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
345 N- { [ 1 -(Cyclopentylacetyl)-4-piperidinyl]methyl} -1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
346 N- { [ 1 -(Cyclopropylcarbonyl)-4-piperidinyl]methyl} -1 -ethyl -4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
347 l-Ethyl-N-({l-[(4-oxocyclohexyl)carbonyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran- 4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
348 l-Ethyl-N-({l-[(4-fluorophenyl)acetyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
349 l-Ethyl-N-({l-[(l-methyl-5-oxo-3-pyrrolidinyl)carbonyl]-4-piperidinyl}methyl)-4- (tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
350 Methyl 3 -[( 1 -ethyl-5 - { [(phenylmethyl)aminoj carbonyl } - 1 H-pyrazolo [3 ,4-b]pyridin-4- yl)aminoJcyclohexanecarboxylate
351 3-[(l-Ethyl-5-{[(phenylmethyl)amino]carbonyl}-lH-pyrazolo[3,4-b]pyridin-4- yl)amino] cyclohexanecarboxylic acid
352 l-Ethyl-N-(phenylmethyl)-4-(4-piperidinylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
353 Ethyl l-ethyl-4-({l-[(methyloxy)acetyl]-4-piperidinyl}amino)-lH-pyrazolo[3,4-b]pyridine- 5 -carboxylate
354 Ethyl l-(l-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxylate
355 4-(Cyclohexylamino)-l-ethyl-N-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide 356 l-Ethyl-N-(4-fluorophenyl)-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
357 1 -Ethyl-6-methyl-N- { [4-(methylsulfonyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4- ylamino)- lH-pyrazolo[3 ,4-b]pyridine-5 -carboxamide
358 N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
360 1 -Ethyl-N-[3 -( 1 -piperidinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
361 l-Ethyl-N-[4-(l-methylethyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
362 l-Ethyl-N-(2-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
363 N-{3-[(Dimethylamino)carbonyl]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
364 N- {4-[(Difluoromethyl)oxy]phenyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3 ,4-b]pyridine-5 -carboxamide
365 N-{4-[Acetyl(methyl)amino]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
366 l-Ethyl-N-(4-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
367 l-Ethyl-N-[4-(4-moφholinyl)-2-(trifluoromethyl)phenyl]-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
368 1 -Ethyl-N-4-pyridinyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide
369 l-Ethyl-N-{4-[(4-methyl-l-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
370 l-Ethyl-N-[2-(2-oxo-l-pyrrolidinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
371 l-Ethyl-N-[3-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
372 N-{3-[Acetyl(methyl)amino]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
373 1 -Ethyl-N- {3 -[(methylsulfonyl)amino]phenyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
374 l-Ethyl-N-(4-fluoro-2-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
375 N-(4-Chlorophenyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
376 N-(3-Chloro-2-cyanophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
377 l-Ethyl-N-[3-(l-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
379 l-Ethyl-N-[2-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
380 N-{2-[Acetyl(methyl)amino]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
381 l-Ethyl-N-[3-(4-moφholinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
382 N-(4-Chloro-3 -cyanophenyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- bJpyridine-5 -carboxamide
383 l-Ethyl-N-(3-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
384 N-(3-Chlorophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
386 N-[3-[(Acetylamino)methyl]-4-(methyloxy)phenyl]-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
387 l-Ethyl-N-[4-(l-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
388 N-(3-{[Cyclohexyl(methyl)amino]carbonyl}phenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
389 1 -Ethyl-N- [2-(4-moφholinyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
390 N-{3-[(Acetylamino)sulfonyl]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
391 N-(3-Chloro-4-hydroxyphenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
392 l-Ethyl-N-{4-[(methylsulfonyl)amino]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
393 l-Ethyl-N-{3-[(methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
394 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N- [3 -(trifluoromethyl)phenyl] - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
395 1 -Ethyl-N-3 -pyridinyl-4-(te1xahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
396 N-(3 ,4-Dichlorophenyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
397 N-[3 -(Aminosulfonyl)-4-chlorophenyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
398 1 -Ethyl-N-[3 -(4-moφholinyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
399 l-Ethyl-N-[4-(4-moφholinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
400 l-Ethyl-N-{2-[(4-methyl-l-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
401 N-{2-[(Dimethylamino)carbonyl]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide 402 N-[2-Chloro-4-(trifluoromethyl)phenyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
403 N- {2-[(Acetylamino)methyl]phenyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
404 N-(2-ChlorophenyT)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide
405 N-(3-Chloro-2-fluorophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
406 l-Ethyl-N-(3-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide
407 N-(2-Cyano-3 -fluorophenyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- bJpyridine-5 -carboxamide
408 1 -Ethyl-N- [4-(propylsulfonyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5-carboxamide
409 N- {4-[(Dimethylamino)carbonyl]phenyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
411 l-Ethyl-N-[4-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
413 N- {4-[(Acetylamino)methyl]phenyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
414 l-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4-bJpyridine-5-carboxamide
415 N-[2-(Aminosulfonyl)ethyl] -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
416 N-(2-Amino-2-oxoethyl)-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide (non-preferred name)
417 4-(Cyclohexylamino)- 1 -ethyl-N- {2-[(methylsulfonyl)amino] ethyl } - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
418 4-(Cyclohexylamino)-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
419 4-(Cyclohexylamino)-l-ethyl-N-[(l-methyl-lH-pyrazol-4-yl)methyl]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
420 4-(Cyclohexylamino)- 1 -ethyl-N- { [3 -(methylsulfonyl)phenyljmethyl} - 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide
421 N- { [3 -(Aminocarbonyl)phenyl]methyl } -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
422 4-(Cyclohexylamino)- 1 -ethyl-N-(tetrahydro-2-furanylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine- 5-carboxamide
423 4-(Cyclohexylamino)-N-({4-[(dimethylamino)sulfonyl]phenyl}methyl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
424 N-[(5-Chloro-2-pyridinyl)methyl]-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
425 4-(Cyclohexylamino)- 1 -ethyl-N- { [4-(methylsulfonyl)phenyl]methyl } - 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide 426 4-(Cyclohexylamino)-l-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
427 4-(Cyclohexylamino)-l-ethyl-N-{4-[(methylamino)carbonyl]phenyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
428 4-(Cyclohexylamino)-l-ethyl-N-({3-[(methylamino)carbonyl]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
429 N- { [4-(Aminocarbonyl)phenyl]methyl} -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3,4- b]pyridine-5-carboxamide
430 4-(Cyclohexylamino)- 1 -ethyl-N- [(4-hydroxyphenyl)methyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
431 4-(Cyclohexylamino)- 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl } - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
432 4-(Cyclohexylamino)-N-[(3 ,4-difluorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine- 5-carboxamide
433 4-(Cyclohexylamino)- 1 -ethyl-N- { [4-(trifluoromethyl)phenyl]methyl } - 1 H-pyrazolo[3 ,4- b]pyridine-5 -carboxamide
434 4-(Cyclohexylamino)-l-ethyl-N-({3-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
435 4-(Cyclohexylamino)-N-[(2,5-difluorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-b]pyridine- 5 -carboxamide
436 4-(Cyclohexylamino)-l-ethyl-N-[(4-methylphenyl)methyl]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
438 4-(Cyclohexylamino)-l-ethyl-N-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
439 4-(Cyclohexylamino)- 1 -ethyl-N-[(2-hydroxyphenyl)methyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
440 4-(Cyclohexylamino)-N-[(3 ,4-dichlorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine- 5 -carboxamide
441 4-(Cyclohexylamino)-N-[(3,5-dichlorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-b]pyridine- 5 -carboxamide
442 4-(Cyclohexylamino)-l-ethyl-N-(2-phenylethyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
443 4-(Cyclohexylamino)-l-ethyl-N-(l,2,3,4-tetrahydro-l-naphthalenyl)-lH-pyrazolo[3,4- bJpyridine-5 -carboxamide
444 4-(Cyclohexylamino)- 1 -ethyl-N- { [2-(methylsulfinyl)phenyl]methyl } - 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide
445 4-(Cyclohexylamino)- 1 -ethyl-N-[2-(4-hydroxyphenyl)ethyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
446 N- {2-[4-(Aminosulfonyl)phenyl] ethyl } -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
447 4-(Cyclohexylamino)-l-ethyl-N-({2-[(methylamino)carbonyl]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
448 4-(Cyclohexylamino)-l-ethyl-N-{[2-(methylsulfonyl)phenyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide 449 Methyl 2-[({[4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridin-5- yl]carbonyl}amino)methyl]benzoate
450 4-(Cyclohexylamino)-l-ethyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
451 N-[4,5-Bis(methyloxy)-2,3-dihydro-lH-inden-2-yl]-4-(cyclohexylamino)-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
452 4-(Cyclohexylamino)- 1 -ethyl-N- { [2-fluoro-3 -(trifluoromethyl)phenyl]methyl} - 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide
453 4-(Cyclohexylamino)-N-[(3,4-dimethylphenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-b]pyridine- 5-carboxamide
454 4-(Cyclohexylamino)- 1 -ethyl-N- [2-(4-fluorophenyl)ethyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide
455 4-(Cyclohexylamino)-l-ethyl-N-[2-(4-methylphenyl)ethyl]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
456 4-(Cyclohexylamino)- 1 -ethyl-N- {2-[4-(methyloxy)phenyl] ethyl} - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
457 4-(Cyclohexylamino)- 1 -ethyl-N-(2 -pyridinylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide xrifluoroacetate
458 4-(Cyclohexylamino)-N-[(3 ,5 -difluorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine- 5 -carboxamide
459 4-(Cyclohexylamino)-N-(2,3 -dihydro- 1 H-inden- 1 -yl)- 1 -ethyl- lH-pyrazolo [3 ,4-b]pyridine-5- carboxamide
460 4-(Cyclohexylamino)-N-{[4-(dimethylamino)phenyl]methyl}-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide trifluoroacetate
461 4-(Cyclohexylamino)-l-ethyl-N-[(2-fluorophenyl)methyl]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
462 N-{[2,4-Bis(methyloxy)phenyl]methyl}-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
463 N-[(6-Chloro-2-pyridinyl)methyl] -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide trifluoroacetate
464 N-({2-[Acetyl(methyl)amino]phenyl}methyl)-4-(cyclohexylamino)-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate
465 4-(Cyclohexylamino)-l-ethyl-N-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
466 4-(Cyclohexylamino)-N-[( lR)-2,3 -dihydro- lH-inden-1 -yl] - 1 -ethyl-lH-pyrazolo[3 ,4- bJpyridine-5 -carboxamide
467 4-(Cyclohexylamino)-N-[(2,6-dichlorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-bJpyridine- 5 -carboxamide
468 Methyl 3-[({[4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridin-5- yl] carbonyl } amino)methyl]benzoate
469 4-(Cyclohexylamino)-N-(2,3 -dihydro- 1 H-inden-2-yl)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
470 Methyl 4-[( { [4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)methyl]benzoate
471 4-(Cyclohexylamino)-l-ethyl-N-(lH-tetrazol-5-ylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
472 4-(Cyclohexylamino)-N-({4-[(difluoromethyl)oxy]phenyl}methyl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
473 4-(Cyclohexylamino)- 1 -ethyl-N- [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] - lH-pyrazolo [3,4- b]pyridine-5 -carboxamide
474 N-[(2-Chloro-6-fluorophenyl)methyl]-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
475 N- { [2-(Aminocarbonyl)phenyl]methyl} -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5-carboxamide
477 4-(Cyclohexylamino)-N-{[2-(dimethylamino)phenyl]methyl}-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
478 4-(Cyclohexylamino)-l-ethyl-N-[(4-fluorophenyl)methyl]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
479 4-(Cyclohexylamino)- 1 -ethyl-N- { [3 -(trifluoromethyl)phenyl]methyl} - 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide
480 4-(Cyclohexylamino)-N-[(2,6-difluorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-b]pyridine- 5-carboxamide
481 4-(Cyclohexylamino)- 1 -ethyl-N- [(3 -fluorophenyl)methyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
482 4-(Cyclohexylamino)- 1 -ethyl-N- { [2-(trifluoromethyl)phenyl]methyl } - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
483 N-(5-Chloro-2,3-dihydro-lH-inden-2-yl)-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
484 4-(Cyclohexylamino)- 1 -ethyl-N-( {4-[(methylamino)carbonyl]phenyl } methyl)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide
485 4-(Cyclohexylamino)- 1 -ethyl-N- [4-(methyloxy)phenyl] - lH-pyrazolo[3 ,4-b]pyridine-5 - carboxamide
486 4-(cyclohexylamino)-l-ethyl-N-[(6-oxo-l,6-dihydro-3-pyridinyl)methyl]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
487 4-(Cyclohexylamino)- 1 -ethyl-N-(3 -pyridinylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
488 4-[({[4-(Cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridin-5- yljcarbonyl} amino)methyl]benzoic acid
489 3 -[( { [4-(Cyclohexylamino)- 1 -ethyl- lH-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)methyl]benzoic acid
490 4-(Cyclohexylamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide hydrochloride
491 4-(Cyclohexylamino)-N-(2,3 -dihydro- 1 H-inden-2-yl)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide methanesulphonate
492 N-({2-[(l,l-Dimethylethyl)oxy]-3-pyridinyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate 493 N-[(3-Chloro-4-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
494 N-[(4-Chloro-2-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-bJpyridine-5-carboxamide
495 N-({2-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
496 l-Ethyl-N-({2-[(l-methylethyl)oxy]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
497 l-Ethyl-N-({3-[(l-methylethyl)oxy]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
498 N-({3-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
499 l-Ethyl-N-{[4-hydroxy-3-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
500 N-[(5-Acexyl-2-hyc oxyphenyl)methyl]-l-ethyl-4-(texrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
501 l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
502 N-{[4-(Acetylamino)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
503 l-Ethyl-N-[2-(3-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
504 N-[2-(3 -Chlorophenyl)ethyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide
505 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(2- {4-[(trifluoromethyl)oxy]phenyl} ethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
506 l-Ethyl-N-{2-[3-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
507 N-[2-(4-Acetylphenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
508 N-[2-(3,4-Dichlorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
509 N-{2-[3-(Aminosulfonyl)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
510 N-{2-[3,4-Bis(methyloxy)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
512 N-[2-(2,3-Dichlorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
513 N- {2-[3 ,5 -Bis(methyloxy)phenyl] ethyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
514 l-Ethyl-N-{2-[3-methyl-4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
515 N-[2-(2,6-Difluorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-bJpyridine-5-carboxamide
516 N-{2-[2,6-Bis(methyloxy)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
517 l-Ethyl-N-[2-(2-methylphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
518 N-[(3,4-Dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
519 N-[4,5-Bis(methyloxy)-2,3-dihycko-lH-inden-2-yl]-l-ethyl-4-(tehahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
521 N- {2-[4-(Aminosulfonyl)phenyl] ethyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide
522 1 -Ethyl-N- { [2-(methylsulfmyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
523 l-Ethyl-N-(2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine- 5 -carboxamide
524 N-{[4-(Dimethylamino)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
525 l-Ethyl-N-[2-(4-fluorophenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
526 l-Ethyl-N-[2-(4-methylphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide
527 N- { [3 -(Aminosulfonyl)phenyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
528 l-Ethyl-N-[(4-methylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
530 1 -Ethyl-N- { [4-fluoro-3 -(trifluoromethyl)phenyljmethyl} -4-(tetrahydro-2H-pyran-4- ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
531 Methyl 2-[( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl] carbonyl } amino)methyl]benzoate
532 N-[(6-Chloro-2-pyridinyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate
533 N-(2,3-Dihydro-lH-inden-l-yl)-l-ethyl-4-(texrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
534 N-({2-[Acetyl(methyl)amino]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
535 N-[(lS)-2,3-Dihydro-lH-inden-l-yl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
536 N-[(lR)-2,3-Dihydro-lH-inden-l-yl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
537 1 -Ethyl-N-( {3-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
538 1 -Ethyl-N-(phenylmethyl)-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide 540 N-[2-(Dimethylamino)ethyl]-l-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide
541 N-Butyl-l-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide
542 N,l-Diethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
544 l-Ethyl-N-(l-phenyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
545 l-ethyl-N-{l-[(ethylamino)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
546 Formic acid - l-ethyl-N-[l-methyl-2-(4-methyl-l-piperazinyl)ethyl]-4-(tetrahydro-2H-pyran- 4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide (1:1)
547 Methyl [4-( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)-l-piperidinyl]acetate
548 l-Ethyl-N-{[4-(4-moφholinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate
549 1 -Ethyl-N-( {3-[(4-methyl- 1 -piperazinyl)methyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate
550 N- { [5 -(Aminocarbonyl)-3 -pyridinyljmethyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate
551 1 -Ethyl-N- { [4-( 1 -methylethyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide
552 N- { [3 -(Cyclopentyloxy)-4-(methyloxy)phenyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- lH-pyrazolo[3 ,4-b]pyridine-5-carboxamide
553 l-Ethyl-N-({4-[(4-methyl-l-piperazinyl)methyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate
554 N-[(2,4-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
555 N-[(2,4-Difluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
556 N-[(2-Chloro-4-fluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
557 N-{2-[2-Chloro-3-(methyloxy)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
558 Methyl 3 -[( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridin-5- yl]carbonyl}amino)methyl]benzoate
559 l-Ethyl-N-{[3-(l-pyrrolidinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate
560 l-Ethyl-N-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide
561 N-{[2,5-Bis(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
562 N-{[2,6-Bis(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
563 1 -Ethyl-N-[(2-fluorophenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
564 N-[(3,5-Difluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
565 N-[(4-Chlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
567 N-Cyclohexyl- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide
568 1 -Ethyl-N- {2-[4-(methylsulfonyl)phenyl]ethyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide
569 l-Ethyl-N-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
570 N-( {4-[(Cyclopropylamino)carbonyl]phenyl } methyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
571 1 -Ethyl-N- { [4-(4-methyl-l -piperazinyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
572 1 -Ethyl-N- { [4-(l -pyrrolidinylmethyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
573 1 -Ethyl-N-[6-(methyloxy)- 1 -oxo-2,3 -dihydro- lH-inden-2-yl] -4-(terrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
574 N-[(2,5-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
575 N-[(3,5-Diethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
576 N-[(2,3-Difluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
577 1 -Ethyl-N- { [2-(methylsulfonyl)phenyl]methyl } -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
578 1 -Ethyl-N-[(3 -hydroxyphenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
579 N- { [3 , 5 -Bis(methyloxy)phenyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
580 l-Ethyl-N-[2-(4-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
581 N-[(3,5-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
582 N-{[2,4-Bis(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
583 l-Ethyl-N-{[2-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
584 N-[(2,4-Dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide 585 1 -Ethyl-N-( {2-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
586 l-Ethyl-N-{2-[4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
587 N-[(2-Chlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
588 l-Ethyl-N-[(2-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
589 N-(l,3-Benzodioxol-5-ylmethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
590 1 -Ethyl-N-[3 -(methyloxy)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
591 N-(Cyclohexylmethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
592 l-Ethyl-N-(l,2,3,4-tetrahydro-l-naphthalenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
593 Methyl 4-[({[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridin-5- yl]carbonyl}amino)methyl]benzoate
594 N-[(3,4-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3 ,4-b]pyridine-5 -carboxamide
595 N-{[4-(Anιinocarbonyl)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
596 N-[(2,6-Difluorophenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide
597 N- { [3 -(Aminocarbonyl)phenyljmethyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
598 l-Ethyl-N-[(4-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
599 l-Ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
600 1 -Ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
601 1 -Ethyl-4-(texrahydro-2H-pyran-4-ylamino)-N- { [3 -(trifluoromethyl)phenyljmethyl } - 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
602 N-[4-(2-Amino-2-oxoethyl)phenyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
603 l-Ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
604 1 -Ethyl-N- {4-[2-(methylamino)-2-oxoethyl]phenyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
605 1 -Ethyl-N-[(3 -fluorophenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
606 1 -Ethyl-N-( {4-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-{[4-(Aminosulfonyl)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N- { [2-(Aminocarbonyl)phenyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide N-({3-[(Dimethylamino)methyl]phenyl}methyl)-l-ethyl-4-(texrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-{[3-Chloro-4-(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide N-( 1 -Acetyl-4-piperidinyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N- { [2-(trifluoromethyl)phenyl]methyl} - 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-(5-Chloro-2,3-dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-({3-[(Acetylamino)methyl]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide l-Ethyl-N-[(4-fluorophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide l-Ethyl-N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide l-Ethyl-N-[(2-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide l-Ethyl-N-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide l-Ethyl-4-(texrahydro-2H-pyran-4-ylamino)-N-[(2,3,4-trifluorophenyl)methyl]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-[(4-Chloro-2-fluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-[(4-Bromo-2-fluorophenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-[(3,5-Dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-[(2,3-Dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-[(2,3-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide N-[(4-Cyanophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide N-[(4-Bromophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide 629 l-Ethyl-N-{[5-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
630 l-Ethyl-N-[(4-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- bJpyridine-5 -carboxamide
631 N- {[4-(l , 1 -Dimethylethyl)phenyl]methyl} -1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
632 N-[(3-Cyanophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- bJpyridine-5 -carboxamide
633 N-[(2,6-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
634 N-[(5 -Chloro-2-methylphenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
635 N-[(3,5-Dibromophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
636 l-Ethyl-N-[(4-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
637 1 -Ethyl-N- { [3 -fluoro-4-(trifluoromethyl)phenyl]methyl } -4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
638 l-Ethyl-N-[(2-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
639 N-[(2-Bromophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
640 1 -Ethyl-N- { [4-(hydroxymethyl)phenyl]methyl } -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-bJpyridine-5 -carboxamide
641 l-Ethyl-N-{[3-(hydroxymethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
642 1 -Ethyl-N- { [3 -(hydroxymethyl)-2-methylphenyl]methyl} -4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
643 N-{[2,3-Dichloro-6-(hydroxymethyl)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
644 N-[(2,4-Dichloro-6-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
645 l-Ethyl-N-{[4-(2-methylpropyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
646 N-[(2,5-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
647 l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[(2,4,5-trifluorophenyl)methylJ-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
648 l-Ethyl-N-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
649 N-[(2-Chloro-6-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
650 4- [( { [ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridin-5- yl]carbonyl}amino)methyl]benzoic acid sodium salt
651 3-[({[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridin-5- yljcarbonyl} amino)methyl]benzoic acid
652 Ethyl 1 -ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino} - 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxylate
653 l-Ethyl-4-{[4-(hydroxyirnino)cyclohexyl]amino}-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
654 N- { [4-(Dimethylamino)phenyl]methyl} - 1 -ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino } - lH-pyrazolo[3,4-b]pyridine-5-carboxamide
655 l-Ethyl-4-({4-[(ethyloxy)imino]cyclohexyl}amino)-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
656 l-Ethyl-4-({4-[(methyloxy)imino]cyclohexyl}amino)-N-{[4-(methyloxy)phenyl]methyl}- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide
657 4-[(4- {[(1,1 -Dimethylethyl)oxy]imino} cyclohexyl)amino]- 1 -ethyl-N- { [4- (methyloxy)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
658 1 -Ethyl-N- { [4-(methyloxy)phenyl]methyl } -4-[(7-oxohexahydro- 1 H-azepin-4-yl)amino] - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
659 Ethyl l-ethyl-4-[(7-oxohexahydro-lH-azepin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxylate
660 4- { [cis-4-(Butylamino)cyclohexyl]amino} -N-(2,3-dihydro- lH-inden-2-yl)- 1 -ethyl- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
661 4-[(trans-4-Aminocyclohexyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide
662 4-[(trans-2-Aminocyclohexyl)amino] - 1 -ethyl-N-(phenylmethyl)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide
663 4-[(cis-2-Aminocyclohexyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine- 5 -carboxamide
664 4-[(3-Aminocyclohexyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide
Example Name
No.
665 Ethyl 1 -ethyl-4- {[(lSR,3RS)-3-hydroxycyclohexyl]amino}-lH-ρyrazolo[3,4- b]pyridine-5-carboxylate
666 N, 1 -Diethyl-4- { [( 1 SR,3RS)-3 -hydroxycyclohexyl] amino } - lH-pyrazolo [3,4- b]pyridine-5-carboxamide
667 l-Ethyl-N-(4-fluorophenyl)-4-{[(lSR,3RS)-3-hydroxycyclohexylJamino}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide 668 l-Ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-(l,3-thiazol-2-ylmethyl)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide 669 l-ethyl-N-[(4-fluorophenyl)methyl]-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}- lH-pyrazolo[3,4-b]pyridine-5-carboxamide 670 l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4- (methylsulfonyl)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
671 N-{[3,4-bis(methyloxy)phenyl]methyl}-l-ethyl-4-{[(lSi?,3RS)-3- hydroxycyclohexyl] amino }- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide 672 l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-(2-pyridinylmethyl)-lH- pyrazolo [3, 4-b]pyridine-5 -carboxamide
673 l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-[(l-methyl-lH-pyrazol-4- yl)methyl]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
674 N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-{[(lSR,3RS)-3- hydroxycyclohexyl]amino}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
675 l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4- (methyloxy)phenyl]methyl}-lH-pyrazolo[3,4-bJpyridine-5-carboxamide
676 N-[(2,4-dimethylphenyl)methyl]-l-ethyl-4-{[(lSR,3RS)-3- hydroxycyclohexyl]amino}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide 667 N-[(2,3 -Dichlorophenyl)methyl] - 1 -ethyl-4-[(4-oxocyclohexyl)amino] - 1H- pyrazolo[3,4-b]pyridine-5-carboxamide
678 N-[(3-Chloro-4-methylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo [3 ,4-b Jpyridine-5 -carboxamide
679 N-[(4-Chloro-2-methylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide
680 N-[(2,4-Dimethylphenyl)methyl] - 1 -ethyl-4- { [4- (hydroxyimino)cyclohexyl]amino}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
681 N-[(3,4-Dimethylphenyl)methyl]-l-ethyl-4-{[4- (hydroxyimino)cyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide 682 N-[(2,3-Dichlorophenyl)methyl]-l-ethyl-4-{[4-
(hydroxyimino)cyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide
683 N-[(3-Chloro-4-methylphenyl)methyl]-l-ethyl-4-{[4- (hydroxyimino)cyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide
684 N-[(4-Chloro-2-methylphenyl)methyl]-l-ethyl-4-{[4- (hydroxyimino)cyclohexyl]amino}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
685 N-({4-[(Difluoromethyl)oxy]ρhenyl}methyl)-l -ethyl-4- {[4- (hydroxyimino)cyclohexyl]amino}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
686 1 -Ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino} -N- { [4- (trifluoromethyl)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide Example 1: Ethyl 4-(cyclopentylamino)-l-ethyl-lH-pyrazoIo[3,4-b]pyridine-5- carboxylate
That is, Example 1 is NHR3 = HN
Figure imgf000151_0001
Intermediate 1 (0.05 lg) and cyclopentyl amine (0.019g) were suspended in ethanol (2ml) and triethylamine (0.14ml) was added. The mixture was stined under nitrogen and heated at 80°C for 16h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between dichloromethane (DCM) and water. The layers were separated and the organic layer was loaded directly onto an solid phase extraction (SPE) cartridge (silica, 5g) which was eluted sequentially with; (i) DCM, (ii) DCM : Et2O (2:1), (iii) DCM : Et2O (1:1), (iv) Et2O, (v) EtOAc, (vi) MeOH. Fractions containing desired material were combined and concentrated in vacuo to afford Example 1 (0.074g). LCMS showed MFf" = 303; TRET = 3.45min.
Similarly prepared were the following:
Figure imgf000151_0002
Figure imgf000151_0003
* For alternative synthesis of Example 5, see Example 207 hereinafter Example 3 ^Intermediate 32): Ethyl l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000152_0001
Instead of the method shown above for Examples 1-5 (called Method A), the compound of Example 3 can also be made: either using the minor variation of Method A described in detail under "Intermediate 32" hereinabove, or using the following Method B:
Example 3, Method B: Intermediate 1 (2.5g) was dissolved in acetonitrile (15ml).
4-Aminotetrahydropyran hydrochloride (l.lg) and N,N-diisopropylethylamine (9.4ml) were added and the mixture stined under nitrogen at 85°C for 16h. A trace of starting material remained, so an additional portion of 4-aminotetrahydropyran hydrochloride (0.1 lg) was added and stirring continued at 85°C for a further 16h. The mixture was then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was washed with further water (2x20ml) then dried (Na SO4) and concentrated in vacuo. The residue was further purified by chromatography using Biotage (silica, 90g), eluting with cyclohexane : ethyl acetate to afford Example 3 (2.45g). LCMS showed MH+ = 319; TRET = 2.90min.
Example 6: Ethyl 4-(cyclopentylamino)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxylate
Figure imgf000152_0002
Intermediate 3 (0.045g) was placed in a Reactivial™ and treated with cyclopentyl amine (0.07ml). The mixture was heated at 90°C for 2h, then allowed to cool to room temperature and partitioned between chloroform (2ml) and water (1ml). The layers were separated and the organic phase was evaporated to a brown solid, which was purified by mass directed autoprep HPLC, to afford Example 6 as a white solid (0.008g). LCMS showed MH+= 289; TRET = 3.22 min. Example 7: Ethyl l-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxylate
Figure imgf000153_0001
Intermediate 3 (0.035g) was placed in a Reactivial™ and treated with 4-amino tetrahydropyran (0.06ml). The mixture was heated at 90°C for 2h, then allowed to cool to room temperature and partitioned between chloroform (2ml) and water (1ml). The layers were separated and the organic phase was concentrated, then applied to a preparative TLC plate (silica, 20cm x 20cm x 1mm) which was eluted with ethyl acetate. The required band was removed from the plate and the silica washed with ethyl acetate (2 x 15ml). Concentration of the ethyl acetate solution in vacuo afforded Example 7 as a white solid (0.008g). LCMS showed MH+= 305; TRET = 2.67 min.
Example 8: Ethyl l-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-lH-pyrazolo[3,4- b]pyridine-5-carboxylate
Figure imgf000153_0002
Intermediate 1 (0.05g) and (S)-(-)-3-aminotetiahydrofuran 4-toluene sulphonate (0.052g) were suspended in ethanol (1ml) and triethylamine (0.14ml) was added. The mixture was stined under nitrogen and heated at 80°C for 24h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM (2ml) and water (1.5ml). The layers were separated and the organic layer concentrated to dryness. Purification was carried out using an SPE cartridge (silica, 5g), eluting with a gradient of EtOAc : cyclohexane; (1:16 then, 1:8, 1:4, 1:2, 1:1 and 1:0). Fractions containing desired material were combined and concentrated in vacuo to afford Example 8 (0.052g). LCMS showed MH+ = 305; TRET = 2.70min. Similarly prepared were the following:
Figure imgf000154_0001
Figure imgf000154_0003
Example 13: Ethyl 4-[(l,l-dioxidotetrahydrothien-3-yl)amino]-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000154_0002
intermediate 1 (0.05g) and Intermediate 13 (0.027g) were suspended in ethanol (1ml) and triethylamine (0.14ml) was added. The mixture was stined under nitrogen and heated at 80°C for 24h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM (2ml) and water (1.5ml). The layers were separated and the organic layer concentrated to dryness. Purification was carried out using an SPE cartridge (silica, 5g), eluting with a gradient of EtOAc : cyclohexane; (1:8 then 1:4, 1:2, 1:1 and 1:0). Fractions containing desired material were combined and concentrated in vacuo to afford Example 13 (0.045g) as a mixture of enantiomers. LCMS showed MH+ = 353; TRET = 2.60min.
Similarly prepared was the following:
Figure imgf000155_0001
Figure imgf000155_0004
Example 19 (reference example, as an intermediate): Ethyl 4-(cyclopentylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000155_0002
Intermediate 2 (0.035g) was placed in a Reactivial™ and treated with cyclopentyl amine (0.05ml). The mixture was heated at 90°C for 1.5h, then allowed to cool to room temperature and partitioned between chloroform (2ml) and water (1ml). The layers were separated and the organic phase was concentrated. The residual solid was triturated with Et2O and the insoluble off-white solid collected and air-dried to afford Example 19 (0.016g). LCMS showed MH+= 275; TRET = 2.58 min.
Example 20 (reference example, as an intermediate): Ethyl 4-(tetrahydro-2H- pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000155_0003
that is:
Figure imgf000156_0001
Example 20 NHR3 = HN-4 O
Intermediate 2 (0.035g) was placed in a Reactivial™ and treated with 4- aminotetrahydropyran (0.05ml). The mixture was heated at 90°C for 1.5h, then allowed to cool to room temperature and partitioned between chloroform (2ml) and water (1ml). The layers were separated and the organic phase was concentrated. The crude product was purified by mass directed autoprep HPLC to afford Example 20 as an off-white solid (0.01 lg). LCMS showed MH+= 291; TRKT = 2.08 min.
Alternative synthetic method for Example 20:
Intermediate 2 (2g) was suspended in 4-aminotetrahydropyran (2g), and the mixture was heated at 90 °C for 6h. The residual mixture was allowed to cool to room temperature and partitioned between chloroform (50ml) and water (50ml). The phases were separated and the organic phase was evaporated to dryness. The residue was triturated with Et2O (30ml) and the insoluble solid was collected and dried to afford Example 20 as a cream solid (2.24g). LCMS showed MH+= 291; TRET = 2.19min.
Example 21: N-benzyl-l-ethyI-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide
Figure imgf000157_0001
that is, Example 21 is:
Figure imgf000157_0002
Three alternative methods, A, B and C, have been used to make Example 21, as follows:
Example 21, Method A:
A solution of the 4-chloro Intermediate 17 (0.031g, 0.1 mmol) in ethanol (1.9ml) was treated with triethylamine (0.07ml, 0.5 mmol), followed by a 0.1M ethanolic solution of 4-aminotetiahydropyran (hitermediate 8, 1.1ml of the 0.1M ethanolic solution = 0.11 mmol). The mixture was heated at reflux (80°C) for 18h. A further portion of 4-amino- tetrahydropyran (0.01ml of undiluted amine, not a solution thereof) was then added and heating continued for a further 24h. Nolatiles were removed in vacuo and the residue dissolved in dichloromethane (DCM), then applied to an solid phase extraction (SPE) cartridge (aminopropyl, lg) which was eluted first with DCM, then with methanol. Fractions containing desired material were concentrated in vacuo to afford Example 21 (0.004g). LCMS showed MH+ = 380; TRET = 2.92min.
Example 21 , Method B:
Intermediate 17 (0.031g, 0.1 mmol) was dissolved in acetonitrile (1ml). 4-Aminotetrahydropyran hydrochloride (Intermediate 8A, 0.015g, 0.11 mmol) and Ν,Ν- diisopropylethylamine (0.08ml, 0.5 mmol) were added and the mixture stined under nitrogen at 85°C for 16h, then concentrated in vacuo. The residue was partitioned between dichloromethane (DCM) and water. The layers were separated and the organic layer was concentrated in vacuo to afford Example 21 (0.027g). LCMS showed MH+ = 380; TRET = 2.92 min. Example 21 , Method C:
This alternative route C to Example 21 involves formation of the ester of Example 3
Intermediate 32 (
Figure imgf000158_0001
using one of the methods described above, conversion of the ester of Example 3 / Intermediate 32 into the carboxylic acid (Intermediate 33) using the method given above for lntermediate 33, and then amide bond formation to fonn Example 21 using the method of Examples 81-84 below.
The following compounds can be similarly prepared using one or more of Methods A, B or C above, preferably Method A or B:
Figure imgf000158_0002
Figure imgf000158_0003
Figure imgf000159_0002
Example 39: N-Benzyl-4-(cyclopentylamino)-l-ethyl~lH~pyrazolo[3,4-b]pyridine-5- carboxamide
that is, Example 39 is:
Figure imgf000159_0001
A solution of Intennediate 17 (0.03 lg, 0.1 mmol) in ethanol (1ml) was treated with triethylamine (0.07ml, 0.5 mmol), followed by a 0.1M ethanolic solution of cyclopentyl amine (1.1ml of the 0.1M ethanolic solution = 0.11 mmol). The mixture was heated at reflux (80°C) for 18h. A further portion of cyclopentyl amine (0.009ml of undiluted amine, not a solution thereof) was then added and heating continued for a further 24h. Nolatiles were removed in vacuo and the residue dissolved in DCM, then applied to an SPE cartridge (aminopropyl, lg) which was eluted first with DCM, then with methanol. The DCM fraction was concentrated in vacuo, then applied to an SPE cartridge (silica, 0.5g) which was eluted sequentially with (i) DCM, (ii) Et2O, (iii) EtOAc and (iv) MeOH. Fractions containing desired material were combined to afford Example 39 (0.007g). LCMS showed MFf = 364; TRET = 3.38min.
Similarly prepared were the following:
Figure imgf000160_0001
Figure imgf000160_0002
Example 57: 4-[(l-Acetylpiperidin-4-yl)amino]-l-ethyl-N-(pyridin-4-ylmethyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000161_0001
that is, Example 57 is:
Figure imgf000161_0002
A solution of Intermediate 22 (0.03g, ca. 0.1 mmol) in ethanol (1ml) was treated with triethylamine (0.07ml, 0.5 mmol), followed by a 0.1M ethanolic solution of intermediate 6 (1.1ml of the solution = 0.11 mmol). The mixture was heated at reflux (80°C) for 18h. A further portion of Intermediate 6 (0.01ml, undiluted) was then added and heating continued for a further 24h. Nolatiles were removed in vacuo and the residue dissolved in DCM, then applied to an SPE cartridge (aminopropyl, lg) which was eluted first with DCM, then with methanol.
The DCM fraction was concentrated in vacuo, then applied to an SPE cartridge (silica, 0.5g) eluting with (I) DCM, (ii) EtOAc and (iii) a stepwise gradient of chloroform : methanol (from 99:1 up to 4:1). Fractions containing desired material were combined to afford Example 57 (0.003 g). LCMS showed MH+ = 422; TRET = 2. lmin.
Example 61: Ν-Benzyl-4-(cyclopentylamino)-l-methyl-lH-pyrazolo[3,4-b]pyridine- 5-carboxamide
Figure imgf000161_0003
A solution of Intermediate 28 (0.03g, 0.1 mmol) in ethanol (1ml) was treated with a 0.1M ethanolic solution of cyclopentyl amine (1.1ml of solution = 0.11 mmol). Triethylamine (0.07ml, 0.5 mmol) was then added and the mixture heated at reflux (85°C), under nitrogen for 12h. A further portion of cyclopentyl amine (0.009ml, undiluted) was then added and heating continued for a further 36h. The mixtures were concentrated in vacuo and the residue tieated with chloroform. A small amount of insoluble material was collected by filtration, then the filtrate applied to an SPE cartridge (aminopropyl, lg) which was eluted first with DCM, then with methanol. Fractions containing desired material were combined to afford Example 61 (0.039g). LCMS showed MH+ = 350; TRET = 2.88min.
Similarly prepared were the following:
Figure imgf000162_0001
Figure imgf000162_0002
Example 74: 4-[(l-Acetylpiperidin-4-yl)amino]-N-benzyl-l-methyl-lH-pyrazolo[3,4- b]pyridine-5-carboxamide
that is, Example 74 is:
Figure imgf000163_0001
A solution of Intermediate 28 (0.03 g, 0.1 mmol) in ethanol (1ml) was treated with a 0.1M ethanolic solution of Lntermediate 6 (1.1ml of solution = 0.11 mmol). Triethylamine (0.07ml, 0.5 mmol) was then added and the mixture heated at reflux (85°C), under nitrogen for 12h. A further portion of Intermediate 6 (0.1 mmol) was then added and heating continued for a further 36h. The mixtures were concentrated in vacuo and the residue treated with chloroform. A small amount of insoluble material was collected by filtration, then the filtrate applied to an SPE cartridge (aminopropyl, lg) which was eluted first with DCM, then with methanol. Fractions containing desired material were combined and concentrated in vacuo. The residue was further purified by SPE (silica, 0.5g) eluting with (i) DCM, (ii) chloroform, (iii) EtOAc and (iv) a stepwise gradient of chloroform : methanol (from 99:1 up to 4:1). Fractions containing desired material were combined to afford Example 74 (0.029g). LCMS showed MH+ = 407; TRET = 2.57 min.
Example 81: l-Ethyl-N-methyl-4-(tetrahydro-2H-pyran-4-yIamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
Example 81 NR4R5 = NHMe
Figure imgf000163_0002
To a stined suspension of Intennediate 33 (0.025g, ca. 0.08 to 0.09 mmol) in chloroform (2ml) was added thionyl chloride (0.025ml) and the mixture stined at room temperature for lh. The mixture was cooled to 0°C and methylamine added (2M solution in THF, 0.69ml = 1.38 mmol). After returning to room temperature the mixture was stined for a further lh, then quenched by addition of water (4ml) and the layers separated. The organic layer was concentrated then applied to an SPE cartridge (silica, lg) which was eluted with (i) DCM, (ii) Et2O (2:1), (iii) EtOAc, (iv) MeOH: EtOAc (1:9). Fractions containing desired material were combined to afford Example 81 (0.019g). LCMS showed MH+ = 304; TRET = 2.19min.
Similarly prepared:
Figure imgf000164_0001
Figure imgf000164_0003
Example 83 : N,l -Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo [3,4- 6]pyridine-5-carboxamide; also named l-ethyl-A'-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-Z>]pyridine-5-carboxamide
Figure imgf000164_0002
hi an alternative embodiment to the process described for Examples 81-84 above, Example 83 can be made according to the following method:
A mixture of Intermediate 33 (3.0g, 10.33mmol), EDC (2.25g, 11.7mmol), and HOBT (1.68g, 12.4mmol) was stined at room temperature for 1 hour. Ethylamine (6.2ml, 12.4mmol, 2M-solution in THF) was added, and stirring was continued at room temperature for 22 hours. The solvents were removed in vacuo, and the residual solid was dissolved in chloroform (250ml) and washed successively with water (70ml) and 5%- sodium hydrogen carbonate solution (70ml). After drying over anhydrous sodium sulphate, the organic solution was evaporated in vacuo to give a pale orange solid (4.15g). This solid was dissolved in a mixture of dichloromethane (15ml) and chloroform (5ml) and purified by- column chromatography (Biotage, silica, lOOg), eluting initially with EtOAc-cyclohexane (2:1) and finally with neat EtOAc. The product containing fractions were combined and evaporated to give Example 83 as a pale yellow solid (3.05g). LCMS showed MH+ = 318; TRET = 2.33min. 1H NMR (400MHz in d6-DMSO, 27°C, δppm) 9.76 (d, IH) 8.35 (s, IH) 7.94 (s, IH) 5.99 (br m, IH) 4.47 (q, 2H) 4.16- 4.01 (m's, 3H) 3.62 (m, 2H) 3.48 (m, 2H) 2.13 (m, 2H) 1.77 (m, 2H) 1.49 (t, 3H) 1.28 (t, 3H).
Example 85: N-B enzy 1-1 -ethyl-4- [(3 S)-tetr ahy drofuran-3-ylamino] -1 H-pyrazolo [3,4- b]pyridine-5-carboxamide
Figure imgf000165_0001
That is, Example 85 is: wherein NHR3 ;
Figure imgf000165_0003
Figure imgf000165_0002
Intermediate 41 (0.017g, 0.062 mmol) was dissolved in DMF (2ml), then treated with HATU (0.023g) followed by diisopropylethyl amine (0.021ml) and the mixture stined for 10 min. Benzylamine (0.007ml) was then added and stirring continued for a further 64h. The mixture was concentrated in vacuo and the residue dissolved in DCM (1.5ml) then treated with saturated aqueous sodium bicarbonate solution (1.5ml). This mixture was stined for 30 min, then the layers were separated and the organic layer was applied to an SPE cartridge (silica, lg) which was eluted sequentially with a gradient of ethyl acetate: cyclohexane (1:4, then 1:2, 1:1, 2:1 and 1:0). Fractions containing desired material were concentrated in vacuo to afford Example 85 (0.017g). LCMS showed MH+ = 366; TRET = 2.80min.
Similarly prepared were the following:
Figure imgf000166_0001
Figure imgf000166_0003
Example 91 : N-Benzvl-l-ethyl-4-(tetrahvdro-2H-thiopyran-4-vlamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000166_0002
Intermediate 43 (0.019g) was dissolved in DMF (2ml), then treated with HATU (0.024g) followed by diisopropylethyl amine (0.022ml) and the mixture stined for 10 min. Benzylamine (0.007ml) was then added and stirring continued for a further 64h. The mixture was concentrated in vacuo and the residue dissolved in DCM (1.5ml) then treated with saturated aqueous sodium bicarbonate solution (1.5ml). This mixture was stined for 30 min, then the layers were separated and the organic layer applied to an SPE cartridge (silica, lg) which was eluted sequentially with a gradient of ethyl acetate: cyclohexane (1 :4, then 1 :2, 1:1 and 1 :0). Fractions containing desired material were concentrated in vacuo to afford Example 91 (0.023g). LCMS showed MH+ = 396; TRET = 3.26min. Example 92: 1 -Ethyl-N-(4-fluorophenyl)-4- [(3 S)-tetrahy drof ur an-3-ylamino] -1 H- pyrazolo[3,4-b]pyridine-5-carboxamide
that is, Example 92 is: NHR3 ■
Figure imgf000167_0002
Figure imgf000167_0001
Intermediate 41 (0.017g) was dissolved in DMF (2ml), then treated with HATU (0.023g) followed by diisopropylethyl amine (0.021ml) and the mixture stined for 10 min. 4- Fluoroaniline (0.006ml) was then added and stirring continued for a further 64h. The mixture was concentrated in vacuo and the residue dissolved in DCM (1.5ml) then treated with saturated aqueous sodium bicarbonate solution (1.5ml). This mixture was stined for 30 min, then the layers were separated and the organic layer concentrated in vacuo. The crude mixture was purified by mass directed autoprep HPLC to afford Example 92 (0.013g). LCMS showed MH+ = 370; TRET = 2.91min.
Similarly prepared were the following:
Figure imgf000167_0003
Figure imgf000167_0004
Figure imgf000168_0002
Example 99
In all of Examples 22 to 98, where a 4-amino 5-carboxamide Example of the following Formula I has been synthesised from the 4-chloro derivative, then an alternative final-step synthesis is as follows:
Figure imgf000168_0001
Formula IV Formula I
An intermediate of Formula IN above (0.1 mmol) was dissolved in acetonitrile (1ml). An amine of formula R3ΝH2 (0.11 mmol, 1.1 mole equivalents) and N.N- diisopropylethylamine (0.5mmol, 5 mole equivalents) were added and the mixture stirred under nitrogen at 85°C for 16h. After concentration in vacuo, the residue was partitioned between dichloromethane (DCM) and water. The layers were separated and the organic layer was concentrated in vacuo to afford an Example of Formula I.
Example 100
Figure imgf000169_0001
Example 100 NR4R5 =
Figure imgf000169_0002
Intermediate 33 (0.048mmol) was dissolved in DMF (0.5ml), then treated with HATU (0.048mmol) followed by diisopropylethyl amine (0.096mmol) and the mixture stined for 10 min. 4-Methylsulfonylbenzylamine (0.052mmol, available from Acros Organics) was then added and stirring continued for a further 16 hours. The mixture was concentrated in vacuo. The crude mixture was purified by mass directed autoprep HPLC to afford Example 100 (0.013g). LCMS showed MH+= 458 ; TRET = 2.22min.
Similarly prepared, but replacing the 4-methylsulfonylbenzylamine with the same or similar number of moles of another amine R4R5NH, were the following compounds (Examples 102 to 182):
Figure imgf000169_0003
Figure imgf000169_0004
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0002
Example 109: l-EthyI-4-(tetrahydro-2H-pyran-4-ylamino)-N-(l,3-thiazol-2- ylmethyl)-lH-pyrazolo[3,4- »]pyridine-5-carboxamide
Figure imgf000177_0001
An alternative process for preparing Example 109 is given below: 1-Hydroxybenzotriazole (0.215g, 1.59mmol) and l-[3-(dimethylamino)propyl]-3-ethyl- carbodiimide hydrochloride (0.357g, 1.86mmol) were added to a suspension of intermediate 33 (0.384g, 1.32mmol) in DMF (10ml). After stirring at room temperature for 30 minutes, (l,3-thiazol-2-ylmethyl)amine (0.182g, 1.59mmol) (commercially available from MicroChemistiy Building Blocks (Russia) or Matrix Scientific (USA), or preparable as disclosed in Synthesis 1998, 641, or Tetrahedron 1995, 51, 12731) was added. The reaction was stined for 18 hours and then partitioned between ether and water. The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (Biotage, silica90g) eluting with cyclohexane: EtOAc followed by EtOAc. The material was triturated with cyclohexane and filtered to afford Example 109 (0.244g) as a pale yellow solid. LCMS showed MH+ 387; TRET = 2.49min. IH NMR (400MHz in CDC13, δppm) δ 9.74 (d, IH) 8.50 (s, IH) 7.94 (s, IH) 7.74 (d, IH), 7.33 (d, IH), 7.17 (m, IH), 4.94 (d, 2H) 4.45 (q, 2H) 4.15 - 4.00 (m, 3H), 3.63 (m, 2H). 2.15 (m, 2H) 1.85 - 1.73 (m, 3H) 1.48 (t, 3H).
Example 167: N-{[3,4-Bis(methyIoxy)phenyI]methyl}-l-ethyl-4-(tetrahydro-2H- pyran-4-yIamino)-lH-pyrazoIo[3,4-Z>]pyridine-5-carboxamide
Figure imgf000179_0001
Ln an alternative embodiment to the process described above for Examples 100-182, Example 167 can be made according to the following method:
A mixture of Lntermediate 33 (0.498g, 1.72mmol), EDC (0.46g, 2.41mmol), and HOBT (0.278g, 1.68mmol) was stined at room temperature for 0.25 hours. Neratrylamine (3,4-dimethoxybenzylamine, 0.31ml, 2.05mmol, obtainable from Aldrich or Synlett, 1999, 4, 409) was added, and stirring was continued at room temperature for 22 hours. The reaction mixture was partitioned between Et O and water. The aqueous phase was extracted with Et2O and the combined organic phases washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (Biotage, silica 40g) eluting with EtOAc : cyclohexane (2:1). The material was further purified by SPE (SCX-2, lOg) eluting with methanol then ammonia in methanol (0.5M). The ammonia methanol fractions were combined and evaporated in vacuo to afford Example 167 as a white foam (0.633g). LCMS showed MH+ = 440; TRET = 2.65min. 1H ΝMR (400MHz in CDC13, 27°C, δppm) 9.78 (d, IH) 8.37 (s, IH) 7.94 (s, IH) 6.94 - 6.82 (m, 3H) 6.29 (br m, IH) 4.56 (d, 2H) 4.46 (q, 2H) 4.15-4.01 (m's, 3H) 3.89 (s, 6H) 3.63 (m, 2H) 2.15 (m, 2H) 1.78 (m, 2H) 1.49 (t, 3H).
Example 178 l-Ethyl-N-[(l-methyl-lH-pyrazol-4-yl)methyl]-4-(tetrahydro-2H- pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5~carboxamide
Figure imgf000179_0002
The IH ΝMR data for Example 178 (as prepared by the process described in Examples 100-182 above) was as follows: IH NMR (400MHz in CDCl3,δppm) δ 9.90 (m, IH) 8.37 (s, IH) 7.94 (s, IH) 7.49 (s, IH), 7.40 (s, IH) 6.39 (m, IH) 4.50 - 4 .42 (m, 4H) 4.15 - 4.00 (m, 3H) 3.89 (s, 3H), 3.63 (m, 2H) 2.52 (m, 2H) 2.20-2.10 (m, 2H) 1.85 - 1.73 (m, 3H) 1.48 (t, 3H).
Example 183: Ethyl 4-(cyclohexylamino)-l-(3-ethoxy-3-oxopropyl)-lH- pyrazolo [3,4-6] pyridine-5-carboxylate
Figure imgf000180_0001
A vigorously stined mixture of Intermediate 48 (40mg), anhydrous potassium carbonate (57mg) and ethyl 3-bromopropanoate (0.027ml) in anhydrous DMF (1ml) was heated at 65 °C overnight. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane (5ml) and water (5ml). The phases were separated and the organic phase was evaporated to a residual oil which was purified by mass directed autoprep HPLC to afford Example 183 (5mg). LCMS showed MH+= 389; TRET = 3.65min.
Example 185: Ethyl l-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-Z>]pyridine-5-carboxylate
Figure imgf000180_0002
Sodium hydride (0.067g, 60% dispersion in oil) was added to a stined solution of
Example 20 (0.47g) in DMF (19ml), followed by n-propyl iodide (0.17ml). The mixture was stined at 23 °C for 16 hours, then concentrated, diluted with chloroform (30ml) and washed with 1:1 water :brine solution (30ml), separated and the organic layer concentrated. The residue was purified on a SPE catridge (silica, lOg) eluting with 10ml volumes of dichloromethane, 1:1 diethyl etherxyclohexane, and diethyl ether. The combined 1:1 diethyl ether: cyclohexane, and diethyl ether, fractions were concentrated to give Example 185 as a clear gum (0.23g). LCMS showed MH+ = 333; TRET = 3.14min.
Example 186: Ethyl l-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)~ lH-pyrazolo[3,4-6]pyridine-5-carboxylate
Figure imgf000181_0001
2-Bromoethanol (0.008ml) was added to a solution of Example 20 (0.03g) in anhydrous DMF (1.5ml), with 2-tert-butylimino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2- diazaphosphorine (polymer bound, 2.3mmol/g loading, 0.045g). The mixture was shaken at 23 °C for 16 hours, then the solution drained from the resin, and the resin was washed with DMF. The combined organics were concentrated, and the residue purified on a SPE cartridge (silica, lg) eluting with 70-100% ethyl acetate in cyclohexane. The combined fractions were concentrated to give Example 186 as a white solid (0.01 lg). LCMS showed MH1" =335; TRET = 2.47min.
Example 187: _N-[4-(Methylsulfonyl)benzyl]-l-n-propyl-4-(tetrahydro-2H- pyran-4-ylamino)-lH-pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000181_0002
Intermediate 50 (0.03g) was stined in DMF (1ml) with DLPEA (0.035ml) and HATU (0.038g) for 20 min. 4-(Methylsulfonyl)benzylamine hydrochloride (0.024g) was added to the mixture and the solution was stined for 8 hours at 23 °C. The solution was concentrated and the residue dissolved in dichloromethane (6ml) then washed with saturated sodium bicarbonate solution (6ml) and 1:1 brine:water (6ml), separated by hydrophobic frit. The organic layer was concentrated to give Example 187 as a white solid (0.039g). LCMS showed MH+ = 472; TRET = 2.67min. Example 188: N-(4-Fluorophenyl)-l -n-propyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000182_0001
The synthetic method is as described in Example 187, except that in place of 4- (methylsulfonyl)benzylamine hydrochloride, 4-fluoroaniline (0.01ml) was added to the mixture. The resultant product required further purification, which was performed by mass directed autoprep HPLC, giving Example 188 as a clear gum (0.03 g). LCMS showed MH4" = 398; TRET = 3.13min.
Example 189: Ethyl l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-Z>]pyridine-5-carboxylate
Figure imgf000182_0002
4-Aminotetrahydropyran hydrochloride (Intermediate 8A, 0.413g, 3.0mmol) was added to a mixture of Intermediate 51 (0.268g, l.Ommol) and N,N-diisopropylethylamine (0.87ml, 5.0mmol) in acetonitrile (3ml). The resulting mixture was heated at 85 °C for 24 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1.5ml) and applied to a SPE cartridge (silica, 5g). The cartridge was eluted successively with Et2O, EtOAc and EtOAc-MeOH (9/1). Fractions containing the desired product were combined and concentrated in vacuo to give the desired product contaminated with starting material (Intennediate 51). Further purification using a SPE cartridge (silica, 5g) eluting with ethyl acetate-cyclohexane (1/3) afforded Example 189 (0.248g). LCMS showed MH1" = 333; TRET = 2.75min. Example 190: Ethyl 4-(cycIohexylamino)-l-ethyl-6-methyl-lH-pyrazolo[3,4- b] py ridine-5-carb oxylate
Figure imgf000183_0001
Cyclohexylamine (0.149g, 1.5mmol) was added to a mixture of Intermediate 51 (0.201g, 0.75mmol) and N,N-diisopropylethylamine (0.65ml, 3.73mmol) in acetonitrile (3ml). The resulting mixture was heated at 85 °C for 40 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1.5ml) and applied to a SPE cartridge (silica, 5g). The cartridge was eluted successively with Et2O, EtOAc and MeOH. Fractions containing the desired product were combined and concentrated in vacuo to afford Example 190 (0.128g). LCMS showed MH+ = 331; TRET = 3.64min.
Example 191: 4-(Cyclohexylamino)-l -ethyl-6-methyl-Λ7- [4-
(methylsuIfonyl)benzyl]-lH-pyrazolo[3,4-δ]pyridine-5-carboxamide
Figure imgf000183_0002
A mixture of Intermediate 52 (0.014g, 0.046mmol), HATU (0.018g, 0.048mmol) and
DLPEA (0.022ml, 0.125mmol) in DMF (1ml) was shaken at room temperature for lOmin. l-[4-(Methylsulfonyl)phenyl]methanamine (0.009g, 0.046mmol) was then added, and the mixture was shaken for several minutes to give a solution. This solution was stored at room temperature for 16 hours. The solution was concentrated in vacuo, and the residue was dissolved in chloroform (0.5ml) and applied to a SPE cartridge (aminopropyl, 0.5g). The cartridge was eluted successively with chloroform (1.5ml), EtOAc (1.5ml) and EtOAc-MeOH (9:1, 1.5ml). Fractions containing the desired product were concentrated in vacuo to afford Example 191 (0.005g). LCMS showed MIT" = 470; TRET = 2.54min. Example 192: N-Benzyl-4-(cyclohexylamino)-l-ethyl-6-methyl-lH- pyrazolo[3,4-£]pyridine-5-carboxamide
Figure imgf000184_0001
Example 192 was prepared from Intermediate 52 using a method analagous to Example 191. LCMS showed MH+ = 392: TRET = 2.43.
Example 193: 4-(Cyclohexylamino)-l-ethyl-N-(4-fluorophenyl)-6-methyl-lH- pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000184_0002
Example 193 was prepared from intermediate 52 using an analagous method to Example 191. LCMS showed MH1" = 396; TRET = 2.6min.
Example 194: 4-(Cyclohexylamino)-l -ethyl-6-methyl-N- [4-
(trifluoromethyI)benzyl]-lH-pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000184_0003
Example 194 was prepared from Intermediate 52 using an analagous method to Example 191. LCMS showed MH+ = 460; TRET = 2.74min. Example 195: 4-(Cydohexylamino)-N-(2,3-dihydro-lH-mden~2-yl)-l-ethyI-6- methyI-lH-pyrazolo[3,4-i?]pyridme-5-carboxamide
Figure imgf000185_0001
Example 195 was prepared from Intermediate 52 using an analagous method to Example 191. LCMS showed MH+ = 418; TRET = 2.55min.
Example 196: N-Benzyl-l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000185_0002
Example 196 was prepared from Intermediate 53 using an analagous method to Example 191. LCMS showed MH+ = 394; TRET = 2.02min.
Example 197: N-Benzyl-l-ethyl-4-[(2-oxoazepan-3-yl)amino]-lH- pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000185_0003
3-Aminoazepan-2-one (0.043g, 0.335mmol, commercially available from Sigma-Aldrich Company Ltd) was added to a mixture of Lntermediate 17 (0.021g, 0.067mmol) and DLPEA (0.058ml, 0.335mmol) in acetonitrile (0.5ml). The resulting mixture was heated at 85 °C for 48 hours. Nolatiles were removed in vacuo, and the residue was dissolved in chloroform (0.5ml) and applied to a SPE cartridge (silica, 0.5g) which was eluted successively with diethyl ether (1.5ml), ethyl acetate (1.5ml) and ethyl acetate-methanol (9/1, 1.5ml). Fractions containing the desired material were concentrated in vacuo to afford Example 197 (0.009g). LCMS showed MH+ = 407; TRET = 2.81min.
Similarly prepared, but replacing the 3-aminoazepan-2-one with the same or similar number of moles of another amine R3ΝH2 were the following compounds:
Figure imgf000186_0001
Figure imgf000186_0003
Example 201 : N-Benzyl-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- ->]pyridine-5-carboxamide
Figure imgf000186_0002
Intennediate 54 (0.048g, 0.32mmol) was added to a mixture of Intermediate 17 (0.050g, 0.16mmol) and DLPEA (0.17ml, 0.98mmol) in acetonitrile (3ml). The resulting mixture was heated under reflux. After 12 hours, further quantities of Intermediate 54 (0.044g, 0.29mmol), DLPEA (0.17ml, 0.98mmol) and acetonitrile (1ml) were added to reaction mixture which was maintained under reflux. After 36 hours, the reaction mixture was concentated in vacuo, and the residual oil was dissolved in dichloromethane (8ml) and washed with 5% sodium bicarbonate solution (2ml). Evaporation of the organic solution gave a viscous oil which was dissolved in dichloromethane (2ml) and applied to a SPE cartridge (silica, 5g). The cartridge was eluted successively with a gradient of ethyl acetate-cyclohexane (1:16, then 1:8, 1:4, 1:2, 1:1 and 1:0). Fractions containing the desired material were concentrated in vacuo to afford Example 201 (0.018g). LCMS showed MH+ = 392; TRET = 2.95min.
Example 202: l-EthyI-/Y-(2-hvdroxy-l-methylethvl)-4-(tetrahvdro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-£]pyridine-5-carboxamide
Figure imgf000187_0001
Intermediate 33 (O.lg, 0.34mmol), EDC (0.066g, 0.34mmol) and HOBT (0.05g, 0.37mmol ) were suspended in DMF (2ml) and stined at room temperature under nitrogen for 15 min. 2-aminopropan-l-ol (0.026g, 0.34mmol) and triethylamine (0.036g, 0.36mmol) were added and the mixture was stined at room temperature under nitrogen for 6 hours. Solvents were removed in vacuo and the residue partitioned between DCM and water. The organic layer was concentrated and applied to an SPE cartridge (aminopropyl, 5g), which was eluted with methanol. Concentration in vacuo afforded Example 202 (0.095g). LCMS showed MH+ = 348, TRET= 2.15min. - 186 -
Example 203: Methyl (2S)-2-riri-ethvl-4-ftetrahydro-2H-pvran-4-vlamino)-lH- pyrazolo[3,4-6]pyridin-5-yl]carbonyl}amino)-3-hydroxypropanoate
Figure imgf000188_0001
Reaction scheme:
Figure imgf000188_0002
Intermediate 33 intermediate 33 (O.lg, 0.34mmol), EDC (0.066g, 0.34mmol) and HOBT (0.05g, 0.37mmol) were suspended in DMF (2ml) and stined at room temperature under nitrogen for 15 mins. L-Serine methyl ester hydrochloride (0.054g, 0.34mmol) and triethylamine (0.036g, 0.36mmol) were added and the mixture stirred at room temperature under nitrogen for 18 hours. Solvents were removed in vacuo and the residue was partitioned between DCM and water. The organic layer was concentrated in vacuo and applied to an SPE cartridge (aminopropyl, 5g), which was eluted with methanol. Concentration in vacuo afforded an impure residue which was further purified by SPE cartridge (silica, 5g), eluting with ethyl acetate followed by 5% methanol/ethyl acetate. The desired fractions were concentrated in vacuo to afford Example 203 (0.055g). LCMS showed MF4 = 393; TRET = 2.22min.
Example 204 Ethyl l-ethyl-4-[(4-hydroxycyclohexyl)amino]-lH-pyrazolo[3,4- 6]pyridine-5-carboxylate
Figure imgf000189_0001
Intermediate 1 (1.5g, 5.9mmol) was dissolved in acetonitrile (80ml). Trans-4- aminocyclohexanol (0.817g, 7.1mmol, commercially available from TCI- America; alternatively (e.g. as the HCl salt) from Aldrich) and diisopropylethylamine (6.18ml, 35.5mmol) were added and the mixture was stined at 85°C for 16h. The mixture was concentrated in vacuo, and the residue was partitioned between DCM (120ml) and water (30ml). The phases were separated and the organic phase was dried (Na2SO4) and evaporated to give a pale yellow solid. The solid was dissolved in a mixture of DCM (10ml) and chloroform (3ml), and applied in equal portions to two SPE cartridges (silica, 20g) which were eluted sequentially with a gradient of EtOAc: cyclohexane (1:16, then 1:8, 1:4, 1:2, 1:1 and 1:0). Fractions containing the desired material were combined and evaporated in vacuo to give Example 204 (1.893g) as a white solid. LCMS showed MH1" = 333; TRET = 2.79min.
Example 205: Ethyl l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- 6]pyridine-5-carboxylate
Figure imgf000189_0002
Example 204 (1.893g, 5.7mmol) was suspended in acetone (12ml) and the stined suspension was treated at 0°C with Jones reagent (1.81ml). After 30min, a further quantity of Jones reagent (1.81ml) was added to the reaction mixture which was maintained at 0°C. After a further 2h, a final portion of Jones reagent (1.44ml) was added to the reaction mixture, and stirring at 0°C was continued for lh. Isopropanol (3.8ml) was added to the reaction mixture, followed by water (15ml). The resulting mixture was extracted with ethyl acetate (2 x 40ml). The combined organic extracts were washed with water (8ml), dried (Na2SO4) and evaporated to a grey solid. The solid was dissolved in DCM (10ml) and applied in equal portions to two SPE cartridges (silica, 20g) which were eluted sequentially with a gradient of ethyl acetate: cyclohexane (1:16, then 1:8, 1:4, 1:2, and 1:1). Fractions containing the desired material were combined and evaporated in vacuo to give Example 205 (1.893g) as a white solid. LCMS showed MH+ = 331; TRET = 2.84min. Example 207 (= Example 5): Ethyl 4-[(l-acetyl-4-piperidinyl)amino]-l-ethyl-lH- pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000190_0001
Intennediate 1 (2.58g), Intennediate 6 (2.0g) and N,N-diisopropylethylamine (8.9ml) were dissolved in acetonitrile (98ml). The reaction mixture was heated at 85 °C for 24h then an additional portion of intermediate 6 (0.18 g) was added and heating continued for a further lOh. The reaction was concentiated in vacuo and the residues partitioned between DCM and water. The phases were separated and the organic phase evaporated in vacuo. The residue was purified by chromatography using Biotage (silica 90g) eluting with DCM : MeOH (5%) to afford Example 207 (1.55g) as a white solid. LCMS showed MH+ 360; TRET= 2.71 min.
Example 209: Ethyl 4-[(4-aminocyclohexyl)amino]-l-ethyl-lH-pyrazolo[3,4- 6]pyridine-5-carboxylate
Figure imgf000190_0002
Example 209 was prepared from Intermediate 1 and (4-aminocyclohexyl)amine using an analogous method to that used for the preparation of Example 207. LCMS showed MH4 = 332; TRET = 2.18min
Example 210: l-Ethyl-N-[(l-oxido-3-pyridinyl)methyl1-4-(tetrahydro-2H-pyran- 4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide.
Figure imgf000190_0003
A solution of røetα-chloroperoxybenzoic acid (45mg, 0.26mmol) in chloroform (1ml) was added dropwise at 0 C to a stined solution of Example 138 (0.1 g, 0.26mmol) in chloroform (1.5ml). After 1.5h at 0 C, a further quantity of etα-chloroperoxybenzoic acid (45mg, 0.26mmol) in chloroform (1ml) was added, and stirring was continued at 0 C for 1.5h. A trace of starting material remained, so an additional quantity of meta- chloroperoxybenzoic acid (22mg, 0.13mmol) in chloroform (0.6ml) was added. After
3.5h at 0 C, 2M sodium carbonate solution (1ml), was added to the reaction mixture. The phases were separated by passage through a hydrophobic frit and the aqueous phase was extracted with more chloroform (2ml). The combined organic extracts were evaporated to a residual foam which was purified by mass directed autoprep HPLC to afford Example 210 (44mg). LCMS showed MH+ = 397; TRET = 2.13min.
Example 211 : l-Ethyl-N-[(l-oxido-2-pyridinyl)methvn-4-(tetrahydro-2H-pyran- 4-ylamino)-lH-pyrazolo[3,4-/7]pyridine-5-carboxamide
Figure imgf000191_0001
Example 211 was prepared from Example 600 using an analogous method to that used for the preparation of Example 210. LCMS showed MH+ = 397; TRET = 2.20min
Example 212: 1 -Ethyl-N- [(1 -oxido-4-pyridinyl)methyl] -4-(tetrahy dro-2H-py r an- 4-ylamino)-lH-pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000191_0002
Example 212 was prepared from Example 33 using an analogous method to that used for the preparation of Example 210. LCMS showed MH+ = 397; TRET = 2.13min
Examples 214 to 230
Figure imgf000191_0003
General Procedure
Intennediate 17 (0.15mmol) was treated with an aliquot of the amine (0.95ml, equivalent to 0.19mmol) from a stock solution in acetonitrile (0.2M) and Ν,Ν- diisopropylethylamine (0.24mmol). The mixture was heated at reflux for 20h then concentrated in vacuo. The residue was purified by SPE (silica) to give the desired product.
Figure imgf000192_0002
Example 225: l-ethyl-4-[(l-methylcyclohexyl)amino]-N-(phenylmethyl)-lH- pyrazolo[3,4-#]pyridine-5-carboxamide
Figure imgf000192_0001
A prefened method for the preparation of Example 225 involving 1- methylcyclohexylamine and a longer reaction time is as follows: A solution of intermediate 17 (46mg), 1-methylcyclohexylamine (26mg) and diisopropylethylamine (94mg) in acetonitrile (1ml) was stined and heated at reflux for 77h. More 1-methylcyclohexylamine (102mg), diisopropylethylamine (93mg) and acetonitrile (1ml) were added and the reaction mixture was heated at reflux for a further 68h. The solution was cooled and concentrated in vacuo. The residue was triturated in ethyl acetate and filtered. The filtrate was purified by mass directed autoprep. HPLC to give Example 225 (19mg). LCMS showed MH+ = 392; TRET = 3.46min.
Examples 231, 247 and 257, shown below and also involving 1- methylcyclohexylamine, can also preferably be prepared in a similar manner.
Examples 231 - 239
Figure imgf000193_0001
General Procedure
Intermediate 55 (0.15mmol) was treated with an aliquot of the amine (0.95ml, equivalent to 0.19mmol) from a stock solution in acetonitrile (0.2M) and N, N- diisopropylethylamine (0.24mmol). The mixture was heated at reflux for 20h then concentrated in vacuo. The residue was purified by SPE (silica) to give the desire product.
Figure imgf000193_0002
Figure imgf000194_0002
Examples 240 - 249
Figure imgf000194_0001
General Procedure
Intermediate 56 (0.15mmol) was treated with an aliquot of the amine (0.95ml, equivalent to 0.19mmol) from a stock solution in acetonitrile (0.2M) and N,N- diisopropylethylamine (0.24mmol). The mixture was heated at reflux for 20h then concentrated in vacuo. The residue was purified by SPE (silica) to give the desire product.
Figure imgf000194_0003
Figure imgf000195_0002
Examples 250 - 258
Figure imgf000195_0001
General Procedure
Intermediate 57 (0.15mmol) was treated with an aliquot of the amine (0.95ml, equivalent to 0.19mmol) from a stock solution in acetonitrile (0.2M) and N, N- diisopropylethylamine (0.24mmol). The mixture was heated at reflux for 20h then concentrated in vacuo. The residue was purified by SPE (silica) to give the desire product.
Figure imgf000195_0003
Figure imgf000196_0002
Examples 259 - 275
Figure imgf000196_0001
General Procedure
A mixture of hitermediate 58 (O.lmmol), HATU (O.lmmol) and DLPEA (0.4mmol) in DMF (0.4ml) was shaken at room temperature for 10 min. A solution of the amine (O.lmmol) in DMF (0.2ml) was then added and the mixture agitated for several minutes to give a solution. The solution was stored at room temperature for 16 hours then concentiated in vacuo. The residue was dissolved in chloroform (0.5ml) and applied to a SPE cartridge (aminopropyl, 0.5g). The cartridge was eluted successively with chloroform (1.5ml), EtOAc (1.5ml) and EtOAc:MeOH (9:1, 1.5ml). Fractions containing the desired product were concentrated in vacuo and the residue purified by mass directed autoprep HPLC.
Figure imgf000196_0003
Figure imgf000197_0001
Figure imgf000198_0003
Example 260 (Alternative Procedure)
N-[(2,4-dimethylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo[3,4-6]pyridine-5-carboxamide
Figure imgf000198_0001
Alternative procedure for preparing Example 260:
A solution of Intermediate 58 (45mg), HATU (63mg) and DLPEA (39mg) in acetonitrile (5ml) was stined for lOmin. A solution of 2,4-dimethylbenzylamine (24mg) (available from Salor; or ICN Biomedicals, Inc.; or Synthesis, 1982, 12, 1036) in acetonitrile (1ml) was added. The reaction mixture was stined for 18h. The solution was concentrated and the residue partitioned between ethyl acetate (25ml) and 0.5M sodium bicarbonate (20ml). The organic phase was separated, washed with water (20ml), dried over Na2SO4 and concentrated to leave a gum which was applied to an SPE cartridge (5g). The cartridge was eluted with ethyl acetate. Fractions containing the desired compound were combined and concentrated in vacuo to give Example 260 (32mg). LC-MS showed MH+ = 420; TRET = 3.16min. δH (CDC13): 1.49 (3H, t), 2.11 (2H, m), 2.33 (3H, s), 2.35 (3H, s), 2.40 (2H, m), 2.52 (2H, m), 2.61 (2H, m), 4.36 (IH, m), 4.47 (2H, q), 4.55 (2H, d), 6.14 (IH, t), 7.01 + 7.18 (2H, AA'BB'), 7.04 (IH, s), 8.01 (IH, s), 8.36 (IH, s), 9.96 (IH, d).
Example 276 - 287
Figure imgf000198_0002
General Procedure
A mixture of Intermediate 59 (O.lmmol), HATU (O.lmmol) and DLPEA (0.4mmol) in DMF (0.4ml) was shaken at room temperature for 10 min. A solution of the amine (O.lmmol) in DMF (0.2ml) was then added and the mixture agitated for several minutes to give a solution. The solution was stored at room temperature for 16 hours then concentrated in vacuo. The residue was dissolved in chloroform (0.5ml) and applied to a SPE cartridge (aminopropyl, 0.5g). The cartridge was eluted successively with chloroform (1.5ml), EtOAc (1.5ml) and EtOAc:MeOH (9:1, 1.5ml). Fractions containing the desired product were concentrated in vacuo and the residue purified by mass directed autoprep HPLC.
Figure imgf000199_0001
Figure imgf000200_0003
Example 288: 4-f(4,4-Difluorocvclohexvl)aminol-l-ethyl-A^-(phenvlmethvl -lH- pyrazolo[3,4-b]pyridine-5-carboxamide and Example 289: 1 -Ethyl-4- [(4-fluoro- S-cyclohexen-l-y^aminol-N- henylmethy^-lH-pyrazololS^-όlpyridine-S- carboxamide.
Figure imgf000200_0001
Diisopropylethylamine (0.113ml, 0.65mmol) was added to a stined mixture of Lntermediate 17 (40mg, 0.13mmol) and Intennediate 63 (45mg, 0.26mmol) in acetonitrile (2ml). The mixture was stined at 85°C. After 18h, a further portion of intermediate 63 (22.5mg, 0.13mmol) and diisopropylethylamine (0.113ml, 0.65mmol) was added to the reaction mixture and stining was continued at 90°C for 24h. The mixture was then concentrated in vacuo and the residue was partitioned between DCM (20ml) and water (5ml). The phases were separated and the aqueous phase was extracted with further DCM (10ml). The combined organic extracts were dried (Na2SO ) and evaporated in vacuo to give a brown oil (65mg) which was partially purified on a SPE cartridge (silica, lOg), eluting with ethyl acetate : petroleum ether (1:8; 1:4; 1:2; 1:1 and 1:0). The resulting two-component pale-brown oil (34mg) was separated by mass directed auto prep HPLC to give Example 288 (19mg) as a white foam (LCMS showed ME4 = 414; TRET = 3.24min) and Example 289 (9mg) as a white solid (LCMS showed MH+ = 394; TRET = 3.21min).
Examples 290 - 319
Figure imgf000200_0002
General Procedure
A mixture of intermediate 60 (O.lmmol), HATU (O.lmmol) and DLPEA (0.4mmol) in DMF (0.4ml) was shaken at room temperature for 10 min. A solution of the amine (O.lmmol) in DMF (0.2ml) was then added and the mixture agitated for several minutes to give a solution. The solution was stored at room temperature for 16 hours then concentiated in vacuo. The residue was dissolved in chloroform (0.5ml) and applied to a SPE cartridge (aminopropyl, 0.5g). The cartridge was eluted successively with chloroform (1.5ml), EtOAc (1.5ml) and EtOAc:MeOH (9:1, 1.5ml). Fractions containing the desired product were concentiated in vacuo and the residue purified by mass directed autoprep HPLC.
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Example 320 l-Ethyl-N-4-piperidinyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazoIo[3,4-#]pyridine-5-carboxamide
Figure imgf000204_0001
A solution of hydrogen chloride in dioxan (30ml, 4M, 0.12mol) was added to a suspension of Example 126 (1.3g, 2.75mmol), in dioxan (10ml) and the mixture was stined at room temperature for 6h. The reaction mixture was left to stand for 14h, then the solution was evaporated, azeotroping with DCM to give a white solid the hydrochloride salt. The solid was suspended in ethyl acetate (50ml) and washed with sodium hydroxide solution (2N, 50ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to give Example 318 as a white solid (995mg). LCMS showed MH+ = 373; TRET = 1.89min.
Example 321 l-Ethyl-7Y-(4-piperidinylmethyl)-4-(tetrahydro-2H-pyran-4- ylammo)-lH-pyrazoIo[3,4-d]pyridine-5-carboxamide
Figure imgf000204_0002
A solution of hydrogen chloride in dioxan (30ml, 4M, 0,12mol) was added to a suspension of Intermediate 72 (1.2g, 2.5mmol), in dioxan (10ml) and the mixture was stined at room temperature for 6h. The reaction mixture was left to stand for 14h, then the solution was evaporated, azeotroping with DCM to give a white solid (1.24g). A portion of the solid (68mg) was suspended in ethyl acetate and washed with 2M-sodium hydroxide solution. The organic layer was dried over Na2SO and concentiated in vacuo to afford Example 321 as a white solid (60mg). LCMS showed MH+ = 387; TRET = 1.92min.
Example 322 l-Ethvl-A/-ri-(ethvlsulfonyl)-4-piperidinyIl-4-(tetrahydro-2H- pyran-4-ylamino)-lH-pyrazolo[3,4- ]pyridine-5-carboxamide
Figure imgf000204_0003
Triethylamine (0.023ml, 0.16mmol) was added to a solution of Example 320 (0.043g, 0.115mol) in DCM (1ml). The mixture was cooled (ice/water bath for lOmin) and ethane sulfonyl chloride (0.014ml, 0.138mmol) was added. The resultant solution was stined at room temperature for 18h, then the solvent was removed with a steam of nitrogen. The residue was dissolved in dichloromethane (1.5ml) and stined with water (1.5ml). The organic layer was separated and blown down with nitrogen, and applied to a SPE cartridge (silica, 2g) eluting with 60%- 100% ethyl acetate in cyclohexane. The desired fractions were concentrated in vacuo to afford Example 322 as a white solid (32mg). LCMS showed MH+ = 465; TRET = 2.52min
Similarly prepared were the following, using the same or a similar number of moles of reagents and the same or similar volumes of solvents:
Figure imgf000205_0001
Figure imgf000205_0002
Example 329 N-fl-(Cyclopropylcarbonyl)-4-piperidinyn-l-ethyI-4-(tetrahydro- 2H-pyran-4-ylamino)-lH-pyrazolo[3,4-£]pyridine-5-carboxamide
Figure imgf000206_0001
Cyclopropane carboxylic acid (0.011ml, 0.138mmol), EDC (0.031g, 0.161nτmol) and HOBT (0.019g, 0.138mmol) were suspended in DMF (2ml) and stined at room temperature for lh. Example 320 (0.043g, 0.115mmol) was added and the mixture was stined at room temperature for 16 hours. Most of the solvent was removed using a stream of nitrogen and the residue was partitioned between DCM (3ml) and water (3ml). The organic layer was blown down with nitrogen and applied to a SPE cartridge (aminopropyl, lg), which was eluted with methanol. Concentration by blowing down with nitrogen afforded an impure residue which was further purified by SPE cartridge (silica, lg), eluting with 50-100% EtOAc in cyclohexane followed by 5% methanol inEtOAc. The desired fractions were concentrated in vacuo to afford Example 329 as a white solid (49mg). LCMS showed MH+ = 441; TRET = 2.23min
Similarly prepared, using the same or similar numbers of moles of reagents and volumes of solvents, and using Example 320 as the starting material to make Examples 330 to 343, but using Example 321 (similar number of moles) instead of Example 320 as the starting material to make Examples 344 to 349, were the following:
Figure imgf000206_0002
Figure imgf000206_0003
Figure imgf000207_0001
Figure imgf000208_0003
Example 350 Methyl 3-[(l-ethyI-5-{[(phenylmethyl)amino]carbonyI}-lH- pyrazolo[3,4-£]pyridin-4-yI)amino]cyclohexanecarboxylate
Figure imgf000208_0001
Example 350 was prepared from Intermediate 17 and using an analogous method to that used for the preparation of Example 207. LCMS showed MH+ = 436; TRET = 3.20.
Example 351 3-[(l-Ethvl-5-{f(phenylmethyl)amino1carbonyll-lH-pyrazolo[3,4- 6]pyridin-4-yl)amino]cyclohexanecarboxylic acid
Figure imgf000208_0002
2M-Sodium hydroxide solution (0.5ml) was added to a stined suspension of Example 350 (0.12g, 0.275mmol) in methanol (3.5ml) and water (0.8ml). After stirring overnight at room temperature, the reaction solution was concentrated, diluted with water (3ml) and acidified with 2M-hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give Example 351, as a white solid (0.105g). LCMS showed MH4" = 422; TRET = 2.95min. Example 352:l-Ethvl-N-(phenvlmethyl)-4-(4-piperidinylamino)-lH-pyrazolo[3,4- b] pyridine-5-carb oxamide
Figure imgf000209_0001
Aqueous hydrochloric acid (20ml, 5M) was added to a solution of Intermediate 65 (2.58g, 5.40mmol) in tetrahydrofuran (10ml). The reaction mixture was stined at 20 °C for 22h then evaporated in vacuo. The residue was partitoned between DCM and water. The aqueous phase was basified with aqueous sodium hydroxide solution (2M) and extracted with diethyl ether. The organic phases was evaporated in vacuo to give Example 352 as a white solid (2.04g). LCMS showed MH+ = 379; TRET = 2.10min.
Example 353: Ethyl l-ethyl-4-({l-[(methyloxy)acetyl]-4-piperidinyl}amino)-lH- pyrazolo[3,4-6]pyridine-5-carboxylate
Figure imgf000209_0002
Methoxyacetyl chloride (0.016mg, 0.144mmol) and triethylamine (0.02mol, 0.144mmol) were added to a solution of Example 352 (0.046g, 0.122mmol) in DCM in a Reactivial. The reaction was stined for 22h at 20 °C then diluted with DCM and washed with aqueous sodium hydrogen carbonate solution. The organic phase was separated and applied directly to a SPE cartridge (silica 2g). The cartridge was eluted with DCM : MeOH (1% followed by 3%) to give Example 353 as a white solid (0.05g). LCMS showed MH+ = 451; TRET = 2.66min.
Example 354: Ethyl l-(l-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-6]pyridine-5-carboxylate
Figure imgf000210_0001
Prepared in a similar manner to example 186 using Example 20 (0.03 g, O.lmmol), with isopropylbromide (lOuL, 0.11 mmol), a further 0.11 mmol of alkylating agent was added after 16 hours. The final compound was formed as a clear gum (16mg). LCMS showed MH+ = 333; TRET = 3.16min.
Example 355: 4-(Cvclohexvlamino)-l-ethvl-N-methyl-lH-pyrazolo[3.4- 6]pyridine-5-carboxamide
Figure imgf000210_0002
Intermediate 64 (0.02g, 0.084mmol) and diisopropylethylamine (0.044ml, 0.252mmol) were suspended in N-methyl pyrrolidinone (1ml) and cyclohexylamine (0.012ml, O.lmmol) was added. The mixture was heated at 85°C with stining in a Reactivial™ for 8h, then concentrated in vacuo. The residue was partitioned between DCM (2ml) and water (2ml). The layers were separated and the organic layer was concentrated in vacuo, then purified by mass directed autoprep HPLC to afford Example 355 (0.012g). LCMS showed MH+ = 302; TRET = 2.85min.
Example 356: l-Ethvl-N-(4-fluorophenvl)-6-methvl-4-(tetrahvdro-2H-pvran-4- ylamino)-lH-pyrazoIo[3,4-6]pyridine-5-carboxamide
Figure imgf000210_0003
Example 356 was prepared from Intermediate 53 using an analogous method to Example 191. LCMS showed MH" = 398; TRET = 2.18min.
Example 357: l-Ethvl-6-methvl-N-(r4-(methvlsuIfonvl)phenvnmethvll-4- (tetrahydro-2H-pyran-4-ylamino)-lH-pyrazoIo[3,4-6]pyridine-5-carboxamide
Figure imgf000211_0001
Example 357 was prepared from Intermediate 53 using an analogous method to Example 191. LCMS showed MH+ = 472; TRET = 2.15min.
Example 358: N-(2,3-Dihvdro-lH-inden-2-vl)-l-ethvl-6-methyl-4-(tetrahvdro- 2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000211_0002
Example 358 was prepared from intermediate 53 using an analogous method to Example 191. LCMS showed MH+ = 394; TRET = 2.04min.
Examples 360 - 414
Figure imgf000211_0003
General Procedure intermediate 33 (1.89g) was treated with thionyl chloride (10ml) and the mixture heated under reflux for 2h. Excess thionyl chloride was removed in vacuo to afford Intermediate 73, presumed to be the acid chloride of hitermediate 33 as a cream solid. The solid was suspended in tetrahydrofuran (32.5ml) and an aliquot of the suspension added to a mixture of the amine (O.l lmmol) and N,N-diisopropylethylamine (0.165 - 0.22mmol) in THF (0.5ml). The reaction mixture was agitated for 24h and the solvent removed in vacuo. The residue was purified by mass directed autoprep HPLC.
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Example 414: l-EthyI-4-(tetrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4- 6]pyridine-5-carboxamide
Figure imgf000215_0002
Example 414 was prepared from intermediate 59 using the general method described for examples 360 - 413 method. LCMS showed MH+ = 398; TRET = 2.90min.
Examples 415 - 487
Figure imgf000216_0001
General Procedure
A mixture of intermediate 61 (O.lmmol), HATU (O.lmmol) and DLPEA (0.4mmol) in DMF (0.4ml) was shaken at room temperature for 10 min. A solution of the amine (O.lmmol) in DMF (0.2ml) was then added and the mixture agitated for several minutes to give a solution. The solution was stored at room temperature for 16 hours then concentrated in vacuo. The residue was dissolved in chloroform (0.5ml) and applied to a SPE cartridge (aminopropyl, 0.5g). The cartridge was eluted successively with chlorofonn (1.5ml), EtOAc (1.5ml) and EtOAc:MeOH (9:1, 1.5ml). Fractions containing the desired product were concentrated in vacuo and the residue purified by mass directed autoprep HPLC.
Figure imgf000216_0002
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Example 488: 4-[(I[4-(CvcIohexvlamino)-l-ethvl-lH-pyrazolof3.4-^lpvridin-5- yl]carbonyl}amino)methyl]benzoic acid
Figure imgf000222_0001
2M-Sodium hydroxide solution (29μL, 0.058mmol) was added to a stined solution of Example 470 (6mg, 0.014mmol) in methanol (28μL) and water (2μL). The resulting solution was stirred at 50°C under nitrogen. After 16h, the mixture was diluted with water (0.5ml) and adjusted to pH 4 with acetic acid. The precipitated solid was collected by filtration and dried in vacuo to afford Example 488 as a white solid (4.5mg). LCMS showed MH+ = 422; TRET = 3.26min.
Example 489: 3-f({[4-(Cyclohexvlamino)-l-ethvl-lH-pvrazolo[3,4- >lpyridin-5- yI]carbonyl}amino)methyIJbenzoic acid
Figure imgf000222_0002
2M-Sodium hydroxide solution (83μL, 0.166mmol) was added to a stined solution of Example 468 (18mg, 0.042mmol) in methanol (88μL) and water (5μL). The resulting solution was stined at 50°C under nitrogen. After 16h, a further quantity of 2M- sodium hydroxide solution (29μL, 0.058mmol) was added to the reaction mixture. After 24h, the reaction mixture was diluted with water (0.5ml) and adjusted to pH 4 with acetic acid. The mixture was extracted with ethyl acetate (2 x 0.5ml), and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (21mg). This solid was purified on an SPE cartridge (silica, lg) eluting with ethyl acetate: cyclohexane (1:1) followed by methanol. Fractions containing the desired product were combined and concentrated to afford Example 489 as a white solid (4.6mg). LCMS showed MH+ = 422; TRET = 3.22min. Example 490: 4-(Cvclohexvlamino)-/y-(2,3-dihvdro-lH-inden-2-vl)-l-ethvl-lH- pyrazoIo[3,4-£]pyridine-5-carboxamide hydrochloride
Figure imgf000223_0001
A solution of Example 469 (71mg, 0.17mmol) in anhydrous THF (2ml) was treated with hydrogen chloride in dioxane (4M, 0.3ml). After standing at ambient temperature for 16 hours the resulting solid was collected by filtration and dried under vacuum to give Example 490 as rod like crystals (36mg). LCMS showed MH+= 404; TREτ = 3.60min.
Example 491 : 4-(CvclohexvIamino)-N-(2,3-dihvdro-lH-inden-2-vI)-l-ethvl-lH- pyrazolo[3,4-£]pyridme-5-carboxamide methanesulphonate
Figure imgf000223_0002
A solution of Example 469 (71mg, 0.17mmol) in anhydrous THF (2ml) was treated with anhydrous methane sulphonic acid (11.4μL, 0.17mmol). After standing at ambient temperature for 16 hours the resulting solid was collected by filtration and dried under vacuum to give Example 491 as rod like crystals (23mg). LCMS showed MH+= 404; TRET = 3.59min.
Examples 492 - 649
Figure imgf000224_0001
General Procedure
A mixture of Intermediate 33 (O.lmmol), HATU (O.lmmol) and DLPEA (0.4mmol) in DMF (0.4ml) was shaken at room temperature for 10 min. A solution of the amine (O.lmmol) in DMF (0.2ml) was then added and the mixture agitated for several minutes to give a solution. The solution was stored at room temperature for 16 hours then concentrated in vacuo. The residue was dissolved in chloroform (0.5ml) and applied to a SPE cartridge (aminopropyl, 0.5g). The cartridge was eluted successively with chloroform (1.5ml), EtOAc (1.5ml) and EtOAc:MeOH (9:1, 1.5ml). Fractions containing the desired product were concentrated in vacuo and the residue purified by mass directed autoprep HPLC.
Figure imgf000224_0002
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Example 518 : N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran- 4-yIamino)-lH-pyrazoIo[3,4- 7]pyridine-5-carboxamide; also known as: Λ/-(3,4-dimethylben2yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazoIo[3,4-b]pyridine-5-carboxamide
Figure imgf000236_0001
An alternative process for preparing Example 518 is given below: To a solution of Intermediate 33 (3.5g, 12.07mmol) in DMF (500ml) was added HATU (4.5g, 12.07mmol) and the mixture stined at room temperature for 30 min. 3,4-Dimethylbenzylamine (1.63g, 12.07mmol, obtainable from Matrix Scientific, Columbia, USA or by a process described in Chem. Ber., 1969, 102, 2770) was added followed by DLPEA (4.5ml, 26.55mmol) and the solution stined at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 (200ml) and ethyl acetate (250ml), the aqueous phase re-extracted with ethyl acetate (2x200ml), the organic extracts combined, dried (Na2SO4) and evaporated. The resultant viscous oil was recrystallised from hot ethyl acetate (ca. 100ml) to give the title compound as a white crystalline solid (3.36g, 80%). LCMS showed MH+= 408; Tret = 3.06min. δH (D6 DMSO) 1.36 (3H, t), 1.51 (2H, m), 2.00 (2H, m), 2.18 (3H, s), 2.19 (3H, s), 2.50 (2H, m), 3.61 (2H. m), 3.83 (2H, m), 4.17 (IH, m), 4.36 (2H, q), 4.38 (2H, d), 7.02-7.09 (3H, m), 8.17 (IH, s), 8.62 (IH, s), 8.93 (IH, t), 9.96 (IH, d): δc (D6 DMSO) 14.65, 18.91, 19.33, 32.81, 41.06, 41.86, 48.57, 64.94, 101.69, 102.18, 124.44, 128.22, 129.24, 133.28, 134.31, 135.78, 136.91, 149.26, 149.59, 151.36, 168.81
Example 518A: N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H- pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide hydrochloride; also known as: 7Y-(3,4-dimethylbenzyI)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo [3 ,4-b] pyridine-5-carboxamide hydrochloride
Figure imgf000236_0002
A solution of Example 518 (1.3g, 3.19mmol) in anhydrous tetrahydrofuran (200ml) was treated with a solution of hydrogen chloride in dioxane (4M, 8ml) and the mixture stined at ambient temperature for 16 hours. The resultant white precipitate was collected by filtration and recrystallised from hot methanol (100ml) to give the title compound Example 518A as a white crystalline solid (1.12g, 79%).
LCMS showed MH+= 408; Tret = 3.21min. δH (D6 DMSO) 1.39 (3H, t), 1.59 (2H, m), 2.01 (2H, m), 2.19 (3H, s), 2.20 (3H, s), 3.64 (2H, t), 3.83 (2H, m), 4.28 (IH, m), 4.40 (2H, d), 4.50 (2H, q), 7.04-7.11 (3H, m), 9.40 (IH, s (br)), 10.72 (IH, s (br)).
Example 650: 4-[({ri-Ethvl-4-(tetrahvdro-2H-pyran-4-ylamino)-lH-pvrazolo[3,4- b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid sodium salt.
Figure imgf000237_0001
2M-Sodium hydroxide solution (98μL, 0.196mmol) was added to a stined solution of Example 593 (22mg, 0.049mmol) in methanol (104μL) and water (6μL). The resulting solution was stined at 50°C under nitrogen. After 16h, the reaction mixture was diluted with water (0.5ml) and adjusted to pH 4 with acetic acid. The mixture was extracted with ethyl acetate (2 x 0.5ml), and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (15mg). This solid was suspended in water (0.5ml) and treated with 2M-sodium hydroxide solution (15μL). Evaporation of solvent in vacuo afforded Example 650 as a white solid (1 lmg). LCMS showed MH = 425; TRET = 2.69min.
Example 651 : 3-f({[l-Ethvl-4-(tetrahvdro-2H-pyran-4-vlamino)-lH-pyrazolo[3,4- b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid
Figure imgf000237_0002
2M-Sodium hydroxide solution (98μL, 0.196mmol) was added to a stined solution of Example 558 (22mg, 0.049mmol) in methanol (104μL) and water (6μL). The resulting solution was stined at 50°C under nitrogen. After 16h, the reaction mixture was diluted with water (0.5ml) and adjusted to pH 4 with acetic acid. The precipitated solid was collected by filtration and dried in vacuo to afford Example 651 as a white solid (15mg). LCMS showed MH+ = 425; TRET = 2.72min.
Example 652: Ethyl l-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-lH- pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000238_0001
A mixture of Example 205 (200mg), hydroxylamine hydrochloride (50mg) and anhydrous potassium carbonate (420mg) in acetonitrile (10 ml) was stined and heated at reflux for 17 hours. The solution was cooled and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to give Example 652 as a white powder (203mg). LCMS showed MH+ = 346; TRET = 2.84min.
Example 653 : l-Ethyl-4-{ [4-(hydroxyimino)cyclohexyl] amino}-N-{ [4-
(methyloxy)phenyI]methyI}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000238_0002
A mixture of Example 263 (217mg), hydroxylamine hydrochloride (43mg) and anhydrous potassium carbonate (355mg) in acetonitrile (10 ml) was stined and heated at reflux for 17 hours. The solution was cooled and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated, dried over Na2SO and concentrated in vacuo to give Example 653 as a yellow solid (186mg). LCMS showed MH+ = 437; TRET = 2.82min. δH (CDC13) 1.49 (3H, t), 1.80 (2H, m), 2.2-2.4 (4H, m), 2.54 (IH, m), 3.13 (IH, dt), 3.81 (3H, s), 4.13 (IH, m), 4.46 (2H, q), 4.54 (2H, d), 6.28 (IH, t), 6.90 + 7.28 (4H, AA'BB'), 7.98 (IH, s), 8.36 (IH, s), 9.84 (IH, d). Hydroxyl proton not visible. The following examples were prepared by a similar procedure, e.g. using the same or a similar number of moles of reagents and the same or similar volumes of solvents:
Figure imgf000239_0001
Figure imgf000239_0002
Figure imgf000240_0003
See later for alternative preparation of Example 681.
Example 655: l-Ethyl-4-({4- [(ethyloxy)imino] cyclohexyl} amino)-N-{ [4- (methyloxy)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000240_0001
A mixture of Example 263 (25mg), ethoxyamine hydrochloride (R2 ()NΗ2 where
R26 = Et, 20mg) and diisopropylethylamine (30mg) in acetonitrile (3 ml) was stined and heated at reflux for 3.25 hours. The solution was cooled and concentrated in vacuo. The residue was applied to an SPE cartridge (5g). The cartridge was eluted with EtOAc. Fractions containing the desired product were concentrated in vacuo to give Example 655 as a colourless gum (20mg). LCMS showed MH+ - 465; TRET = 3.28min.
The following examples were prepared by a similar procedure, e.g. using the same or a similar number of moles of reagents and the same or similar volumes of solvents:
Figure imgf000240_0002
Figure imgf000240_0004
Example 658: l-EthyI-N-{[4-(methyloxy)phenyl]methyI}-4-[(7-oxohexahydro-lH- azepin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000241_0001
A suspension of cyanuric chloride (2,4,6-trichloro-l,3,5-triazine) (150mg) in DMF (0.2 ml) was stirred for 30 minutes at room temperature. The suspension was diluted to 7ml with DMF, with stirring. A 1.0ml portion of the resultant suspension was removed and added to Example 653 (52mg). The resultant solution was stined for 90 hours at room temperature, then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated and washed consecutively with saturated sodium carbonate, 10% w/v citric acid and saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was applied to an SPE cartridge (2g). The cartridge was eluted successively with EtOAc: cyclohexane (1:1), EtOAc and then a (100:8:1) mixture of dichloromethane, ethanol and ammonia. Fractions containing the desired product (eluted in the ammoniacal solution) were concentrated in vacuo to give Example 658 as a colourless oil (llmg). LCMS showed MH+ = 437; TRET = 2.50min.
Example 659: Ethyl l-ethyI-4-[(7-oxohexahydro-lH-azepin-4-yl)amino]-lH- pyrazolo[3,4-b]pyridine-5-carboxylate
Figure imgf000241_0002
Example 659 was prepared from Example 652, using an identical procedure to that used for Example 658. LCMS showed MH+ = 346; TRET = 2.56min. Example 660: 4-{[c s-4-(Butylamino)cyclohexyl]amino}-N-(2,3-dihydro-lH- inden-2-yl)-l-ethyI-lH-pyrazolo[3,4-b]pyridine-5-carboxamide
Figure imgf000242_0001
A solution of Example 258 (25mg), butyraldehyde (5mg) and glacial acetic acid (30mg) in DCM (3ml) was stined for lOmin. Sodium triacetoxyborohydride (21mg) was added. The reaction mixture was stirred for 1.5 hours. Sodium bicarbonate (l.OMolar, 3ml) was added dropwise, with stirring. After stirring for 5 min. the phases were separated. The organic phase was dried over Na SO4 and applied to an SPE cartridge (5g). The cartridge was eluted with a (100:8:1) mixture of dichloromethane, ethanol and ammonia. Fractions containing the desired product were concentrated in vacuo to give Example 660 as an amorphous, cream solid (19mg). LCMS showed MH+ - 346; TRET = 2.56min.
Examples 661 to 664
Figure imgf000242_0002
General Procedure:
Lntermediate 17 (0.16mmol) in acetonitrile (1ml) was treated with the R3NH2 amine
(0.8mmol) in acetonitrile (1ml) and N,N-diisopropylethylamine (0.8mmol). The mixture was heated at 50°C for 18h then concentrated in vacuo. The residue was diluted with water (3ml) and extracted with dichloromethane (2 x 5ml). The combined organic extracts were evaporated, and the residue was purified by mass directed autoprep HPLC to give the desired product containing formic acid. This material was dissolved in chloroform-methanol (10/1, 5.5ml) and washed with 5% sodium hydrogen carbonate solution (1ml) to give after evaporation of solvents the pure product.
Figure imgf000242_0003
Figure imgf000243_0002
** For NE R3 in Examples 214 and 661-663, HR3 is the cis or trans isomer as shown. For Examples 662-664, NΗR3 S the 3-amino- or 2-amino- cyclohex-1- ylamino group in a racemic form.
Example 665 E -3-hydroxycyclohexyl]amino}-lH- pyrazolo[3,4-b]
Figure imgf000243_0001
[cts-(3-hydroxycyclohex-l-yl)amino group, racemic]
3-Aminocyclohexanol (0.611 g, 5.9mmol, as described inJ. Chem. Soc, Perkin Trans 1, 1994, 537) in acetonitrile (10ml) and ethanol (1ml) was added at room temperature to a stined solution of Intennediate 1 (1.24g, 4.9mmol) and diisopropylethylamine (4.26ml, 24.5mmol) in acetonitrile (25ml). The resulting mixture was stined at 85°C for 17h. The mixture was concentrated in vacuo, and the residue was partitioned between DCM (50ml) and water (10ml). The phases were separated and the organic phase was dried (Na2SO ) and evaporated to give an orange-brown oil. The oil was purified by Biotage chromatography (silica lOOg) eluting with 30-50% EtOAc in cyclohexane to give Example 665 as a white foam (0.68 lg). LCMS showed MIT1" = 333; TRET = 2.76min. Examples 666 - 676
Figure imgf000244_0001
[ct5-(3-hydroxycyclohex-l-yl)amino group, racemic]
General Procedure:
A mixture of Intermediate 76 (O.lmmol), HATU (O.lmmol) and DLPEA (0.4mmol) in
DMF (0.5ml) was shaken at room temperature for lOmin. A solution of the amine
HNR4R5 (0.12mmol) in DMF (0.5ml) was then added and the mixture agitated for several minutes to give a solution. The solution was stored at room temperature for
16h, then concentrated in vacuo. The residue was purified by mass directed autoprep
HPLC.
Figure imgf000244_0002
675 ~Λ-i7y°/ Aldrich Intennediate 424 2.81 76
676 NH V- ICN intennediate 422 3.08
Biomedicals, 76 Inc.; or Salor; or Synthesis, 1982, 12, 1036
Example 260 (Alternative Procedure)
N-[(2-4-dimethylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazoIo[3,4-b]pyridine-5-carboxamide
Figure imgf000245_0001
Alternative procedure for preparing Example 260:
A solution of intermediate 58 (45mg), HATU (63mg) and DLPEA (39mg) in acetonitrile (5ml) was stirred for lOmin. A solution of 2,4-dimethylbenzylamine (24mg) (available from Salor; or ICN Biomedicals, Inc.; or Synthesis, 1982, 12, 1036) in acetonitrile (1ml) was added. The reaction mixture was stined for 18h. The solution was concentrated and the residue partitioned between ethyl acetate (25ml) and 0.5M sodium bicarbonate (20ml). The organic phase was separated, washed with water (20ml), dried over Na2SO4 and concentrated to leave a gum which was applied to an SPE cartridge (5g). The cartridge was eluted with ethyl acetate. Fractions containing the desired compound were combined and concentiated in vacuo to give Example 260 (32mg). LC-MS showed MH+ = 420; TRET = 3.16min. δH (CDC13): 1.49 (3H, t), 2.11 (2H, m), 2.33 (3H, s), 2.35 (3H, s), 2.40 (2H, m), 2.52 (2H, m), 2.61 (2H, m), 4.36 (IH, m), 4.47 (2H, q), 4.55 (2H, d), 6.14 (IH, t), 7.01 + 7.18 (2H, AA'BB'), 7.04 (IH, s), 8.01 (IH, s), 8.36 (IH, s), 9.96 (IH, d).
The following Examples 677-679 were prepared in a similar manner to Example 260 (alternative procedure above), for example using the same or a similar number of moles of reagents and the same or similar volumes of solvents:
Figure imgf000246_0001
Figure imgf000246_0003
Examples 680-686 and their preparation are shown above together with Example 653.
Alternative Preparation of Example 681: N-[(3,4-dimethylphenyl)methyl]-l- ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-li?-pyrazolo[3,4-b]pyridme-5- carboxamide
Figure imgf000246_0002
A mixture of Example 261 (35mg), hydroxylamine hydrochloride (lOmg) and diisopropylethylamine (26mg) in acetonitrile (4 ml) was stined and heated at reflux for 2.5 hours. The solution was cooled and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The residue was applied to an SPE cartridge (lOg). The cartridge was eluted with EtOAc: cyclohexane (1:1) and then EtOAc. Fractions containing the desired compound were combined and concentrated in vacuo to give Example 681 as a white, amorphous solid (18mg). LCMS showed MH+ = 435; TRET = 3.08min. δH (CDC13) 1.49 (3H, t), 1.79 (2H, m), 2.24 (6H, s), 2.19-2.38 (4H, m), 2.56 (2H, dt), 4.13 (IH, m), 4.46 (2H, q), 4.53 (2H, d), 6.36 (IH, t), 7.09 (2H, t), 7.12 (IH, s), 7.98 (IH, s), 8.38 (IH, s), 9.79 (IH, d). Hydroxyl proton not visible.

Claims

A compound of formula (I) or a salt thereof:
Figure imgf000248_0001
wherein:
R1 is Cι_4alkyl,
Figure imgf000248_0002
-CH2CH2OH or -OΪ2 H2C02 l-2alkyι;
R2 is a hydrogen atom (H), methyl or Cj fluoroalkyl;
R3 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);
Figure imgf000248_0003
(aa) (bb) (cc)
in which n and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NRlO; where R10 is a hydrogen atom (H), Cι__ιalkyl, Cχ_2fluoroalkyl, CH2C(O)NH2, C(O)NH2, C(O)-Cι_2alkyl, C(O)-Cιfluoroalkyl or -C(O)-CH2O-Cι.2alkyl;
and wherein in R3 the C3_gcycloalkyl or the heterocyclic group of sub-formula (aa), (bb) or (cc) is optionally substituted with one or two substituents independently being oxo (=O); OH; Cχ_2alkoxy; C^fluoroalkoxy; LR2* wherein R is a hydrogen atom (H) or Cχ_5 straight-chain alkyl; Chalky!; Ci -gfluoroalkyl; -CH2OH;
-CH2CH2OH; -CH2NHR22 wherein R22 is H or Cι_2aιkyl; -C(O)OR23 wherein R23 is H or Cι_2alkyl; -C(O)NHR24 wherein R24 is H or Cι_2alkyl; -C(O)R25 wherein R2^ is Ci^alkyl; fluoro; hydroxyimino (=N-OH); or (Cι_4alkoxy)imino (=N-OR 6 where R ^ is Cχ_4alkyl); and wherein any OH, alkoxy, fluoroalkoxy or NFLR2 substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc);
and wherein, when R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, then the cycloalkenyl is optionally substituted with one or two substituents being fluoro or Cχ_.2alkyl provided that if there are two substituents then they are not both
C2alkyl, and the R3 ring carbon bonded to the -NH- group of formula (I) does not partake in the cycloalkenyl double bond;
Figure imgf000249_0001
or R3 is a bicyclic group of sub-formula (dd): dd) or of sub-formula (ee):
Figure imgf000249_0002
Θe' wherein γl, Y2 and Y3 independently are CH2 or oxygen (O) provided that no more than one of γl, Y2 and Y3 is oxygen (O);
and X is NR R5 or OR5a, in which:
R4 is a hydrogen atom (H); Cj.galkyl; Oχ gfluoroalkyl; or C2_6alkyl substituted by one substituent Ru; and
R5 is a hydrogen atom (H); Cj.galkyl; Cχ_g fluoroalkyl; C3_gcycloalkyl optionally substituted by a Cχ_2alkyl group; or -(CH2)n -C3_gcycloalkyl optionally substituted, in the -(CH2)n - moiety or in the C3_gcycloalkyl moiety, by a Cj-^alkyl group, wherein n4 is 1, 2 or 3;
or R5 is C2_6alkyl substituted by one or two independent substituents Rn;
wherein each substituent Ru, independently of any other RU substituent present, is: hydroxy (OH); Cx^alkoxy; phenyloxy; benzyloxy; -NR12R13; -NR15-C(O)R16;
- iS-C^-O-Rlβ; -NR15-C(O)-NH-R15; or -NR15-SO2R16; and wherein any R11 substituent which is OH, alkoxy or -NR4 R13 JS not substituted at any carbon atom, of any R4 or R^ substituted alkyl, which is bonded to the nitrogen of N 4R5;
or R5 is -(CH2)n n-C(O)Rl6; -(CH2)n 12-C(O)NR12R13; -CHR19-C(O)NR1 Rl3; -(CH2)n 12-C(O)OR16; -(CH )n 12-C(O)OH; -CHR19-C(0)0R16; -CHR19-C(O)OH; -(CH2)n 12-SO2-NR1 R13; -(CH2)n 12-SO2R16; or -(CH2)n 12-CN; wherein n11 is 0, 1, 2, 3 or 4 and n12 is 1, 2, 3 or 4;
or R5 is -(CH2)n 13-Het wherein n13 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or
7-membered saturated or partly-saturated heterocyclic ring 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^ - moiety when n^3 is 1 and are not bound to the nitrogen of N R5 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) are present as NRI7 where R 7 is as defined herein; and wherein one or two of the carbon ring-atoms independently are optionally substituted by Cχ_2alkyl;
or R5 is phenyl optionally substituted with, independently, one, two or three of: a halogen atom; Cx.galkyl; Cχ_2fluoroalkyl; Cχ_4alkoxy; Cχ_2nuoroalkoxy;
C3.6cycloalkyloxy; -C(O)R16a; -C(O)OR 0; -S(O)2-R16a; R16a-S(O)2-NR15as
R7R8N-S(O)2s C1.2alkyl-C(O)-R15aN-S(O)2-;
Figure imgf000250_0001
Ph-S(O)-;
R7R8N-CO-; -NR15-C(0)R16; R7R8N; OH; Cι. alkoxymethyl; Ci^alkoxyethyl;
Cι.2alkyl-S(O)2-CH2-; R7R8N-S(O)2-CH2-; C1_2alkyl-S(O)2-NR15a-CH2-;
-CH2-OH; -CH2CH2-OH; -CH2-NR7R8; -CH2-CH2-NR7R8; -CH2-C(O)OR30;
-CH2-C(O)-NR7R8; -CH2-NR15a-C(O)-Cι.3alkyl; -(CH2)n 14-Het1 where n*4 is 0 or 1; cyano (CN); Ar^a; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, Cχ_2alkyl, Cifluoroalkyl, Cχ_2alkoxy or C\ fluoroalkoxy; or where two adjacent substituents, on the R^ optionally substituted phenyl, taken together are -O-(CMe2)-O- or -O-(CH2)n 14-O- where n14 is 1 or 2; wherein R7 and R8 are independently a hydrogen atom (H); C^alkyl; C3_6cycloalkyl; or phenyl optionally substituted by one or two of: fluoro, chloro,
Cχ_2alkyl, Cifluoroalkyl, Cχ_2alkoxy or C\ fluoroalkoxy; or R7 and R8 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n 8-X7-(CH2)n 9- or -C(O)-X7-(CH2)n 10- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5, n8 and n9 and nlO independently are 2 or 3 , and X7 is O or NR* wherein R* is H, Cχ_2alkyl or C(O)Me; or R5 has the sub-formula (x), (y), (yl) or (z):
Figure imgf000251_0001
(x) (y) (yi) (2)
wherein in sub-formula (x), n = 0, 1 or 2; in sub-formula (y) and (yl), m = 1 or 2; and in sub-formula (z), r = 0, 1 or 2;
wherein in sub-formula (x) and (y) and (yl), none, one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+-O") provided that no more than one of A, B, D, E and F is nitrogen-oxide; and the remaining of A, B, D, E and F are independently CH or CR ;
provided that when n is 0 in sub-formula (x) then one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+-O~) and no more than one of A, B, D, E and F is nitrogen-oxide;
wherein, each R6, independently of any other R^ present, is: a halogen atom; Ci-.galkyl; Cχ_4ffuoroalkyl; C _4alkoxy; Cχ_2fluoroalkoxy; C3_5cycloalkyloxy;
-C(O)Rl6a; -C(O)OR30; -S(O)2-R16a; R16a-S(O)2-NRl5a-; R7R8N-S(O)2-;
Cι_2alkyl-C(O)-Rl5aN_s(θ)2-; C1.4alkyl-S(O)-; Ph-S(O)-; R7R8N-CO-;
-NR15-C(O)R16; R7R N; OH; Cι_4alkoxymethyl; Cι_4alkoxyethyl;
Cι.2alkyl-S(O)2-CH2-; R7R8N-S(O)2-CH2-; C1.2alkyl-S(O)2-NR15a-CH2-;
-CH2-OH; -CH2CH2-OH; -CH2-NR7R8; -CH2-CH2-NR7R8; -CH2-C(O)OR30;
-CH2-C(O)-NR7R8; -CH2-NR15a-C(O)-C1_3alkyl; -(CH2)n 14-Het1 where n14 is 0 or 1; cyano (CN); Ar^b; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, Cχ_2alkyl, Cifluoroalkyl, Cχ_2alkoxy or Cχfluoroalkoxy; or where two adjacent R^ taken together are -O-(CMe2)-O- or
-O-(CH2)n 14-O- where n14 is 1 or 2; wherein R7 and R8 are as herein defined;
wherein sub-formula (y) and (yl), independently, are optionally substituted by oxo (=O) at a ring carbon adjacent the 6-membered aromatic ring;
wherein in sub-formula (z), G is O or S or NR9 wherein R9 is a hydrogen atom (H), Cχ_4alkyl or Cifluoroalkyl; none, one, two or three of j, L, M and Q are nitrogen; and the remaining of L, L, M and Q are independently CH or CR6 where R^, independently of any other R^ present, is as defined herein;
or R4 and R5 taken together are -(CH2)p 1- or -C(O)-(CH2)p 2- or -(CH2)p3-X5-(CH2)p4- or -C(O)-χ5-(CH2)p 5-, in which: pi = 3, 4, 5 or 6, p2 is 2, 3, 4, or 5, and p3 and p4 and p5 independently are 2 or 3 and X^ is O or NR 7; and wherein, when R4 and R^ taken together are -(CH2)p - or -C(O)-(CH2)p2-, the
NR R5 heterocycle is optionally substituted by one R 8 substituent wherein R is: Cχ_4alkyl; C _2fluoroalkyl; C3_5cycloalkyl; C^alkoxy (not substituted at a ring- carbon bonded to the NR R5 ring-nitrogen); Cifluoroalkoxy (not substituted at a ring-carbon bonded to the NR R^ ring-nitrogen); OH (not substituted at a ring-carbon bonded to the NR4R5 ring-nitrogen); -(CH2)p 7-C(O)R16 wherein p7 is 0, 1, 2 or 3; -(CH2)p 7-C(O)ORl6; -(CH2)p 7-OC(O)Rl6; -(CH2)p 7-C(O)NRl Rl3; -(CH2)P 7-NR15C(O)R16; -(CH2)P 7-NR15C(O)NR12R13; -(CH2)P 7-NR15C(O)OR16; -(CH2)p 7-SO2R16; -(CH2)p7-SO2 NRl2Rl3;
-(CH2)p 7-NR15SO2R16; -(CH2)p 7-OH; -(CH2)p 7-ORl6; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, Cifluoroalkyl, C _2alkoxy or Cifluoroalkoxy;
or R4 and R5 taken together are -(CH^1- or -C(O)-(CH2)p 2- or
-(CH2)p 3-X5-(CH2)p4- or -C(O)-X5-(CH2)p 5- as defined herein, and wherein the
NR R5 heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, Cχ_2alkyl, Cχfluoroalkyl, Cχ_2alkoxy or
Cifluoroalkoxy; and
R^a is Cχ.galkyl; Cχ_g fluoroalkyl; C3_gcycloalkyl; -(CH2)n a-C3_6cycloalkyl wherein n a is 1 or 2; phenyl optionally substituted with one or two of: a halogen atom, Cχ_2alkyl, trifluoromethyl, C^alkoxy or trifluoromethoxy; or R^a has the sub-formula (x), (y), (yl) or (z) as defined herein;
and wherein:
R 2 and R 3 independently are H; Cχ_5alkyl; C3_gcycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, Cχfluoroalkyl, Cχ_2alkoxy or Cχfluoroalkoxy; or Rl2 and Rl3 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n 8-X12-(CH2)n 9- or -C(O)-X12-(CH2)n 10- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5, n8 and n9 and n10 independently are 2 or 3 and Xi2 is O or NR 4a wherein R14a is H, Cι_2alkyl or C(O)Me;
Rl5 is a hydrogen atom (H); Cχ_4alkyl; C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl, Cifluoroalkyl, C _2alkoxy or Cj fluoroalkoxy;
Rl5a ; independent of other R ^a, [s a hydrogen atom (H) or C^alkyl;
Rl6 and R ^a independently are: Cι_6alkyl;
C3_gcycloalkyl optionally substituted by one oxo (=O), OH or Cj-^alkyl substituent;
C3_6cycloalkyl-CH2-; pyridinyl optionally substituted on a ring carbon atom by one of: a halogen atom, Cχ_2alkyl, Cifluoroalkyl, C^alko y or Cifluoroalkoxy;
Ar5c; phenyl optionally substituted by one or two of: a halogen atom, Cχ_2alkyl,
Cifluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy; benzyl optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, C _2alkyl, Cifluoroalkyl, Cι_2alko y or Cifluoroalkoxy; or a A-, 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 NR27 where R27 is H, Cι_2alkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one C _2alkyl or oxo (=O) substituent, provided that any oxo (=O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
wherein A >a , Ar^b and Ar^c independently is/are a 5-membered aromatic heterocyclic ring containing one O, S or NRl^a m jhe 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^alkyl, Cifluoroalkyl, -CH2OH, -CH2-OCι_2alkyl, OH
(including the keto tautomer thereof) or -CH2-NR 8R29 wherein R28 and R29 independently are H or methyl;
and Rl7 is a hydrogen atom (H); Cι_4alkyl; Cifluoroalkyl; C3_gcycloalkyl; -(CH2)p 6-C(O)R16 wherein p6 is 0, 1, 2 or 3; -(CH2)p 6-C(O)NRl2Rl3; -(CH2)p 6-C(O)ORl6; -(CH2)p 6-C(O)OH; -SO2R16; -C(O)-CH2-NR12R13;
-C(O)-CH2-NRl5a.c(O)-Ci_3alkyl; -C(O)-CH2-O-Cι_3alkyl; or phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, C _2alkyl, Cifluoroalkyl, Cι_2alkoxy or
Cifluoroalkoxy;
R19is C _4alkyl; -(CH2)n 20-OR20 wherein n20 is 1, 2, 3 or 4 and R 0 is a hydrogen atom (H) or Cι_ alkyl; -CH(Me)-OH; -CH2-SH; -CH2-CH2-S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyl); and
R3^, independent of other R3^, is a hydrogen atom (H), Cι_4alkyl or C3_6cycloalkyl; and
Het , independent of other Het , 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 R3 is H, Cι_2 lkyl or -C(O)Me; and wherein the ring is optionally substituted at carbon by one Cι_2alkyl or oxo (=O) substituent, provided that any oxo (=O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
provided that: when R3 is the heterocyclic group of sub-formula (bb), nl is 1, and Y is NR O, then: either (a) Rl° is not C^alkyl, Cifluoroalkyl or CH2C(O)NH2; or (b) R O is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxarnide or 1-ethyl- N-(4-fluorophenyl)-4-[( 1 -methylpiperidin-4-yl)amino] - lH-pyrazolo [3 ,4-b]pyridine-5- carboxamide;
and provided that: where X is OR^a, the compound is other than the compound wherein Rl is methyl, X is OEt, and R3 is cyclopentyl. A compound of formula (IA) or a salt thereof:
Figure imgf000255_0001
wherein:
X is NR4R5 or OR5a, in which:
R4 is hydrogen, Cι_2 lkyl or Cι_2fluoroalkyl, and
R5 is hydrogen, Ci.galkyl, Cj.g fluoroalkyl, or C3_gcycloalkyl, phenyl optionally substituted with one or two of: a halogen atom, Cι_2alkyl, trifluoromethyl,
Cχ_2alkoxy or trifluoromethoxy; or R^ has the sub-formula (x), (y) or (z):
Figure imgf000255_0002
(X) (y) (z)
wherein in sub-formula (x) and (z), n = 1 or 2; and in sub-formula (y), m = 1 or 2; wherein in sub-formula (x) and (y), none, one or two of A, B, D, E and F are nitrogen; and the remaining of A, B, D, E and F are CH or C .6 where R6 is a halogen atom, Cι_4alkyl, Cifluoroalkyl, Cι_2alkoxy, Cifluoroalkoxy,
Cι_2alkylsulphonyl (Cι_2alkyl-SO2-), Ci.2alkyl-SO2-NH-, R7R8N-SO2-,
R7R8N-CO-, R7R8N, OH, Cι_4alkoxymethyl, or Cι_2alkyl-SO2-CH2-, wherein R7 and R8 are independently hydrogen or Cι_2alkyl; wherein in sub-formula (z), G is O or S or NR9 wherein R9 is C _4alkyl or Cι_4fluoroalkyl; none, one or two of I, L, M and Q are nitrogen; and the remaining of J, L, M and Q are CH or CR6 where R° is as defined herein;
or R4 and R^ taken together are -(CH2)p- where p = 3, 4 or 5;
R^a is Cι_galkyl; Cι_ fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, Cι_2alkyl, trifluoromethyl, Cχ_2alkoxy or trifluoromethoxy; or R^a has the sub-formula (x), (y) or (z) as defined herein;
Figure imgf000256_0001
R3 is C3_gcycloalkyl or a heterocyclic group being in which Y is O, S, SO2, or NR O; where RlO is hychOgen, Cι_4alkyl, Cι_2fluoroalkyl, C(O)-Cι.2alkyl, or C(O)-CF3;
and wherein in R3 the C3_gcycloalkyl or heterocyclic group is optionally substituted with one or two substituents being OH, Cχ_2alkoxy, trimethoxy, or Cι_2 alkyl group; and wherein any OH, alkoxy or trimethoxy substituent is not substituted at the ring carbon attached to the -NH- group of formula (LA) and is not substituted at either ring carbon bonded to the Y group of the heterocyclic group; and
R = Cχ_4alkyl or Cι_2 fluoroalkyl;
provided that:
Figure imgf000256_0002
when R3 is the heterocyclic group being ' and Y is N l 0. then: either (a) R ° is hydrogen, C(O)-Cι_2alkyl, or C(O)-CF3; or (b) R O is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide or 1-ethyl- N-(4-fluorophenyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide;
and provided that: where X is OR^a, the compound is other than the compound wherein R is methyl, X is OEt, and R3 is cyclopentyl.
A compound of formula (LB) or a salt thereof:
Figure imgf000256_0003
wherein: Rl is Cι_4alkyl, C1.3 fluoroalkyl, -CH2CH OH or -CH2CH2CO2Ci.2alkyl;
R2 is a hydrogen atom (H), methyl or Cifluoroalkyl;
R3 is optionally substituted C3_gcycloalkyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);
Figure imgf000257_0001
(aa) (bb) (cc) in which n and n2 independently are 1 or 2; and in which Y is O, S, SO2, or N lO; where Rl° is a hydrogen atom (H), C^alkyl, Cifluoroalkyl, CH2C(O)NH2, C(O)NH2, C(O)-C1.2alkyl, or C(O)-Cι fluoroalkyl;
and wherein in R3 the C3_gcycloalkyl or the heterocyclic group of sub-formula (aa),
(bb) or (cc) is optionally substituted with one or two substituents being oxo (=O), OH, Cι_2alkoxy, Cifluoroalkoxy, or Cι_2alkyl; and wherein any OH, alkoxy or fluoroalkoxy substituent is not substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (LB) and is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc);
and X is NR4R5 or OR5a, in which:
R4 is a hydrogen atom (H); Cι_6alkyl; C .3 fluoroalkyl; or C2_6alkyl substituted by one substituent R 1 ; and
R5 is a hydrogen atom (H); Ci.galkyl; C g fluoroalkyl; C3_gcycloalkyl optionally substituted by a Cι_2alkyl group; or -(CH2)n 4-C3_gcycloalkyl optionally substituted, in the -(CH2)n 4- moiety or in the C3_gcycloalkyl moiety, by a C _2alkyl group, wherein n4 is 1, 2 or 3;
or R5 is C2-6 lkyl substituted by one or two independent substituents Rl ;
wherein each substituent Rl 1, independently of any other Rl 1 substituent present, is: hydroxy (OH); C^alkoxy; phenyloxy; benzyloxy; -NR12R13; -NR15-C(O)Rl6; -NR15-C(0)-0-R16; -NR15-C(0)-NH-R 5; or -NR15-S02R16; and wherein any R! substituent which is OH, alkoxy or -N 12R13 is not substituted at any carbon atom, of any R4 or R^ substituted alkyl, which is bonded to the nitrogen of NR R5;
or R5 is -(CH2)nπ-C(O)Rl6; -(CH2)nH-C(O)NRl2Rl3; -CHR19-C(O)NR12R13; -(CH2)n 12-C(O)ORl6; -CHR19-C(O)OR16; -(CH2)n12-SO2-NRl2Rl3; -(CH2)n12-SO2R16; or -(CH2)n 12-CN; wherein n11 is 0, 1, 2, 3 or 4 and n12 is 1, 2, 3 or 4;
or R5 is -(CH2)n^3-Het wherein n^ is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or
7-membered saturated or partly-saturated heterocyclic ring 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^- moiety when nl3 is 1 and are not bound to the nitrogen of NR R^ when nl3 is 0; wherein any ring-nitrogens which are present and which are not unsaturated (i.e. which do not partake in a double bond) are present as 7 where Rl7 is as defined herein; and wherein one or two of the carbon ring-atoms independently are optionally substituted by C _2alkyl;
or R5 is phenyl optionally substituted with one or two of: a halogen atom; Cχ_4alkyl; Cifluoroalkyl; Cι_4alkoxy; Cχ_2 fluoroalkoxy; Cι_2alkylsulphonyl
(C1.2alkyl-SO2-); Cι_2alkyl-SO2-NH-; R7R8N-SO2-; R7R8N-CO-; -NR15-C(O)R16; R7R8N; OH; C^alkoxymethyl; Cι_4alkoxyethyl; Ci_2 lkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one or two of fluoro, chloro, Chalk !, C fluoroalkyl, C _2alkoxy or C fluoroalkoxy; wherein R7 and R8 are independently a hydrogen atom (H); Cι_4alkyl; C3_gcycloalkyl; or phenyl optionally substituted by one or two of: fluoro, chloro,
Cι_2alkyl, Cifluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy; or R7 and R8 together are
-(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n 8-X7-(CH2)n 9- or
-C(O)-X7-(CH2)n10- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5, n8 and n9 and nlO independently are 2 or 3, and X7 is O or NRI4 wherein R is H or Cι_2alkyl;
or R has the sub-formula (x), (y) or (z):
Figure imgf000258_0001
(x) (y) (z)
wherein in sub-formula (x), n = 1 or 2; in sub-formula (y), m = 1 or 2; and in sub- formula (z), r = 0, 1 or 2; wherein in sub-formula (x) and (y), none, one or two of A, B, D, E and F are nitiogen; and the remaining of A, B, D, E and F are independently CH or CR^;
where R^ is a halogen atom; Cι_4alkyl; Cifluoroalkyl; Cι_4alkoxy; Cifluoroalkoxy; Cι_2alkylsulρhonyl (Cι_2alkyl-SO2-); Cι.2alkyl-SO2-NH-; R7R8N-SO2-; R7R8N-CO-; -NR15-C(0)R16; R7R8N; OH; Cι.4alkoxymethyl; Cι_4alkoxyethyl; Ci_2alkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one or two of fluoro, chloro, Cι_2 alkyl, Cifluoroalkyl, Cι_2alkoxy or
Cifluoroalkoxy; wherein R7 and R8 are as herein defined;
wherein in sub-fonnula (z), G is O or S or NR9 wherein R9 is a hydrogen atom (H), Cι_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^ is as defined herein;
or R4 and R5 taken together are -(CH2)pl- or -C(O)-(CH2)p 2- or -(CH2)p3-X5-(CH2)p 4- or -C(O)-χ5-(CH2)p 5-, in which: pi = 3, 4, 5 or 6, p2 is 2, 3, 4, or 5, and p3 and p4 and p^ independently are 2 or 3 and X^ is O or I7; wherein Rl7 is a hydrogen atom (H); C^alkyl; Cι_2 fluoroalkyl;
C3_6cycloalkyl; -(CH2)p 6-C(O)Rl6 wherein p6 is 0, 1, 2 or 3;
-(CH )p 6-C(O)NRl2Rl3; -(CH2)p 6-C(O)ORl6; -SO2R16; or phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of: a halogen atom, Cι_2 alkyl, Cifluoroalkyl, Cι_2 alkoxy or
Cifluoroalkoxy; and wherein, when R4 and R^ taken together are -(CH2)pl- or -C(O)-(CH2)p 2-, the NR R^ heterocycle is optionally substituted by one R 8 substituent wherein Rl 8 is: Cι_4alkyl; Cifluoroalkyl; C3_6cycloalkyl; Cι_2alkoxy (not substituted at a ring-carbon bonded to the NR R^ ring-nitrogen); Cifluoroalkoxy
(not substituted at a ring-carbon bonded to the NR4R^ ring-nitrogen); OH (not substituted at a ring-carbon bonded to the NR4R5 ring-nitrogen); -(CH2)p 7-C(O)Rl6 wherein p7 is 0, 1, 2 or 3; -(CH2)p 7-C(O)ORl6; -(CH2)p 7-OC(O)Rl6; -(CH2)p 7-C(O)NRl2Rl 3 ; -(CH2)p 7-NR 5C(O)Rl 6; -(CH2)P 7-NR15C(O)NR12R13; -(CH2)P 7-NR15C(O)OR16; -(CH2)p 7-SO2R16;
-(CH2)p 7-SO2 NRl2Rl3; -(CH2)P 7-NR15S02R16; -(CH2)p 7-OH; -(CH2)p 7-ORl6; or phenyl optionally substituted by one or two of: a halogen atom, Cι_2alkyl, Cifluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy; or R4 and R5 taken together are -(CH2)pl- or -C(O)-(CH2)p 2- or
-(CH2)p 3-X5-(CH2)p 4- or -C(O)-X5-(CH2)p 5- as defined herein, and wherein the R4R^ heterocycle is fused to a phenyl ring optionally substituted on the phenyl by one or two of: a halogen atom, Cχ.2 alkyl, Cifluoroalkyl, Cι_2 alkoxy or
Cifluoroalkoxy; and
R^a is Ci.galkyl; Cι_g fluoroalkyl; C3_gcycloalkyl; phenyl optionally substituted with one or two of: a halogen atom, Cι_2alkyl, trifluoromethyl, Cι_2 lkoxy or trifluoromethoxy; or R^a has the sub-formula (x), (y) or (z) as defined herein
and wherein:
Rl2 and Rl3 independently are H; C^alkyl; C3_6"cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cι_2 alkyl, Cifluoroalkyl, Cι_2 alkoxy or Cifluoroalkoxy;
or Rl2 and Ri 3 together are -(CH2)n 6- or -C(O)-(CH2)n 7- or -C(O)-(CH2)n 7-C(O)- or -(CH2)n8-X12-(CH2)n 9- or -C(O)-χl2-(CH2)n 10- in which: n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5, n8 and n9 and nlO independently are 2 or 3 and χl2 is O or NRI4 wherein Rl is H or Cι_2 alkyl;
Rl5 is a hydrogen atom (H); Cι_4alkyl; C3_6cycloalkyl; or phenyl optionally substituted by one or two of: a halogen atom, Cι_2 alkyl, Cifluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy;
R!°~ is Cι_4alkyl; C3_6cycloalkyl; pyridinyl; or phenyl optionally substituted by one or two of: a halogen atom, C^alkyl, Cifluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy; and
Rl9is a hydrogen atom (H); C^alkyl; -(CH2)n 20-OR20 wherein n20 is 1,
2,
3 or 4 and R20 is a hydrogen atom (H) or Cι_4alkyl; -CH(Me)-OH; -CH2-SH; -CH2-CH2-S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyl);
provided that: when R3 is the heterocyclic group of sub-formula (bb), nl is 1, and Y is RlO, then: either (a) Rl° is not C^alkyl, Cifluoroalkyl or CH2C(O)NH2; or (b) RlO is methyl and the compound is: l-ethyl-N-(2-ethylbutyl)-4-[(l- methylpiperidin-4-yl)amino] - 1 H-pyrazolo [3 ,4-b]pyridine-5-carboxamide or 1 -ethyl- N-(4-fluorophenyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide; and provided that: where X is OR^a, the compound is other than the compound wherein Rl is methyl, X is OEt, and R3 is cyclopentyl.
4. A compound or salt as claimed in claim 1 or 3, wherein R2 is a hydrogen atom (H).
5. A compound or salt as claimed in claim 1, 2, 3 or 4, wherein R is Ci .3 alkyl, Cifluoroalkyl or -CH2CH2OH.
6. A compound or salt as claimed in any preceding claim, wherein Rl is ethyl, n-propyl, C fluoroalkyl or -CH2CH2OH.
7. A compound or salt as claimed in any preceding claim, wherein Rl is ethyl.
8. A compound or salt as claimed in any preceding claim, wherein in R3 there is one substituent or no substituent.
9. A compound or salt as claimed in any preceding claim, wherein, where R3 is optionally substituted C3_gcycloalkyl, then R3 is not optionally substituted C5cycloalkyl, i.e. it is not optionally substituted cyclopentyl.
10. A compound or salt as claimed in claim 9, wherein, where R3 is optionally substituted C3_gcycloalkyl, then R3 is optionally substituted Cg.gcycloalkyl.
11. A compound or salt as claimed in claim 9, wherein, where R3 is optionally substituted C3_gcycloalkyl, then R3 is optionally substituted cyclohexyl.
12. A compound or salt as claimed in any preceding claim, wherein, where R3 is optionally substituted C3_gcycloalkyl, then the one or two optional substituents is or independently are: oxo (=O); OH; NHR21 wherein R21 is a hydrogen atom (H); methyl; -CH2F; -CHF2; -C(O)OR23 wherein R23 is H; fluoro; hydroxyimino (=N-OH); or (Cι_ alkoxy)imino (=N-OR26 where R 6 is C^alkyl).
13. A compound or salt as claimed in any preceding claim, wherein, where R3 is optionally substituted C3_gcycloalkyl, then the one or two optional substituents is or independently are OH, oxo (=O) or hydroxyimino (=N-OH).
14. A compound or salt as claimed in any preceding claim, wherein, where R3 is optionally substituted C3_gcycloalkyl, then the one or two optional substituents if present is or are substituent(s) at the 3-, 4- or 5- position(s) of the R3 cycloalkyl ring, (wherein the 1 -position of the R3 cycloalkyl ring is deemed to be the connection point to the -NH- in formula (I) or (IA) or (LB)).
15. A compound or salt as claimed in any preceding claim, wherein, where R3 is optionally substituted C cycloalkyl, then R3 is cyclohexyl (i.e. unsubstituted), 3- hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-l-yl), 4-oxo-cyclohexyl (i.e. 4- oxocyclohexan-1-yl), 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan- 1-yl), 4-(Cι_2alkoxyimino)cyclohexyl, 1-methylcyclohexyl or 3-methylcyclohexyl.
16. A compound or salt as claimed in any preceding claim, wherein, where R3 is optionally substituted mono-unsaturated-C5_7cycloalkenyl, then R3 is optionally substituted mono-unsaturated-Cβcycloalkenyl (i.e. optionally substituted mono-unsaturated-cyclohexenyl), and wherein the R3 cycloalkenyl is optionally substituted with one or two substituents being fluoro or methyl.
17. A compound or salt as claimed in any preceding claim, wherein, where R3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is O, S, SO2, NH or
N-C(O)methyl.
18. A compound or salt as claimed in any preceding claim, wherein, where R3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is O.
19. A compound or salt as claimed in any preceding claim, wherein RlO is a hydrogen atom (H) or C(O)methyl.
20. A compound or salt as claimed in any preceding claim, wherein where R3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then R3 is the heterocyclic group of sub-formula (bb) and nl is 1.
21. A compound or salt as claimed in any preceding claim, wherein, in R3, the heterocyclic group of sub-formula (aa), (bb) or (cc) is unsubstituted (wherein, where
Y is NR O, RlO is not classified as a substituent).
22. A compound or salt as claimed in any of claims 1 to 20, wherein, in the R3 heterocyclic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents is or are oxo (=O).
23. A compound or salt as claimed in any preceding claim, wherein when R3 is the heterocyclic group of sub-formula (aa) then Y is O, S, SO2 or NH, and when R3 is the heterocyclic group of sub-formula (bb) and Y is NRlO, then Rl° is not Cι_4alkyl, Cifluoroalkyl or CH2C(O)NH2.
24. A compound or salt as claimed in any preceding claim, wherein, where R3 is a bicyclic group of sub-formula (dd) or (ee), then R3 is of sub-formula (ee) wherein γl, Y2 and Y3 are all CH2.
25. A compound or salt as claimed in any preceding claim, wherein NHR3 is of sub-formula (a), (al), (b), (c), (c 1), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (g), (gl), (g2), (g3), (g4), (h), (i), (j), (k), (kl), (L), (m), (ml), (m2), (m3), (m4), (m5), (n), (o), (ol), (o2), (o3), (o4), (o5), (p), (pi), (p2), (p3), (p4), (p5), (p6), (pi), (p8) or
(q):
(a) (a1) (b) (c) (c1) (C2)
Figure imgf000264_0002
(c3) (c4) (c5) (C6) (C7)
Figure imgf000264_0003
(d) (e) (f) (g) (gi) (g2) (g3) (g4)
Figure imgf000264_0004
(h) 0) 0) (k) (k1) (L)
Figure imgf000264_0005
(m) (m2)
Figure imgf000264_0006
Figure imgf000264_0007
(n) (P) (p1) (P2) (P3)
Figure imgf000264_0008
(P5) (p6) (P7) (p8) (q) (o)
Figure imgf000264_0009
26. A compound or salt as claimed in claim 25, wherein NHR3 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), (L), (m), (ml), (m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (o4), (o5), (p), (p2), (p3), (p5), (p6), (p7) or (q).
27. A compound or salt as claimed in claim 25, wherein NHR3 is of sub-formula (c), (d), (e), (f), (gl), (h), (i), 0), (k), (m), (ml), (n), (o), (ol), (p), or (q).
28. A compound or salt as claimed in claim 26 or 27, wherein NHR3 is of sub- formula (c), (cl), (c 4), (c 5), (h), (i), ), (k), (ml), (m2), (n), (o), (o2), (o3), (p2), (p5), (p6) or (q).
29. A compound or salt as claimed in claim 26 or 27, wherein NHR3 is of sub- fonnula (c), (h), (k), (n), (o) or (o2).
30. A compound or salt as claimed in claim 25, wherein R3 is tetrahydro-2H- pyran-4-yl; that is NHR3 is of sub-formula (h).
31. A compound or salt as claimed in any preceding claim, wherein X is R R^ .
32. A compound or salt as claimed in any preceding claim, wherein R4 is a hydrogen atom (H), Cι_4alkyl, -(CH2)n 3-OH or -(CH2)n 3-NRl2Rl3 wherein n3 is 2 and Rl and Rl3 independently are H or Ci alkyl.
33. A compound or salt as claimed in any preceding claim, wherein R4 is a hydrogen atom (H).
34. A compound or salt as claimed in any preceding claim, wherein R^ is: Ci.galkyl;
Cifluoroalkyl;
C3_gcycloalkyl (unsubstituted); unsubstituted -(CH2)n^-C5-6cycloalkyl wherein n4 is 1 or 2;
Figure imgf000265_0001
is 2 or 3, and each substituent RU, independently of any other RU substituent present, is Cι_4alkoxy, -NR15-C(0)-NH-R15, or
- R15-S02R1 , and any RU substituent which is alkoxy is not substituted at any carbon atom, of the R$ substituted alkyl, which is bonded to the nitrogen of NR R^; or -(CH2)nn-C(O)Rl6; -(CH2)n 12-C(O)NRl2Rl3; -(CH2)nl2-C(O)ORl6;
-(CH2)nl2-SO2-N[Rl2Rl3; -(CH2)nl2-SO2R16; or -(CH2)n 12-CN wherein n11 is 1 or 2 and nl2 is 1 or 2.
35. A compound or salt as claimed in any of claims 1 to 33, wherein R^ is -(CH2)nl -Het, n 3 is 0, 1 or 2, and Het is a 5- or 6-membered saturated saturated heterocyclic ring.
36. A compound or salt as claimed in any of claims 1 to 33, wherein R^ is phenyl optionally substituted with, independently, one or two of: a halogen atom; Chalky!; Cifluoroalkyl; Cι_2 alkoxy; trifluoromethoxy; Cι_2alkylsulphonyl
(Ci_2alkyl-SO2-); Ci_2alkyl-SO2-NH-; R7R8N-SO2S R7R8N-CO-; -NR.15-C(O)R16; R7R8N; OH; C^alkoxymethyl; Cι.2alkyl-SO2-CH2-; cyano (CN); or phenyl optionally substituted by one of fluoro, Cι_2 alkyl, Cifluoroalkyl, Cι_2alkoxy or Cifluoroalkoxy.
37. A compound or salt as claimed in claim 35, wherein R is phenyl optionally substituted with one or two of: a halogen atom, Cι_2alkyl, trifluoromethyl,
Cι_2alkoxy, trifluoromethoxy, R R8N-SO2-, R7R8N-CO-, or Ci_2alkyl-SO2-CH2-.
38. A compound or salt as claimed in any of claims 1 to 33, wherein R^ has the sub-formula (x) or (y) or (yl) or (z).
39. A compound or salt as claimed in any of claims 1 to 33, wherein R^ has the sub-formula (x).
40. A compound or salt as claimed in any preceding claim, wherein n = 1, m = 1, and r = 1.
41. A compound or salt as claimed in any preceding claim, wherein, in sub- formula (x), (y) and/or (yl): none, one or two of A, B, D, E and F are nitrogen; none, one, two or three of A, B, D, E and F are CR^; and the remaining of A, B, D, E and F are CH
42. A compound or salt as claimed in claim 41, wherein, in sub-formula (x), (y) and/or (yl), none or one of A, B, D, E and F are nitrogen.
43. A compound or salt as claimed in any preceding claim, wherein in sub- formula (x), (y), (yl) and/or (z), each R^, independently of any other R present, is a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, C4alkyl, trifluoromethyl, -CH2OH, methoxy, ethoxy, Cifluoroalkoxy, OH,
Cι_3alkylS(O)2-, Cι_3alkylS(O)2-NH-, Me2N-S(O)2-, H2N-S(O)2-, -CONH2, -CONHMe, -CO2H, cyano (CN), NMe2, t-butoxymethyl, or Cι_3alkylS(O)2-CH2-.
44. A compound or salt as claimed in claim 43, wherein in sub-fonnula (x), (y), (yl) and/or (z), each R6, independently of any other R^ present, is a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, -CH2OH, methoxy, difluoromethoxy, methylsulphonyl, methyl-S02-NH- or methyl-S02-CH2--
45. A compound or salt as claimed in any preceding claim, wherein R^ is of sub- formula (x) and is: benzyl, (monoalkyl-phenyl)methyl, [mono(fluoroalkyl)-phenyl]methyl, (monohalo-phenyl)methyl, (monoalkoxy- phenyl)methyl, [mono(fluoroalkoxy)-ρhenyl]methyl, [mono(N,N- dimethylamino)-phenyl]methyl, [mono(methyl-Sθ2-NH-)-phenyl]methyl,
[mono(methyl-Sθ2-)-ρhenyl]methyl, (dialkyl-phenyl)methyl, (monoalkyl- monohalo-phenyl)methyl, [mono(fluoroalkyl)-monohalo-phenyl]methyl, (dihalo- ρhenyl)methyl, (dihalo-monoalkyl-phenyl)methyl, [dihalo-mono(hydroxymethyl)- phenyljmethyl, or (dialkoxy-phenyl)methyl.
46. A compound or salt as claimed in claim 45, wherein R^ is: (monoC 1 -.3 alkyl-phenyl)methyl ; (monoC \ fluoroalkyl -phenyl)methyl ;
(monoC _2alkoxy-phenyl)methyl ; [mono (C 1 fluoroalkoxy)-phenyl]methyl ;
(diC 1 _2alkyl-phenyl)methyl ; (monoC \ _2alkyl-monohalo-phenyl)methyl ; (dihalo- phenyl)methyl; (dihalo-monoCι_2alkyl-phenyl)methyl; or [dihalo- mono(hydroxymethyl)-phenyl]methyl.
47. A compound or salt as claimed in claim 46, wherein R^ is:
(4-C 1.3 alkyl-phenyl)methyl ; (4-C 1 fluoroalkyl-phenyl)methyl ; (4-C \ _2alkoxy- phenyl)methyl ; (4-C 1 fluoro alkoxy-phenyl)methyl ; (3 ,4-dimethyl-phenyl)methyl ;
(2,4-dimethyl-phenyl)methyl; (3 ,5-dimethyl-phenyl)methyl; (2,3-dimethyl- phenyl)methyl; (2,5-dimethyl-phenyl)methyl; (4-methyl-3-chloro-phenyl)methyl; (3-methyl-4-chloro-phenyl)methyl; (2-methyl-4-chloro-phenyl)methyl; (2-chloro- 4-fluorophenyl)methyl; (2,4-difluoro-phenyl)rnethyl, (4-bromo- 2-fluorophenyl)methyl ; (4-chloro-2-fluorophenyl)methyl ; (3 ,4-dichloro- phenyl)methyl; (2,4-dichloro-phenyl)methyl; (2,6-dichloro-phenyl)methyl; (2,3-dichloro-phenyl)methyl; (2,4-dichloro-6-methyl-phenyl)methyl; or [2,3-dichloro- 6-(hydroxymethyl)-phenyl]methyl.
48. A compound or salt as claimed in any of claims 1 to 44, wherein R^ has the sub-formula (z), r is 1, none or one of J, L, M or Q is CR^, and if one of J, L, M or Q is CR6 then R^ is methyl or Cifluoroalkyl, and R9 is a hydrogen atom (H) or methyl.
49. A compound or salt as claimed in claim 1, which is:
Ethyl 4-(cyclopentylamino)-l-ethyl-lH-ρyrazolo[3,4-b]pyridine-5-carboxylate,
Ethyl 4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridme-5-carboxylate,
Ethyl l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylate,
Ethyl 4-[( 1 -acetylpiperidin-4-yl)amino] - 1 -ethyl- 1 H-pyrazolo[3 ,4-b]pyridine-5 -carboxylate, Ethyl l-methyl-4-(texrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxylate,
Ethyl l-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-lH-pyrazolo[3,4-b]pyridine-5-carboxylate,
Ethyl l-ethyl-4-[(3R)-texrahydrofuran-3-ylamino]-lH-pyrazolo[3,4-b]pyridine-5-carboxylate,
Ethyl 1 -ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxylate,
Ethyl 1 -ethyl-4-(tetrahydrothien-3 -ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate,
Ethyl 4-(cyclopropylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate,
Ethyl 4-[( 1 , 1 -dioxidotetrahydrothien-3 -yl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxylate,
Ethyl 4-[( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino] - 1 -ethyl- lH-pyrazolo[3 ,4- b]pyridine-5 -carboxylate,
N-Benzyl- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, l-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide,
N-Cyclopentyl-4-(cyclopentylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N-cyclopentyl- 1 -ethyl- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Cyclopentyl-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-[(l-Acetylpiperidin-4-yl)amino]-N-cyclopentyl-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Cyclopentyl- 1 -ethyl-5 -(pynolidin- 1 -ylcarbonyl)- 1 H-pyrazolo [3 ,4-b]pyridin-4-amine,
N-Cyclohexyl- 1 -ethyl-5 -(pyrrolidin- 1 -ylcarbonyl)- lH-pyrazolo [3 ,4-b]pyridin-4-amine,
1 -Ethyl-5 -(pyrrolidin- 1 -ylcarbonyl)-N-tetrahydro-2H-pyran-4-yl- 1 H-pyrazolo [3 ,4-b]pyridin-
4-amine,
4-(Cyclopentylamino)- 1 -ethyl-N-(pyridin-4-ylmethyl)- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-(pyridin-4-ylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-N-(pyridin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclopentylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Benzyl-4-(cyclopentylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Benzyl-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-[( 1 -Acetylpiperidin-4-yl)amino] -N-benzyl- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclopentylamino)-l-ethyl-N-(2-ethylbutyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-(2-ethylbutyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(2-ethylbutyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-N-(2-ethylbutyl)-4-[(l-methylpiperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-[( 1 -Acetylpiperidin-4-yl)amino] - 1 -ethyl-N-(2-ethylbutyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide,
4-(Cyclopentylamino)-l-ethyl-N-(4-fluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-(4-fluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
1 -Ethyl-N-(4-fluorophenyl)-4-[( 1 -methylpiperidin-4-yl)amino] - 1 H-pyrazolo [3 ,4-b]pyridine-
5-carboxamide,
4-[(l-Acetylpiperidin-4-yl)amino]-l-ethyl-N-(4-fluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclopentylamino)- 1 -ethyl-N-n-propyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-n-propyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-[( 1 -Acetylpiperidin-4-yl)amino] - 1 -ethyl-N-n-propyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-[(l-Acetylpiperidin-4-yl)amino]-l-ethyl-N-(pyridin-4-ylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-Benzyl-4-(cyclopentylamino)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-Benzyl-4-(cyclohexylamino)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Benzyl- 1 -methyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclopentylamino)-N-(2-ethylbutyl)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-N-(2-ethylbutyl)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2-Ethylbutyl)-l-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide,
4-(Cyclopentylamino)-N-(4-fluorophenyl)-l-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclohexylamino)-N-(4-fluorophenyl)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-(4-Fluorophenyl)-l-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclopentylamino)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetylpiperidin-4-yl)amino] -N-benzyl- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, l-Ethyl-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-N,N-dimethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, 1 -Ethyl-N-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide,
1 -Ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide,
N-Benzyl- 1 -ethyl-4-[(3 S)-tetrahydrofuran-3 -ylamino] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-Benzyl-l-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl- 1 -ethyl-4-(tetrahydrothien-3 -ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Benzyl-4-(cyclopropylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-Benzyl-4-[( 1 , 1 -dioxidotetrahydrothien-3 -yl)amino] - 1 -ethyl- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-Benzyl-4-[( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-Benzyl-l-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
1 -Ethyl-N-(4-liuorophenyl)-4-[(3 S)-tetrahydrofuran-3 -ylamino] - 1 H-pyrazolo [3 ,4-b]pyridine-
5-carboxamide, l-Ethyl-N-(4-fluorophenyl)-4-[(3R)-tetrahydrofuran-3-ylamino]-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide,
1 -Ethyl-N-(4-fiuorophenyl)-4-(tetrahydro-2H-thiopyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N-(4-fluorophenyl)-4-(tetrahydrothien-3 -ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide,
4-(Cyclopropylamino)-l-ethyl-N-(4-fluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-[( 1 , 1 -Dioxidotetrahydrothien-3 -yl)amino] - 1 -ethyl-N-(4-fluorophenyl)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-N-(4-fluorophenyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[4-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[3-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-5- { [5-methoxy-6-(trifluoromethyl)-2,3 -dihydro- lH-indol- 1 -yl] carbonyl} -N- tetrahydro-2H-pyran-4-yl-lH-pyrazolo[3,4-b]ρyridin-4-amine,
N-[(5-Chloropyridin-2-yl)methyl]-l-ethyl-4-(tetrahydro-2H-pyraιι-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(4-Chlorobenzyl)- 1 -ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(3-Chlorobenzyl)-l-ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-4-(tetiahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, N-(2-tert-Butoxyethyl)- 1 -ethyl-4-(tetiahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- b]pyridine-5-carboxamide, l-Ethyl-4-(tetiahydro-2H-pyran-4-ylamino)-N-(l,3-thiazol-2-ylmethyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(pyrimidin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- [(2-methyl- 1 ,3-thiazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[3-(tert-Butoxymethyl)benzyl]-l-ethyl-4-(tetiahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4- ylamino)-l H-pyrazolo [3, 4-b]pyridine-5 -carboxamide, l-Ethyl-N-(pyrazin-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-5- {[4-(pyridin-2-ylcarbonyl)piperazin- 1 -yl]carbonyl} -N-tetrahydro-2H- pyran-4-yl- 1 H-pyrazolo [3 ,4-b]pyridin-4-amine,
N-(2-Chloro-6-fluorobenzyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(6-oxo-l,6-dihydropyridin-3-yl)methyl]-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[3-(Aminocarbonyl)benzyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- {4-[(methylamino)carbonyl]phenyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[2-(l-methyl-lH-imidazol-4-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N- {2-[(Anilinocarbonyl)amino] ethyl} - 1 -ethyl-4-(tetrahyαro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(lH-tetiaazol-5-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-4-(tetiahydro-2H-pyran-4-ylamino)-N-[2-(lH-l,2,4-triazol-l-yl)ethyl]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)phenyl]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, tert-Butyl 4-( { [ 1 -ethyl-4-(tetiahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- b]pyridin-5-yl] carbonyl} amino)piperidine- 1 -carboxylate,
1 -Ethyl-N- {3-[(methylsulfonyl)amino]propyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[2-(Dimethylamino)benzyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(l-ethylpyrrolidin-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(tetiahydrofuran-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-ethyl-N-tetrahydro-2H-pyran-4-yl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N- {4-[(Dimethylamino)sulfonyl]benzyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{3-[(methylsulfonyl)amino]benzyl}-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide, l-Ethyl-N-(4-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylammo)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-N-[3 -(2-oxopyrrolidin- 1 -yl)propyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(pyridin-3-ylmethyl)-4-(tetiahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-N-(l-methylpiperidin-4-yl)-4-(tetrahydiO-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-(l-ethylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-N-(2-piperidin- 1 -ylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-(3 -morpholin-4-ylpropyl)-4-(tetraliydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(3-Ethoxypropyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-(Cyclohexylmethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-[3-(Dimethylamino)propyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3, 4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-neopentyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- b]pyridine-5-carboxamide, l-ethyl-N-(4-methoxybenzyl)-4-(tetiahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-N-{2-[(phenylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[2-(Acetylamino)ethyl]-l-ethyl-4-(tetiahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{2-[(2-methoxyphenyl)(methyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(2-oxo-2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lΗ- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2,5-Difluorobenzyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)benzyl]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N 1 -Diethyl-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- b]pyridine-5-carboxamide,
N-Cyclopropyl- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
Ν-(2-amino-2-oxoethyl)-l-ethyl-4-(tetrahydro-2Η-pyran-4-ylamino)-lΗ- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(3-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-(3,4-Difluorobenzyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, Ethyl 3-( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridin-5- yl]carbonyl} amino)propanoate,
N-(l-Benzylpiperidin-4-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-Butyl-4- { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3 ,4-b]pyridin-
5-yl]carbonyl}piperazine- 1 -carboxamide, l-Ethyl-4-(tetrahydro-2H-ρyran-4-ylamino)-N-(l,3,4-thiadiazol-2-yl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[2-(2-oxoimidazolidin-l-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(3 ,4-Dimethoxybenzyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(3-Chlorobenzyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-5-[(4-methylpiperazin- 1 -yl)carbonyl]-N-tetrahydro-2H-pyran-4-yl- 1H- pyrazolo [3 ,4-b]pyridin-4-amine, l-Ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
1 -Ethyl-5- { [4-(4-methoxyphenyl)piperazin- 1 -yl] carbonyl} -N-tetrahydro-2H-pyran-4- yl- lH-pyrazolo [3 ,4-b]pyridin-4-amine,
1 -Ethyl-N- {4-[(methylsulfonyl)methyl]phenyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
Ν-[3-(dimethylamino)-3-oxopropyl]-l-ethyl-4-(tetrahydro-2Η-pyran-4-ylamino)-lΗ- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(l-methyl-lH-imidazol-5-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- {4-[(methylamino)sulfonyl]phenyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2-Cyanoethyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4- b]pyridine-5-carboxamide,
1 -Ethyl-N-[(1 -methyl- lH-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-methyl-N-[(l-methyl-lH-imidazol-2-yl)methyl]-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(2-thien-2-ylethyl)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-[2-(4-Chlorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[2-(2-methoxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
Ethyl 4-(cyclohexylamino)- 1 -(3-ethoxy-3-oxopropyl)- lH-pyrazolo[3,4-b]pyridine-5- carboxylate,
Ethyl l-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxylate,
Ethyl l-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxylate,
Ν-[4-(Methylsulfonyl)benzyl]-l-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, N-(4-Fluorophenyl)-l-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
Ethyl l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxylate,
Ethyl 4-(cyclohexylamino)-l-ethyl-6-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxylate,
4-(Cyclohexylamino)- 1 -ethyl-6-methyl-N-[4-(methylsulfonyl)benzyl] - 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-Benzyl-4-(cyclohexylamino)-l-ethyl-6-methyl-lH-pyrazolo[3,4-b]pyridme-5- carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-(4-fluorophenyl)-6-methyl-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-6-methyl-N- [4-(trifluoromethyl)benzyl] - 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cyclohexylamino)-N-(2,3-dihydro- lH-inden-2-yl)- 1 -ethyl-6-methyl- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-Benzyl-l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
N-Benzyl-l-ethyl-4-[(2-oxoazepan-3-yl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-l-ethyl-4-[(3-hydroxycyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-l-ethyl-4-[(4-hydroxycyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-l-ethyl-4-[(3-hydroxycyclopentyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-Benzyl-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
1 -Ethyl-N-(2-hydroxy- 1 -methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
Methyl (2S)-2-( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3,4- b]pyridin-5-yl]carbonyl}amino)-3-hydroxypropanoate,
Ethyl l-ethyl-4-[(4-hydroxycyclohexyl)amino]-lΗ-pyrazolo[3,4-b]pyridine-5-carboxylate,
Ethyl l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxylate,
Ethyl 4-[( 1 -acetyl-4-piperidinyl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate,
Ethyl 4-[(4-aminocyclohexyl)amino] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxylate,
Ethyl-Ν-[(l-oxido-3-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-[(l-oxido-2-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(l-oxido-4-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
4-[(cis-4-Aminocyclohexyl)amino] - 1 -ethyl-N-(phenylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide,
4-(Cyclobutylamino)-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cycloheptylamino)-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-4-[(4-methylcyclohexyl)amino]-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-4-[(3-methylcyclohexyl)amino]-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-4-[(l-methylcyclohexyl)amino]-N-(ρhenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-4-{[(3S)-2-oxo-3-pyrrolidinyl]amino}-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-[(2,5-Dioxo-3-pyrrolidinyl)amino]-l-ethyl-N-(phenylmethyl)-lH-ρyrazolo[3,4-b]pyridine-
5-carboxamide,
4-(l-Azabicyclo[2.2.2]oct-3-ylamino)-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide, l-Ethyl-4-[(l-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclobutylamino)- 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl} - 1 H-pyrazolo [3 ,4-b]pyridine-
5 -carboxamide,
4-(Cycloheptylamino)- 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl} - lH-pyrazolo[3 ,4- b]pyridine-5 -carboxamide,
4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-[(4-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl-4-[(3 -methylcyclohexyl)amino] -N- { [4-(methyloxy)phenyl]methyl} - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(cis-4-Aminocyclohexyl)amino]-l-ethyl-N-{[4-(methyloxy)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cycloheptylamino)- 1 -ethyl-N-( {4-[(methylsulfonyl)amino]phenyl } methyl)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclobutylamino)-l-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-({4-
[(methylsulfonyl)amino]phenyl } methyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-l-ethyl-N-({4-
[(methylsulfonyl)amino]phenyl} methyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide, l-Ethyl-4-[(4-methylcyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-4-[(3 -methylcyclohexyl)amino] -N-( {4- [(methylsulfonyl)amino]phenyl} methyl)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-[(l-methylcyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
4-[(cis-4-Aminocyclohexyl)amino]-l-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cycloheptylamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclobutylamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, N-(2,3 -Dihydro- 1 H-inden-2-yl)- 1 -ethyl-4-[(3 -methylcyclohexyl)amino] - lH-pyrazolo [3,4- b]pyridine-5 -carboxamide,
N-(2,3 -Dihydro- 1 H-inden-2-yl)- 1 -ethyl-4- [(4-methylcyclohexyl)amino] - lH-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[(lR,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(lR,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-(2,3 -Dihydro- 1 H-inden-2-yl)- 1 -ethyl-4-[( 1 -methylcyclohexyl)amino] - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[(cis-4-Aminocyclohexyl)amino] -N-(2,3 -dihydro- 1 H-inden-2-yl)- 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2,4-Dimethylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[(3,4-Dimethylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[(3,4-Dichlorophenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [4-(methyloxy)phenyl]methyl} -4- [(4-oxocyclohexyl)amino] - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-{[4-(Dimethylamino)phenyl]methyl}-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-[(4-oxocyclohexyl)amino]-N-{[4-(trifiuoromethyl)phenyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { [4-(methylsulfonyl)phenyl]methyl } -4-[(4-oxocyclohexyl)amino] - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(4-fluorophenyl)-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
1 -Ethyl-4-[(4-oxocyclohexyl)amino] -N-(2-pyridinylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide trifluoroacetate,
N-(2,3 -Dihydro- 1 H-inden-2-yl)- 1 -ethyl-4- [(4-oxocyclohexyl)amino] - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-(l-Acetyl-4-piperidinyl)-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide,
1 -Ethyl-N-[( 1 -methyl- 1 H-pyrazol-4-yl)methyl] -4-[(4-oxocyclohexyl)amino] - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N,l-Diethyl-4-[(4-oxocyclohexyl)amino]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide l-Ethyl-4-[(4-oxocyclohexyl)amino]-N-(l,3-tniazol-2-ylmethyl)-lH-pyrazolo[3,4-b]pyridine-
5 -carboxamide,
1 -Ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-3 -ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-3 -ylamino)-N- { [4-(trifluoromethyl)phenyl]methyl} - 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { [4-(methylsulfonyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- {4- [(methylsulfonyl)methyl]phenyl} -4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide, 1 -Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-
5-carboxamide, l-Ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide trifluoroacetate,
N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-4-(texrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-( 1 -Acetyl-4-piperidinyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N- [( 1 -methyl- 1 H-pyrazol-4-yl)methyl] -4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N, 1 -Diethyl-4-(tetrahydro-2H-pyran-3 -ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-3 -ylamino)-N-( 1 ,3 -tniazol-2-ylmethyl)- 1 H-pyrazolo [3,4- b]pyridine-5-carboxamide,
4-[(4,4-Difluorocyclohexyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-4-[(4-fluoro-3-cyclohexen-l-yl)amino]-N-(phenylmethyl)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-(2,3 -dihydro- 1 H-inden-2-yl)- 1 -ethyl- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(3 ,4-dichlorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl-N- [(3 -fluorophenyl)methyl] - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(3 ,4-difluorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(2,5 -difluorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[3-(trifluoromethyl)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[4-(triiiuoromethyl)phenyl]methyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(2,6-difluorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(3 -chlorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl } - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl-N- [4-(methyloxy)phenyl]- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-N-({4-[(dimethylamino)sulfonyl]phenyl}methyl)-l-ethyl-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl-N-( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyi)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino]-N- { [2-(dimethylamino)phenyl]methyl} - 1 -ethyl- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(2,4-dichlorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl -N-[(2-fluorophenyl)methyl] - 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-[(2-chloro-6-fluorophenyl)methyl] - 1 -ethyl- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N-( {4- [(difluoromethyl)oxy]phenyl } methyl)- 1 -ethyl- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-N-{[3-chloro-4-(methyloxy)phenyl]methyl}-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, 4-[(l-Acetyl-4-piperidinyl)amino]-N-[(5-chloro-2-pyridinyl)methyl]-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)arnino]-N-(5-chloro-2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] - 1 -ethyl-N-( 1 ,3 -thiazol-2-ylmethyl)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
4-[(l-Acex l-4-piperidinyl)arnino]-N-(2,2-diphenylethyl)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino]-N- { [4-(aminosulfonyl)phenyl]methyl} -1 -ethyl- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-({3-[(methylamino)carbonyl]phenyl}methyl)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-[( 1 -Acetyl-4-piperidinyl)amino] -N- { [4-(aminocarbonyl)phenyl]methyl} - 1 -ethyl- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(l-Acetyl-4-piperidinyl)amino]-l-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-4-piperidinyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, l-Ethyl-N-(4-piperidinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-Ethyl-N-[l-(ethylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-{ 1 -[(1 -methylethyl)sulfonyl]-4-piperidinyl} -4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[l-(Cyclopentylsulfonyl)-4-piperidinyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[l-(methylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { 1 -[(phenylmethyl)sulfonyl]-4-piperidinyl} -4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[l-(phenylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[l-(propylsulfonyl)-4-piperidmyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[ 1 -(Cyclopropylcarbonyl)-4-piperidinyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[l-(3-furanylcarbonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[ 1 -(3 ,3 -Dimethylbutanoyl)-4-piperidinyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[l-(2-ethylbutanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[l-(Cyclopentylacetyl)-4-piperidinyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[l-(2-methylpropanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-4- piperidinyl] - lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(l-propanoyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[l-(N-Acexylglycyl)-4-piperidinyl]-l-ethyl-4-(texrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[l-(4-morpholinylacetyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { 1 -[(4-oxocyclohexyl)carbonyl] -4-piperidinyl} -4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[l-(l-piperidinylacetyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{l-[(l-methyl-5-oxo-3-pyrrolidinyl)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H- pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- { 1 -[(3 -methyl-3 -oxetanyl)carbonyl] -4-piperidinyl} -4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { 1 -[(4-fluorophenyl)acetyl]-4-piperidinyl} -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N- { [ 1 -(3 ,3 -Dimethylbutanoyl)-4-piperidinyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N- { [ 1 -(Cyclopentylacetyl)-4-piperidinyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [ 1 -(Cyclopropylcarbonyl)-4-piperidinyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-({l-[(4-oxocyclohexyl)carbonyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-({l-[(4-fluorophenyl)acetyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-( { 1 -[(1 -methyl-5-oxo-3-pynolidinyl)carbonyl]-4-piperidinyl}methyl)-4-
(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
Methyl 3-[(l-ethyl-5-{[(phenylmethyl)amino]carbonyl}-lH-pyrazolo[3,4-b]pyridin-4- yl)amino]cyclohexanecarboxylate,
3 -[( 1 -Ethyl-5 - { [(phenylmethyl)amino] carbonyl} - 1 H-pyrazolo [3 ,4-b]pyridin-4- yl)amino]cyclohexanecarboxylic acid,
1 -Ethyl-N-(phenylmethyl)-4-(4-piperidinylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
Ethyl l-ethyl-4-({l-[(methyloxy)acetyl]-4-piperidinyl}amino)-lH-pyrazolo[3,4-b]pyridine-5- carboxylate,
Ethyl 1 -( 1 -methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxylate,
4-(Cyclohexylamino)- 1 -ethyl-N-methyl- 1 H-pyrazolo[3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(4-fluorophenyl)-6-methyl-4-(texrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl -6-methyl-N- { [4-(methylsulfonyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(2,3-Dihydro-lH-inden-2-yl)-l-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[3-(l-piperidinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[4-( 1 -methylethyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-(2-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide,
N-{3-[(Dimethylamino)carbonyl]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-{4-[(Difluoromethyl)oxy]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, N- {4-[Acetyl(methyl)amino]phenyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-(4-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-[4-(4-morpholinyl)-2-(hifluoromethyl)phenyl]-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-4-pyridinyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, l-Ethyl-N-{4-[(4-methyl-l-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[2-(2-oxo-l-pyrrolidinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[3 -(methylsulfonyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-{3-[Acetyl(methyl)amino]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{3-[(methylsulfonyl)amino]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(4-fluoro-2-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-(4-Chlorophenyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-
5-carboxamide,
N-(3-Chloro-2-cyanophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-[3-(l-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[2-(methylsulfonyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-{2-[Acetyl(methyl)amino]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[3-(4-morpholinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-(4-Chloro-3-cyanophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-(3-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-(3-Chlorophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide,
N-[3 - [(Acetylamino)methyl] -4-(methyloxy)phenyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[4-(l-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-(3-{[Cyclohexyl(methyl)amino]carbonyl}phenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[2-(4-morpholinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-{3-[(Acetylamino)sulfonyl]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-(3-Chloro-4-hydroxyphenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-{4-[(methylsulfonyl)amino]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-{3-[(methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N- [3 -(trifluoromethyl)phenyl] - lH-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N-3 -pyridinyl-4-(texrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-(3,4-Dichlorophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[3-(Aminosulfonyl)-4-chlorophenyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[3 -(4-morpholinyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-[4-(4-morpholinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-{2-[(4-methyl-l-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-{2-[(Dimethylamino)carbonyl]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[2-Chloro-4-(trifluoromethyl)phenyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- {2-[(Acetylamino)methyl]phenyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-(2-Chlorophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridine-
5-carboxamide,
N-(3-Chloro-2-fluorophenyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N-(3 -fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-
5-carboxamide,
N-(2-Cyano-3 -fluorophenyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N-[4-(propylsulfonyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N- {4-[(Dimethylamino)carbonyl]phenyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[4-(methylsulfonyl)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide,
N-{4-[(Acetylamino)methyl]phenyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[2-(Aminosulfonyl)ethyl]-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
N-(2-Amino-2-oxoethyl)-4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- {2-[(methylsulfonyl)amino] ethyl } - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- [( 1 -methyl- 1 H-pyrazol-4-yl)methyl] - 1 H-pyrazolo [3 ,4- b]pyridine-5-carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- { [3 -(methylsulfonyl)phenyl]methyl} - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N- { [3 -(Aminocarbonyl)phenyl]methyl} -4-(cyclohexylamino)-l -ethyl- lH-pyrazolo[3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-(tetrahydro-2-furanylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclohexylamino)-N-({4-[(dimethylamino)sulfonyl]phenyl}methyl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, N-[(5-Chloro-2-pyridinyl)methyl]-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-
5 -carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-l -ethyl-N- {4-[(methylamino)carbonyl]phenyl} - 1 H-pyrazolo [3,4- b]pyridine-5-carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-({3-[(methylamino)carbonyl]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [4-(Aminocarbonyl)phenyl]methyl} -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-[(4-hydroxyphenyl)methyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- { [4-(methyloxy)phenyl]methyl } - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N- [(3 ,4-difluorophenyl)methyl] - 1 -ethyl- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-{[4-(trifluoromethyl)phenyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-({3-[(methylsulfonyl)amino]phenyl}methyl)-lH- pyrazolo[3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N- [(2,5 -diliuorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-[(4-methylphenyl)methyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-(2- {4-[(methylsulfonyl)amino]phenyl} ethyl)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-[(2-hydroxyphenyl)methyl]-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclohexylamino)-N-[(3 ,4-dichlorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-N-[(3,5-dichlorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-(2-phenylethyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- { [2-(methylsulfinyl)phenyl]methyl } - lH-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- [2-(4-hydroxyphenyl)ethyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N- {2-[4-(Aminosulfonyl)phenyl] ethyl } -4-(cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-({2-[(methylamino)carbonyl]phenyl}methyl)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- { [2-(methylsulfonyl)phenyl]methyl } - 1 H-pyrazolo[3 ,4- b]pyridine-5 -carboxamide,
Methyl 2-[({[4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]ρyridin-5- yl]carbonyl}ammo)methyl]benzoate,
4-(Cyclohexylamino)-l-ethyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[4,5-Bis(methyloxy)-2,3-dihydro-lH-inden-2-yl]-4-(cyclohexylamino)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- { [2-fluoro-3 -(trifluoromethyl)phenyl]methyl } - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, 4-(Cyclohexylamino)-N-[(3 ,4-dimethylphenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- [2-(4-iiuorophenyl)ethyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- [2-(4-methylphenyl)ethyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- {2-[4-(methyloxy)phenyl] ethyl } - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-(2 -pyridinylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide trifluoroacetate,
4-(Cyclohexylamino)-N-[(3 ,5 -difluorophenyl)methyl] - 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-N-(2,3 -dihydro- 1 H-inden- 1 -yl)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-N- { [4-(dimethylamino)phenyl]methyl} - 1 -ethyl- 1 H-pyrazolo[3 ,4- b]pyridine-5 -carboxamide trifluoroacetate,
4-(Cyclohexylamino)- 1 -ethyl-N- [(2-fluorophenyl)methyl] - lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
N-{[2,4-Bis(methyloxy)phenyl]methyl}-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[(6-Chloro-2-pyridinyl)methyl]-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-
5 -carboxamide trifluoroacetate,
N-({2-[Acetyl(methyl)amino]phenyl}methyl)-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide trifluoroacetate,
4-(Cyclohexylamino)- 1 -ethyl-N- { [4-fluoro-3 -(trifluoromethyl)phenyl]methyl} - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N-[(lR)-2,3-dihydro-lH-inden-l-yl]-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N-[(2,6-dichlorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
Methyl 3-[({[4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridin-5- yl]carbonyl}amino)methyl]benzoate,
4-(Cyclohexylamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
Methyl 4-[({[4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyridin-5- yl]carbonyl}amino)methyl]benzoate,
4-(Cyclohexylamino)- 1 -ethyl-N-( lH-tetrazol-5 -ylmethyl)- lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-N-( {4-[(difluoromethyl)oxy]phenyl} methyl)- 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] - 1 H-pyrazolo [3 ,4- b]pyridine-5-carboxamide,
N-[(2-Chloro-6-fluorophenyl)methyl]-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-{[2-(Aminocarbonyl)phenyl]methyl}-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N- { [2-(dimethylamino)phenyl]methyl} - 1 -ethyl- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- [(4-fluorophenyl)methyl] - 1 H-pyrazolo[3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- { [3 -(1rifluoromethyl)phenyl]methyl} - 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-N-[(2,6-difluorophenyl)methyl]-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide, 4-(Cyclohexylamino)- 1 -ethyl-N-[(3 -fluorophenyl)methyl] - lH-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-{[2-(trifluoromethyl)phenyl]methyl}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-(5-Chloro-2,3-dihydro-lH-inden-2-yl)-4-(cyclohexylamino)-l-ethyl-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)-l-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N- [4-(methyloxy)phenyl] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-(cyclohexylamino)- 1 -ethyl-N-[(6-oxo- 1 ,6-dihydro-3 -pyridinyl)methyl] - 1 H-pyrazolo[3 ,4- b]pyridine-5 -carboxamide,
4-(Cyclohexylamino)- 1 -ethyl-N-(3 -pyridinylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide,
4-[( { [4-(Cyclohexylamino)- 1 -ethyl- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)methyl]benzoic acid,
3-[( { [4-(Cyclohexylamino)- 1 -ethyl-lH-pyrazolo[3,4-b]pyridin-5 - yljcarbonyl} amino)methyl]benzoic acid,
4-(Cyclohexylamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide hydrochloride,
4-(Cyclohexylamino)-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide methanesulphonate,
N-({2-[(l,l-Dimethylethyl)oxy]-3-pyridinyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate,
N-[(3-Chloro-4-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(4-Chloro-2-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-({2-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-( {2-[( 1 -methylethyl)oxy]phenyl } methyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-({3-[(l-methylethyl)oxy]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-({3-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-{[4-hydroxy-3-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(5-Acetyl-2-hydroxyphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyι-an-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-4-(tehahydro-2H-pyran-4-ylamino)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [4-(Acetylamino)phenyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[2-(3-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[2-(3-Chlorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl -4-(tetrahydro-2H-pyran-4-ylamino)-N-(2- {4-[(trifluoromethyl)oxy]phenyl} ethyl)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-{2-[3-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[2-(4-Acetylphenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, N-[2-(3,4-Dichlorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-{2-[3-(Aminosulfonyl)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- {2-[3 ,4-Bis(methyloxy)phenyl] ethyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[2-(2,3-Dichlorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-{2-[3,5-Bis(methyloxy)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{2-[3-methyl-4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[2-(2,6-Difluorophenyl)ethyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-{2-[2,6-Bis(methyloxy)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[2-(2-methylphenyl)ethyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-[(3 ,4-Dimethylphenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[4,5-Bis(methyloxy)-2,3-dihydro-lH-inden-2-yl]-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [2-(methylsulfinyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-(2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-
5 -carboxamide,
N- { [4-(Dimethylamino)phenyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[2-(4-fluorophenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-[2-(4-methylphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N- { [3 -(Aminosulfonyl)phenyl]methyl} - 1 -ethyl -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-[(4-methylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [4-fluoro-3 -(trifluoromethyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
Methyl 2-[( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)methyl]benzoate,
N-[(6-Chloro-2-pyridinyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate,
N-(2,3 -Dihydro- 1 H-inden- 1 -yl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3,4- b]pjτidine-5 -carboxamide,
N-({2-[Acetyl(methyl)amino]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(lS)-2,3-Dihydro-lH-mden-l-yl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[( lR)-2,3 -Dihydro- lH-inden-1 -yl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-({3-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-(phenylmethyl)-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[2-(Dimethylamino)ethyl]-l-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-Butyl- 1 -ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N,l-Diethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-(l-phenyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5-carboxamide, l-ethyl-N-{l-[(ethylamino)carbonyl]-4-piperidinyl}-4-(te1rahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
Formic acid - l-ethyl-N-[l-methyl-2-(4-methyl-l-piperazinyl)ethyl]-4-(tetrahydro-2H-pyran-
4-ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide (1:1),
Methyl [4-( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo [3 ,4-b]pyridin-5 - yl] carbonyl} amino)- 1 -piperidinyl] acetate,
1 -Ethyl-N- { [4-(4-morpholinylmethyl)phenyl]methyl } -4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate, l-Ethyl-N-({3-[(4-methyl-l-piperazinyl)methyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate,
N- { [5 -(Aminocarbonyl)-3 -pyridinyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate, l-Ethyl-N-{[4-(l-methylethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [3 -(Cyclopentyloxy)-4-(methyloxy)phenyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-( {4-[(4-methyl- 1 -piperazinyl)methyl]phenyl } methyl)-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide trifluoroacetate,
N-[(2,4-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2,4-Difluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2-Chloro-4-fluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-{2-[2-Chloro-3-(methyloxy)phenyl]ethyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
Methyl 3-[({[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4-b]pyridin-5- yl] carbonyl } amino)methyl]benzoate, l-Ethyl-N-{[3-(l-pyrrolidinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate, l-Ethyl-N-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3 ,4-b]pyridine-5 -carboxamide,
N-{[2,5-Bis(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [2,6-Bis(methyloxy)phenyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-[(2-fluorophenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-[(3,5-Difluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(4-Chloropiιenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-Cyclohexyl- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxamide, 1 -Ethyl-N- {2-[4-(methylsulfonyl)phenyl]ethyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-{[2-fluoro-3-(xrifluoromethyl)phenyl]methyl}-4-(texrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-({4-[(Cyclopropylamino)carbonyl]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4- ylamino)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { [4-(4-methyl-l -piperazinyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [4-(l -pyrrolidinylmethyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[6-(methyloxy)-l-oxo-2,3-dihydro-lH-inden-2-yl]-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2,5-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N- [(3 ,5-Diethylphenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-[(2,3-Difluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{[2-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[(3-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-{[3,5-Bis(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[2-(4-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[(3 ,5 -Dichlorophenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-{[2,4-Bis(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [2-(methyloxy)phenyl]methyl } -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2,4-Dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-({2-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{2-[4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(2-Chlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-[(2-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-(l,3-Benzodioxol-5-ylmethyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[3 -(methyloxy)phenyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-(Cyclohexylmethyl)- 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-(l,2,3,4-tetrahydro-l-naphthalenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
Methyl 4-[( { [ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)methyl]benzoate,
N-[(3,4-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, N-{[4-(Aminocarbonyl)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2,6-Difluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [3 -(Aminocarbonyl)phenyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-[(4-hydroxyphenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [6-(methyloxy)-3 -pyridinyl]methyl } -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N- { [3 -(trifluoromethyl)phenyl]methyl} - 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[4-(2-Amino-2-oxoethyl)phenyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-N-{4-[2-(methylamino)-2-oxoethyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N-[(3 -fluorophenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N- { [4-(Aminosulfonyl)phenyl]methyl } - 1 -ethyl -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [2-(Aminocarbonyl)phenyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-({3-[(Dimethylamino)methyl]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-{[3-Chloro-4-(methyloxy)phenyl]methyl}-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-(l-Acetyl-4-piperidinyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N- { [2-(trifluoromethyl)phenyl]methyl } - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-(5-Chloro-2,3-dihydro-lH-inden-2-yl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-({3-[(Acetylamino)methyl]phenyl}methyl)-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- [(4-fluorophenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- [(2-ethylphenyl)methyl] -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[(2,3,4-trifluorophenyl)methyl]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(4-Chloro-2-fluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, N-[(4-Bromo-2-fluorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(3 ,5 -Dimethylphenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2,3-Dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]ρyridine-5 -carboxamide,
N-[(2,3-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(4-Cyanophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[(4-Bromophenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide, l-Ethyl-N-{[5-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[(4-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N- { [4-( 1 , 1 -Dimethylethyl)phenyl]methyl} - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(3 -Cyanophenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4- b]pyridine-5 -carboxamide,
N-[(2,6-Dichlorophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(5-Chloro-2-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(3,5-Dibromophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[(4-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [3 -fluoro-4-(1rifluoromethyl)phenyl]methyl } -4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-[(2-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
N-[(2-Bromophenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [4-(hydroxymethyl)phenyl]methyl } -4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-N- { [3 -(hydroxymethyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { [3 -(hydroxymethyl)-2-methylphenyl]methyl} -4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- { [2,3 -Dichloro-6-(hydroxymethyl)phenyl]methyl } - 1 -ethyl-4-(tetrahydro-2H-pyran-4- ylamino)- 1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N-[(2,4-Dichloro-6-methylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { [4-(2-methylpropyl)phenyl]methyl} -4-(tetrahydro-2H-pyran-4-ylamino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(2,5-dimethylphenyl)methyl]-l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[(2,4,5-trifluorophenyl)methyl]-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-Ethyl-N-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
N- [(2-Chloro-6-methylphenyl)methyl] - 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide, 4-[( { [ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)methyl]benzoic acid sodium salt,
3 -[( { [ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl]carbonyl}amino)methyl]benzoic acid,
Ethyl 1 -ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino} - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxylate,
1 -Ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino } -N- { [4-(methyloxy)phenyl]methyl } - 1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N- { [4-(Dimethylamino)phenyl]methyl} - 1 -ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino} -
1 H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-4-( {4-[(ethyloxy)imino]cyclohexyl} amino)-N- { [4-(methyloxy)phenyl]methyl} - 1H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
1 -Ethyl-4-( {4-[(methyloxy)imino] cyclohexyl } amino)-N- { [4-(methyloxy)phenyl]methyl } - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(4-{[(l,l-Dimethylethyl)oxy]imino}cyclohexyl)amino]-l-ethyl-N-{[4-
(methyloxy)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
1 -Ethyl-N- { [4-(methyloxy)phenyl]methyl } -4- [(7-oxohexahydro- 1 H-azepin-4-yl)amino] - 1 H- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
Ethyl 1 -ethyl-4-[(7-oxohexahydro- 1 H-azepin-4-yl)amino] - 1 H-pyrazolo [3 ,4-b]pyridine-5 - carboxylate,
4-{[cis-4-(Butylamino)cyclohexyl]amino}-N-(2,3-dihydro-lH-inden-2-yl)-l-ethyl-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide,
4-[(trans-4-Aminocyclohexyl)amino] - 1 -ethyl-N-(phenylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-
5 -carboxamide,
4-[(trans-2-Aminocyclohexyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-
5 -carboxamide,
4-[(cis-2-Aminocyclohexyl)amino] - 1 -ethyl-N-(phenylmethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carboxamide,
4-[(3-Aminocyclohexyl)amino]-l-ethyl-N-(phenylmethyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,
Ethyl l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-lH-ρyrazolo[3,4- b]pyridine-5-carboxylate,
Nl-Diethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-lH-pyrazolo[3,4- b]pyridine-5 -carboxamide, l-Ethyl-N-(4-fluorophenyl)-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-Ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-(l,3-thiazol-2-ylmethyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-ethyl-N-[(4-fluorophenyl)methyl]-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-lH- pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4-
(methylsulfonyl)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N- {[3,4-bis(methyloxy)phenyl]methyl}-l -ethyl-4- {[(lSR,3RS)-3- hydroxycyclohexyl]amino}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-(2-pyridinylmethyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-[(l-methyl-lH-pyrazol-4- yl)methyl]-lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(3,4-dimethylphenyl)methyl]-l-ethyl-4-{[(lSR,3RS)-3- hydroxycyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, l-ethyl-4-{[(lSR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4-
(methyloxy)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, N-[(2,4-dimethylphenyl)methyl]-l-ethyl-4-{ [(lSR,3RS)-3- hydroxycyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide,
N-[(2,3-Dichlorophenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(3-Chloro-4-methylphenyl)methyl]-l-ethyl-4-[(4-oxocyclohexyl)amino]-lH- pyrazolo[3,4-b]pyridine-5-carboxamide,
N- [(4-Chloro-2-methylphenyl)methyl] - 1 -ethyl-4- [(4-oxocyclohexyl)amino] - 1H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N- [(2,4-Dimethylphenyl)methyl]- 1 -ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide,
N- [(3 ,4-Dimethylphenyl)methyl] - 1 -ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino } - lH-pyrazolo[3,4-b]pyridine-5-carboxamide,
N- [(2,3-Dichlorophenyl)methyl] - 1 -ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyiidine-5-carboxamide,
N-[(3-Chloro-4-methylphenyl)methyl]-l-ethyl-4-{[4-
(hydroxyimino)cyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide,
N- [(4-Chloro-2-methylphenyl)methyl] - 1 -ethyl-4- { [4-
(hydroxyimino)cyclohexyl] amino } - lH-pyrazolo [3 ,4-b]pyridine-5-carboxamide,
N-({4-[(Difluoromethyl)oxy]phenyl } methyl)- 1 -ethyl-4- { [4-
(hydroxyinuno)cyclohexyl]anuno}-lH-pyrazolo[3,4-b]pyridine-5-c-uboxamide, or
1 -Ethyl-4- { [4-(hydroxyimino)cyclohexyl] amino } -N- { [4-
(trifluoromethyl)phenyl]methyl}-lH-pyrazolo[3,4-b]pyridine-5-carboxarnide; or a salt thereof.
50. A compound or salt as claimed in claim 1, which is a compound of Example 260, 261, 263, 266, 431, 493, 494, 518, 528, 584, 626, 643, 653, 679, 680, 681, 682, 683, 684, 685 or 686, as defined by the structures and/or names described herein, or a salt thereof.
51. A compound or salt as claimed in claim 1 , which is a compound of Example 21, 22, 83, 100, 109, 167, 172, 178 or 600, as defined by the structures and/or names described herein, or a salt thereof.
52. A compound or salt as claimed any preceding claim, which is the compound or a pharmaceutically acceptable salt thereof.
53. A compound or salt as claimed in any preceding claim, which is in a particle- size-reduced form.
54. A compound or salt as claimed in claim 53, wherein the particle size (D50 value) of the size-reduced compound or salt is about 0.5 to about 10 microns.
55. A compound or salt as claimed in any preceding claim, for use as an active therapeutic substance in a mammal such as a human.
56. A pharmaceutical composition comprising a compound of fonnula (I) or (IA) or (LB), as defined in any of claims 1 to 54, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
57. A pharmaceutical composition as claimed in claim 56 which is suitable for and/or adapted for inhaled administration.
58. A pharmaceutical composition as claimed in claim 57, in which the compound or salt is in a particle-size-reduced form.
59. A pharmaceutical composition as claimed in claim 58, wherein the particle size (D50 value) of the size-reduced compound or salt is about 0.5 to about 10 microns.
60. A composition as claimed in claim 56, for the treatment and/or prophylaxis of an inflammatory and/or allergic disease or cognitive impairment in a mammal such as a human.
61. The use of a compound of formula (1) or (IA) or (LB), as defined in any of claims 1 to 54, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of an inflammatory and/or allergic disease or cognitive impairment in a mammal such as a human.
62. A method of treatment and/or prophylaxis of an inflammatory and/or allergic disease or cognitive impairment in a mammal such as a human in need thereof, which method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), as defined in any of claims 1 to 49, or a pharmaceutically acceptable salt thereof.
63. A composition, the use or a method as claimed in claim 60, 61 or 62, wherein the composition or medicament or method is for the treatment and/or prophylaxis of chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis in a mammal such as a human.
64. A composition, the use or a method as claimed in claim 60, 61 or 62, wherein the composition or medicament or method is for the treatment and/or prophylaxis of chronic obstructive pulmonary disease (COPD) in a mammal such as a human.
65. A composition, the use or a method as claimed in claim 60, 61 or 62, wherein the composition or medicament or method is for the treatment and/or prophylaxis of asthma in a mammal such as a human.
66. A composition, the use or a method as claimed in any of claims 60 to 65, wherein the composition or medicament is for oral administration and is a pharmaceutical composition as defined in claim 56, or wherein the method comprises oral administration to the mammal of a pharmaceutical composition suitable for oral administration and as defined in claim 56.
67. A composition, the use or a method as claimed in claim 64 or 65, wherein the composition or medicament is for inhaled administration and is a pharmaceutical composition as defined in claim 57, 58 or 59, or wherein the method comprises inhaled administration to the mammal of a pharmaceutical composition as defined in claim 57, 58 or 59.
68. A combination comprising a compound of formula (I), as defined in any of claims 1 to 54, or a pharmaceutically acceptable salt thereof , together with a β2-adrenoreceptor agonist, an anti-histamine, an anti-allergic, or an anti-inflammatory agent.
69. A combination as claimed in claim 68, comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof, together with a β -adrenoreceptor agonist.
70. A combination comprising a compound of formula (I), as defined in any of claims 1 to 54, or a pharmaceutically acceptable salt thereof, together with a muscarinic (M) receptor antagonist.
71. A combination as claimed in claim 70, wherein the muscarinic (M) receptor antagonist is a M3 receptor antagonist.
72. A pharmaceutical composition comprising a combination as defined in any of claims 68 to 71, together with one or more pharmaceutically acceptable carriers and/or excipients, the composition being a separate or combined pharmaceutical composition for administration of the individual compounds of the combination either sequentially or simultaneously.
73. A pharmaceutical composition as claimed in claim 72 for inhaled adminitration, and wherein the combination is as defined in claim 69, 70 or 71.
74. A combination or pharmaceutical composition as claimed in any of claims 68 to 73, for the treatment and/or prophylaxis of chronic obstructive pulmonary disease (COPD) in a mammal such as a human.
PCT/EP2003/011814 2002-09-16 2003-09-12 Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors WO2004024728A2 (en)

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EP03778283A EP1539753B1 (en) 2002-09-16 2003-09-12 Pyrazolo(3,4-b)pyridine compounds, and their use as phosphodiesterase inhibitors
CA002497550A CA2497550A1 (en) 2002-09-16 2003-09-12 Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors
AU2003285300A AU2003285300B2 (en) 2002-09-16 2003-09-12 Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors
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AT03778283T ATE442367T1 (en) 2002-09-16 2003-09-12 PYRAZOLO(3,4-B)PYRIDINE COMPOUNDS AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS
DK03778283T DK1539753T3 (en) 2002-09-16 2003-09-12 Pyrazolo (3,4B9 pyridine compounds and their use as phosphodiesterase inhibitors)
ES03778283T ES2331119T3 (en) 2002-09-16 2003-09-12 PIRAZOLO COMPOUNDS (3,4-B) PIRIDINE, AND ITS USE AS PHOSPHODESTERASE INHIBITORS.
MXPA05002887A MXPA05002887A (en) 2002-09-16 2003-09-12 Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors.
DE60329193T DE60329193D1 (en) 2002-09-16 2003-09-12 PYRAZOLO (3,4-B) PYRIDINE COMPOUNDS AND THEIR USE AS PHOSPHODIESTERASINHIBITORS
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BR0314392-9A BR0314392A (en) 2002-09-16 2003-09-12 Compound or salt thereof, pharmaceutical composition, use of a compound, method of treatment and / or prophylaxis of an inflammatory and / or allergic disease or cognitive impairment in a mammal, and, combination
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US10/527,866 US20060089375A1 (en) 2002-09-16 2003-09-12 Pyrazolo[3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors
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IL166898A IL166898A (en) 2002-09-16 2005-02-15 Pyrazolo[3,4-b]pyridine compounds and their use as phosphodiesterase inhibitors
NO20050841A NO20050841L (en) 2002-09-16 2005-02-16 Pyrazolo [3,4-B] pyridine compounds and their use as phosphodiesterase inhibitors
IS7709A IS7709A (en) 2002-09-16 2005-02-24 Pyrazolo [3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors
US12/013,529 US20080175914A1 (en) 2002-09-16 2008-01-14 Pyrazolo[3,4-b]Pyridine Compounds, and their Use as Phosphodiesterase Inhibitors
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