Indian Patents
Title of Invention

PYRAZOLO [3,4-b] PYRIDINE COMPOUNDS, AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS .
Abstract The invention relates to a compound of formula (I) or a salt thereof: Formula (I) wherein: Rl is C1-4alkyl, C1-3fluo- roalkyl or -(CH2)2OH; R2 is a hydrogen atom (H), methyl or C1fluoroalkyl; R3a is a hydrogen atom (H) or C1-3alkyl; R3 is optionally substituted branched C3-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted mono-unsaturated-C5-7cycloalkenyl, op tionally substituted phenyl, or an optionally substituted heterocyclic group of sub-formula (aa), or (bb) or (cc) in which nl and n2 independently are 1 or 2; and Y is O, S, SO2, or NR4; and wherein Het is of sub-formula (i), or (ii), or (iii), or (iv) or (v). The com- pounds 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.
Full Text 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 (PDE) 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-
mernbered 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, CH 553 799 and T.Denzel, Archiv der Pharmazie, 1974, 307(3), 177-186
disclose 4,5-disubstituted 1H-pyrazolo[3,4-b]pyridines unsubstituted at the 1-position.
US 3,833,598 and GB 1,417,489 (E.R.Squibb & Sons) disclose 4-amino derivatives of
pyrazolo[3,4-b]pyridine-6-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,
R6,R7-phenyl, etc.; or NR3R4 can be a 5-6-membered heterocyclic group in which an
additional nitrogen is present, namely optionally substituted pyrrolidino, piperidino,
pyrazolyl, dihydropyridazinyl or piperazinyl. At the 5-position of the pyrazolo[3,4-
b]pyridine is group R5 which is hydrogen, lower alkyl, phenyl, phenyl-lower-alkyl or

halogen; R5 is preferably hydrogen, methyl or chlorine. The compounds are mentioned as
being central nervous system depressants useful as tranquilizers or ataractic agents for the
relief of anxiety and tension states. The compounds are also mentioned as increasing the
intracellular concentration of adenosine-3',5'-cyclic monophosphate and for alleviating
the symptoms of asthma. The compounds are also mentioned as having anti-
inflammatory properties and as being useful as anti-inflammatory agents, for example, to
reduce local inflammatory conditions such as those of an edematous nature or resulting
from proliferation of connective tissue in various mammalian species such as rats and
dogs.
US 4,115,394 and GB 1,511,006 (E.R.Squibb & Sons) disclose 4-amino derivatives of 6-
phenyl-pyrazolo[3,4-b]pyridines. The 4-amino group NR3R4 is an acyclic amino group
wherein R3 and R4 may each be hydrogen, lower alkyl, phenyl, phenyl-lower-alkyl or
substituted phenyl. At the 5-position of the pyrazolo[3,4-b]pyridine is group R5 which is
hydrogen, lower alkyl, phenyl or phenyl-lower-alkyl; R5 is preferably hydrogen. The
compounds are mentioned as having anti-inflammatory properties and as being useful as
anti-inflammatory agents, for example, to reduce local inflammatory conditions such as
those of an edematous nature or resulting from proliferation of connective tissue in
various mammalian species such as rats and dogs. The compounds are also mentioned
(a) as having diuretic activity, and (b) as increasing the intracellular concentration of
adenosme-3',5'-cyclic monophosphate and for alleviating the symptoms of asthma.
Japanese laid-open patent application JP-2002-20386-A (Ono Yakuhin Kogyo KK)
published on 23 January 2002 discloses pyrazoiopyridine compounds of the following
formula:
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 C1-8 alkyl group substituted by a hydroxy group or a C1-8
alkoxy group, 7) a phenyl group, 8) a group -C(O)R8,9) a group -SO2NR9R10 10) a
group -KR11 SO2Rl2 11) a group -NR13C(O)RM or 12) a group -CH=NR15 R6 and R7
denote,) a hydrogen atom, ii) a C1-8 alkyl group, iii) a C1-8 alkyl group substituted by a
C1-8 alkoxy group, iv) a trihalomethyl group, y) a C3-7 cycloalkyl group, vi) a C1-8
alkyl group substituted by a phenyl group or vii) a 3-15 membered mono-, di- or tricyclic
hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms
R denotes 1) a hydrogen atom or 2) a C1-8 alkoxy group. R3 denotes 1) a hydrogen

atom or 2) a C1-8 alkyl group. R4 denotes 1) a hydrogen atom, 2) a C1-8 alkyl group, 3)
a C3-7 cycloalkyl group, 4) a C1-8 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 C1-8 alkyl group, 3) a C3-
7 cycloalkyl group, 4) a C1-8 alkyl group substituted by a C3-7 cycloalkyl group or 5) a
phenyl group which maybe substituted by 1-3 substituents. In group R3, a hydrogen
atom is preferred. In group R4, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are
preferred. The compounds of JP-2002-203 86-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 A1 (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 1-ethyl-4-n-butylamiao-1H-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 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives, including
ethyl 4-cyclopentylammo-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, and their
affinities and antagonist activities at A1- and A2A-adenosine receptors, and the latter
paper discloses their affinities at various binding sites of the GABAA-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 the
Web on 09/24/2002), pp. 4875-4887, disclose a series of 4-amino-1-(2-chloro-2-
phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters as A1-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-
hjpyridines and 1H-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)NH2
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.
S.S.Chakravorti et al., Indian J. Chem., 1978,16B(2), 161-3 discloses the compounds
4-hydroxy-l,3-diphenyl-5-(3',4'-dihydroisoqumo1-1'-yl)-pyrazolo[3,4-b]pyridineand
l,3-diphenyl-4-hydroxy-5-(3'-methyl-3',4'-dihydroisoquino1-l'-yl)-

pyrazolo[3,4-b]pyridine. These two compounds were tested for antifilarial activity but
were found to have no significant microfilaricidal activity.
G. Sabitha et al., Synthetic Commun., 1999,29(4), 655-665 discloses a synthetic route to
5-substituted-6-ammo-1-phenyl-3-(me1hyl or phenyl)-pvrazolo[3,4-b]pyridines wherein
the 5-substituent of the pyrazolo[3,4-b]pyridine is benzimidazo1-2-yl,
5-chloro-benzoxazo1-2-yl, or benzothiazo1-2-yl. Though declared to be "biologically
interesting molecules", there is however no disclosure that these compounds had been
tested in any pharmacological tests and there is no disclosure of any general or specific
biological activity of these compounds.
On 8th April 2003, Chemical Abstracts (CAS) registered on their database a compound
with the CAS Registry Number 502143-17-1, with the chemical name "1H-Pyrazolo[3,4-
b]pyridin-4-amine, N-butyl-5-(4,5-dihydro-1H-imidazol-2- yl)-1-ethyl-" and bearing the
laboratory code NSC 235755. As at 5th November 2003, the CAS entry for this
compound had no associated literature references and therefore it appears that no
chemical synthesis and no uses of the compound have been disclosed as at 5th November
2003. The structure of the compound from the CAS database is as follows:

It is desirable to find new compounds which bind to, and preferably inhibit,
phosphodiesterase type TV (PDE4).
The present invention provides a compound of formula (I) or a salt thereof (in particular,
apharmaceutically acceptable salt thereof):

wherein:
R1 is C1-4alkyl, C1-3fluoroalkyl or -(CH2)2OH;
R2 is a hydrogen atom (H), methyl or C1fluoroalkyl;

R3 is optionally substituted branched C3-6alkyl, optionally substituted C3-8cycloalkyl,
optionally substituted mono-unsaturated-C5-7cycloalkenyl, optionally substituted phenyl,
or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc):
in which n1 and n2 independently are 1 or 2; and Y is O, S, SO2, or NR4; where R4 is a
hydrogen atom (H), C1-2alkyl, C1-2fluoroalkyl, CH2C(O)NH2, C(O)NH2,
C(O)-C1-2alkyl, or C(O)-C1fluoroalkyl;
wherein in R3 the optionally substituted branched Cs.galkyl is optionally substituted with
one or two substituents being oxo (=O), OH, C1-2alkoxy or C1-2fluoroalkoxy; and
wherein any such substituent is not substituted at the R3 carbon atom attached (bonded)
to the -NH- group of formula (I);
wherein in R3 the phenyl is optionally substituted with one substituent being fluoro,
chloro, C1-2alkyl, C1-2fluoroalkyl, C1-2alkoxy, C1-2fluoroalkoxy or cyano, or with two
or three fluoro substituents;
wherein in R3 the C3-8cycloalkyl 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; C1-2alkoxy; C1-2fluoroalkoxy; NHR21 wherein R21 is a
hydrogen atom (H) or C1-4 straight-chain alkyi; C1-2alkyl; C1-2fluroalkyl (e.g.
C1fluoroalkyl such as -CH2F or -CHF2); -CH2OH; -CH2CH2OH; -CH2NHR22 wherein
R22 is H or C1-2alkyl; -C(O)OR23 wherein R23 is H or C1-2alkyl; -C(O)NHR24
wherein R24 is H or C1-2alkyl; -C(O)R25 wherein R25 is C1-2alkyl; fluoro;
hydroxyimino (=N-OH); or (C1-4alkoxy)imino (=N-OR26 where R26 is C1-4alkyl); and
wherein any OH, alkoxy, fluoroalkoxy or NHR21 substituent is not substituted at the R3
ring carbon attached (bonded) to the -NH- group of formula (I) and is not substituted at
either R3 ring carbon bonded to the Y group of the 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 independently
being fluoro or C1-2alkyl 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;

and R3a is a hydrogen atom (H) or straight-chain C1-3alkyl;
provided that when R3a is C1-3alkyl then R3 is tetrahydro-2H-pyran-4-yl, cyclohexyl
(i.e. unsubstituted), 3-hydroxy-cyclohexyl, 4-oxo-cyclohexyl or
4-(hydroxyimino)cyclohexyl;
and wherein Het is of sub-formula (i), (ii), (iii), (iv) or (v):

wherein:
W1, W2, W4 and W5 is N; and W3 is NR.W ;
X1, X3 and X4 is N or CRX; X2 is O, S or NRX ; and X5 is CRX1RX2 or CRX3RX4;
Yl, Y2 and Y3 is CRY or N; Y4 is O, S or NRY ; and Y5 is CRY1RY2;
Z1 and Z5 is O, S or NRZ; and Z2, Z3 and Z4 is N or CRZ;
wherein:
RW is a hydrogen atom (H) or C1-2alkyl;
Rx, RX2, RY and RY2 independently are:
a hydrogen atom (H);
C1-8alkyl;
C3-6cycloalkyl optionally substituted by one or two C1-2alkyl groups and/or by one
oxo (=O) group;
-(CH2)n2a-C3-6cycloalkyl optionally substituted, in the -(CH2)n2a- moiety or in
the C3-6cycloalkyl moiety, by a C1-2alkyl group, or optionally substituted in
the C3-6cycloalkyl moiety by a -CH2C(O)NHC1-2alkyl group, wherein n2a is
1, 2 or 3;

-(CH2)n3-S(O)2-R5, -CH(C1-2a]kyl)-S(O)2-R5, -CMe2-S(O)2-R5, or
C~3-5cycloalkyl substituted at the connecting carbon atom by -S(O)2-R5,
wherein n3 is 1 or 2;
and R5 is C1-4alkyl (e.g. C1-3alkyl), -NR15R16, phenyl, carbon-linked-
pyridinyl or benzyl (wherein the phenyl and benzyl are independently
optionally substituted on the aromatic ring by one or two substituents
independently being fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy,
C1fluoroalkoxy or OH, and wherein the pyridinyl is optionally substituted by
one methyl, methoxy or OH (including any tautomer thereof));
wherein R15 is H, C1-4alkyl (e.g. C1-2alkyl), phenyl, benzyl (wherein the
phenyl and benzyl are independently optionally substituted on the aromatic
ring by one or two substituents independently being fluoro, chloro, C1-2alkyl,
C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy), CH(Me)Ph, or carbon-linked-
pyridinyl optionally substituted by one methyl, methoxy or OH (including any
tautomer thereof);
and R16 is H or C1-2alkyl;
or wherein R15 and R16 together are -(CH2)n3a-X3a-(CH2)n3b- in which
n3a and n3b independently are 2 or 3andX3a is a bond, -CH2-, O, orNR8a
wherein R8a is H or C1-2alkyl, acetyl, -S(O)2Me or phenyl, and wherein the
ring formed by NR15R16 is optionally substituted on a ring carbon by one or
two substituents independently being methyl or oxo (=O);
-(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7, -CMe2-NR6R7 or C~3-5cycloalkyl
substituted at the connecting carbon atom by -NR6R7, wherein n4 is 0,1, 2 or
3;
and R6 and R7 independently are H, C1-6alkyl (e.g. C1-4alkyl),
C3-6cycloalkyl, -CH2-C3-6cycloalkyl, -C(O)R17, -S(O)2R18, phenyl, benzyl
(wherein the phenyl and benzyl are independently optionally substituted on
the aromatic ring by one or two substituents independently being fluoro,
chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy), or carbon-
linked-pyridinyl optionally substituted by one methyl, methoxy or OH
(including any tautomer thereof);
and wherein R17 and Rl8 independently are C1-6alkyl (e.g. C1-4alkyl or
C1-2alkyl or isopropyl or n-propyl), C3-6cycloalkyl, optionally substituted 5-
membered heteroaryl being furyl (furanyl, e.g. 2-furyl) or 1,3-oxazolyl or
isoxazolyl or oxadiazolyl or thienyl (e.g. 2- or 3- thienyl) or 1,3-thiazolyl or
isothiazolyl or pyrrolyl or imidazolyl or pyrazolyl (all independently
optionally substituted by one oxo and/or one or two methyl), or phenyl or
benzyl (wherein the phenyl and benzyl are independently optionally
substituted on the aromatic ring by one or two substituents independently

being fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy
or OH), or carbon-linked-pyridinyl optionally substituted, by one methyl,
methoxy or OH (including any tautomer thereof);
or R6 and R7 together are -(CH2)n5-X5-(CH2)n6- in which n5 and n6
independently are 2 or 3 and X5 is a bond, -CH2-, O, or NR8 wherein R8 is H,
C1-2alkyl, acetyl, -S(O)2Me or phenyl, and wherein the ring formed by
NR^R7 is optionally substituted on a ring carbon by one or two substituents
independently being methyl or oxo (=O);
-(CH2)n7-0-R9; wherein n7 is 0,1,2 or 3 and R9 is H, C1-6alkyl, C3-6cycloalkyl,
-CH2-C3-6cycloalkyl, -C(O)R17, phenyl, or benzyl (wherein the phenyl and
benzyl are independently optionally substituted on the aromatic ring by one or
two of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or
C1fluoroalkoxy); wherein n7 is 0 only when the -(CH2)n7-O-R9 is bonded to
a carbon atom in the Het ring; and wherein n7 is not 0 when Het is of sub-
formula (v) (i.e. n7 is not 0 for RX2 and for RY2);
-(CH2)n11-C(O)-NR10R11, -CHC1-2alkyl)-C(O)NR10R11,
-CMe2-C(O)-NR10R11, or C~3-5cycloalkyl substituted at the connecting
carbon atom by -C(O)-NR10R11, wherein n11 is 0,1 or 2;
and wherein R10 and R11 independently are: H; C1-6alkyl;
C1fluoroalkyl; C2-4alkyl substituted by one OH or -OC1-2alkyl other than
at the connection point; C3-6cycloalkyl optionally substituted by one or two
methyl groups; -CH2-C3-6cycloalkyl optionally substituted by one methyl,
NH2 or NHMe group; -(CH2)n17-Het2; carbon-linked-pyridinyl optionally
substituted by one methyl, methoxy or OH (including any tautomer thereof);
phenyl; benzyl; or -CH(C1-2alkyl)Ph [wherein the phenyl, benzyl, and
-CH(C1-2alkyl)Ph are independently optionally substituted on the aromatic
ring by one or two substituents independently being: fluoro, chloro,
C1-2alkyl, C1fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy, OH, -NRl0aRl0b
(wherein R10a is H or C1-2alkyl and Rl0b is H, C1-2alkyl, -C(O)-C1-2alkyl
or -S(O)2-C1-2alkyl), -C(O)-NR10cR10d (wherein R10c andR10d
independently are H or C1-2alkyl), or -S(O)2-R10e (wherein Rl0e is
C1-2alkyl, NH2, NHMe or NMe2)],
wherein n17 is 0,1 or 2 and wherein Het2 is a 4-, 5- or 6- membered
saturated heterocyclic ring containing one O or S ring atom or one NR27 ring
group wherein R27 is H, C1-2alkyl, -C(O)Me, or -S(O)2Me, wherein the Het2
ring is optionally substituted on a ring carbon by one or two substituents
independently being methyl or oxo (=O);

and wherein when n17 is 2 then the Het2 ring can optionally contain one
additional ring N atom at the Het2 ring position bonded to the -(CH2)n17-
moiety; provided that, when Het2 contains one O or S or NR27 ring
atom/group and one additional ring N atom, then the O/S/NR27 ring
atom/group and the one additional ring N atom are not directly bonded to each
other, and are separated by more than one carbon atom;
or R10 and R11 together are -(CH2)n8-X6-(CH2)n9- in which n8 and n9
independently are 2 or 3 and X6 is a bond, -CH2-, O, or NR12 wherein R12 is
H, C1-2alkyl, acetyl, -S(O)2Me or phenyl, and wherein the ring formed by
NR10R11 is optionally substituted on a ring carbon by one or two substitaents
independently being methyl or oxo (=O);
-(CH2)n12-C(O)-OR13 wherein n12 is 0,1 or 2; and wherein R13 is H, C1-6alkyl,
C3-6cycloalkyl, -CH2-C3-6cycloalkyl, phenyl, or benzyl (wherein the phenyl
and benzyl are independently optionally substituted on the aromatic ring by
one or two of (independently) fluoro, chloro, C1-2alkyl, C1fluoroalkyl,
C1-2alkoxy or C1fluoroalkoxy);
-(CH2)n13-C(O)-R13a wherein n13 is 0,1 or 2; and wherein R13a is a hydrogen
atom (H), C1-6alkyl, C1fluoroalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl,
benzyl, or phenyl; wherein the phenyl and benzyl are independently optionally
substituted on the aromatic ring by one or two of (independently) fluoro,
chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
-(CH2)n14-Het1,-CH(C1-2alkyl)-Het1, -CMe2-Het1, or C~3-5cycloalkyl
substituted at the connecting carbon atom by Het1, wherein n14 is 0,1 or 2
and wherein Het1 is a 4-, 5-, 6- or 7-membered saturated heterocyclic ring;
wherein said heterocyclic ring Het1 contains one O or S ring atom and/or
oneNR14 ring group whereinR14 is H, C1-4alkyl, C3-6cycloalkyl, benzyl,
phenyl, -C(O)Rl9, or -S(O)2R19;
wherein R19, independent of any other R19, is C1-6alkyl (e.g. C1-4alkyl
or C1-3alkyl), C3-6cycloalkyl, thienyl (e.g. 2-thienyl), furyl (furanyl, e.g.
furan-2-yl), or phenyl or benzyl; wherein the phenyl and benzyl are
independently optionally substituted by one or two of (independently) fluoro,
methyl or methoxy;
and wherein said heterocyclic ring Het1 is optionally substituted (at a
position or positions other than any NR14 position) by one or two oxo (=O)
and/or one C1-4alkyl substituents;
provided that, when the heterocyclic ring Het1 contains one O or S ring
atom and one NR14 ring group then: (a) the O/S ring atom and the NR14 ring
group are not directly bonded to each other, and (b) the O/S ring atom and the

NR14 ring group are separated by more than one carbon atom unless Het1
contains an -NR14-C(O)-O- or -NR14-C(O)-S- moiety as part of the ring; or
-(CH2)n10-Ar, -CH(C1-2alkyl)-Ar, -CMe2-Ar, or C~3-5cycloalkyl substituted at the
connecting carbon atom by Ar, wherein n10 is 0,1 or 2 and
(i) Ar is phenyl optionally substituted by one or two substituents
independently being fluoro, chloro, bromo, C1-2alkyl, C1-2fluoroalkyl,
C1-2alkoxy, C1-2fluoroalkoxy, OH, -NR11aR11b (wherein R11a is H or
C1-2alkyl and R11b is H, C1-2alkyl, -C(O)-C1-2alkyl or -S(O)2-C1-2alkyl),
cyano, -C(O)-NR11CR11d (wherein R11c and R11d independently are H or
C1-2alkyl), -C(O)-OR11e wherein R11e is H or C1-2alkyl, or -S(O)2-R1lf
(wherein R11f is C1-2alkyl, NH2, NHMe or NMe2); or the phenyl Ar is
optionally substituted at two adjacent Ar ring atoms by the two ends of a chain
which is: -(CH2)4-, -(CH2)3-, or -CH=CH-CH=CH-; or
(ii) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic
ring containing 1,2, 3 or 4 heteroatoms (e.g. 1,2 or 3 heteroatoms) selected
from O, N or S; and wherein when the heterocyclic aromatic ring Ar contains
2, 3 or 4 heteroatoms (e.g. 2 or 3 heteroatoms), one is selected from O, N and
S and the remaining heteroatom(s) are N; and wherein the heterocyclic
aromatic ring Ar is optionally substituted by one or two groups independently
being C1-4alkyl (e.g. C1-2alkyl) or OH (including any keto tautomer of an
OH-substituted aromatic ring), or the heterocyclic aromatic ring Ar is
optionally substituted at two adjacent Ar ring atoms by the two ends of a chain
which is: -(CH2)4-, -(CH2)3-, or -CH=CH-CH=CH-;
RX1 and RY1 independently are a hydrogen atom (H), C1-2alkyl or C1fluoroalkyl;
RX3 and RX4 together are -(CH2)n15-X7-(CH2)n16- wherein n15 and n16
independently are 1 or 2 and X7 is a bond, -CH2-, O, or NRX5 wherein RX5 is H,
C1-2alkyl, acetyl or -S(O)2Me; and
RZ is a hydrogen atom (H) or C1-2alkyl,
provided that:
when R3 is the heterocyclic group of sub-formula (bb), n1 is 1, and Y is NR4, then R4 is
not C1-2alkyl, C1-2fluoroalkyl or CH2C(O)NH2-
Preferably, R3a is a hydrogen atom (H) or methyl.
It is particularly preferred that R3a is a hydrogen atom (H).

In one optional embodiment of the invention, R3 is optionally substituted branched
C3-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted phenyl, or an
optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc):

in which n1 and n2 are 1 or 2; and Y is O, S, SO2, or NR4; where R4 is a hydrogen atom,
C1-2alkyl, C1-2fluoroalkyl, C(O)MH2, C(O)-C1-2alkyl, or C(O)-C1fluoroalkyl; provided
that Y is not NR4 when the heterocyclic group is of sub-formula (aa).
Alternatively or additionally, in one optional embodiment of the invention, in R3 the
branched C3-6alkyl is optionally substituted with one or two substituents being oxo (=O),
OH, C1-2alkoxy or C1-2fluoroalkoxy; and wherein any such substituent is not substituted
at the R3 carbon atom attached to the -NH- group of formula (I).
Alternatively or additionally, in one optional embodiment of the invention, in R3 the
phenyl is optionally substituted with one substituent being fluoro, chloro, C1-2alkyl, C1-
2fluoroalkyl, C1-2alkoxy, C1-2fluoroalkoxy or cyano.
Alternatively or additionally, in one optional embodiment of the invention, in R3 the C3.
8cycloalkyl or the heterocyclic group of sub-formula (aa), (bb) or (cc) is optionally
substituted with one or two substituents being oxo (=O), OH, C1-2alkoxy,
C1-2fluoroalkoxy, or C1-2alkyl; and wherein any OH, alkoxy or fluoroalkoxy substituent
is not substituted at the R3 ring carbon attached 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, in one optional embodiment of the invention, Het is of sub-
formula (i), (ii), (iii) or (iv):


wherein:
W1, W2 and W4 is N; and W3 is NRW;
Xl, X3 and X4 is N or CRX; and X2 is O, S or NRX ;
Y1, Y2 and Y3 is CRY or N; and Y4 is O, S or NRY ;
Z1 is O, S or NRZ; and Z2, Z3 and Z4 is N or CRZ;
and wherein:
RW is a hydrogen atom (H) or C1-2alkyl; and
RZ is a hydrogen atom (H) or C1-2alkyl.
Alternatively or additionally, in one optional embodiment of the invention, RX and RY
independently are:
a hydrogen atom (H);
C1-8alkyl;
C3-6cycloalkyl;
-(CH2)n3-SO2-R5 wherein n3 is 1 or 2 andR5 is C1-3alkyl or -NH-C1-2alkyl;
-(CH2)n4-NR6R7 wherein n4 is 0,1 or 2, and R6 and R7 independently are H,
C1-6alkyl e.g. C1-4alkyl, -C(O)-C1-2alkyl or -SO2-C1-2alkyl; or R6 and R7
together are -(CH2)n5-X5-(CH2)n6- in which n5 and n6 independently are 2
or 3 and X5 is a bond, -CH2-, O, or NR8 wherein R8 is H or C1-2alkyl;
-(CH2)n7-0-R9 wherein n7 is 1 or 2 and R9 is H or C1-6alkyl;
-C(O)-NR10R11 wherein R10 and R11 independently are H or C1-6alkyl; or R10
and R11 together are -(CH2)n8-X6-(CH2)n9- in which n8 and n9
independently are 2 or 3 and X6 is a bond, -CH2-, O, or NR12 wherein R12 is
H or C1-2alkyl;
-C(O)-OR13 wherein R13 is H or C1-6alkyl;
a 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing one O ring atom or
one NR14 ring group wherein R14 is H or C1-4alkyl, said heterocyclic ring
being optionally substituted (at a position or positions other than any NR14
position) by one oxo (=O) and/or one C1-4alkyl substituent; or
-(CH2)n10-Ar wherein n10 is 0,1 or 2 and
(i) Ar is phenyl optionally substituted by one or two substituents being fluoro,
chloro, C1-2alkyl, C1-2fluoroalkyl, C1-2alkoxy, C1-2fluoroalkoxy or cyano;
or
(ii) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic
ring containing 1,2 or 3 heteroatoms selected from O, N or S; and wherein
when the heterocyclic aromatic ring Ar contains 2 or 3 heteroatoms, one is
selected from O, N and S and the remaining heteroatom(s) are N; and wherein

the heterocyclic aromatic ring Ar is optionally substituted by one or two
C1-4alkyl groups.
Alternatively or additionally, in one optional embodiment of the invention, Het is of sub-
formula (i), (ii), (iii), (iv) or (v):

wherein:
W1, W2, W4 and W5 is N; and W3 is NRW ;
X1, X3 and X4 is N or CRX; X2 is O, S or NRX; and X5 is CRX1RX2;
Y1, Y2 and Y3 is CRY or N; Y4 is O, S or NRY ; and Y5 is CRY1RY2;
Z1 and Z5 is O, S or NRZ; and Z2, Z3 and Z4 is N or CRZ;
and wherein:
RW is a hydrogen atom (H) or C1-2alkyl; and
RZ is a hydrogen atom (H) or C1-2alkyl.
In one optional embodiment of the invention, RX, RX2, RY and RY2 independently are,
or RX and RY independently are:
a hydrogen atom (H);
C1-8alkyl;
C3-6cycloalkyl optionally substituted by a C1-2alkyl group;
-(CH2)n2a-C3-6cycloalkyl optionally substituted, in the -(CH2)n2a- moiety or in
the C3-6cycloalkyl moiety, by a C1-2alkyl group, wherein n2a is 1, 2 or 3;
-(CH2)n3-SO2-R5 whereinn3 is 1 or 2 and R5 is C1-2alkyl or -NH-C1-2alkyl or
phenyl;
-(CH2)n4-NR6R7 wherein n4 is 0, 1, 2 or 3, and R°" and R7 independently are H,
C1-2galkyl e.g. C1-4alkyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl,
-C(O)-Cj.2alkyl, -S02-C1-2alkyl, phenyl, or benzyl (wherein the phenyl or
benzyl are independently optionally substituted on the aromatic ring by one of
fluoro, chloro, C1-2alkyl, Cifiuoroalkyl, Cx_2alkoxy or C1fluoroalkoxy); or
R6 and R7 together are -(CH2)n5-X5-(CH2)n6- in which n$ and n6
independently are 2 or 3 and X^ is a bond, -CH2-, O, or NR8 wherein R8 is H
orC1-2alkyl;

-(CH2)n7-0-R9; wherein rP is 0,1, 2 or 3 and R9 is H or C1-2alkyl; wherein n? is
0 only when the -(CH2)n7-0-R9 is bonded to a carbon atom in the Het ring;
and wherein n7 is not 0 when Het is of sub-formula (v) (i.e. n7 is not 0 for
RX2 and for RY2);
-C(O)-NR10R11 whereinR10 andR11 independently are H, C1-6alkyl,
C3-6cycloalkyl, -CH2-C3-6cycloalkyl, phenyl, or benzyl (wherein the phenyl
or benzyl are independently optionally substituted on the aromatic ring by one
of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy);
or R10 and R11 together are -(CH2)n8-X6-(CH2)n9- in which n8 and n9
independently are 2 or 3 and X6 is a bond, -CH2-, O, or NR12 wherein R12 is
HorC1-2alkyl;
-C(O)-OR13 wherein R13 is H, C1-2alkyl, C3-6cycloalkyl, -CH2-C3gcycloalkyl,
phenyl, or benzyl (wherein the phenyl or benzyl are independently optionally
substituted on the aromatic ring by one of fluoro, chloro, C1-2alkyl,
C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy);
-C(O)-R13a wherein R13a is a hydrogen atom (H), C1-6alkyl, C1-2fluoroalkyl,
C3-8cycloalkyl, -CH2-C3-6cycloalkyl, benzyl, or phenyl; wherein the phenyl
or benzyl are independently optionally substituted on the aromatic ring by one
of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
a 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing one O ring atom or
one NR14 ring group wherein R14 is H or C1-4alkyl, said heterocyclic ring
being optionally substituted (at a position or positions other than any NR14
position) by one oxo (=O) and/or one C1-4alkyl substituent; or
-(CH2)n10-Ar wherein n10 is 0,1 or 2 and
(i) Ar is phenyl optionally substituted by one or two substituents being fluoro,
chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy or cyano;
or
(ii) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic
ring containing 1,2 or 3 heteroatoms selected from O, N or S; and wherein
when the heterocyclic aromatic ring Ar contains 2 or 3 heteroatoms, one is
selected from 0, N and S and the remaining heteroatom(s) are N; and wherein
the heterocyclic aromatic ring Ar is optionally substituted by one or two
C1-4alkyl groups; and
RXI and RYI independently are a hydrogen atom (H), C1-2alkyl or C1fluoroalkyl.
In compounds, for example in the compounds of formula (I), an "alkyl" group or
moiety may be straight-chain or branched. Alkyl groups, for example C1-8alkyl or

C1-6alkyl or C1-4alkyl or C1-3alkyl or C1-2alkyl, which maybe employed include
C1-6alkyl or C1-4alkyl or Chalkyl or C1-2alkyl 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-1-yl, or the like.
A corresponding meaning is intended for "alkoxy", "alkylene", and like terms
derived from alkyl. For example, "alkoxy" such as C1-6alkoxy or C1-4alkoxy or
C1-2alkoxy includes methoxy, ethoxy, propyloxy, and oxy derivatives of the alkyls listed
above. "Alkylsulfonyl" such as C1-4alkylsulfonyl includes methylsulfonyl
(methanesulfonyl), etibylsulfonyl, and others derived from the alkyls listed above,
"Alkylsulfonyloxy" such as C1-4alkylsulfonyloxy includes methanesulfonyloxy
(methylsulfonyloxy), ethanesulfonyloxy, et al.
"Cycloalkyl", for example C3-8cycloalkyl, includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, a
C3-8 cycloalkyl group is C3-6gcycloalkyl or C5-6cycloalkyl, that is the cycloalkyl group
contains a 3-6 membered or 5-6 membered carbocyclic ring respectively.
"Fluoroalkyl" includes alkyl groups with one, two, three, four, five or more
fluorine substituents, for example C1-2fluoroalkyi or C1-2fluoroalkyl or C1-2fluoroalkyl
such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-
trifluoroethyl (CF3CH2-), 2,2-difluoroethyl (CHF2-CH2-), or 2-fluoroethyl
(CH2F-CH2-), etc. "Fluoroalkoxy" includes C1-4fluoroalkoxy or C1-2fluoroalkoxy such
as trifiuoromemoxy, pentafluoroethoxy, monofluoromethoxy, difluoTorhethoxy, etc.
"Fluoroalkylsulfonyl" such as C1-4fluoroalkylsulfonyl 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.
By "carbon-linked-pyridinyl" is meant pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.
Preferably, R1 is C1-2alkyl, C1-3fluoroalkyl or -(CH2)2OH; more preferably C1-3alkyl,
C1-2fluoroalkyl or -(CH2)20H; still more preferably C2-3alkyl, C2fluoroalkyl or
-(CH2)2OH; and yet more preferably C2alkyl or C2fluoroalkyl. When R1 is C1-4alkyl
or C1-3fluoroalkyl, it can be straight-chained or branched. R1 can for example be
methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C2fluoroalkyl or
-(CH2)2OH; and more preferably R1 is ethyl, n-propyl, C2fhioroalkyl (e.g.
C1fluoroalkyl-CH2- such as CF3-CH2-) or -(CH2)2OH. R1 is most preferably ethyl.

Preferably, R2 is a hydrogen atom (H) or methyl, more preferably a hydrogen atom (H).
Where R3 optionally substituted phenyl, preferably the phenyl is optionally substituted
with one substituent being fluoro, chloro, C1-2alkyl, C1-2fluoroalkyl, C1-2alkoxy,
C1-2fluoroalkoxy or cyano. Where R3 is optionally substituted phenyl, the optional
substituent can be at the 2-, 3- or 4-position of the phenyl ring, e.g. at the 4-position. For
example, R3 can be phenyl or fluorophenyl; in particular 4-fluorophenyl.
R3 is preferably optionally substituted branched C3-6alkyl, optionally substituted
C3-8cycloalkyl, or an optionally substituted heterocyclic group of sub-formula (aa), (bb)
or (cc). R3 is more preferably optionally substituted C1-2gcycloalkyl, or an optionally
substituted heterocyclic group of sub-formula (aa), (bb) or (cc).
Preferably, in R3 there is one substituent or no substituent.
Where R3 is optionally substituted branched C3-6alkyl, then preferably R3 is optionally
substituted branched C1-2alkyl and/or unsubstituted C3-6alkyl such as isopropyl,
isobutyl, sec-butyl, t-butyl, 3-methylbutan-2-yl, or 2-ethylbutan-1-yl. Where R3 is
optionally substituted branched C3-6alkyl, it is most preferably isobutyl, sec-butyl,
t-butyl or 3-methylbutan-2-yl (for example (R)-3-methylbutan-2-yl or (S)-3-methylbutan-
2-yl).
In one optional embodiment, where R3 is optionally substituted C3-8cycloalkyl, it is not
optionally substituted C5cycloalkyl, i.e. not optionally substituted cyclopentyl. In this
case, more preferably, R3 is optionally substituted C6-8cycloalkyl or optionally
substituted C6-7cycloalkyl.
Where R3 is optionally substituted C3-8gcycloalkyl, it is more preferably optionally
substituted C6cycloalkyl (i.e. optionally substituted cyclohexyl); for example
C6cycloalkyl optionally substituted with one or two substituents independently being
(e.g. being) oxo (=O), OH, C1-2alkoxy, C1-2fluoroalkoxy (e.g. trifluoromethoxy), or
C1-2alkyl, and wherein any OH, alkoxy or fluoroalkoxy substituent is not substituted at
theR3 ring carbon attached (bonded) to the -NH- group of formula (I).
Where R3 is optionally substituted C3-8gcycloalkyl, the one or two optional substituents
preferably comprise (e.g. is or independently are (e.g. is or are)) oxo (=O); OH;
Cjalkoxy; C1fluoroalkoxy (e.g. trifluoromethoxy); NHR21 wherein R21 is a hydrogen
atom (H) or C1-2 straight-chain alkyl; C1-2alkyl such as methyl; C1fluoroalkyl 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; hydxoxyimino (=N-OH); or (C1-2alkoxy)imino (=N-OR26 where R26 is
C1-2alkyl); and wherein any OH, alkoxy, fluoroalkoxy or NHR21 substituent is not
substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I) and
is not substituted at either R3 ring carbon bonded to the Y group of the heterocyclic group
(aa), (bb) or (cc).
More preferably, where R3 is optionally substituted C3-8cycloalkyl, the one or two
optional substituents comprise (e.g. is or independently are (e.g. is or are)) oxo (=O); OH;
NHR21 wherein R21 is a hydrogen atom (H); C1-2alkyl such as methyl; Cifiuoroalkyl
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 (C1-2aIkoxy)irnino
(=N-OR26 where R26 is C1-2alkyl).
Still more preferably, where R3 is optionally substituted C3-8gcycloalkyl, the one or two
optional substituents comprise (e.g. is or independently are (e.g. is or 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 (C1-2alkoxy)imino (=N-OR26
where R26 is C1-2alkyl). Yet more preferably, where R3 is optionally substituted
C3-8cycloalkyl, 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
(C1-2alkoxy)imino (=N-OR26 where R26 is C1-2aLkyl).
Most preferably, where R3 is optionally substituted C3-8cycloalkyl, the one or two
optional substituents comprise (e.g. is or independently are (e.g. is or are)) OH, oxo (=O)
or hydroxyimino (=N-OH). For example, where R3 is optionally substituted
C3-8cycloalkyl, the one or two optional substituents preferably comprise (e.g. is or are)
OH and/or oxo (=O).
Optionally, in R3, the C3-8cycloalkyl is unsubstituted.
Where R3 is optionally substituted C3-8cycloalkyl, e.g. optionally substituted
C1-2gcycloalkyl such as optionally substituted C6cycloalkyl (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 C3-8cycloalkyl, 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 3-, 4- or 5-position,
e.g. the 3- or 5-position, of the R3 cycloalkyl (e.g. C6-8cycloalkyl) ring. For example,
any OH, alkoxy, fluoroalkoxy, -CH2OH, -CH2CH2OH, -CH2NH22, -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 C3-8cycloalkyl, 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. C6-8gcycloalkyl e.g. cyclohexyl) ring.
Where R3 is optionally substituted C3-8cycloalkyl, 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. C6-8cycloalkyl e.g.
cyclohexyl) ring.
Where R3 is optionally substituted C3-8cycloalkyl, any oxo (=O), hydroxyimino
(=N-OH); or (C1-4alkoxy)imino (=N-OR26) substituent is preferably at the 3- or
4-position, preferably at the 4-position, of the R3 cycloalkyl (e.g. C1-2cycloalkyl e.g.
cyclohexyl) ring.
Where R3 is optionally substituted C3-8cycloalkyl, R3 is preferably cyclohexyl (i.e.
unsubstituted) or cyclohexyl substituted by one oxo (=O), OH, NHR21, C1-2alkyl,
C1-2fiuoroalkyl, -CH2OH, -C(O)OR23, -C(O)NHR24, -C(O)R25, fluoro, hydroxyimino
(=N-OH) or (C1-4alkoxy)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, C1-2alkyl, C1-2fluoroalkyl, -C(O)OR23,
fluoro, hydroxyimino (=N-OH) or (C1-4alkoxy)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),
C1-2alkyl or OH substituent, for example R3 can be cyclohexyl (i.e. unsubstituted) or
cyclohexyl substituted by one oxo (=O) 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), hydWyimino (=N-OH) or (C1-4alkoxy)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-1-yl) or 3-oxo-cyclohexyl, but R3 is more
preferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-
hydroxycyclohexan-1-yl), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-1-yl), 4-
(hydroxyimino)cyclohexyl (i.e. 4-(hy&oxyimino)cyclohexan-1-yl),
4-(C1-2alkoxyimino)cyclohexyl, 1-methylcyclohexyl or 3-methylcyclohexyl. In one
embodiment, R3 can optionally be cyclohexyl (i.e. unsubstituted) or 3-hydroxy-
cyclohexyl or 4-oxo-cyclohexyl. Where R3 is optionally substituted Cgcycloalkyl, R3 is
most preferably cyclohexyl (i.e. unsubstituted), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-
1-yl) or 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-1-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-C5-6cycloalkenyl, more preferably optionally
substituted mono-unsaturated-C6cycloalkenyl (i.e. optionally substituted
mono-unsaturated-cyclohexenyl = optionally substituted cyclohexenyl). Still more
preferably, the R3 cyclohexenyl is optionally substituted cyclohex-3-en-1-yl.
Where R3 is optionally substituted mono-unsaturated-C5-7cycloalkenyl, preferably the
R3 cycloalkenyl is optionally substituted with one or two substituents independently
being fluoro or methyl; preferably if there are two substituents then they are not both
methyl. Preferably, the R3 cycloalkenyl is optionally substituted with one substituent
being fluoro or C1-2alkyl (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- positions) of the cycloalkenyl ring.
Where R3 is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is preferably
O, S, SO2, NH or N-C(O)-Me (for example O, S, SO2 or N-C(O)-Me), more preferably
O, NH or N-C(O)-Me, still more preferably O or N-C(O)-Me, most preferably O. (When
Y is NH or N-C(O)-Me, then R4 is H or -C(O)-Me).

Preferably, R4 is a hydrogen atom (H), C1-2alkyl, C(O)NH2, C(O)-Me or C(O)-CF3.
Optionally, R4 can be a hydrogen atom (H), C1-2alkyl, C(O)-Me or C(O)-CF3, more
preferably H, C(O)-Me or C(O)-CF3, still more preferably H or C(O)-Me.
Preferably, Y is not N-C(O)-Me when the heterocyclic group is of sub-formula (aa).
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, in R3, the
heterocyclic group is of sub-formula (bb).
In sub-formula (bb), n1 is preferably 1. In sub-formula (cc), n2 is preferably 1. That is,
six-membered rings are preferred in the R3 heterocyclic group.
Preferably, in R3, the heterocyclic group of sub-formula (aa), (bb) or (cc) is
unsubstituted. (In this connection, where Y is NR4, R4 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); C1-2alkyl (e.g. methyl) or C1-2fluoroalkyl (e.g. C1fluoroalkyl 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- positions) 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 C1-2alkyl, C1fluoroalkyl, 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 NR4, then preferably R4
is not C(O)-Me. More preferably, when R3 is the heterocyclic group of sub-formula (aa)
and Y is NR4, then R4 is preferably not C(O)R, i.e. or e.g. R4 is preferably not
C(O)NH2, C(O)-C1-2alkyl or C(O)-C1fluoroalkyl. In one embodiment, Y is O, S, SO2
or NH when R3 is the heterocyclic group of sub-formula (aa).
When R3 is the heterocyclic group of sub-formula (aa), preferably Y is not NR4.
Optionally, according to one embodiment of the invention, NHR3 or NR3R3a is not
. More preferably, when R3 is the heterocyclic group of sub-formula (bb)

and Y is NR4, and optionally when n1 is 1, then preferably R4 is not methyl. More
preferably, when R^ is the heterocyclic group of sub-formula (bb) and Y is NR4, and
optionally when n1 is 1, then R4 is preferably not alkyl or substituted alkyl, i.e. or e.g. R4
is preferably not C1-2alkyl, C1-2fluoroalkyl or CH2C(O)NH2. In one embodiment,
when R3 is the heterocyclic group of sub-formula (bb), Y is preferably O, S, SO2 or
NR4, wherein R4 is H, C(O)NH2, C(O)-C1-2alkyl or C(O)-C1fluoroalkyl or more
preferably Y is H or C(O)-Me. More preferably, for sub-formula (bb), Y is O or NR4.
Preferably, NHR3 or NR3R3a is of sub-formula (a), (al), (b), (c), (c 1), (c 2), (c 3), (c 4),
(c 5), (d), (e), (f), (g), (gl), (g2), (g3), (g4), (h), (hi), (i), (j), (k), (kl), (L), (m), (ml), '
(m2), (m3), (m5), (n), (o), (ol), (o2), (o3), (o4), (o5), (p), (p2), (p3), (p5), (p6), (p7), (p8),
(q), (r), (s), (t), (tl) or (t2):



In the sub-formulae (a) to (t2) etc above, the -NH- connection point of the NHR3 or
NR3R3a group to the 4-position of the pyrazolopyridine of formula (I) is underlined.
Generally, in this specification, for a group or radical, where NH or N are underlined,
then this indicates the connection point.

When NHR.3 or NR3R3a is of sub-formula (n), then preferably it is a cis-(3-
hy&oxycyclohex-1-yl)amino group, eg in any enantiomeric form or mixture of forms but
it can be racemic.
Preferably, Het is of sub-formula (i), (ii), (iii) or (v); more preferably Het is of sub-
formula (i), (ii), or (v); still more preferably Het is of sub-formula (i).
Xl, X3 and/or X4 independently is/are often N (a nitrogen atom).
yl, Y2 and/or Y3 independently is/are often CRT.
Suitably, Z1 and/or Z5 independently is/are O or S. Preferably, Z1 and/or Z5 is O.



Alternatively, when Het is of sub-formula (v), Het can for example be of sub-formula
(va) or (vb), more preferably of sub-formula (va):



Alternatively, when Het is of sub-formula (ii), Het can for example be of sub-formula
(iia):




For the Het group in general, preferably, one of Rx and RY (or RX2 and RY2) is as
defined herein and the other of Rx and RY (or RX2 and RY2) is as hydrogen atom (H) or
C1-2alkyl. More preferably, one of RX and RY (or RX2 and RY2) is as defined herein
and the other of RX and RY (or RX2 and RY2) is as hydrogen atom (H).
Overall, for the Het group in general, it is preferred that one of Rx and RY, and for Het
of sub-formula (v) one of RX2 and RY2, is:
C1-8alkyl;
optionally substituted C3-6cycloalkyl;
-(CH2)n3-S(O)2-R5, -CH(C1.2alkyl)-S(O)2-R5, -CMe2-S(O)2-R5, or
C3.5cycloalkyl substituted at the connecting carbon atom by -S(O)2-R^;
preferably -(CH2)n3-S(O)2-R5;
-(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7, -CMe2-NR6R7, or C3.5cycloalkyl
substituted at the connecting carbon atom by -NR^R7; preferably
-(CH2)n4-NR6R7 or -CH(Me)-NR%7;
-(CH2)n11-C(O)-NR10R11, -CH(C1-2alkyl)-C(O>NR10R1!,
-CME2-C(O)-NR10R11, or C~3-5cycloalkyl substituted at the connecting
carbon atom by -C(O)-NR10R11; preferably -(CH2)n1 1-C(O)-NR10R11;
-(CH2)n14-Hetl, -CH(C1-2alkyl)-Het1, -CMe2-Hetl, or C~3-5cycloalkyl substituted
at the connecting carbon atom by Het1; preferably -(CH2)n14-Hetl;
-(CH2)n10-Ar, -CH(C1-2alkyl)-Ar, -CMe2-Ar, or C~3-5cycloalkyl substituted at the
connecting carbon atom by Ar; preferably -(CH2)n10-Ar;
(i) wherein Ar is optionally substituted phenyl, or more preferably (ii) wherein
Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic ring .
Overall, for the Het group in general, it is more preferred that one of RX and RY, and for
Het of sub-formula (v) one of RX2 and RY2, is:
-(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7, -CMe2-NR6R7, or C3.5cycloalkyl
substituted at the connecting carbon atom by -NR6R7; preferably
-(CH2)n4-NR6R7 or -CH(Me)-NR6R7;
-(CH2)n11-C(O)-NR10Rl!, -CH(C1.2alkyl)-C(O)-NR10R11,
-CMe2-C(O)-NR10R11, or C~3-5cycloalkyl substituted at the connecting
carbon atom by -C(O)-NR10R11; preferably -(CH2)n11-C(O)-NR10R11;
-(CH2)n14-Hetl, -CH(C1-2alkyl)-Hetl, -CMe2-Het1, or C~3-5cycloalkyl substituted
at the connecting carbon atom by Het1; preferably -(CH2)n14-Het1; or

-(CH2)n10-Ar, -CH(C1-2alkyl)-Ar, -CMe2-Ar, or C~3-5cycloalkyl substituted at the
connecting carbon atom by Ar; preferably -(CH2)n10-Ar;
(i) wherein Ar is optionally substituted phenyl, or or more preferably (ii)
wherein Ar is an optionally substituted 5- or 6-membered heterocyclic
aromatic ring.
Optionally, one of Rx and RY can be: C1-2alkyl; C3-6cycloalkyl; -(CH2)n3-SO2-R5;
-(CH2)n4-NR6R7; -(CH2)n7-O-R9; -C(O)-NR10R11; -C(O)-OR13; or the 4-, 5-, 6- or
7-membered optionally substituted saturated heterocyclic ring Het1. More preferably,
one of Rx andRY is: C1-2alkyl; -(CH2)n3-SO2-R5; or the 4-, 5-, 6- or 7-membered
optionally substituted saturated heterocyclic ring Het1. In these cases, as mentioned
above, it is preferred that the other of Rx and RY is a hydrogen atom (H) or C1-2alkyl.
When Rx, RX2, RY and/or RY2 is C1-8galkyl, then preferably it/they independently
is/are C1-2galkyl, e.g. C3-6alkyl and/or C1-2alkyl such as methyl, isopropyl, isobutyl or t-
butyl.
When Rx, Rx2, RY and/or RY2 is optionally substituted C3-6cycloalkyl, then optionally
it/they independently can be C3-6cycloalkyl optionally substituted by a C1-2alkyl group.
When Rx, RX2, RY and/or RY2 is optionally substituted C3-6cycloalkyl, then preferably
it/they independently is/are C3-6cycloalkyl (i.e. unsubstituted), for example cyclopropyl
or cyclobutyl.
When Rx, RX2, RY and/or RY2 is optionally substituted -(CH2)n2a-C3-6cycloalkyl,
then preferably it/they independently is/are -(CH2)n2a-C3-6cycloalkyl optionally
substituted, in the -(CH2)n2a- moiety or in the C3-6cycloalkyl moiety, by a C1-2alkyl
group, wherein n2a is 1,2 or 3.
When Rx, Rx2, RY and/or RY2 is optionally substituted -(CH2)n2a-C3-6cycloalkyl;
then n2a is preferably 1 or 2 or more preferably 1; and/or preferably Rx, RX2, RY and/or
RY2 independently is/are optionally substituted -(CH2)n2a-C5.6cycloalkyl or optionally
substituted -(CH2)n2a-C6cycloalkyl. When Rx, RX2, RY and/or RY2 is optionally
substituted -(CH2)n2a-C3-6cycloalkyl, then preferably it/they independently is/are
-(CH2)n2a-C3-6cycloalkyl (i.e. not substituted). More preferably Rx, R^, RY and/or
RY2 independently is/are (cyclohexyl)methyl-, that is -CH2-cyclohexyl.When Rx, Rx2,
RY and/or RY2 is -(CH2)n3-S(O)2-R5, -CH(C1-2alkyl)-S(O)2-R5 (e.g.

-CH(Me)-S(O)2-R5), -CMe2-S(O)2-R5, or C~3-5cycloalleyl substituted at the connecting
carbon atom by -S(O)2-R5, then preferably it/they independently is/are
-(CH2)n3-S(O)2-R5.
When Rx, RX2, RY and/or RY2 is C~3-5cycloalkyl substituted at the connecting carbon
atom by -S(O)2-R5, then preferably it/they independently is/are C3cycloalkyl
(cyclopropyl) substituted at the connecting carbon atom by -S(O)2-R5, for example
(see for example Example 178).
When Rx, RX2, RY and/or RY2 is -(CH2)n3-S(O)2-R5, then preferably n3 is 1.
Preferably, R5 is C1-2alkyl (e.g. C1-2alkyl), -NR15R16, or optionally substituted phenyl.
R5 is more preferably C1-3alkyl or -NH-C1-2alkyl or phenyl; still more preferably R5 is
C1-3alkyl or C1-2alkyl such as methyl. Most preferably, -(CH2)n3-S(O)2-R5 is
-CH2SO2Me.
Preferably, R15 is H, C1-2alkyl (e.g. C1-2alkyl), optionally substituted phenyl or
optionally substituted benzyl; and/or preferably R^ is H or methyl, e.g. H.
When R15 and R16 together are -(CH2)n3a-X3a-(CH2)n3b-, then: preferably n3a and/or
n3b independently are 2; and/or preferably X3a is a bond, -CH2-, O, or NR8a wherein
R8a is C1-2alkyl or acetyl; and/or preferably the ring formed by NR15R16 is not
substituted on a ring carbon or is substituted on a ring carbon by one methyl or oxo (=O)
substituent.
When RX, RX2, RY and/or RY2 is -(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7 (e.g.
-CH(Me)-NR6R7), -CMe2-NR6R7, or C~3-5cycloalkyl (e.g. C3cycloalkyl) substituted at
the connecting carbon atom by -NR6R7, then preferably it/they independently is/are
-(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7 (e.g. -CH(Me)-NR6R7), or -CMe2-NR6R7;
more preferably it/they independently is/are -CH(Me)-NR6R7 or still more preferably
-(CH2)n4-NR6R7
When Rx, RX2, RY and/or RY2 is -(CH2)n4-NR6R7, then preferably n4 is 0 only when
the -(CH2)n4_NR6R7 is bonded to a carbon atom in the Het ring.

When RX, RX2, RY and/or RY2 is -(CH2)n4-NR6R7 , then preferably n4 is 0,1 or 2;
more preferably n4 is 0 or 1, still more preferably n4 is I.
In one optional embodiment of the invention, R6 and R7 independently are H, Chalkyl
e.g. C1-4alkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, -C(O)-C1-2alkyl, -SO2-C1-2alkyl,
phenyl, or benzyl (wherein the phenyl and benzyl are independently optionally
substituted on the aromatic ring by one of fluoro, chloro, C1-2alkyl, C1fluoroalkyl,
C1-2aIkoxy or C1fluoroalkoxy); or R6 and R7 together are -(CH2)n5-X5-(CH2)n6- in
which n5 and n6 independently are 2 or 3 and X5 is a bond, -CH2-, O, or NR8 wherein
R8 is H or C1-2alkyl, and wherein the ring formed by NR6R7 is not substituted on a ring
carbon.
In one optional embodiment of the invention, R6 and R7 independently are H, C1-6alkyl
e.g. C1-4alkyl, -C(O)-C1-2alkyl or -SO2-C1-2alkyl; or R6 and R7 together are
-(CH2)n5-X5-(CH2)n6- in which n5 and n^ independently are 2 or 3 and X5 is a bond,
-CH2-, O, or NR8 wherein R8 is H or C1-2alkyl, and wherein the ring formed by NR6R7
is not substituted on a ring carbon.
R6 is preferably H or C1-2alkyl. R7 is preferably C1-6alkyl, -C(O)R17 or -S(O)2R18,
for example C1-6alkyl. Where R6 and/or R7 is Chalkyl, then it/they independently
is/are preferably C1-2alkyl e.g. methyl.
Preferably, R17 and R18 independently are C1-6alkyl (e.g. C1-4alkyl or C1-2alkyl or
isopropyl or n-propyl), C3-6cycloalkyl, optionally substituted 5-membered heteroaryl
being furyl (furanyl, e.g. 2-furyl) or thienyl (e.g. 2- or 3- thienyl) (the furyl or thienyl
being independently optionally substituted by one oxo and/or one or two methyl), or
phenyl or benzyl (wherein the phenyl and benzyl are independently optionally substituted
on the aromatic ring by one or two substituents independently being fluoro, chloro,
C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy).
In an alternative preferable embodiment, R6 and R7 together are -(CH2)n5-X5-(CH2)n6-,
in which case it is preferable that n5 is 2 and/or n6 is 2. Preferably, when R6 and R7
together are -(CH2)n5-X5-(CH2)n6-, and when the ring formed by NR6R7 is substituted
on a ring carbon by one or two substituents being oxo (=O), then the one or two oxo
substituents are substituted on a ring carbon atom adjacent to (bonded to) the connecting
nitrogen N of NR6R7. When R6 and R7 together are -(CH2)n5-X5-(CH2)n6-, then
preferably the ring formed by NR6R7 is optionally substituted on a ring carbon by one or

two substituents independently being methyl or oxo (=O) only when X5 is a bond or
-CH2-.
When R6 and R7 together are -(CH2)n5-X5-(CH2)n6-, it is preferable that the ring
formed by NR^R7 is not substituted on a ring carbon or is substituted on a ring carbon by
one methyl or oxo (=O) substituent.
Preferably, R8 is Chalkyl or phenyl.

When Rx, RX2, RY and/or RY2 is -(CH2)n7-O-R9, then in one embodiment n7 is 1,2 or
3 and/or R9 is H, C1-2galkyl or phenyl, or more preferably R9 is H or C1-2galkyl. n7 is
preferably 1 or 2, more preferably 1. R9 is preferably C1-4alkyl such as methyl or t-butyl.
For example, -(CH2)n7-O-R9 can be -CE^-O-tBu or -CH2-O-Me.
When Rx, RX2, RY and/or RY2 is (CH2)n11-C(O)-NR10R11,
-CH(C1-2alkyl)-C(O)-NR10R11 (e.g. -CH(Me)-C(O)-NR10R11),
-CMe2-C(O)-NR10R11, or C~3-5cycloalkyl (e.g. C3cycloalkyl) substituted at the
connecting carbon atom by -C(O)-NR10R11, then: preferably it/they independently is/are
-(CH2)n11-C(O)-NR10R11, -CH(C1-2alkyl)-C(O)-NR10R11 (e.g.
-CH(Me)-C(O)-NR10R11, or -CMe2-C(O)-NR10R11; more preferably
-(CH2)n11-C(O)-NR10R11; still more preferably -CH2-C(O)-NR10R11 or
-C(O)-NR10R11.

When Rx, R*2, RY and/or RY2 is -(CH2)nl 1-C(O>NR10Rl l, then n11 is preferably 0
or 1, more preferably 1.
Preferably R10 is H or C1-6alkyl (e.g. C1-2alkyl or C1-2aUcyl or methyl), or R10 and
Rll together are -(CH2)n8-X6-(CH2)n9-.
Preferably, R10 and R11 independently are, and more preferably R11 is:
H; C1-2galkyl; C1-2fluoroalkyl; C2-3alkyl substituted by one OH or -OC1-2alkyl other
than at the connection point; C3-6cycloalkyl optionally substituted by one or two methyl
groups; -CH2-C3-6cycloalkyl optionally substituted by one NHMe group (preferably
unsubstituted); -(CH2)n17-Het2; optionally substituted carbon-linked-pyridinyl,
optionally substituted phenyl; optionally substituted benzyl; or optionally substituted
-CH(C1-2alkyl)Ph.
More, preferably, R10 and R11 independently are, and still more preferably R11 is: H;
C1-6alkyl; C3-6cycloalkyl optionally substituted by one or two methyl groups;
-CH2-C3-6cycloalkyl (unsubstituted); -(CH2)1117-Het2; optionally substituted carbon-
linked-pyridinyl; optionally substituted phenyl, optionally substituted benzyl; or
optionally substituted -CH(C1-2alkyl)Ph (e.g. optionally substituted -CH(Me)Ph).
Preferably, in R10 and/or R11, the phenyl, the benzyl and the -CH(C1-2alkyl)Ph (e.g.
-CH(Me)Ph) are independently optionally substituted on the aromatic ring by one or two
substituents independently being: fluoro, chloro, C1.2alkyl (e.g. methyl), C1fluoroalkyl
(e.g. CF3), C1-2alkoxy (e.g. methoxy), C1fluoroalkoxy (e.g. CF3O- or CHF2O-),
-NR10aR10b (wherein R10a is H or methyl and R10b is H, C1-2alkyl (e.g. methyl),
-C(O)Me or -S(O)2Me), -C(O)-NR10cR10d (wherein R10c and R10d independently are
H or C1-2alkyl, e.g. H or Me), or -S(O)2-R10e (wherein R10e is C1-2alkyl (e.g. methyl),
NH2, NHMe or NMe2). One substituent is preferred.
In RlO and/or R* 1, and/or (independently) in R^, and/or (independently) in R\$, and/or
(independently) in R^ and/or R?, and/or (independently) in R*?, and/or (independently)
in Rl 8; the carbon-linked-pyridinyl is preferably optionally substituted by one OH
(including any keto tautomer thereof), and more preferably is not substituted.
In Rl° andVor R11, for -(CH2)n17-Het2, preferably n*? is 0 or 1; and/or preferably Het2
is a 5- or 6- membered saturated optionally substituted heterocyclic ring containing one O
or S (preferably O) ring atom or one NR27 ring group. Preferably, R27 is C1-2alkyl or
-C(O)Me. Preferably, the Het2 ring is substituted on a ring carbon by one or two
substituents being methyl or is not substituted on a ring carbon.

In one embodiment when RX, RX2, RY and/or RY2 is -(CH2)n11C(O)-NR10R11,
-CH(C1-2alkyl)-C1-2-NR10R11 or -CMe2-C(O)-NR10R11, then optionally: R10 and
R11 independently are H of C1-2alkyl; or R10 and R11 together are
-(CH2)n8-X6-(CH2)n9- in which n8 and n9 independently are 2 or 3 and X6 is a bond,
-CH2-, O, or NR12 wherein R12 is H or C1-2alkyl, and wherein the ring formed by
NR10R11 is not substituted on a ring carbon.
Preferably R10 is H and/or optionally R11 is C1-6alkyl e.g. C1-4alkyl such as isopropyl.
For example, -(CH2)n11-C(O)NR10R11 such as -C(O)-NR10R11 can be
In an alternative preferable embodiment, when R10 and R11 together are
-(CH2)n8-X6-(CH2)n9-, then preferably n8 is 2 and/or n9 is 2. When R10 and R11
together are -(CH2)n8-X6-(CH2)n9-, which is a preferable feature of the invention, then
preferably X^ is a bond, -CH2-, O, or NR12 wherein R12 is H or C1-2alkyl, and wherein
the ring formed by NR10R11 1 is not substituted on a ring carbon.
When R10 and R11 together are -(CH2)n8-X6-(CH2)ri9-, it is preferable that the ring
formed by NR10R11 is not substituted on a ring carbon or is substituted on a ring carbon
by one methyl or oxo (=O) substituent.



. (In the above-illustrated most preferred groups, and generally in this
specification for a group or radical, where NH or N are underlined, then this indicates the
connection point.)
Still more preferably, When Rx, RX2, RY and/or RY2 is -(CH2)n11(CO-NR10R11,
-CH(C1-2alkyl)-C(O)-NR10R11, -CMe2-C(O)-NRl0R11, or C~3-5cycloalkyl substituted
at the connecting carbon atom by -C(O)-NR10R11, then preferably it/they independently
is/are-(CH2)n11-C(O)-NR10R11 (more preferably-CH2-C(O)-NR10R11 or
-C1-2-NR10R11) wherein NR10R11 is one of the above-illustrated most preferred
groups.
The -(CH2)n11-C(O)-NR10R11 group is preferably as defined in any of Examples 36,
58, 84, 85-90, 95-96,126-147 or 148-155. These Examples illustrate some of the above-
illustrated preferred NR10R11 groups, and some of these Examples give literature
references and/or commercial sources for amines R10R11NH, Which may be used to
prepare the compounds of Formula (I) containing the -(CH2)n11-C(O)-NR10R11 group
as RX, RX2, RY and/or- RY2.
When RX, RX2, RY and/or RY2 is -(CH2)n12-C(O)-ORl3 , n12 is preferably 0 or 1,
more preferably 1. In one preferred embodiment when RX, RX2, RY and/or RY2 is
-(CH2)n12-C(O)-OR13 R13 is H or C1-6alkyl. When R13 is C1-6alkyl, then R13 is
preferably C1-4alkyl or C1-3alkyl such as methyl (e.g. RX, RY and/or RX2 can be
-CO2Me) or ethyl.
When RX, RX2, RY and/or RY2 is -(CH2)n13-C(O)-Rl3a, n13 is preferably 0 or 1,
more preferably 1. When Rx, RX2, RY and/or RY2 is -(CH2)n13-C(O)-R13a, then
suitably R13a is C1-2galkyl, C1-2fiuoroalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl,
benzyl, or phenyl (wherein the phenyl and benzyl are independently optionally
substituted on the aromatic ring by one or two of (independently) (e.g. one of) fluoro,

chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy). More preferably R13a
is C1-6alkyl or C1-4alkyl or C1-2alkyl.
When Rx, RX2, RY and/or RY2 is -(CH2)n14-Het1, -CH(C1-2alkyl)-Het1 (e.g.
-CH(Me)-Het1), -CMe2-Het1, or C~3-5cycloalkyl (e.g. C3cycloalkyl) substituted at the
connecting carbon atom by Het1, wherein n14 is 0,1 or 2, then: (a) n14 is preferably 0 or
1, and/or (b) -(CH2)n14-Het1 is more preferred than -CH(Me)-Het1 or -CMe2-Het1, or
C~3-5cycloalkyl substituted at the connecting carbon atom by Ar.
When Rx, RX2, RY and/or RY2 is -(CH2)n14-Hetl, -CH(C1-2alkyl)-Hetl (e.g.
-CHOleJ-Het1), -CMe2-Het1, or C~3-5cycloalkyl (e.g. C3cycloallcyl) substituted at the
connecting carbon atom by Het1, wherein n14 is 0,1 or 2 and wherein Het1 is the 4-, 5-,
6- or 7-membered optionally substituted saturated heterocyclic ring containing one O or S
ring atom and/or one NR14 ring group, then the optionally substituted saturated
heterocyclic ring Het1 is preferably 4-, 5- or 6-membered, more preferably preferably 5-
or 6-membered. When Het1 is 6-membered, then any O or S ring atom and/or any NR14
ring group independently can be present at the 2-, 3- or 4- ring position, preferably at the
4- ring position, with respect to the connecting ring-atom in Het1. When the optionally
substituted saturated heterocyclic ring Het1 is 4-membered, then preferably the
heterocyclic ring Het1 is not optionally substituted by oxo (=O).
When R14 and/or a or the optional ring substituent is C1-4alkyl, it is suitably C1-2a&yl
such as methyl. Preferably, R14 is C1-4alkyl (e.g. C1-2alkyl), C(O)R19 or S(O)2R19.
Preferably, Rl9 is C1-4alkyl (e.g. methyl or isobutyl), C3-6cycloalkyl such as
cyclopropyl or cyclohexyl, 2-thienyl, furan-2-yl, phenyl (unsubstituted), or benzyl
(unsubstituted); more preferably R14 is C1-4alkyl (e.g. methyl or isobutyl).
When Rx R^, RY and/or RY2 is -(CH2)n14-Het1 and n14 is 0, and when the saturated
heterocyclic ring Het1 is optionally substituted (at a position other than any NR14
position) by C1-2alkyl, then preferably the optional Cj.4alkyl is substituted at the carbon
atom directly attached to the 5-membered ring in sub-formula (i), (ii), (iii), (iv) or (v) of
Het.
The heterocyclic ring Het1 is preferably optionally substituted (at a position or positions
other than any NR14 position) by one oxo (=O) and/or one C1-4alkyl substituent;
preferably by one oxo (=O) substituent. Any oxo (=O) substituent is preferably
substituted on a ring carbon adjacent to (bonded to) any NR14 ring group present.
Preferably, in Het1, the one or two oxo (=O) substituents are only present when there is a
NR14 ring group present.


foregoing wherein the connection point [which connects to the -(CH2)n14-,
-CH(C1-2alkyl)- or -CHMe2- or connecting-C~3-5cycloalkyl moiety or connects to the
5-membered ring of sub-formula (i), (ii), (iii), (iv) or (v) in Het] is at a different ring
carbon atom of Het1.
When RX, RX2, RY and/or RY2 is -(CH2)n10-Ar, -CH(C1-2alkyl)-Ar (e.g.
-CH(Me)-Ar), -CMe2-Ar, or C~3-5cycloalkyl (e.g. C3cycloalkyl) substituted at the
connecting carbon atom by Ar, then preferably it/they independently is/are -(CH2)n10-Ar
or -CH(Me)-Ar, preferably -(CH2)n10-Ar such as -CH2~Ar.
When Rx, RX2, RY and/or RY2 is -(CH2)n10-Ar then preferably n10 is 0 or 1; more
preferably n10 is 1.
When Ar is optionally substituted phenyl, preferably the phenyl is optionally substituted
by one or two substituents (preferably one) independently being fluoro, chloro, bromo,
C1-2alkyl, Cifiuoroalkyl, C1-2alkoxy, C1fluoroalkoxy, -NRllaRllb (wherein R1 la is H
or methyl and R1lb is H, C1-2alkyl, -C(O)Me or -S(O)2Me), -C1-2-NR1lcR1ld
(wherein R1lc and R1ld independently are H or methyl), -C1-2-OR1le wherein R11e is
H, or -S(O)2-R11f (wherein R11f is methyl, NH2, NHMe or NMe2). When Ar is
optionally substituted phenyl, more preferably -(CH2)n10-Ar can be as defined for RX,
RX2, RY and/or RY2 in any of Examples 49-55, 83,103,107,120-125,179,181-184,
189 or 190.

When Ar is phenyl optionally substituted at two adjacent Ar ring atoms by the two ends
of a chain which is: -(CH2)4-, -(012)3-, or -CH=CH-CH=CH-, then it can be for
example naphthyl e.g. 1-naphthyl or 2-naphthyl.
When Ar is the optionally substituted 5- or 6-membered heterocyclic aromatic ring
containing 1,2,3 or 4 heteroatoms (e.g. 1, 2 or 3 heteroatoms) selected from O, N or S ,
then Ar can be optionally substituted: furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl,
imidazolyl, oxadiazolyl (e.g. 1,3,4- or 1,2,4- or 1,2,5- oxadiazolyl), thiadiazolyl (e.g.
1,3,4- or 1,2,4-), pyridyl, triazolyl (e.g. 1,2,3- or 1,2,4- triazolyl), tetrazolyl, triazinyl,
pyridazyl, pyrimidinyl, pyrazolyl, isothiazolyl (1,2-thiazolyl), or isoxazolyl (1,2-
oxazolyl). When Ar is the optionally substituted 5- or 6-membered heterocyclic aromatic
ring, the ring is preferably optionally substituted by one or two independent C1-2alkyl
groups or by one OH group (including any keto tautomer thereof); more preferably the
ring is optionally substituted by one or two independent C1-2alkyl (e.g. methyl) groups;
and still more preferably there is/are one or no substituents. When Ar is the optionally
substituted 5- or 6-membered heterocyclic aromatic ring, preferably it is 5-membered.
When Ar is the 5- or 6-membered heterocyclic aromatic ring, more preferably
-(CH2)n10-Ar can be as defined for Rx, RX2, RY and/or RY2 in any of Examples 71,
79, 80, 97-100,104-106,108,112-114,117,158 or 186.
When the heterocyclic aromatic ring Ar is substituted at two adjacent Ar ring atoms by
the two ends of a chain which is: -(CH2)4-, -(CH2)3-, or -CH=CH-CH=CH-, then e.g. Ar

(see for example Example 186). Preferably, in these cases -(CH2)n10-Ar is -CH2-Ar.
In R5, R15, R6, R7, R17, R18, R9, Rl3, R13a, and/or Rl9, independent of each other,
the phenyl and/or benzyl is/are preferably independently optionally substituted by one
substituent; or more preferably the phenyl and/or benzyl is/are not substituted. In R*0
and/or R11, independent of each other, the phenyl, benzyl and/or -CH(C1-2alkyl)Ph
is/are preferably independently optionally substituted by one substituent; or more
preferably the the phenyl, benzyl and/or -CH(C1-2alkyl)Ph is/are not substituted. In Ar,
the phenyl and/or the heterocyclic aromatic ring is/are preferably independently
optionally substituted by one substituent; or more preferably the phenyl and/or the
heterocyclic aromatic ring is/are not substituted. In Het1 and/or Het2, independent of
each other, the saturated heterocyclic ring is/are preferably independently optionally
substituted on a ring carbon by one substituent; or more preferably the saturated
heterocyclic ring is/are not substituted on a ring carbon.

When Het is of sub-formula (v), then suitably R^2 and/or R.Y2 independently is/are: a
hydrogen atom (H), C1-2alkyl (e.g. C1-2alkyl such as methyl), C3-6cycloalkyl,
-C(O)-NR10R11, -C(O)-ORl3, or -(CH2)nl0-Ar, more preferably H, C1-6alkyl,
-C(O)-NR10R11, -C(O)-ORl3, or-(CH2)n10-Ar; still more preferably H, C1-6alkyl (e.g.
C1-4alkyl such as methyl), -C(O)-NR10Rl 1, or -(CH2)n10-Ar. In this instance, i.e.
when Het is of sub-formula (v), then Ar is preferably optionally substituted phenyl and/or
n^ is preferably 0 or 1.
Preferably, RX1 and/or RY1 independently is/are a hydrogen atom (H) or C1-2alkyl,
more preferably H or methyl, still more preferably H.
Suitably, Y$ can be CH2 or CMe2- More preferably, Y5 is CH2, i.e. CRY1RY2 wherein
RYl = RY2 = a hydrogen atom (H).
X5 can suitably be CHRX2 or CMe2, for example CHMe, CH-CO2Me or CMe2-
It is particularly preferred that the compound of formula (I) or the salt thereof is:



















A second aspect of the present invention provides a compound of formula (IA) or a salt
thereof (in particular, a pharmaceutically acceptable salt thereof):
wherein:
R1 is C1-4alkyl, C1-2fluoroalkyl or -(CH2)2OH;
R2 is a hydrogen atom (H), methyl or C1fluoroalkyl;
R3 is optionally substituted branched C3-6alkyl, optionally substituted C3-8cycloalkyl,
optionally substituted phenyl, or an optionally substituted heterocyclic group of sub-
formula (aa). (bb) or (cc):

in which n1 and n2 independently are 1 or 2; and Y is O, S, SO2, or NR4; where R4 is a
hydrogen atom (H), C1-2alkyl, C1-2fluoroalkyl, CH2C(O)NH2, C(O)NH2,
C(O)-C1-2alkyl, or C1-2-C1fluoroalkyl;
wherein in H? the optionally substituted branched C1-2galkyl is optionally substituted with
one or two substituents being oxo (=O), OH, C1-2alkoxy or C1-2fluoroalkoxy; and
wherein any such substituent is not substituted at the R3 carbon atom attached (bonded)
to the -NH- group of formula (IA);
wherein in R3 the phenyl is optionally substituted with one substituent being fluoro,
chloro, C1-2alkyl, C1-2fluoroalkyl, C1-2alkoxy, C1-2fluoroalkoxy or cyano;
wherein in R3 the C3-8cycloalkyl or the heterocyclic group of sub-formula (aa), (bb) or
(cc) is optionally substituted with one or two substituents being oxo (=O), OH,
C1-2alkoxy, C1-2fluoroalkoxy, or C1-2alkyl; and wherein any OH, alkoxy or

fluoroalkoxy substituent is not substituted at the R3 ring carbon attached (bonded) to the
-NH- group of formula (IA) and is not substituted at either R3 ring carbon bonded to the
Y group of the heterocyclic group (aa), (bb) or (cc);
and wherein Het is of sub-formula (i), (ii), (in), (iv) or (v):

wherein:
W1, W2, W4 and W5 is N; and W3 is NRW;
X1, X3 and X4 is N or CRX; X2 is O, S or NRX; and X5 is CRX1RX2;
Yl, Y2 and Y3 is CRY or N; Y4 is O, S or NRY ; and Y5 is CRY1RY2;
Z1 and Z5 is O, S or NRZ; and Z2, Z3 and Z4 is N or CRZ;
wherein:
RW is a hydrogen atom (H) or C1-2alkyl;
Rx, RX2, RY and RY2 independently are:
a hydrogen atom (H);
C1-2alkyl;
C3-6cycloalkyl optionally substituted by a C1-2alkyl group;
-(CH2)n2a-C3-6cycloalkyl optionally substituted, in the -(CH2)n2a- moiety or in
the C3-6cycloalkyl moiety, by a C1-2alkyl group, wherein n2a is 1,2 or 3;
-(CH2)n3-SO2-R5 wherein n3 is 1 or 2 and R5 is C1-3alkyl or -NH-C1-2alkyl or
phenyl;
-(CH2)n4-NR6R7 wherein n4 is 0,1, 2 or 3, and R6 and R7 independently are H,
C1-6alkyl e.g. C1-2alkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl,
-C(O)-C1-2alkyl, -SO2-C1-2alkyl, phenyl, or benzyl (wherein the phenyl or
benzyl are independently optionally substituted on the aromatic ring by one of
fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy); or
R6 and R7 together are -(CH2)n5-X5-(CH2)n6- in which n5 and n6

independently are 2 or 3 and X5 is a bond, -CH2-, O, or NR8 wherein R8 is H
orC1-2alkyl;
-(CH2)n7-0-R9; wherein n7 is 0,1, 2 or 3 and R9 is H or C1-2alkyl; wherein n7 is
0 only when the -(CH2)n7-0-R9 is bonded to a carbon atom in the Het ring;
and wherein n7 is not 0 when Het is of sub-formula (v) (i.e. n7 is not 0 for
RX2andforRY2);
-C(O)-NR10R11 wherein R10 and R11 independently are H, C1-6alkyl,
C3-6cycloalkyl, -CH2-C3-6cycloalkyl, phenyl, or benzyl (wherein the phenyl
or benzyl are independently optionally substituted on the aromatic ring by one
of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy);
or Rl 0 and R1! together are -(CH2)n8-X6-(CH2)n9- in which n8 and n9
independently are 2 or 3 and X6 is a bond, -CH2-, O, or NR12 wherein R12 is
HorC1-2alkyl;
-C(O)-OR13 wherein R13 is H, C1-2galkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl,
phenyl, or benzyl (wherein the phenyl or benzyl are independently optionally
substituted on the aromatic ring by one of fluoro, chloro, C1-2alkyl,
C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy);
-C(O)-Rl3a wherein R13a is a hydrogen atom (H), C1-6alkyl, C1fluoroalkyl,
C3-6cycloalkyl, -CH2-C3-6cycloalkyl, benzyl, or phenyl; wherein the phenyl
or benzyl are independently optionally substituted on the aromatic ring by one
of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, Cj^alkoxy or C1fluoroalkoxy;
a 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing one O ring atom or
one NR14 ring group wherein R14 is H or C1-4alkyl, said heterocyclic ring
being optionally substituted (at a position or positions other than any NR14
position) by one oxo (=O) and/or one C1-2alkyl substituent; or
-(CH2)n10-Ar wherein n10 is 0,1 or 2 and
(i) Ar is phenyl optionally substituted by one or two substituents being fluoro,
chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy or cyano;
or
(ii) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic
ring containing 1,2 or 3 heteroatoms selected from O, N or S; and wherein
when the heterocyclic aromatic ring Ar contains 2 or 3 heteroatoms, one is
selected from O, N and S and the remaining heteroatom(s) are N; and wherein
the heterocyclic aromatic ring Ar is optionally substituted by one or two
C1-4alkyl groups;
RX1 and RY1 independently are a hydrogen atom (H), C1-2alkyl or C1fluoroalkyl; and
RZ is a hydrogen atom (H) or C1-2alkyl.

Preferably, in formula (IA), when R3 is the heterocyclic group of sub-formula (bb), n1 is
1, and Y is NR4, then R4 is not C1-2alkyl, C1-2fluoroalkyl or CH2C(O)NH2.
Examples 1-48 are examples of compounds or salts of the second aspect of the invention
(Formula (IA)).
The preferred or optional features for the compound of formula (IA) or salt thereof 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), 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, formic, acetic, propionic,
fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic,
benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-
naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic
solvent, to give the salt which is usually isolated for example by crystallisation and
filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I)
can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate,
maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate,
salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate,
ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt.
In one embodiment, the pharmaceutically acceptable acid addition salt can be 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 (e.g. triethylamine,
ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a
suitable solvent such as an organic solvent, to give the base addition salt which is usually
isolated for example by crystallisation and filtration.

Other suitable pharmaceutically acceptable salts include pharmaceutically
acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-
earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular
pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may
be present in the the compound of formula (I).
Other non-pharmaceutically acceptable salts, eg. oxalates, may be used, for
example in the isolation of compounds of the invention, and are included within the scope
of this invention.
The invention includes within its scope all possible stoichiometric and non-
stoichiometric forms of the salts of the compounds of formula (I).
Also included within the scope of the invention are all solvates, hydrates and
complexes of compounds and salts of the invention.
Certain groups, substituents, compounds or salts included in the present invention
may be present as isomers. The present invention includes within its scope all such
isomers, including racemates, enantiomers and mixtures thereof.
Certain of the groups, e.g. heteroaromatic ring systems, included in compounds
of formula (I) or their salts may exist in one or more tautomeric forms. The present
invention includes within its scope all such tautomeric forms, including mixtures. For
example, when Het is of sub-formula (i), Y1 is CRY, and X1 is CRX wherein RX is OH,
then the compounds of formula (I) or their salts include the keto form (Kl), the enol form
(El), and mixtures thereof, as shown below, unless otherwise indicated; and when Het is
of sub-formula (i) and Y1 is CRY wherein RY is OH, then the compounds of formula (I)
or their salts include the keto form (K2), the enol or hydroxy-imine form (E2), and
mixtures thereof, as shown below, unless otherwise indicated:

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 formula (I) The
methods are sometimes illustrated for the circumstance where R2 is H or Me. However,

some or all of these processes are thought to be usable with appropriate modification, e.g.
of starting materials and reagents, for making compounds of Formula (I) wherein R2 is
C1fluoroalkyl.
Process A
Compounds of formula (T) which are compounds of Formula I(ia) (that is, compounds of
formula (I) wherein Het is of sub-formula (ia)) can be prepared by the cyclisation reaction
of a compound of Formula II, for example in the presence of a dehydrating agent such as
phosphorous oxychloride (POCl3) or Burgess reagent
[(Methoxycarbonylsulphamoyl)triethylammonium hydroxide], and/or preferably in a
suitable solvent (e.g. organic solvent, preferably anhydrous) such as acetonitrile (e.g. for
POCl3) or THF and/or DMF (e.g. for Burgess reagent). The reaction may require heating,
for example heating to from about 70 to about 150 °C or heating to from about 70 to
about 120 °C or heating to from about 70 to about 90 °C:

For the Formula II to Formula I(ia) cyclisation reaction, the conditions can for example
be as described in (a) Examples 1-3 or 43 (POCl3 and acetonitrile), or (b) in Examples
32, 34-37, 35 (alternative synthesis), 38-40,44, 66 or 97-125 (Burgess reagent, with THF
and/or DMF).
Compounds of Formula II may themselves be prepared by reacting a compound of
Formula HI with a suitably substituted hydrazine derivative of formula RYCONHNH2,
under standard coupling conditions. For example a coupling reagent such as
1-(3-dimemylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) may be used e.g.
in the presence of hydroxybenzotriazole (HOBT), for example in a suitable solvent such
as DMF:


Where the required hydrazine derivative RYCONHNH2 is not readily available,
compounds of Formula II may alternatively be prepared by initially reacting a compound
of Formula m with a carbazate ROCONHNH2 such as t-butylcarbazate tBuOCONHNH2
under coupling conditions to form a compound of formula IV. For example a coupling
reagent such as EDC may be used, e.g. in the presence of hydroxybenzotriazole, for
example in a suitable solvent such as DMF:

Subsequent Boc-deprotection of the resultant acid hydrazide derivative (compound of
Formula IV) to afford a hydrazide derivative of Formula V, can be achieved using a
dilute acid such as 2M hydrochloric acid in an organic solvent such as dioxane.
The compound of Formula V can be converted to the compound of Formula II (the
desired hydrazide derivative). This can be achieved by reaction of the compound of
Formula V with an acid of formula RYCO2H under coupling conditions. For example a
coupling agent such as EDC may be used e.g. in the presence of hydroxybenzotriazole

(HOBT), for example in a suitable solvent such as DMF. Alternatively, an activated acid
derivative of formula RYCO-X10 where X is a leaving group such as chloro (acid
chloride) or -O-CO-R30 or -O-SO2-R30 (where R30 can e.g. be RY or alkyl or aryl such
as methyl, t-butyl or p-methylphenyl) may be used to effect formation of a hydrazide of
Formula II, through reaction with a hydrazide derivative of Formula V.
Compounds of Formula EI can be prepared by hydrolysis of an ester of Formula VI (for
example RA can be C1-2alkyl such as Et), for example according to the method
described by Yu et. al. in J. Med Chem., 2001, 44,1025-1027. This hydrolysis procedure
usually involves reaction with a base such as sodium hydroxide or potassium hydroxide
in a solvent such as ethanol or dioxane (e.g. NaOH in EtOH), one or both solvents
preferably containing some water:

Compounds of Formula VI can be prepared, e.g. according to the method described by
Yu et. al. in J. Med Chem., 2001,44,1025-1027, by reaction of a compound of Formula
VII with an amine of Formula R3R3aNH. The reaction is best carried out in the presence
of abase such as trieraylamine or diisopropylethyl amine in a solvent such as ethanol or
dioxane (e.g. NEta in EtOH) and may require heating:

Many amines of Formula R3R3aNH, e.g. those amines wherein R3R3aN are of sub-
formulae (a) to (t2), are either commercially available, or syntheses therefor have been
published and/or described herein, or they can be prepared from commercially available
or synthesizable compounds e.g. from other amines of Formula R3R3aNH or derivatives
thereof. For amines R3R3aNH whose preparations and/or specific commercial sources
are described herein, see e.g. Intermediates 21,21A, 25, 50, 54-57, and 140-163.

Compounds of Formula VII are also described in the above reference and can. be prepared
first by reaction of a compound of Formula VIH with, for example, diethyl
(ethoxymethylene)malonate (R2 = H, to afford RA = Et) or diethyl
2-(1-ethoxyethylidene)malonate (R2 = Me, to afford RA = Et), e.g. with heating,
followed by reaction with phosphorous oxychloride, again preferably with heating. See
for example Intermediate 1 synthesis and G. Yu et. al., J. Med Chem., 2001,44,1025-
1027 hereinafter, where R2 = H and R1 = ethyl; and see Intermediate 58 synthesis
hereinafter where R2 = Me and R1 = ethyl:

Where, for example, the desired amino pyrazole of Formula Vm is not commercially
available, preparation of the Formula VIH pyrazole can be achieved, for example using
methods described by Dorgan et. al. in J. Chem. Soc, Perkin Trans. 1980,1 (4), 938-42,
involving reaction of cyanoethyl hydrazine with a suitable aldehyde R1aCHO in a solvent
such as ethanol, with heating, followed by reduction, for example reduction with sodium
in a solvent such as t-butanol. R1a should be chosen so as to contain one less carbon atom
than R1, for example Rla= methyl will afford R1 = ethyl.

Alternatively, e.g. where the desired amino pyrazole of Formula VIII is not commercially
available, preparation of the compound of Formula VI can be achieved from the
compound of Formula VII (e.g. Intermediate 1 wherein Rl = ethyl), using a generalised
version of the reaction scheme shown in Example 43, especially that part relating to
conversion of Intermediate 1 to Intermediate 38. In this method: the 4-chloro
pyrazolopyridine of Formula VII (e.g. Intermediate 1) is optionally converted to the 4-
alkoxy (e.g. C1-4alkoxy such as ethoxy) pyrazolopyridine (e.g. Intermediate 35); the R1
group is removed (to e.g. Intermediate 36 wherein R^ is H rather than alkyl), the 4-amino
R3R3aN group is inserted by displacing the 4-chloro or 4-alkoxy group by reaction with
R3R3aNH (e.g. to Intermediate 37); and the pyrazolopyridine is alkylated at N-1 by
reacting it with R1-X40 where X40 is a group displaceable by the N-1 nitrogen of the
pyrazolopyridine in order to re-insert the desired R1 group (e.g. Intermediate 38

synthesis). X40 can for example be a halogen, e.g. CI, Br or I; or X40 can be
-O-SO2-R40 where R40 is C1-2alkyl, C1-2fluoroalkyl, or phenyl optionally substituted
by C1-2alkyl.
Process B
Compounds of formula (I) which are compounds of Formula I(ia) (that is, compounds of
formula (I) wherein Het is of sub-formula (ia)) can alternatively be prepared by reaction
of a compound of Formula IX with an amine of formula R3R3 aNH, preferably in a
solvent (e.g. organic solvent) such as ethanol or acetonitrile, and/or preferably in the
presence of a base such as DIPEA. Heating may be required to effect the conversion:

For the reaction of a compound of Formula DC with an amine of formula R3R3aNH to
prepare the compound of Formula I(ia), the reaction conditions, e.g. solvents, mole ratios,
temperatures and/or reaction times, can optionally be as described in Examples 9,10-11
and/or 12-27.
The reaction of Formula DC with R3R3aNH to give Formula I(ia) can be generalised for
any compound of Formula (I), containing any Het group as defined herein, starting from a
compound of Formula DCa:

Compounds of Formula DC can themselves be prepared by cyclisation of a compound of
Formula X, preferably in the presence of a dehydrating agent such asphosphorous
oxychloride or Burgess reagent [(Methoxycarbonylsulphamoyl)triethylammonium
hydroxide], in a suitable solvent (e.g. organic solvent, preferably anhydrous) such as

acetonitrile (e.g. for POCl3) or THF and/or DMF (e.g. for Burgess reagent). The reaction
may require heating, for example heating to from about 70 to about 150 °C or heating to
from about 70 to about 120 °C or heating to from about 70 to about 90 °C:

Compounds of Formula X can be prepared by initial activation of an acid of Formula XI,
for example with an amide coupling reagent such as EDC/HOBT or with thionyl chloride,
followed by reaction of the thus formed activated intermediate with an acid hydrazide of
Formula RYCONHNH2:

Examples of reactions of the compound of Formula XI to Formula X and of the
compound of Formula X to Formula DC are presented in Intermediates 12 to 15.
Acids of Formula XI can themselves be prepared by hydrolysis of an ester of Formula
VII (e.g. as described in Process A) using a base such as potassium hydroxide in a solvent
such as aqueous dioxane dioxane/water):

Process C
Compounds of Formula XII (that is, compounds of formula (I) wherein Het is of
sub-formula (ib)) can be prepared by reaction of a compound of Formula II with a reagent

capable of inserting sulfur, such as Lawesson's reagent, usually in a suitable solvent such
as acetonitrile. The reaction may require heating:

The reaction conditions, e.g. solvents, mole ratios, temperatures and/or reaction times,
can optionally be as described in Examples 4, 5 or 6.
Process D
Compounds of Formula XIII [which are compounds of formula (I) wherein Het is of
sub-formula (ic)] can be prepared by reaction of a compound of Formula VI (RA can be
C1-2alkyl such as Et) with an amidoxime of formula RXC(=NOH)NH2 , preferably in the
presence of a base such as sodium ethoxide and/or preferably in a suitable solvent (e.g.
anhydrous and/or organic solvent) such as ethanol, and preferably in the presence of
molecular sieves (e.g. 4 Angstrom and/or powdered molecular sieves) or under other
conditions effective for removing water. The reaction mixture may optionally be heated,
for example to reflux:

The reaction conditions, e.g. solvents, mole ratios, temperatures and/or reaction times,
can optionally be as described in Examples 7,28-29, 30, 31,48, 82-84, 92, 93 and/or
178-187.
Process E
Compounds of Formula XTV (which are compounds of formula (I) wherein Het is of
sub-formula (if)) can be prepared by reaction of a compound of Formula XV with a
suitable acetimidate Rx-C(=NH)ORE, where RE is C1-6alkyl e.g. methyl, (such as

methyl acetimidate (Rx = Me)), preferably in the presence of a base (such as
triethylamine or sodium ethoxide) and/or in a suitable solvent (e.g. anhydrous and/or
organic solvent) such as ethanol:

Compounds of Formula XV may themselves be prepared by reaction of a compound of
Formula m with a suitably substituted hydrazine derivative of Formula RZNHNH2, under
coupling conditions. For example a coupling agent such as EDC may be used, e.g. in the
presence of hydroxybenzotriazole (HOBT), in a suitable solvent such as DMF:

Process F
To make a compound of formula (I) wherein Het is of sub-formula (id) (optionally
substituted l,3-oxazo1-2-yl), methods known to the skilled person can be used.
For example, the 5-carboxylic acid compound of Formula HI can be converted directly or
indirectly to a compound of formula (I) wherein Het is of sub-formula (id) (i.e. to a 5-
(optionally-substituted l,3-oxazo1-2-yl)-pyrazolopyridine). Alternatively or additionally,
a compound of formula (I), wherein Het is of sub-formula (va) in which RX1 and RY1
are H and RX1 is RX and RY1 is RY [i.e. the corresponding 5-(optionally-substituted
4,5-dihydro-l,3-oxazo1-2-yl)-pyrazolopyridine], can be dehydrogenated to a compound of
formula (I) wherein Het is of sub-formula (id); e.g. by the method shown in Example 41
(DBU, CCl4, CH3CN, Pyridine) or a modification of this method or by an analogous
method for example using an oxidising agent.
The dehydrogenation (oxidation) of the 4,5-dihydro-l,3-oxazo1-2-yl compound of
formula (I) (wherein Het is of sub-formula (va) in which RX1 and RY1 are H and RX1 is
RX and RY1 is RY) to the corresponding l,3-oxazo1-2-yl compound of formula (I)

wherein Het is of sub-formula (id) can be carried out using reagents and conditions
known to the skilled man (see for example the following reviews: T.G. Gant et al.,
Tetrahedron, 1994, 50(8), 2297-2360; MLReuman et al., Tetrahedron, 1985,41(5), 837-
860; and references cited therein). For this dehydrogenation reaction, preferably an
oxidising agent is used such as nickel peroxide, manganese dioxide (MnO2), or 2,3-
dichloro-5,6-dicyano-l ,4-benzoquinone (DDQ).
A compound of formula (I) wherein Het is of sub-formula (va) can be prepared by
cyclisation of a compound of Formula XXVIII, for example in the presence of Burgess
reagent and/or preferably in a suitable solvent (e.g. organic solvent, preferably
anhydrous) such as THF.

The compound of Formula XXVH1 can be prepared from the compound of Formula III
by reaction with the compound of Formula XXIX under coupling conditions (e.g. EDC
with or without HOBT), optionally in the presence of a base such as Et3N, and preferably
in a suitable solvent such as DMF.
Process G
Compounds of the invention of Formula XVI (1,2,4-oxadiazoles), which are compounds
of formula (I) wherein Het is of sub-formula (ic) and Rx is -CH2C(O)NR10R11 can be
prepared by reaction of a compound of the Formula XVII with an amine of Formula

R10R11NH, under coupling conditions. Standard coupling conditions can be used
known to the skilled person. For example a coupling agent such as TBTU may be used,
preferably in the presence of hydroxybenzotriazole. However, it is more preferable that
the coupling agent is oxalyl chloride, which in the reaction forms the corresponding acid
chloride from the carboxylic acid of the compound of Formula XVII; in this embodiment
it is preferable that the acid chloride is not isolated, i.e. the solvent in which it is formed
is preferably not removed to a substantial extent. Preferably, whatever the coupling agent
/ coupling conditions, the reaction is carried out in the presence of a base such as
diisopropylethylamine, and/or in a suitable solvent (e.g. organic solvent, preferably
anhydrous) such as DMF and/or dicloromethane.

The reaction conditions for the Formula XVII to Formula XVI reaction, e.g. solvents,
mole ratios, temperatures and/or reaction times, can optionally be as described in
Examples 85-90, 95-96 and/or 148-155.
Compounds of Formula XVII may themselves be prepared by reaction of a compound of
Formula XVIII (RG is preferably tBu) with a hydrolysing agent (e.g. an acid such as
trifluoroacetic acid) in a solvent such as dichloromethane:

Compounds of Formula XVIII can be prepared by reaction of a compound of Formula VI
(RA = H) with an amidoxime of formula RGOC(=O)CH2C(=NOH)NH2 and a coupling
agent, for example TBTU, preferably in the presence of hydroxybenzotriazole, preferably
in the presence of a base such as diisopropylemylamine and/or in a suitable solvent such
as DMF, followed by reaction with l,l'-carbonyldiimidazole:


Process H
Compounds of Formula XIX, which are compounds of formula (I) wherein Het is of
sub-formula (ic) and Rx is -CH2-NR6R7 wherein R7 is C(O)R17, may be prepared from
compounds of Formula XX. For example, this can be by reaction of the compound of
Formula XX with a carboxylic acid R17COOH in the presence of a coupling agent, for
example TBTU, preferably with hydroxybenzotriazole, and preferably in the presence of
a base such as diisopropylethylamine in a suitable solvent such as DMF. Alternatively or
additionally, the compound of Formula XX can be reacted with an activated derivative of
the carboxylic acid moiety of R17COOH (e.g. by reaction with an acid chloride
R17C(O)Cl), preferably in the presence of a base such as diisopropylethylamine and/or in
a suitable solvent (e.g. organic) such as dichloromethane and/or chloroform.

The reaction conditions for the Formula XX to Formula XIX reaction, e.g. solvents, mole
ratios, temperatures and/or reaction times, can optionally be as described in any of
Examples 159-165.
Compounds of Formula XX, which are compounds of formula (I) wherein Het is of
sub-formula (ic) and RX is -CH2-NR6R7 wherein R7 is H, may be prepared by
deprotecting compounds of Formula XXI wherein RH is benzyl or C1-6alkyl such as tBu
e.g. by reaction with an acid such as trifluoroacetic acid (e.g. where RH is C1-2galkyl
such as tBu) or by hydrogenation (e.g. where RH is benzyl), preferably in a suitable
solvent such as dichloromethane:


Compounds of Formula XXI can be prepared by reaction of a compound of Formula VI
(but wherein RA is OH) with an amidoxime of formula
RHOC(=O)N(R6)CH2C(=NOH)NH2 and a coupling agent, for example TBTU, preferably
in the presence of hydroxybenzotriazole, and preferably in the presence of a base such as
diisopropylethylarnine, and/or preferably in a suitable solvent such as DMF, followed by
reaction with a base such as l,8-diazabicyclo[5.4.0]undec-7-ene:

Process I
Compounds of Formula XXII, which are compounds of formula (I) wherein Het is of
sub-formula (ic) and RX is -CH2-NR6R7 wherein R7 is -S(O)2R18, may be prepared
from compounds of Formula XX by reaction with a sulphonyl chloride Rl8S(O)2Cl,
preferably in the presence of a base such as triethylamine and/or pyridine, and/or
preferably in a suitable solvent (e.g. organic) such as dichloromethane and/or chloroform:

The reaction conditions, e.g. solvents, mole ratios, temperatures and/or reaction times,
can optionally be as described in any of Examples 166-172.

Process J
Compounds of Formula XXHI are compounds of formula (I) wherein Het is of
sub-formula (ic) and Rx is -CH2-NR6R7, wherein R6 and R7 together are
-(CH2)n5-X5-(CH2)n6- in which n5 and n6 independently are 2 or 3, and wherein the
ring formed by NR6R7 is substituted by one oxo (=O) substituent at a carbon atom within
(CH2)n6 which carbon atom is bonded to the nitrogen.
Compounds of Formula XXIII can be prepared by reaction of a compound of the type
Formula XX wherein R6 = H with acid chlorides of the type
xJ-(CH2)n5-X5-(CH2)(n6-1)-COCl, where XJ is a leaving group, preferably in the
presence of a base such as triemylamine and/or preferably in a suitable solvent, for
example dichloromethane or tetrahydrofuran, preferably followed by treatment with a
base such as sodium hydride in a suitable solvent such as DMF. The leaving group XJ
can for example be a halogen atom such as CI, Br or I; or X^ can for example be
-O-SO2-RJ where RJ is C1-4alkyl, C1-2fluoroalkyl, or phenyl optionally substituted by
C1-2alkyl e.g. 4-methylphenyl.

For examples of reaction conditions for the Formula XX to Formula XXIII reaction, see
for example Intermediates 119 and/or 120 and/or subsequent Examples 173 and/or 174.
Process K
Compounds of the type Formula XXIV, which are compounds of formula (I) wherein Het
is of sub-formula (iia), can be prepared from compounds of the type Formula XXV by
reaction with R^C(O)X^ where X& is a leaving group, preferably in a solvent such as
acetic acid, pyridine, diglyme and/or dichloromethane. XK can for example be chloro;
or RYC(O)XK can be an anhydride such as [RY(C=O)]2O; or RYC(O)XK can be an
activated carboxylic acid derivative prepared from the reaction of RYC(O)OH with a
coupling reagent such as EDC or TBTU with or without the presence of HOBT.


For the Formula XXV to Formula XXW reaction, the reaction conditions can for
example be as described in Examples 188,189 and/or 190.
Compounds of the type Formula XXV can be prepared from compounds of the type
Formula XXVI by reaction with hydroxylamine or a hydroxylamine salt, preferably in the
presence of a base such as potassium carbonate, sodium alkoxide or a tertiary amine,
and/or preferably in a suitable solvent such as ethanol or methanol:

Compounds of the type Formula XXVI may themselves be prepared from compounds of
Formula XXVII by reaction with a dehydrating agent such as Burgess Reagent,
preferably in a solvent, for example tetrahydrofuran:

Compounds of the type Formula XXVII can be prepared from carboxylic acid
compounds of Formula IE, for example by reaction with thionyl chloride followed by
ammonia in a suitable solvent such as dioxane:


Process L - Conversion of a compound of formula (I) or a salt thereof into a
different compound of formula (I) or a salt thereof
One compound of formula (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 LI to L10:
LI. An oxidation process. For example, the oxidation process can comprise or be
oxidation of an alcohol to a ketone (e.g. using Jones reagent) or oxidation of an alcohol or
a ketone to a carboxylic acid.
L2. A reduction process, for example reduction of a ketone or a carboxylic acid to an
alcohol.
L3. Acylation, for example acylation of an amine or of a hydroxy group.
L4. Alkylation, for example alkylation of an amine or of a hydroxy group.
L5. Hydrolysis, e.g. hydrolysis of an ester to the corresponding carboxylic acid or salt
thereof, for example in the presence of base (e.g. alkali-metal hydroxide, preferably also
in the presence of water) or in the presence of acid (e.g. aqueous HCl, or HCl in an
anhydrous organic solvent such as dioxane).
The hydrolysis can for example be hydrolysis of an ester compound, in which RX,
RX2, RY or RY2 is -(CH2)n12-C(O)-OR13 wherein R13 is not a hydrogen atom (H), to
the corresponding carboxylic acid wherein R13 is a hydrogen atom (H). See for example
Example 57 and Intermediate 83.
The hydrolysis can for example be hydrolysis of an ester compound, wherein R3
is substituted by -C(O)OR23 in which R23 is C1-2alkyl (e.g. NHR3 or NR3R3a is of
sub-formula (p8)), to the corresponding carboxylic acid or salt thereof wherein R23 is H
(e.g. NHR3 or NR3R3a is of sub-formula (p7)).
L6. Deprotection, e.g. deprotection (e.g. deacylation or t-butyloxycarbonyl (BOC)
removal or benzyloxycarbonyl removal) of an amine group.

L7. Formation of an ester or amide, for example from the corresponding carboxylic acid
and/or an activated derivative of the carboxylic acid (e.g. acid chloride or acid anhydride
or carboxylic acid activated by a coupling agent).
The amide formation can be formation of an amide compound, in which one or
more of Rx, RX2, RY and RY2 is -(CH2)n1 1-C(O)-NR10Rl 1,
-CH(C1-2alkyl)-C(O)-NR10R11, -CMe2-C(O)-NR10R11 or cycloalkyl substituted by
-C(O)-NR10R11, from the corresponding carboxylic acid and/or an activated derivative
of the carboxylic acid. For examples of this amide formation, see Examples 58-59 and/or
126-147 for Het = sub-formula (id), and/or Process G herein for Het = sub-formula (ic)
(e.g. Examples 85-90, 95-96 and/or 148-155).
The amide formation can alternatively be formation of an amide compound, in
which one or more of Rx, RX2, RY and RY2 is -(CH2)n4-NR6R7,
-CH(C1-2alkyl)-NR6R7, -CMe2-NR6R7 or cycloalkyl substituted by -NR6R7, wherein
R6 is C(O)R17, from the corresponding carboxylic acid and/or an activated derivative of
the carboxylic acid. For one example where Het is of sub-formula (ic) see Process H
and/or Examples 159-165.
L8. Conversion of a ketone into the corresponding oxime or oxime ether. This can for
example include conversion of an oxo (=O) substituent within R3, e.g. within the NHR3
or NR3R3a sub-formula (o), into anhydroxyimino (=N-OH) or (C1-4alkoxy)imino
(=N-OR26) substituent within R3, e.g. within the NHR3 or NR3R3a sub-formula (o2),
(o3), (o4) or (o5). This conversion can be carried out in the case of an oxime
(hydroxyimino, =N-OH) by reacting hydroxylamine or a salt thereof (e.g. hydroxylamine
hydrochloride) with the ketone, or in the case of an oxime ether (C1-4alkoxy)irmno,
=N-OR26) by reacting C1-4alkoxylamine or a salt thereof (e.g. hydrochloride salt) with
the ketone. The reaction is preferably carried out in the presence of a base such as
anhydrous potassium carbonate or diisopropylethylarnine and/or in a suitable solvent such
as acetonitrile. The mixture can be heated e.g. to reflux.
L9. Sulfonylation, e.g. sulfonamide formation by reaction of an amine with a sulfonyl
halide e.g. a sulfonyl chloride (e.g. see also Process I).
and/or
L10. Beckmann rearrangement of one compound of formula (I) into another compound
of formula (I). Preferably, this uses cyanuric chloride (2,4,6-trichloro-l,3,5-triazine)
together with a forrnamide such as DMF, e.g. at room temperature (see L.D. Luca, J. Org.
Chem., 2002, 67, 6272-6274). The Beckmann rearrangement can for example comprise
conversion of an (hydroxyimino)cycloalkyl compound of formula (I), e.g. wherein NHR3

or NR.3R3 a is of sub-formula (o2) , into a single-atom-ring-expanded
lactam compound of formula (I), e.g. wherein NHR3 or NR3R3a is of sub-formula (m3)
The present invention therefore also provides a method of preparing a compound of
formula (I) or a salt thereof, comprising:
(a) cyclisation of a compound of formula II to a compound of formula (I) wherein Het is
of sub-formula (ia) (that is: to a compound of Formula I(ia), i.e. to an optionally
substituted l,3,4-oxadiazo1-2-yl derivative at the 5-position of the pyrazolopyridine ring
system), for example in the presence of a dehydrating agent such as phosphorus
oxychloride or Burgess reagent, or
(b) reaction of a compound of formula IXa with an amine of formula R3R3aNH to form a
compound of formula (I), preferably in a solvent (e.g. organic solvent) and/or preferably
in the presence of a base, or
(c) cyclisation of a compound of formula II to a compound of formula (I) wherein Het is
of sub-formula (ib) (i.e. to a compound of Formula XII i.e. to an optionally substituted
l,3,4-thiadiazo1-2-yl derivative at the 5-position of the pyrazolopyridine ring system), for
example in the presence of an agent capable of introducing sulfur such as Lawesson's
reagent, or
(d) reaction of a compound of formula VI, wherein RA is C1-2alkyl such as Et, with an
amidoxime of formula RXC(=NOH)NH2 or a salt thereof, preferably in the presence of a
base such as sodium ethoxide and/or preferably in a suitable solvent (e.g. anhydrous
and/or organic solvent) such as ethanol; or
(e) reaction of a compound of formula XV with an acetimidate RX-C(=NH)ORE, where
RE is C1-6alkyl, to prepare a compound of formula (I) wherein Het is of sub-formula (if)
(i.e. to a compound of Formula XIV, i.e. to an optionally substituted 1,2,4-triazo1- 3-yl or
5-yl derivative at the 5-position of the pyrazolopyridine ring system), preferably in the
presence of a base (such as Iriemylamine or sodium ethoxide) and/or in a suitable solvent
(e.g. anhydrous and/or organic solvent) such as ethanol; or

(f)(i) converting directly or indirectly a compound of Formula HI to a compound of
formula (I) wherein Het is of sub-formula (id); and/or (f)(ii) dehydrogenating a
compound of formula (I), wherein Het is of sub-formula (va) in which RXl and R^l are
H and RX1 is RX and RY1 is RY
to a compound of formula (T) wherein Het is of sub-
formula (id); or
(f)(iii) cyclisation of a compound of Formula XXVIII, for example in the presence of
Burgess reagent and/or preferably in a suitable solvent, to prepare a compound of formula
(I) wherein Het is of sub-formula (va); or
(g) reaction of a compound of the Formula XVII with an amine of Formula R10R11NH
under coupling conditions, to prepare a compound of formula (I) wherein Het is of
sub-formula (ic) and RX is -CH2C(O)NR10R11 (i.e. to prepare a compound of Formula
XVT), the reaction preferably being carried out in the presence of a base such as
diisopropylethylamine, and/or preferably in a suitable solvent (e.g. organic solvent,
preferably anhydrous) such as DMF and/or dicloromethane, and/or preferably in the
presence of oxalyl chloride; or
(h) conversion of a compound of Formula XX into a compound of formula (I) wherein
Het is of sub-formula (ic) and Rx is -CH2-NR6R7 wherein R7 is C(O)R17 (i.e. into a
compound of Formula XIX), preferably either by reaction of the compound of Formula
XX with a carboxylic acid R17COOH in the presence of a coupling agent, and/or by
reaction of the compound of Formula XX with an activated derivative of the carboxylic
acid moiety of R17COOH (e.g. R17C(O)Cl), preferably in the presence of abase and/or a
suitable solvent; or
(i) reaction of a compound of Formula XX with a sulphonyl chloride R18S(O)2Cl to
prepare a compound of formula (I) wherein Het is of sub-formula (ic) and RX is
-CH2-NR6R7 wherein R7 is -S(O)2R18 (i.e. to prepare a compound of Formula XXII),
preferably in the presence of a base such as triethylamine and/or pyridine, and/or
preferably in a suitable solvent such as dichloromethane and/or chloroform; or
(j) reaction of a compound of Formula XX wherein R6 = H with an acid chloride of
formula XJ-(CH2)n5-X5-(CH2)(n6-1)-COCl, where XJ is a leaving group (XJ preferably
being a halogen atom or -O-SO2-RJ where RJ is C1-4alkyl, C1-2fmoroalkyl, or phenyl
optionally substituted by C1-2alkyl), to prepare a compound of formula (I) wherein Het is
of sub-formula (ic) and RX is -CH2-MR6R7, wherein R6 and R7 together are
-(CH2)n5-X5-(CH2)n6- in which n5 and n6 independently are 2 or 3, and wherein the
ring formed by NR6R7 is substituted by one oxo (=O) substituent at a carbon atom within
(CH2)n6 which carbon atom is bonded to the nitrogen (i.e. to prepare a compound of

Formula XXIII); the reaction preferably being in the presence of a base and/or in a
suitable solvent, and/or preferably being followed by treatment with a base; or
(k) reaction of a compound of Formula XXV with RYC(O)XK where XK is a leaving
group, to prepare a compound of formula (I) wherein Het is of sub-formula (iia) (i.e. to
prepare a compound of Formula XXTV); or
(L) conversion of a compound of formula (I) or a salt thereof into a different compound
of formula (I) or a salt thereof;
and optionally converting the compound, of formula (I) into a salt e.g. a pharmaceutically
acceptable salt.
Salt formation processes may optionally be as described elsewhere herein.
Preferred features of methods (a), (b), (c), (d), (e), (f)(i), (f)(ii), (f)(iii), (g), (h), (i), Q),
(k), and (L), independently of each other, are preferably as described above for Processes
A, B, C, D, E, F, G, H, I, J, K, and L with all necessary changes being made. For
example, the conversion process (L) preferably comprises or is one or more of processes
LI to L10 described herein, e.g. hereinabove.
In any of the methods which involve reaction of a carboxylic acid and/or an activated
carboxylic acid derivative with an amine to form an amide, the activated carboxylic acid
derivative preferably comprises a -C(O)X11 group in place of the COOH, wherein X11 is
a leaving group substitutable by an amine. For example X11 can be C1 (wherein the
activated derivative = the acid chloride) or -OC(O)R (wherein the activated derivative =
an anhydride). Alternatively, the activated carboxylic acid derivative can be an activated
ester wherein the leaving group X11 is

The latter activated carboxylic acid derivative can be formed from the carboxylic acid
(X11 = OH) 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 1-(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-(1H-benzotriazole-1-yl)-l,l,3,3-tetramethyluronium
tetrafluoroborate (TBTU) or O-(7-Azaberizotriazo1-1-yl)-N,N,N',N'-tetramethyluromum
hexafluorophosphate (HATU), preferably in the presence of abase such as
dusopropylethylamine (iPr2NEt = D1PEA), 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 present invention also provides: (m) 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.
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 formula (I) or a pharmaceutically
acceptable salt thereof for use as an active therapeutic substance in a mammal such as a
human. The compound or salt can be for use in the treatment and/or prophylaxis of any
of the diseases / conditions described herein (e.g. for use in the treatment and/or
prophylaxis of an inflammatory and/or allergic disease in a mammal) and/or for use as a
phosphodiesterase inhibitor e.g. for use as a phosphodiesterase 4 (PDE4) inhibitor.
"Therapy" may include treatment and/or prophylaxis.
Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable
salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the
treatment and/or prophylaxis of any of the diseases / conditions described herein in a
mammal such as a human, e.g. for the treatment and/or prophylaxis of an inflammatory
and/or allergic disease in a mammal such as a human.
Also provided is a method of treatment and/or prophylaxis of any of the diseases /
conditions described herein in a mammal (e.g. human) in need thereof, e.g. a method of
treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal
(e.g. human) in need thereof, which method comprises administering to the mammal (e.g.
human) a therapeutically effective amount of a compound of formula (I) as herein defined
or a pharmaceutically acceptable salt thereof.

Phosphodiesterase 4 inhibitors are thought to be useful in the treatment and/or
prophylaxis of a variety of diseases / conditions, especially inflammatory and/or allergic
diseases, in mammals such as humans, for example: asthma, chronic obstructive
pulmonary disease (COPD) (e.g. chronic bronchitis and/or emphysema), atopic
dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,
eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,
Crohn's disease, reperfusion injury of the myocardium and brain, chronic
glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple
sclerosis, cognitive impairment (e.g. in a neurological disorder such as Alzheimer's
disease), depression, or pain. Ulcerative colitis and/or Crohn's disease are collectively
often referred to as inflammatory bowel disease.
In the treatment and/or prophylaxis, the inflammatory and/or allergic disease is preferably
chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic
rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is
of COPD or asthma in a mammal (e.g. human).
PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see
M.A.Giembycz, Drugs, Feb. 2000, 59(2), 193-212; Z. Huang et al., Current Opinion in
Chemical Biology, 2001, 5: 432-438; H.J.Dyke et al., Expert Opinion on Investigational
Drugs, January 2002, 11(1), 1-13; C.Burnouf etal., 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 (SL 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; CBurnouf etal., 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., CNSDrug Reviews, 2001, 7(4), 387-398; O'Donnell, Expert
Opinion on Investigational Drugs, 2000,9(3), 621-625; andH.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 compound or salt with the one or more
pharmaceutically acceptable carriers and/or excipients.
The invention also provides a pharmaceutical composition prepared by said
method.
The compounds of formula (I) and/or the pharmaceutical composition may be
administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or
intramuscular), inhaled or nasal administration. Accordingly, the pharmaceutical
composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous, or
intramuscular), inhaled or nasal administration. More preferably, the pharmaceutical

composition is suitable for inhaled or oral administration, e.g. to a mammal such as a
human. Inhaled administration involves topical administration to the lung e.g. by aerosol
or dry powder composition. Oral administration to a human is most preferred.
A pharmaceutical composition suitable for oral administration can be liquid or
solid; for example it can be a syrup, suspension or emulsion, a tablet, a capsule or a
lozenge.
A liquid formulation will generally consist of a suspension or solution of the
compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable
liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or a
non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also
contain a suspending agent, preservative, flavouring and/or colouring agent.
In one preferable embodiment, the pharmaceutical composition is in unit dose
form such as a tablet or capsule for oral administration, e.g. for oral administration to a
human.
A pharmaceutical composition suitable for oral administration being a
tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients
suitable for preparing tablet formulations. The carrier can for example be or include
lactose, cellulose (for example microcrystalline cellulose), or mannitol. The tablet can
also or instead contain one or more pharmaceutically acceptable excipients, for example a
binding agent such as hydroxypropylmethylcellulose or povidone (polyvinylpyrollidone),
a lubricant e.g. an alkaline earth metal stearate such as magnesium stearate, and/or a
tablet disintegrant such as sodium starch glycollate, croscarmellose sodium, or
crospovidone (cross-linked polyvinylpyrollidone). The pharmaceutical composition
being a tablet can be prepared by a method comprising the steps of: (i) mixing the
compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof,
with the one or more pharmaceutically acceptable carriers and/or excipients, (ii)
compressing the resulting mixture (which is usually in powder form) into tablets, and (iii)
optionally coating the tablet with a tablet film-coating material.
A pharmaceutical composition suitable for oral administration being a capsule can
be prepared using encapsulation procedures. For example, pellets or powder containing
the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier
and then filled into a hard gelatin capsule. Alternatively, a dispersion or suspension can
be prepared using any suitable pharmaceutically acceptable carrier, for example an
aqueous gum or an oil and the dispersion or suspension then filled into a soft gelatin
capsule.
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.
Particle size reduction of compound of formula (I) or salt thereof
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 smal1-scale micronisation process is now given:
Micronisation Example
• Purpose: To micronize a compound of formula (I) or a salt thereof- in particular one
of the Examples of the invention (described hereinafter) - usually in an amount of
approximately 600-1000 mg, using a JetpharmaMCl 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. 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 circurnferentially-
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 (V) 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 (V) 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 (V)
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. V-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 performed.
Preferred Experimental Parameters
Balance(s) Used: Sartorius analytical
Venturi outlet insertion depth: 10.0 mm



The above preferred or optional parameters can be varied using the skilled person's
knowledge.
Yield calculations
% yield = [(Material from vessel + Material from cyclone)/Material input amount] x 100
In general, very approximately 50-75 % yields are achievable using this method.
Dry powder inhalable compositions
For pharmaceutical compositions suitable and/or adapted for inhaled
administration, it is preferred that the pharmaceutical composition is a dry powder
inhalable composition. Such a composition can comprise a powder base such as lactose
or starch, the compound of formula (I) or salt thereof (preferably in particle-size-reduced
form, e.g. in micronised form), and optionally a performance modifier such as L-leucine,
mannitol, trehalose and/or magnesium stearate. Preferably, the dry powder inhalable
composition comprises a dry powder blend of lactose and the compound of formula (I) or
salt thereof. The lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is
preferably inhalation-grade and/or fine-grade lactose. Preferably, the particle size of the
lactose is defined by 90% or more (by weight or by volume) of the lactose particles being
less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in
diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g.
10-500 microns) in diameter. More preferably, the particle size of the lactose is defined
by 90% or more of the lactose particles being less than 300 microns (e.g. 10-300 microns
e.g. 50-300 microns) in diameter, and/or 50% or more of the lactose particles being less
than 100 microns in diameter. Optionally, the particle size of the lactose is defined by
90% or more of the lactose particles being less than 100-200 microns in diameter, and/or
50% or more of the lactose particles being less than 40-70 microns in diameter. Most
importantly, it is preferable that about 3 to about 30% (e.g. about 10%) (by weight or by
volume) of the particles are less than 50 microns or less than 20 microns in diameter. For
example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10%
fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).
In the dry powder inhalable composition, preferably, the compound of formula (I)
or salt thereof is present in about 0.1% to about 70% (e.g. about 1% to about 50%, e.g.
about 5% to about 40%, e.g. about 20 to about 30%) by weight of the composition.

An illustrative non-limiting example of a dry powder inhalable composition
follows:
Dry Powder Formulation Example - Dry powder Lactose Blend Preparation
Using a size-reduced e.g. micronised form of the compound of formula (I) or salt thereof
(e.g. as prepared in the Micronisatrion 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 bal1-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 pot. The 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.
Dry powder inhalation devices
Optionally, in particular for dry powder inhalable compositions, a pharmaceutical
composition for inhaled ad'ministration 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 pee1-openable
on demand and the dose, e.g. of the dry powder composition, can be administered by
inhalation via a device such as the DisKUS TM device, marketed by GlaxoSmithKline.
The DisKUS ™ inhalation device is usually substantially as described in GB 2,242,134
A, and 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.
Unit dose form and dosing regimens
Preferably the composition is in unit dose form such as a tablet or capsule for oral
administration, e.g. for oral administration to a human.
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
P2 adrenoreceptor agonist, an anti-mstamine, an anti-allergic or an anti-inflammatory
agent.
The invention thus provides, in a further aspect, a combination comprising a compound
of formula (I) or a pharmaceutically acceptable salt thereof together with another
therapeutically active agent, for example, a P2-adrenoreceptor agonist, an anti-histamine,
an anti-allergic, an anti-inflammatory agent or an antiinfective agent.
Preferably, the P2-adrenoreceptor agonist is salmeterol (eg as racemate or a single
enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamoi, 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 p2-adrenoreceptor agonists are preferred,
especially those having a therapeutic effect over a 12-24 hour period such as salmeterol
or formoterol. Preferably, the p2-adrenoreceptor agonist is for inhaled administration,
e.g. once per day and/or for simultaneous inhaled administration; and more preferably the
P2-adrenoreceptor agonist is in particle-size-reduced form e.g. as defined herein.
Preferably, the P2-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 P2-adrenoreceptor agonist can be as described in WO 00/12078.
Preferred long acting β2-adrenoreceptor agonists include tihose described in WO
02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933.
Especially preferred long-acting β2-adrenoreceptor agonists include compounds of
formula (X) (described in WO 02/066422) (note that the R groups therein are defined
independently of the corresponding R groups of formula (1)):

or a salt or solyate thereof, wherein in formula (X):
m is an integer of from 2 to 8;
n is an integer of from 3 to 11,
with the proviso that m + n is 5 to 19,
Ru is -XS02NR16R17 wherein X is -(CH2)P- or C2-6 alkenylene;
R16 and R17 are independently selected from hydrogen, C1-2alkyl, C3-7cycloalkyl,
C(O)NR18R19, phenyl, and phenyl (C1-4alkyl)-,
or R16 and R17, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-
membered nitrogen containing ring, and R16 and R17 are each optionally substituted by
one or two groups selected from halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, hydroxy-
substituted C1-6alkoxy, -CO2R18, -SO2NR18R19, -CONR18R19, -NR18C(O)R19, or a 5-, 6-
or 7-membered heterocylic ring;
R18 and R19 are independently selected from hydrogen, C1-6alkyl,
C3-6cycloalkyl, phenyl, and phenyl (C1-4alkyl)-; and
p is an integer of from 0 to 6, preferably from 0 to 4;
R12 and R13 are independently selected from hydrogen, C1-2alkyl, C1-6alkoxy, halo,
phenyl, and C1-2haloalkyl; and
R14 and R15 are independently selected from hydrogen and C1-4alkyl with the proviso that
the total number of carbon atoms in R14 and R15 is not more than 4.
Preferred β2-adrenoreceptor agonists disclosed in WO 02/066422 include:


A preferred P2-adrenoreceptor agonist disclosed in WO 03/024439 is:
4-{(li?)-2-[(6-{2-[(2,6-dicWorobenzyl)oxy]ethoxy}hexyl)amin.o]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol.
A combination of a compound of formula (I) or salt together with an anti-histamine is
preferably for oral administration (e.g. as a combined composition such as a combined
tablet), and can be for treatment and/or prophylaxis of allergic rhinitis. Examples of anti-
histamines include methapyrilene, or H1 antagonists such as cetirizine, loratadine (e.g.
Clarityn TM), desloratadine (e.g. Clarinex TM) or fexofenadine (e.g. Allegra TM).
The invention also provides, in a further aspect, a combination comprising a compound of
formula (T) or a pharmaceutically acceptable salt thereof together with an anticholinergic
compound, e.g. a muscarinic (M) receptor antagonist in particular an M1, M2, M1/M2, or
M3 receptor antagonist, more preferably a M3 receptor antagonist, still more preferably a
M3 receptor antagonist which selectively antagonises (e.g. antagonises 10 times or more
strongly) the M3 receptor over the M1 and/or M2 receptor. For combinations of
anticholinergic compounds / muscarinic (M) receptor antagonists 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 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, an elastase inhibitor, a beta-2 integrin antagonist, an
adenosine 2a agonist, a CCR3 antagonist, or a 5-lipoxogenase inhibitor; or an
antiinfective agent (eg. an antibiotic or an antiviral). An iNOS inhibitor is preferably for

oral administration. Suitable iNOS inhibitors (inducible nitric oxide synthase inhibitors)
include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534
and WO 99/62875. Suitable CCR3 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]-11β-hydroxy-16α-methyl-3-
oxo-androsta-l,4-diene-17β-carbothioic acid is-fluoromethyl ester} or Example 41 therein
{which is 6α,9α-difluoro-11β-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 preferred
and is preferably for inhaled administration to a human either (a) at a dose of 250
micrograms once per day or (b) at a dose of 50 to 250 micrograms twice per day.
Also provided is a combination comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof together with P2-adrenoreceptor agonist and an
anti-inflammatory corticosteroid, for example as described in WO 03/030939 A1.
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 A1. Most
preferably, in this "triple" combination, the β2-adrenoreceptor agonist is sahneterol 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(s).
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 pee1-openable on demand; for
example such inhalation device can be substantially as described in GB 2,242,134 A
(DisKUS ™) and/or as described above. Alternatively, the combination inhalation
device can be such that the individual compounds of the combination are adrninistrable
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 pharmaceutical composition for adrninistration of the
individual compounds of the combination either sequentially or simultaneously, or
(b) preparing a combined pharmaceutical composition for administration of the
individual compounds of the combination simultaneously,
wherein the pharmaceutical composition comprises the combination together with
one or more pharmaceutically acceptable carriers and/or excipients.
The invention also provides a combination as defined herein, prepared by a method as
defined herein.

Biological Test Methods
PDE 3, PDE 4B, PDE 4D, PDE 5, PDE 6 Primary assay methods
The activity of the compounds can be measured in the assay methods shown below.
Preferred compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit
PDE4 (e.g. PDE4B and/or PDE4D, preferably PDE4B) more strongly than they inhibit
PDE3 and/or more strongly than they inhibit PDE5 and/or more strongly than they inhibit
PDE6.
PDE enzyme sources and literature references
Human recombinant PDE4B, in particular the 2B splice variant thereof (HSPDE4B2B), is
disclosed in WO 94/20079 and also M.M. McLaughlin et al., "A low .Km, rolipram-
sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of
cDNA, biochemical characterisation of recombinant protein, and tissue distribution of
mRNA", J. Biol. Chem., 1993,268, 6470-6476. Human recombinant PDE4B was
expressed in the PDE-deficient yeast Saccharomyces cerevisiae strain GL62. 100,000 x g
supernatant fractions of yeast cell lysates were used for PDE4B assays and inhibitor
studies.
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 IVD)", 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. Deterre,
"Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited
proteolysis", Eur. J. Biochem., 1991,199,263-269; A. Tar et al. "Purification of bovine
retinal cGMP phosphodiesterase", Methods in Enzymology, 1994, 238, 3-12; and/or D.
Srivastava et al. "Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal
rod cyclic GMP phosphodiesterase", Biochem. J., 1995,308,653-658.
Inhibition of PDE 3, PDE 4B, PDE 4D, PDE 5 or PDE 6 activity: radioactive
Scintillation Proximity Assay (SPA)

The ability of compounds to inhibit catalytic activity at PDE4B or 4D (human
recombinant), PDE3 (from bovine aorta) or 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. about 2 microlitre (ul) volume
of DMSO solution) 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 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
thePDE5 and PDE6 assay [8-3H]Guanosine 3',5'-cyclicphosphate ( Amersham
Phannacia Biotech , code TRK.392) was added to give 0.05uCi per well and ~ 36nM
final concentration. Plates, preferably 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 PvPNQ 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 1 hour
(preferably 35 minutes) to allow the beads to settle. Bound radioactive product was
measured using a WALLAC TRILUX 1450 Microbeta scintillation counter. For
inhibition curves, 10 concentrations (1.5-M - 30uM) of each compound were assayed.
Curves were analysed using ActivityBase and XLfit (ID Businesss Solutions Limited, 2
Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, 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 IMAP Fluorescence
Polarisation (FP) assay (MAP Explorer kit, available from Molecular Devices
Corporation, Sunnydale, CA, USA; Molecular Devices code: R8062) in 384-well format.
The MAP 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 F1-AMP that is produced
on the hydrolysis of fluorescein-labelled (Fl) cyclic adenosine mono-phosphate
(F1-cAMP) to the non-cyclic F1-AMP form. F1-cAMP does not bind. Binding of F1-AMP
product to the beads (coated with the immobilised trivalent cations) slows the rotation of
the bound F1-AMP and leads to an increase in the fluorescence polarisation ratio of
parallel to perpendicular light. Inhibition of the PDE reduces/inhibits this signal increase.

Test compounds (small volume, e.g. ca. 0.5 to 1 ul, preferably ca. 0.5 ul, of
solution in DMSO) 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, 10mM 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. 20-40 ul, preferably ca. 20 ul). Plates were mixed on an orbital shaker
for 10 seconds and incubated at ambient temperature for 40 minutes. IMAP binding
reagent (as described above, from Molecular Devices Corporation, Molecular Devices
code: R7207) 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 Analyst^M 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 (ID Businesss Solutions Limited, 2
Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kindgom).
Results were expressed as pICso 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 IMAP 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:



Many, but not all, of the Examples have been tested for PDE4B inhibition. Of the
Examples tested for PDE4B inhibition, some were tested by the radioactive SPA assay,
some were tested by the FP assay.
Most or substantially all of Examples 1-45, 47-55, 57-81, 83 and 84 have PDE4B
inhibitory activities in the range of pICso = about 6 (± about 0.5) to about 9.1 (± 0.5).
The Examples wherein B? = cyclohexyl (NHR.3 or NR3R3a = sub-formula (c)),
tetrahydro-2H-pyran-4-yl (NHR3 or NR3R3a = group (h)), or certain other types of
substituted cyclohexyl or certain heterocycles, or Examples wherein NHR3 or NR3R3a =
sub-formula (s), usually or often (based on data for R1 = 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 R^ = cyclopropyl (NHR3
or NR3R3a = sub-formula (b)).
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 particular 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 ferrets 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 [PDEIV] in the ferret", Neuropharmacology, 1999,38,
289-297, erratum 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 (GI) 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
administeredPDE4 inhibitors
Pulmonary neutrophil influx has been shown to be a significant component to the
family of pulmonary diseases like chronic obstructive pulmonary disease (COPD) which
can involve chronic bronchitis and/or emphysema (G.F. Filley, Chest. 2000; 117(5);
251s-260s). 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 components) 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 jj.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 performed through a 14 gauge blunt
needle into the exposed trachea. Five, 5 ml washes are performed to collect a total of 25
ml of BAL fluid. Total cell counts and leukocyte differentials are performed on BAL
fluid in order to calculate neutrophil influx into the lung. Percent neutrophil inhibition at
each dose (cf. vehicle) is calculated and a variable slope, sigmoidal dose-response curve
is generated, usually using Prism Graph-Pad. The dose-response curve is used to
calculate an ED50 value (in mg per kg of body weight) for inhibition by the PDE4
inhibitor of the LPS-induced neutrophilia.

Results: Based on current measurements, the compounds of Examples 14,17,23,
35 and 38, administered orally in the above procedure, exhibited neutrophilia-inhibition
ED50 values in the range of about 0.03 mg/kg to about 1 mg/kg, subject to testing
inaccuracies.
Alternative method and results: In an alternative embodiment of the procedure, a
single oral dose of 10 mg/kg or 1 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 current measurements, the compounds
of Examples 2,14, 23 and 38, administered orally in this alternative procedure at a single
dose of 10 mg/kg, exhibited percent neutrophilia-inhibition in the range of about 74% to
about 86%, subject to testing inaccuracies.
Literature:
Filley G.F. Comparison of the structural and inflammatory features of COPD and
asthma. Chest. 2000; 117(5) 251 s-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 J Physiol Lung Cell Mol Physiol. 2000; 279: L895-L902.
In Vivo Assay 2. Rat Pica Model ofemesis
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. In 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-infiammatory 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 a non-emetic or minima1-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 to the invention.
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
compound/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.
The Pica Response ED50 value can be compared to the neutrophilia-inhibition
ED50 values for the same compound administered orally to the rat (measurable by In
Vivo Assay 1 above), so that a Therapeutic Index (TI) in rats can be calculated thus:

In general, the Therapeutic Index (TI) calculated this way is often substantially
different to, for example can often be substantially higher than, the TI (D20/D50)
calculated in the ferret (see In vivo Assay 4 below).
Results: Using the above procedure, and according to current measurements, the
compounds of Examples 14,17, 23, 35 and 38 exhibited a Pica Response ED50 in the
range of about 2 mg/kg to greater than about 50 mg/kg, subject to testing inaccuracies.
Taking the specific Pica Response ED50 values for these compounds together with the
specific rat neutrophilia-inhibition ED50 values measured in In Vivo Assay 1 for
Examples 14,17,23,35 and 38, the Rat Therapeutic Index (TI) for orally-administered

Examples 14,17,23,35 and 38 was calculated using the above equation as being in the
range of from about 12 to about 470, according to current measurements, subject to
testing inaccuracies.
Literature:
Beavo JA, Contini, M., Heaslip, R.J. Multiple cyclic nucleotide
phosphodiesterases. Mol Pharmacol. 1994;46:399-405.
Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT, Minnicozzi M.
Comparison of PDE 4 inhibitors, Rolipram and SB 207499 (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. II. 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.)
administered PDE4 inhibitors. The PDE4 inhibitors are preferably in dry powder or wet
suspension form. It. administration is one model of inhaled administration, allowing
topical delivery to the lung.
Animals: Male CD (Sprague Dawley Derived) rats supplied by Charles River,
Raleigh, NC, USA are 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) is weighed, the drug blend
or inhalation grade lactose (vehicle control) is then added to the tap, the tap closed to
prevent loss of drug, and the tap is re-weighed to determine the weight of drug in the tap.
After dosing, the tap is weighed again to determine the weight of drug that had left the
tap. The needle, a Sigma Z21934-7 syringe needle 19-gauge 152 mm (6 inches) long
with luer hub, is cut by engineering to approximately 132 mm (5.2 inches), a blunt end is

made to prevent them damaging the rat's trachea, and the needle is weighed prior to and
after drug delivery to confirm that no drug is retained in the needles after dosing.
Device for wet suspension administration: This is the similar to'the above but a
blunt dosing needle, whose forward end is slightly angled to the needle axis, is used,
with a flexible plastic portex canula inserted into the needle.
Drugs and Materials: lipopolysaccharide (LPS) (Serotype:0127:B8) (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 added the required volume of
vehicle to the drug, the vehicle being 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 are anaesthetised by placing
the animals in a sealed Perspex chamber and exposing them to a gaseous mixture of
isoflourane (4.5 %), nitrous oxide (3 htres.minute"1) and oxygen (1 litre.minute"1). Once
anaesthetised, the animals are placed onto a stainless steel i.t. dosing support table. They
are positioned on their back at approximately a 35° angle. A light is angled against the
outside of the throat to highlight the trachea. The mouth is opened and the opening of the
upper airway visualised. The procedure varies for wet suspension and dry powder
administration of PDE4 inhibitors as follows:
Dosing with a Wet suspension: A portex cannula is introduced via a blunt metal
dosing needle that had been carefully inserted into the rat trachea. The animals are
intratracheally dosed with vehicle or PDE4 inhibitor via the dosing needle with a new
internal canula used for each different drug group. The formulation is 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 are inserted into
the rat trachea up to a pre-determined point established to be located approximately 1 cm
above the primary bifurcation. Another operator holds the needle at the specified position
whilst 2 x 4ml of air 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 is
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 are placed into sealed Perspex containers and exposed to an aerosol of
LPS (nebuliser concentration 150 ug.mr1) for 15 minutes. Aerosols of LPS are generated
by a nebuliser (DeVilbiss, USA) and this is directed into the Perspex exposure chamber.

Following the 15-minute LPS-exposure period, the animals are returned to the holding
cages and allowed free access to both food and water.
[In 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: 4 hours after LPS exposure the animals are killed by
overdose of sodium pentobarbitone (i.p.). The trachea is cannulated with polypropylene
tubing and the lungs lavaged (washed out) with 3 x 5 mis of heparinised (25 units-ml-1)
phosphate buffered saline (PBS).
Neutrophil cell counts: The Bronchoalveolar lavage (BAL) samples are
centrifuged at 1300 rpm for 7 minutes. The supernatant is removed and the resulting cell
pellet resuspended in 1 ml PBS. A cell slide of the resuspension fluid is prepared by
placing 100µl of resuspended BAL fluid into cytospin holders and then spun at 5000 rpm
for 5 minutes. The slides are allowed to air dry and then stained with Leishmans stain (20
minutes) to allow differential cell counting. The total cells are also counted from the
resuspension. From these two counts, the total numbers of neutrophils in the BAL are
determined. 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 Orally-administered 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 Whiskers™ cat food given 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 axe 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 ferrets 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 rpm 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) % inhibition of UPS-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 (TI), using this assay, is then calculated for each PDE4 inhibitor
using the following equation:

It is noted that the Ferret Therapeutic index (TI) (D20/D50) calculated using this in vivo
Assay 4 is often substantially different to, and for example is often substantially lower
than, the Rat TI (50/50) calculated using the rat oral inflammation and pica feeding
Assays 1+2.
The calculation of TI using the known PDE4 inhibitor roflumilast in this Assay 4 is:

D20 for emesis = 0.46 mg/kg p.o., D50 for ferret neutroplilia = 0.42 mg/kg p.o., Ferret
TI=1.1.
All publications, including but not limited to patents and patent applications, cited in this
specification are herein incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by reference herein as though
fully set forth.

EXAMPLES
The various aspects of the invention will now be described by reference to the following
examples. These examples are merely illustrative and are not to be construed as a
limitation of the scope of the present invention. In this section, "Intermediates" represent
syntheses of intermediate compounds intended for use in the synthesis of the "Examples".


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 ID, 3um ABZ+PLUS
Flow Rate: 3ml/min
Injection Volume: 5µl
Solvent A : 95% acetonitrile + 0.05% formic acid
Solvent B : 0.1% formic acid + 10mMolar ammonium acetate
Gradient: 0% A/0.7min, 0-100% A/3.5min, 100% A/1.1min, 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 (xm).
UV wavelength: 200-320nM
Flow: 20ml/min
Injection Volume: 1ml; or more preferably 0.5 ml
Solvent A : 0.1 % formic acid (or 0.1 % trifluoroacetic acid)
Solvent B : 95% acetonitrile + 5% of (formic acid or trifluoroacetic acid); or more usually
99.95% acetonitrile + 0.05% of (formic acid or trifluoroacetic acid)
Gradient: 100% A/lmin, 100-80% A/9min, 80-1% A/3.5min, 1% A/1.4min, 1-
100%A/0.1min
Microwave
The CEM Discover Focused Microwave Synthesis system was used.
Intermediates and Examples
AU 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:
- ABCRGmbH & 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
















Intermediate 1: Ethyl 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate
Prepared from commercially available 5-amino-1-ethyl pyrazole as described by G. Yu
et. al. in J. Med Chem., 2001,44,1025-1027:

Intermediate 2: Ethyl 4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate


Intermediate 1 (0.051g) and cyclopentyl amine (0.019g) were suspended in ethanol (2ml)
and triethylamine (0.14ml) was added. The mixture was stirred 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 DCM and water. The
organic layer was loaded directly onto an SPE cartridge (silica, 5g) and eluted
sequentially with; (i) DCM, (ii) DCM : Et2O (2:1), (iii) DCM : Et2O (1:1), (iv) Et2O, (v)
EtOAc and (vi) MeOH. Fractions containing desired material were combined and
concentrated in vacuo to afford Intermediate 2 (0.074g). LCMS showed MH+ = 303; TRET
= 3.45min
Intermediate 3; 4-(Cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-S-
carboxylic acid

A solution of Intermediate 2 (2.2g) in ethanol: water (95:5, 16.85ml) was treated with
sodium hydroxide (1.2g) and heated at 50°C for 16h. The mixture was concentrated in
vacuo and the residue re-dissolved in water (0.85ml). The solution was acidified to pH4
using acetic acid and the resultant white precipitate was collected by filtration and dried
under vacuum to afford Intermediate 3 (1.9g). LCMS showed MH+ = 275; TRET =
2.65min
Intermediate 4; N'-Acetyl-4-(Cyclopentylamino)-1-ethyl-l H-pyrazolo [3,4-
b]pyridine-5-carbohydrazide


Intermediate 3 (0.066g), EDC (0.06g) and HOBT (0.035g) were suspended in DMF (2ml)
and the mixture was stirred for 15 minutes. Acetic hydrazide (0.02g) was then added and
the mixture stirred under nitrogen for 18h. Solvents were removed by concentration in
vacuo and the residue partitioned between DCM and water. The layers were separated
and the organic phase was washed with saturated aqueous sodium bicarbonate solution,
then concentrated and applied to an SPE cartridge (aminopropyl, lg) which was eluted
with methanol. Concentration in vacuo afforded Intermediate 4 (0.043 g). LCMS showed
MH+ = 331; TRET = 2.38min.
Intermediate 5: 4-(Cyclopentylamino)-1-ethyl-N'-[(methylsulfonyl)acetyl]-1H-
pyrazolo[3,4-b]pyridine-5-carbohydrazide

Intermediate 3 (0.12g), EDC (0.12g) and HOBT (0.072g) were suspended in DMF (2ml)
and stirred for 15 minutes. Intermediate 8 (0.082g) was then added and the mixture stirred
under nitrogen for 18h. Reaction was incomplete so a further portion of Intermediate 8
was added (0.040g) and stirring continued for a further 66h. Solvents were removed in
vacuo and the residue partitioned between DCM and water. The aqueous phase was
further extracted with DCM and the combined organic layers applied to an SPE cartridge
(silica, 5g) which was eluted sequentially with a gradient of Et2O: MeQH (1:0, 9:1, 8:2,
7:3 and 6:4). Fractions containing desired material were combined and concentrated in
vacuo to afford Intermediate 5 (0.154g). LCMS showed MH4 = 409; TRET = 2.42min.
Intermediate 6: Ethyl 4-(4-fluorophenylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-
5-carboxylate


Intermediate 1 (0.05 lg) and 4-fluoroaniline (0.024g) were suspended in ethanol (2ml)
and triethylamine (0.14ml) was added. The mixture was stirred 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 DCM and water. The
organic layer was loaded directly onto an SPE cartridge (silica, 5g) and eluted
sequentially with; (i) DCM, (ii) DCM : Et2O (2:1), (iii) DCM : Et20 (1:1), (iv) Et2O, (v)
EtOAc, (vi) MeOH. Fractions containing desired material were combined and
concentrated in vacuo to afford Intermediate 6 (0.077g). LCMS showed MH+ = 328; TRBT
= 3.36min.

Intermediate 3 (0.10g) was dissolved in DMF (2ml) and treated with HBTU (0.136g) and
DIPEA (0.116g). A separate portion of Intermediate 3 (0.10g) was dissolved in DMF
(2ml) and treated with EDC (0.096g) and HOBT (0.058g). The resultant suspensions
were both stirred under nitrogen for 15min, then methyl hydrazine (0.017g) added to each
and stirring continued under nitrogen for 18h. The mixtures were independently
concentrated in vacuo and the residues partitioned between DCM and water. The organic
layers were concentrated and each applied to an SPE cartridge (aminopropyl, 2g) which
was eluted with methanol, followed by 10% ammonia in methanol. The two portions of
Intermediate 7 thus afforded were combined (0.16g). LCMS showed MH+ = 303; TRET =
2.22min.


Intermediate 3 (0.060g), EDC (0.06g) and HOBT (0.035g) were suspended in DMF (2ml)
and stirred under nitrogen for 15 minutes. isobutyric acid hydrazide (0.027g) was then
added and the mixture stirred under nitrogen for 18h. Solvents were removed in vacuo
and the residue partitioned between DCM and water. The organic phase was washed with
saturated aqueous sodium bicarbonate solution, then concentrated in vacuo and applied to
an SPE cartridge (aminopropyl, lg) which was eluted with methanol. Concentration in
vacuo afforded Intermediate 10. LCMS showed MH+ = 359; 1W = 2.70min.

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 11 as a white solid
(2.4g). LCMS showed MH+ = 226; TRET = 2.62min.


Intennediate 11 (0.4g) was dissolved in thionyl chloride (3ml) and the mixture was
heated at reflux (95°C) with stirring for lh. After cooling to room temperature, excess
thionyl chloride was removed by evaporation under reduced pressure and the resultant
solid dissolved in anhydrous acetonitrile (2ml). This solution was added to a solution of
acetic hydrazide (0.145g) and diisopropylethylamine (0.465ml) in anhydrous acetonitrile
(2ml), and the mixture stirred for a further 2h. The mixture was concentrated in vacuo
and the residue treated directly with phosphorus oxychloride (4ml). The resultant solution
was stirred and heated at reflux (120°C) for 0.5h, then allowed to cool and purified by
Biotage (silica, 40g), eluting with cyclohexane : EtOAc (1:1) to afford Intermediate 12
(0.32g). LCMS showed MH+ = 264; TRET = 2.55 min.

Intermediate 11 (0.05g) was dissolved in thionyl chloride (1ml) and the mixture was
heated at reflux (95°C) with stirring for 1h. After cooling to room temperature, excess
thionyl chloride was removed by evaporation under reduced pressure and the resultant
solid dissolved in anhydrous acetonitrile (0.5ml). This solution was added to a solution of
isobutyric acid hydrazide (0.025g) and diisopropylethylamine (0.058ml) in anhydrous
acetonitrile (1ml), and the mixture stirred for a further 1.5h. The mixture was
concentrated in vacuo and the residue treated directly with phosphorus oxychloride (2ml).
The resultant solution was stirred and heated at reflux (120°C) for 2h, then allowed to
cool and concentrated in vacuo. The residue was applied to an SPE cartridge (silica, 5g)
which was eluted sequentially with a gradient of EtOAc : cyclohexanl (i) 1:16, (ii) 1:8,
(iii) 1:4, (iv) 1:2, (v) 1:1 and (vi) 1:0. Fractions containing desired material were
combined and concentrated in vacuo to afford Intermediate 13 (0.049g). LCMS showed
MH+ = 292; TRET = 2.96min.


Intermediate 11 (0.40g) was dissolved in thionyl chloride (3ml) and the mixture was
heated at reflux (95°C) with stirring for lh. After cooling to room temperature, excess
thionyl chloride was removed by evaporation under reduced pressure and the resultant
solid dissolved in anhydrous acetonitrile (2ml). This solution was added to a solution of
pivalic acid hydrazide (0.228g) and diiscrpropylemylarnine (0.465ml) in anhydrous
acetonitrile (2ml), and the mixture stirred for a further 1.5h. The mixture was
concentrated in vacuo and the residue treated directly with phosphorus oxychloride (5ml).
The resultant solution was stirred and heated at reflux (120°C) for 1.5h, then allowed to
cool, concentrated in vacuo and purified by Biotage (silica, 40g), eluting with petroleum
ether (40/60) : EtOAc (1:1) to afford Intermediate 14 (0.388g). LCMS showed MH+ =
306; TRET = 3.14 min.

Intermediate 11 (0.68g) was dissolved in thionyl chloride (4ml) and the mixture was
heated at reflux (95°C) with stirring for lh. After cooling to room temperature, excess
thionyl chloride was removed by evaporation under reduced pressure and the resultant
solid dissolved in anhydrous acetonitrile (3ml). This solution was added dropwise over 5
minutes to a solution of Intermediate 8 (0.504g) and diisopropylethylamine (0.787ml) in
anhydrous acetonitrile (12ml), and the mixture then stirred for a further lh. The mixture
was concentrated in vacuo and the residue treated directly with phosphorus oxychloride
(8ml). The resultant solution was stirred and heated at reflux (120°C) for 2.5h, then
allowed to cool, concentrated in vacuo and purified by Biotage (silica, 40g), eluting first
with petroleum ether (40/60) : EtOAc (2:1), then with petroleum ether (40/60) : EtOAc
(1:1). Fractions containing desired material were combined, concentrated in vacuo and
the residue further purified by trituration with diethyl ether to afford Intermediate 15
(0.41g). LCMS showed MH+ = 342; TRET = 2.46 min.


Intermediate 1 (0.20g) and triethylamine (0.55ml) were suspended in ethanol (8ml) and
4-aminotetrahydropyran (Intermediate 21, 0.088g) was added. The mixture was stirred
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 witl; (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 16 (0.21g). LCMS showed MH+ = 319; TRET - 2.93min.

A solution of Intermediate 16 (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 17 as an off-
white solid (0.16g). LCMS showed MH+ = 291; TRET = 2.1 lmin.
An alternative preparation of Intermediate 17 is as follows:
A solution of Intermediate 16 (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 17 as an off-white solid (29.65g). LCMS showed
MH* = 291; TRET = 2.17 min.


A suspension of Intermediate 17 (1.48g), EDC (1.34g) and HOBT (0.83g) in DMF
(20ml) was stirred at room temperature for 30min. t-Butyl carbazate (0.68g) was then
added and stirring continued under nitrogen for a further 66h. The mixture was
concentrated in vacuo and the residue divided into two portions for purification. Each
portion was applied to an SPE cartridge (aminopropyl, 10g) which was eluted with
methanol and the combined eluents were concentrated in vacuo. Further purification was
carried out by Biotage (silica, 40g), eluting with cyclohexane : ethyl acetate (1:4).
Fractions containing desired material were combined and concentrated in vacuo to afford
Intermediate 18 (1.39g). LCMS showed MH+ = 405; TRET = 2.64min.

Intermediate 18 (1.39g) was treated with a 4M solution of hydrochloric acid in dioxane
(8ml) and the mixture stirred under nitrogen for lh. Concentration in vacuo afforded
Intermediate 19 as a white solid (1.17g). LCMS showed MH+ = 305; TRET = 2.04min.


dichloromethane and water. The layers were separated and the organic layer concentrated
in vacuo, then applied to an SPE cartridge (aminopropyl, lg). The column was eluted
with methanol to afford Intermediate 20 as a white solid (0.02g). LCMS showed MH4 =
373; TRET = 2.15rnin.

Commercially available from Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San
Diego, CA 92126. CAS (Chemical Abstracts) Registry Number 38041-19-9.

Stepl: N,N-dibenzyltetrahydro2H-pyran-4-amine
Diben2ylamine (34.5g) and acetic acid (6.7ml) were added to a stirred 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 = 1-98 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 pH 1 with
2M-hvdrogen chloride in diethyl ether. Evaporation of solvents gave a solid which was


A solution of methoxyacetonitrile (12.26g) in ethanol (220ml) was treated with
hydroxylamine hydrochloride (11.95g) followed by potassium carbonate (22.9g) and
heated under reflux for 2 days. The mixture was concentrated in vacuo, then partitioned
between ethylacetate and water. The organic layer was concentrated in vacuo to afford
Intermediate 22 as a colourless liquid (7.6g). 1H NMR (CDC13) 7.16 (3H, s), 7.67 (s, 2H),
9.32 (brs, 2H), 13.08 (1H, s).

Can be prepared in an analogous manner to Intermediate 9, starting from morpholino
acetonitrile (itself commercially available from TCI America, 9211 North Harborgate
Street, Portland, OR 97203, USA).
Intermediate 25: 1-Acetyl-4-aminopiperidine hydrochloride
Prepared from commercially available N1-berizyl-4-aminopiperidine as described by
Yamada et. al. In WO 00/42011:

Can be prepared by oxidation of 3-Methyl-3-oxetanemethanol (commercially available
from e.g. Fluka, CAS (Chemical Abstracts) Registry Number 3143-02-0) according to the
procedure described by H. Fiege et. al. in DE3618142.
Intermediate 27: (4-Methylpiperazin-1-yl)acetic acid


Commercially available from ChemPacific USA Sales Marketing and Research Center,
6200 Freeport Centre, Baltimore, MD 21224, USA (CAS Registry Number 54699-92-2).

Commercially available from Austin Chemical Company, Inc., 1565 Barclay Blvd.,
Buffalo Grove, EL 60089, USA. CAS (Chemical Abstracts) Registry Number 3338-22-5.

Commercially available from MicroChemistry-RadaPharma, Shosse Entusiastov 56,
Moscow 111 123, Russia. CAS (Chemical Abstracts) Registry Number 42346-68-9.

Commercially available from Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San
Diego, CA 92126, USA. CAS (Chemical Abstracts) Registry Number 5337-03-1.

Can be prepared from ethyl bromoacetate as described by Z. Dega-Szafran et. al. in J.
Molecular Structure, 2001, 560,261-273.

A suspension of sodium t-butoxide (24.1 g) in t-butanol (150ml) was cooled in a water
bath and treated drop-wise with a solution of chloroacetic acid (11.4g) in t-butanol

(30ml). The mixture was heated under reflux for 5h then concentrated in vacuo. The
resultant white solid was dried in vacuo for 16h then water (100ml) was added and the
mixture was filtered. The filtrate was treated with diethyl ether (150ml), then cooled in an
ice bath, stirred and acidified to pH1 with 2N sulphuric acid. The layers were separated
and the aqueous layer was further extracted with diethyl ether. The combined organic
extracts were dried (MgSO4) and concentrated in vacuo to afford Intermediate 32 (11.lg).
1H NMR (400MHz, CDC13, δppm) 1.27 (9H, s), 4.04 (2H, s).

Intermediate 17 (O.lg, 0.34mmol), EDC (0.066g, 0.34mmol) and HOBT (0.05g,
0.37mmol) were suspended in DMF (2ml) and stirred 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 Intermediate 33 (0.055g). LCMS showed
MH+ = 393; TRET = 2.22min.


Intermediate 17 (0.1g, 0.34mmol), EDC (0.066g, 0.34mmol) and HOBT (0.05g,
0.37mmol) were suspended in DMF (2ml) and stirred at room temperature under
nitrogen for 15 min. 2-aminopropan-1-ol (0.026g, 0.34mmol) and triemylarnine (0.036g,
0.36mmol) were added and the mixture was stirred 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
(amine-propyl, 5g), which was eluted with methanol. Concentration in vacuo afforded
Intermediate 34 (0.095 g). LCMS showed MH+ = 348, TRET= 2.15min.

Sodium (0.55g, 23.7mmol) was added portionwise to anhydrous ethanol (25ml) at 20 °C
under an atmosphere of nitrogen. After stirring for 1 hour the solution was added to
Intermediate 1 (4.622g, 18.22mmol) and the reaction mixture heated at reflux for 2 hours.
The mixture was evaporated in vacuo and the residue partitioned between
dichloromethane and water. The organic phase was washed with brine, dried (Na2SO4)
and evaporated in vacuo. The residue was purified on SPE cartridges (silica, 4 x 20g)
eluting with dichloromethane, ethyl acetate:petroleum ether (1:4,1:2 then 1:1) followed
by ethyl acetate). Appropriate fractions were combined and evaporated in vacuo to afford
Intermediate 35 as white solid (4.33g). LCMS showed MH+ = 264, TRET= 2.77min.


A mixture of Intermediate 35 (1.0g, 3.8mmol) and N-bromosuccinimide (1.49g,
8.4mmol) in carbon tetrachloride (35ml) was heated at reflux for 3 hours. The reaction
mixture was cooled in an ice-bath and the precipitate filtered. The filtrate was
concentrated in vacuo and the residue dissolved in tetrahydrofuran (12.5ml). Water
(3.5ml) and saturated sodium carbonate solution (3ml) were added and the mixture stirred
at 20 °C for 18 hours. The reaction was diluted with water and extracted with ethyl
acetate. The combined organic phases were dried (Na2SO4) and evaporated in vacuo.
The residue was purified on an SPE cartridge (silica, 20g) eluting with dichloromethane,
chloroform, then chloroform:methanol (99:1,49:1,19:1 then 9:1). Appropriate fractions
were combined and evaporated in vacuo to afford Intermediate 36 as an off-white solid
(0.45g). LCMS showed MH+ = 236, TRET= 2.46min.


Method 1: Intermediate 36 (0.035g) was placed in a Reactivial™ and treated with
4-aminotetrahydropyran (0.05ml). The mixture was heated at 90 ºC for 1.5 hours, then
allowed to cool to room temperature and partitioned between chloroform (2ml) and water
(lml). The layers were separated and the organic phase was concentrated. The crude
product was purified by mass directed autoprep HPLC to afford Intermediate 37 as an
off-white solid (0.01 lg). LCMS showed MH+= 291; TRET = 2.08 min.
Alternative Method 2: Intermediate 36 (2g) was suspended in 4-aminotetrahydropyran
(2g), and the mixture was heated at 90 °C for 6 hours. 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 Et20 (30ml) and the insoluble solid was collected and dried to
afford Intermediate 37 as a cream solid (2.24g). LCMS showed MH+= 291; TRET = 2.19
min.

Sodium hydride (0.067 g, 60% dispersion in oil) was added to a stirred solution of
Intermediate 37 (0.47 g) in DMF (19 ml), followed by n-propyl iodide (0.17 ml). The
mixture was stirred at 23 °C for 16 hours, then concentrated, diluted with chloroform (30
ml) and washed with 1:1 water.brine solution (30 ml), separated and the organic layer
concentrated. The residue was purified on a SPE cartridge (silica, 10 g) eluting with 10
ml volumes of dichloromethane, 1:1 diethyl ethencyclohexane, and diethyl ether. The
combined 1:1 diethyl ether: cyclohexane, and diethyl ether, fractions were concentrated


2M-Sodium hydroxide solution (0.7 ml) was added to a stirred suspension of
Intermediate 38 (0.23 g) in ethanol (5 ml) and water (1.5 ml). After stirring overnight at
room temperature, a further quantity of 2M-sodium hydroxide solution (0.7 ml) was
added, and the reaction mixture was heated at 43 °C for 2.5 hours. The reaction solution
was concentrated, diluted with water (5 ml) and acidified with 2M-hydrochloric acid. The
resulting precipitate was collected by filtration, washed with water and dried to give
Intermediate 39 asa white solid (0.14 g). LCMS showed MH+ = 305; TRET = 2.42min.

Intermediate 40 can be made from Intermediate 39 in a similar way to the process
described for Intermediate 4, for example using a similar or the same number of moles of
reagents and/or volumes of solvents.


Intermediate 1 (0.079g, 0.56mmol), Intermediate 25 (0.129g, 0.51mmol) and
diisopropylethylamine (0.45ml, 2.55mmol) in acetonitrile (2ml) were heated at 85 °C for
36 hours. The reaction mixture was concentrated in vacuo and the residue partitioned
between DCM and water. The phases were separated using a hydrophobic frit
(Whatman). The organic phase was evaporated in vacuo and the residue applied to an
SPE cartridge (silica, 5g). The cartridge was eluted with EtOAc and then DCM / MeOH
(1:1). Fractions containing the desired material were combined and concentrated in
vacuo to afford Intermediate 41 (0.1g). LCMS showed MH+ = 360; TRET = 2.63min.

Intermediate 17 (0.25g, 0.86mmol), EDC (0.23g, 1.2mmol) and HOBT (0.139g,
1.03mmol) were suspended in DMF (5ml) and the suspension was stirred at room
temperature. After 25min, (2R)-2-Amino-2-phenylethanol (0.13g, 0.95mmol,
commercially available from Aldrich) was added, and the mixture was stirred at room
temperature for 20 hours. Solvents were removed in vacuo and the residue was dissolved
in DCM (50ml) and washed successively with water (25ml) and 5% sodium hydrogen
carbonate solution (25ml). The organic layer was dried over anhydrous sodium sulphate
and concentrated in vacuo. The residue was dissolved in dichloromethane (5ml) and
applied to a SPE cartridge (silica, lOg), which was eluted with a gradient of ethyl acetate
-petroleum ether (1:2,1:1 and 1:0). Fractions containing the desired material were
combined and concentrated in vacuo to afford Intermediate 42 as a white foam (0.318g).
LCMS showed MH+ = 410; TRET = 2.55min.


Intermediate 43 was prepared from Intermediate 17 and (25)-2-amino-2-phenylethanol
(commecially available from Lancaster Synthesis) using an analogous method to that for
Intermediate 42. LCMS showed MH+ = 410; TRET = 2.55min.

Intermediate 44 was prepared from Intermediate 17 and (25)-2-amino-3-phenyl-1-
propanol (commercially available from Aldrich) using an analogous method to that for
Intermediate 42. LCMS showed MH+ = 424; TRET = 2.60min.

Intermediate 45 was prepared from Intermediate 17 and (2i?)-2-amino-3-phenyl-1-
propanol (commecially available from Aldrich) using an analagous method to that for
Intermediate 42. LCMS showed MH+ = 424; TRET = 2.59min.


Intermediate 46 was prepared from Intermediate 17 and (1S,2R)-1-amino-1-phenyl-2-
propanol hydrochloride (commercially available from Arch Corporation, 100 Jersey
Avenue, Building D, New Brunswick, NJ 08901, USA) using an analogous method to
that for Intermediate 42. LCMS showed MH+ = 424; TRET = 2.58rnin.

Intermediate 47 was prepared from Intermediate 17 and (li?)-2-amino-1-phenylethanol
(commercially available from Aldrich) using an analogous method to that for
Intermediate 42. LCMS showed MH+ = 410; TRET = 2.62min.

Intermediate 48 was prepared from Intermediate 17 and (lS)-2-amino-1-phenylethanol
(commercially available from Fluka) using an analogous method to that for Intermediate
42. LCMS showed MH+ = 410; TRET = 2.62min.


Intermediate 49 was prepared from Intermediate 17 and 2-amino-2-methyl-1-propanol
(commercially available from Aldrich) using an analogous method to that for
Intermediate 42. LCMS showed MH+ = 362; TRET = 2.28min.

Can be prepared from tetrahydro-4H-pyran-4-one (commercially available from e.g.
Sigma Aldich; CAS (Chemical Abstracts) Registry Number 29943-42-8) according to the
procedure described by H.Hashimoto et al. in Organic Process Research and
Development 2002, 6,70.

Intermediate 1 (1.2g, 4.76mmol), Intermediate 50 (0.79g, 5.2mmol) and
diisopropylethylamine (4ml, 24mmol) in MeCN (8ml) was heated at 70 °C for 24 hours.
The solvent was removed in vacuo and the residue partitioned between DCM and water.
The organic phase was concentrated in vacuo and the residue chromatographed on silica
(50g) eluting with cyclohexane:ethyl acetate (2:1 followed by 1:1 then 1:2). Appropriate
fractions were combined and evaporated to give Intermediate 51 as a brown oil (1.21g).
LCMS showed MH+ = 334; TRET = 2.61min.


Sodium hydroxide (0.43g, 10.8mmol) was added to a solution of Intermediate 51 in
ethanol (10ml, 95%). The reaction mixture was heated at 50 °C for 18 hours. The solvent
was evaporated in vacuo and the residue dissolved in water and acidified to pH 3 by the
addition of aqueous hydrochloric acid. The solution was extracted with DCM. The
organic phase was separated using a hydrophobic frit (Whatman PTFE Folter Media with
Polypropylene Housing 5µM pore size) and the solvent evaporated in vacuo to give
Intermediate 52 as a white solid (0.65g). LCMS showed MH+ = 305; TRET=1.97min.

Intermediate 53 was prepared from Intermediate 52 using an analogous method to that for
Intermediate 4. LCMS showed MH+ = 361; TRET = 1.91min.




Can be prepared from tetrahydro-4H-pyran-4-onc (commercially available from e.g.
Sigma Aldich CAS 29943-42-8) as described by C. Zagar in WO 99/07702.
A solution of hydrogen chloride in dioxan (0.5ml, 2.0mmol, 4M) was added to a stirred
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
stirred at room temperature. After lh, the reaction mixture was evaporated to give
Intermediate 56 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, 1H), 2.45 (m, 2H, partially obscured), 2.29 (m, 2H),
2.16 (m,2H), 1.76 (m,2H).

A mixture of 5-amino-1-ethyIpyrazole (1.614g, 14.5mmol) and diethyl 2-(1-
ethoxyethylidene)malonate (3.68g, 16.0mmol, 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 58 (1.15g). LCMS showed MH+ = 268; TRET
= 3.18min.


4-Aminotetrahydropyran hydrochloride (Intermediate 21, 0.413g, 3.0mmol) was added to
a mixture of Intermediate 58 (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 Et20,
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
(Intermediate 51). Further purification using a SPE cartridge (silica, 5g) eluting with ethyl
acetate-cyclohexane (1:3) afforded Intermediate 59 (0.248g). LCMS showed MH+ = 333;
TRET = 2.75min.

2M-Sodium hydroxide solution (0.75ml, 1.5mmol) was added to Intermediate 59 (0.248g,
0.75mmol) 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 Intermediate 60 (0.168g). LCMS showed MH+ = 305; TRET = 1.86min.


Intermediate 60 (0.255g, 0.84mmol), EDC (0.225g, 1.17mmol) and HOBT (0.136g,
l.Ommol) in DMF (5ml) was stirred at 20 °C for 75 minutes. Pivalic acid hydrazide
(0.107g, 0.92mmol) was added and stirring continued for 18 hours. The reaction mixture
was concentrated in vacuo and the residue partitioned between DCM and water. The
organic phase was washed with aqueous sodium hydrogen carbonate then evaporated in
vacuo to afford Intermediate 61 as a white solid (0.27g).). LCMS showed MH+ = 403;
TRET = 2.13min.

Intermediate 60 (0.253g, 0.83mmol), EDC (0.223g, 1.17mmol) and HOBT (0.135g,
l.Ommol) in DMF (5ml) was stirred at 20 °C for 30 minutes. t-Butyl carbazate (O.llOg,
0.83mmol) was added and stirring continued for 18 hours. The reaction mixture was
concentrated in vacuo and the residue dissolved in DMF (5ml) additional EDC (0.159g0)
and HOBT (0.112g) added. After 30 minutes t-butyl carbazate (0.019g) was added and
stirring continued for 18 hours. The reaction was concentrated in vacuo and the residue
partitioned between DCM and water. The organic phase was washed with aqueous
sodium hydrogen carbonate then evaporated in vacuo. The material was applied to a SPE
cartridge (silica, lOg) and eluted with cyclohexane: ethyl acetate (1:1 followed by 2:1) to
afford Intermediate 62 as a white solid (0.19g). LCMS showed MH+ = 419; TRET =
2.35min.


Intermediate 62 (0.19g, 0.46mmol) was dissolved in 4M hydrogen chloride in dioxane
(5ml) and the reaction mixture stirred overnight at 20 °C. Concentration in vacuo
afforded Intermediate 63 as a white solid (0.161g). LCMS showed MH+ = 319; TRBT =
1.72min.

Intermediate 30 (0.06g, 0.45mmol) and TBTU (0.146g, 0.45mmol) in DMF (5ml) was
stirred at 20 °C for 30 minutes. A mixture of Intermediate 63 (0.16g, 0.45mmol) and
diisopropylethylamine (0.32ml, 1.82mmol) in DMF (1ml) was added and the reaction
mixture stirred overnight under nitrogen. The reaction was concentrated in vacuo and the
residue partitioned between DCM and water. The phases were separated using a
hydrophobic frit (Whatman PTFE Folter Media with Polypropylene Housing 5uM pore
size) and the organic phase evaporated in vacuo. The residue was applied to an SPE
cartridge (aminopropyl, lOg) and eluted with MeOH. Appropriate fractions were
concentrated in vacuo then applied to an additional SPE cartridge (silica, 2g) which was
eluted sequentially with a gradient of MeOH in DCM (i) 2%, (ii) 4%, (iii) 6% and (iv)
10%. Fractions containing the desired material were combined and concentrated in vacuo
to afford Intermediate 64 as a white solid (0.048g). LCMS showed MH+ = 431; TRET =
1.87min.


TBTU (0.050g, 0.15mmol) and diisopropylethylamine (0.04ml, 0.26 mmol) in DMF
(0.5ml) was added to cyclobutylcarboxylic acid (RYCOOH, 0.015g, 0.15mmol). The
reaction mixture was stirred for 40 minutes at 20 °C. A mixture of Intermediate 19
(0.045g, 0.13rnmol) and diisopropylethylamine (0.04ml, 0.26mmol) in DMF (0.5ml) was
added and the reaction mixture stirred for 18h. The solvent was removed in vacuo and
the residue applied to a SPE cartridge (aminopropyl, 2g). The cartridge was eluted with
methanol to afford Intermediate 65 (0.052g). LCMS showed MH+ = 387; TRET = 2.28min.
Similarly prepared using the same or similar numbers of moles of reagents and/or
volumes of solvents were the following:



(4-Methyl-1-piperazinyl)acetonitrile (1.08g, 7.7mmol) (J. Med. Chem., 1999, 42,2870)
was added to a suspension of potassium carbonate (3.2g, 23.1rnmol) and hydroxylamine
hydrochloride (1.06g, 15.4mmol) in ethanol (10ml). The reaction mixture was heated at
reflux for 9 hours then allowed to cool. The reaction was filtered and the solvent
evaporated in vacuo to afford Intermediate 80 (1.53g). lH NMR (400MHz in d6-DMSO,
27°C, δppm) 9.02 (br s, 1H), 5.17 (br s, 2H), 2.78 (s, 2H), 2.31 (br s, 8H), 2.13 (s, 3H).


Commercially available from Sigma-Aldrich, CAS (Chemical Abstracts) Registry
Number 22179-78-8.

Commercially available from the Maybridge Chemical Company, CAS (Chemical
Abstracts) Registry Number 57399-51-6.
Intermediates 83 and 84
The structures of Intermediates 83 and 84 and their preparation are as follows:



Anhydrous hydrogen chloride in dioxane (8ml, 4M solution) was added to Intemediate 84
(0.807g, 1.88mol). The reaction mixture was stirred overnight at room temperature then
evaporated in vacuo. The residue was suspended in ether and the mixture filtered to give
Intermediate 83 as a brown solid (0.525g). LCMS showed MH+ = 373; TRET = 2.62min.

Diisopropyethylarnine (8.3ml, 47.5mmol) was added to a mixture of Intermediate 17
(2.76g, 9.5mmol), TBTU (3.050g, 9.5mmol) and hydroxybenzotriazole (1.28g, 9.5mmol)
in N,N-dimethylformamide (40ml) at room temperature. After stirring for 10 minutes
Intermediate 85 (2.318g, 13.3mmol) was added. The reaction mixture was srirred for 50
minutes then l,r-carbonyldiimidazole (1.54g, 9.5mmol) was added and the reaction
heated at 100 °C for 16 hours. The solvent was removed in vacuo and the residue
partitioned between dichloromethane and water. The organic phase was washed with
aqueous sodium hydrogen carbonate (5%) then dried (Na2SO4) and evaporated in vacuo.
The residue was purified by chromaography using the Biotage system (100g, silica)
eluting with cyclohexane:ethyl acetate (1:1). Intermediate 84 was obtained a brown solid
(0.97g). LCMS showed MH+ = 429 TRET = 3.26min.



A solution of sodium methoxide in methanol (50ml, O.SM) was added to hydroxylamine
hydrochloride (1.78g, 25.62mmol) at room temperature. After stirring for 15 minutes the
solution was filtered and the filtrate added to t-butyl cyanoacetate (3.0g, 21.25mmol,
available from Aldrich). The solution was refluxed for 1.75 hours then cooled and
evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The
aqueous phase was extracted with ethyl acetate and the combined organic phases washed
with brine, dried (MgSO4) and evaporated in vacuo. The residue was suspended in
cyclohexane: ether (1:1) then filtered to give Intermediate 85 as a white solid (1.883g).
1H NMR (400MHZ in CDC13, 27°C, δppm) 8.34 (br s, 1H), 5.05 (br s, 2H), 3.09 (s, 2H),
1.47 (s, 9H).

Intermediate 19 (0.1g, 0.29mmol), TBTU (0.094g, 0.29mmol) and diisopropylethylamine
(0.204ml, 1.17mmol) in N,N-dimethylformamide (1ml) were stirred at room temperature
for 1 hour. The solvent was evaporated in vacuo and the residue dissolved in methanol
and applied to an SPE cartridge (aminopropyl, 5g). The cartridge was eluted with
methanol and appropriate fractions evaporated in vacuo to give Intermediate 86 as a
yellow solid (0.113g). LCMS showed MH+ = 403; TRET = 1.99min.



To a solution of Intermediate 87 (6g, 32.4mmol) in dioxan (15ml) was added a solution
of lithium hydroxide monohydrate (1.53g, 36.4mmol) in water (15ml). The mixture was
stirred for 17h, then washed with diethyl ether (20ml), then with ethyl acetate (20ml) and
acidified with concentrated hydrochloric acid under ethyl acetate (50ml). The combined
aqueous phases were adjusted to pH 2.7 by addition of sodium bicarbonate and extracted
with further ethyl acetate (2x50ml). The combined organic phases were washed with
water (20ml) and saturated brine (20ml), then concentrated in vacuo to afford
Intermediate 88 as a white solid (1.69g). 1H NMR (400MHz in CDC13,27°C, δppm) 2.74
(s, 3H), 3.85 (s, 2H), 5.8-6.2 (br, s, 1H), 7.02 (s, 1H).

General Procedure for Intermediates 89 to 114:
A mixture of carboxylic acid RYCO2H (0.2mmol), diisopropylethylamine (0.105ml,
0.6mmol) and TBTU (0.071g, 0.22mmol) in N,N-dimethylformamide (0.5ml) was
allowed to stand for 10 minutes. A mixture of Intermediate 19 (0.2mmol) and
diisopropylethylamine (0.035ml, 0.2mmol) in N,N-dimethylformamide (0.5ml) was
added. After agitation the reactions were allowed to stand for 16 hours. The solvent was
removed in vacuo and residue was applied to an SPE cartridge (aminopropyl, 0.5g). The
cartridge was eluted with chloroform, ethyl acetatexhloroform (1:1), ethyl acetate, ethyl
acetate:methanol (9:1,2ml). Appropriate fractions were evaporated in vacuo to afford the
Intermediates below.







Prepared from commercially available N-(tert-Butoxycarbonyl)-2-aminoacetonitrile as
decribed by M. Schwarz et. al, WO 02/102799.

Diisopropylethylamine (6.0ml, 34.4mmol) was added to a stirred mixture of Intermediate
17 (2.0g, 6.89mmol), TBTU (2.212g, 6.89mmol) and HOBT (0.931g, 6.89mmol) in dry
dimethylformamide (45ml). After lOmin, the resulting clear solution was treated with
Intermediate 116 (1.89g, lOmmol). The reaction mixture was stirred at room temperature
for 2h. DBU (5.14ml, 34.5mmol) was added, and the reaction mixture was heated at
80°C. After 3.5h at 80°C, the reaction mixture was evaporated in vacuo, and the residue
was dissolved in dichloromethane (150ml) and washed successively with 5% sodium
hydrogen carbonate (50ml) and water (50ml). The organic solution was dried over
anhydrous sodium sulphate and evaporated to give the crude product. Purification by
Biotage chromatography (silica, 100g) eluting with ethyl acetate-petroleum ether (1:1)
afforded Intermediate 117 as a white solid (2.70g). LCMS showed MH+ =444, TRET =
3.06min.

Trifluoroacetic acid (5ml) was added to a stirred solution of Intermediate 117 (1.774g,
4.0mmol) in dry dichloromethane (20ml) at 0°C. After 2h, the reaction mixture was
neutralised by careful addition of 5% sodium hydrogen carbonate solution (150ml) and
solid sodium hydrogen carbonate. The resulting mixture was extracted with chloroform (2
x 100ml). The combined organic extracts were dried over anhydrous sodium sulphate and
evaporated to afford Intermediate 118 as a white solid (1.358g). LCMS showed MH+
=344, TRET = 1.95min.


4-chlorobutanoyl chloride (0.12mmol) was added to a stirred solution of Intermediate 118
(0.1mmol) and diisopropylethylarnine (0.3mmol) in chloroform (1ml) at room
temperature. After stirring at room temperature for 16h, the reaction mixture was applied
to a SPE cartridge (aminopropyl, 2g) and the cartridge was eluted sequentially with
chlororm, ethyl acetate and methanol. Fractions containing the desired product were
combined and blown down under nitrogen. The resulting residue was further purified on a
SPE cartidge (silica, lg) eluting with a gradient of 30-100% ethyl acetate in petroleum
ether to afford Intermediate 119 as a white solid (45mg). ). LCMS showed MH+ =448,
TRET = 2.77min.

5-cbloropentanoyl chloride (0.12mmol) was added to a stirred solution of Intermediate
118 (0.1mmol) and diisopropylethylarnine (0.3mmol) in chloroform (1ml) at room
temperature. After stirring at room temperature for 16h, the reaction mixture was applied
to a SPE cartridge (aminopropyl, 2g) and the cartridge was eluted sequentially with
chlororm, ethyl acetate and methanol. Fractions containing the desired product were
combined and blown down under nitrogen. The resulting residue was further purified on a
SPE cartidge (silica, lg) eluting with a gradient of 30-100% ethyl acetate in petroleum
ether to afford Intermediate 120 as a white solid (46mg). LCMS showed MH+ =462, TRET
= 2.86min.
Intermediate 121: (1E/Z)-N-hydroxy-2-(4-morpholinyl)propanimidamide


Prepared from a-metliyl-4-morpholineacetonitrile using a similar process to that
described for any of Intermediates 9, 22 or 80 using similar or the same number of moles
of reagents and/or volumes of solvents. 1H NMR (27 °C, d4-MeOH) 3.70-3.60 (m, 5H),
3.13-3.07 (m, 2H), 2.83-2.76 (m, 2H), 1.84 (d, J = 5Hz, 3H)
a-Methyl-4-morphoUneacetonitrile can be prepared according to the procedure described
by H.R.Henze et. al. J. Am. Chem. Soc 1957,79,6230.

Can be prepared from cyclohexylacetic acid (commercially available from e.g. Aldrich)
according to the procedure described by T.R. Alessi et al. in US 4895860.

Prepared from 1,1-dimethylethyl 4-(cyanomethyl)-1-piperidinecarboxylate using a
similar process to that described for any of Intermediates 9, 22 or 80 using similar or the
same number of moles of reagents and/or volumes of solvents.
1,1-dimethylethyl 4-(cyanomethyl)-1-piperidinecarboxylate can be prepared from
commercially available 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate according to the
procedure described by A.M.Wilson in WO 00/006159.
Intermediate 124: 1,1-Dimethylethyl 4-({5-[1-ethyl-4-(tetrahydro-2H-pyran-4-
ylamino)-1H-pyrazolo[3,4-6]pyridm-5-yl]-l,2,4-oxadiazo1-3-yl}methyl)-1-
piperidinecarboxylate


A mixture of Intermediate 16 (0.064g, 0.2mmol), Intermediate 80 (0.257g, 1mmol), a
solution of sodium ethoxide in EtOH (0.19ml, 21% solution) and powdered 4A molecular
sieves (0.3 8g) in EtOH (2ml) were stirred at 82 °C under an atmosphere of nitrogen for
18 hours. Additional sodium ethoxide in ethanol (0.19ml, 21% solution), molecular
sieves (0.38g) and ethanol (4ml) were added and the reaction heated for a further 72
hours. The reaction mixture was filtered, the solvent was evaporated in vacuo and the
residue was applied to an SPE cartridge (silica, 2g). The cartridge was eluted with
cyclohexane: ethyl acetate (4:1,2:1,1:1), then ethyl acetate to afford Intermediate 124 as
a colourless oil (0.052g). LCMS showed MH+ = 512; TRET = 3.51min.

A solution of hydrogen chloride in dioxane (1ml) was added to Intermediate 124 (0.052g,
0. lmmol) and the reaction mixture stirred at 20 °C for 2 hours. The solution was
evaporated in vacuo to afford Intermediate 125 as a yellow solid (0.047g). LCMS showed
MH+ = 412; TRET = 2.21min.

Prepared from 1-(phenylsulphonyl)cyclopropoanecarbonitrile (commercially available
from Menai Organics Ltd, Menai Technology Centre, Deiniol Roas, Bangor, Gwynedd,
Wales, LL57 UP, United Kingdom or described in Bull. Chem. Soc. Jpn. 1985 58(2),
765) using a similar process to that described for any of Intermediates 9, 22 or 80 using
similar or the same number of moles of reagents and/or volumes of solvents. LCMS
showed MH+ = 241; TRET = 1 -7 lmin.

Intermediate 127: (1E/Z)-N-Hydroxy-2-phenylethanimidamide

Commercially available from Maybridge Chemical Company Ltd, Trevillett, Tintagel,
Cornwall, PL34 OHW, United Kingdom.
Intermediate 128: (1E/Z)-N-Hydroxy-2-phenylpropanimidamide

Can be prepared from a-methylphenylacetonitirile according to the procedure described
by J. Rheineimer EP 323864.
Intermediate 129: (1E/Z)-N-Hydroxy-2-[4-(methyloxy)phenyl]ethanimidamide

Commercially available from Exploratory Library, Ambinter, 46 quai Louis Bleriot,
Paris, F-75016, France.
Intermediate 130: (1E/Z)-N-Hydroxy-2-[3-(methyloxy)phenyl]ethanimidamide

Can be prepared from according to the procedure described by S.Borg et. Al European
J.Med Chem. 1993, 28(10,) 801.
Intermediate 131: (1E/Z)-2-[4-(Dimethylamino)phenyl]-N-hydroxyethanimidamide

Prepared from 4-(dimethylamino)benzeneacetonitrile (described by Borovicka et al.
i Collect. Czech. Chem. Commun 1955, 20, 437) using a similar process to that described
for any of Intermediates 9, 22 or 80 using similar or the same number of moles of
reagents and/or volumes of solvents. LCMS showed MH+ = 194; TRET = 0.38min.
Intermediate 132: (1E/Z)-2-[3-(Dimethylamino)phenyl]-N-hydroxyethanimidamide


Prepared from 3-(dimethylamino)benzeneacetonitrile (described by M.L. Sznaidman et
al. Bioorganic Medicinal Chemistry Letters 1996, 6(5), 565) using a similar process to
that described for any of Intermediates 9, 22 or 80 using similar or the same number of
moles of reagents and/or volumes of solvents. LCMS showed MH+ = 194; TRET =
0.46min

Prepared from 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridine-3-acetonitrile
(commercially available from hiterchim, 213 Avenue Kennedy, BP 1140, Montlucon,
Cedex 03103, France or Exploratory Library, Ambinter, 46 quai Louis Bleriot, Paris, F-
75016, France) using a similar process to that described for any of Intermediates 9, 22 or
80 using similar or the same number of moles of reagents and/or volumes of solvents.
LCMS showed MH+ = 198; TRET = 0.32min.

Prepared from 4-phenyl-1-piperazineacetonitnle (commercially available from mterchim,
213 Avenue Kennedy, BP 1140, Montlucon, Cedex 03103, France or Exploratory
Library, Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France) using a similar process
to that described for any of Intermediates 9, 22 or 80 using similar or the same number of
moles of reagents and/or volumes of solvents. LCMS showed MH+" = 235; TRET =
1.09min.


A solution of Intermediate 17 (3.263g, 11.25mmol) in tbionyl chloride (17ml) was heated
at 60 °C for 2 hours. The solution was concentrated in vacuo and then co-evaporated
with dichloromethane. The residue was suspended in a solution of ammonia in dioxane
(45ml, 0,5M solution) and the resultant mixture stirred for 18 hours. After concentration
in vacuo the residue was re-suspended in ammonia in dioxane (45ml, 0.5M) and stirred
for a further 16 hours. The solvent was removed in vacuo and the solid suspended in a
mixture of dichloromethane (40ml) and water (40ml). The solid was filtered, washed
with water and dried in vacuo over P2O5 to afford Intermediate 136 as a cream solid
(2.50g). LCMS showed MH+ = 290; TRET = 2.12min

Burgess Reagent 4.53g, 19.0mmol) was added to a suspension of Intermediate 136 (5.0g,
17.3mmol) in THF (80ml). The reaction mixture was stirred at room temperature for 18
hours then a further portion of Burgess Reagent (0.9g, 1.8mmol) was added and stirring
continued for 5 hours. The reaction mixture was concentrated in vacuo and the residue
partitioned between dichloromethane and water. The organic phase was washed with
water, dried and evaporated in vacuo to afford Intermediate 137 as an off-white solid
(4.43g). LCMS showed MH+ = 272; TRET = 2.40min

Intermediate 137 (3.50g, 12.9mmol), hydroxylamine hydrochloride (3.30g, 47.8mmol)
and sodium hydrogencarbonate (4.0lg, 47.8mmol) in EtOH (45ml) were heated at 45 °C

for 1.5 hours then at 50 °C for 2.5 hours. The suspension was concentrated in vacuo and
the solid stirred in dichloromethane (80ml) for 0.5 hours. The mixture was filtered and
the solid stirred in EtOH, the resultant mixture was filtered and the filtrate evaporated.
The solid was then washed with dichloromethane three time to afford Intermediate 138 as
a white solid (1.62g). LCMS showed MH+ = 305; TRET = 1.85min

Intermediate 139 was prepared from Intermediate 17 and (4-arninotetrahydro-2H-pyran-
4-yl)methanol (commercially available from PharmaCore Inc., 4170 Mendenhall Oaks
Pkwy, Suite 140, High point, NC, USA) using an analogous method to that for
Intermediate 42. LCMS showed MH+ = 404, TRET = 2.19min.

Intermediate 141: (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 4XN, United Kingdom (CAS
104530-80-5)
O -HQ-|-OH
Intermediate 142: Tetrahvdro-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.



Intermediate 143: Tetrahydro-3-thiopheneamine
Prepared in an analogous manner to Intermediate 142 from commercially available
tetrahydrothiophene-4-one. The oxime formation is described by Grigg et.al.,
Tetrahedron, 1991,47,4477-4494 and the oxime reduction by Unterhalt et. al., Arch.
Pharm., 1990, 317-318.

Intermediate 144: 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.

Intermediate 145: Tetrahydro-2H-thiopyran-4-amine-l,1-dioxide hydrochloride
Prepared in an analogous manner to Intermediate 11 from commercially available
tetrahydrothiophene-4-one. Oxidation to l,1-dioxo-tetrahydro-l?i,6-thiopyran-4-one is
described by Rule et. al., in J. 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.

Intermediate 146:1,1-DimethyIethyI (4,4-difluorocyclohexyl)carbamate


(Diethylamino)sulphur trifluoride (DAST), (0.06ml, 0.47mmol), was added to a stirred
solution of l,1-dimethylethyl(4-oxocyclohexyl)carbamate, (250mg, 1.17mmol,
commercially available from AstaTech Inc., Philadelphia, USA) in anhydrous
dichloromethane (5ml) and the mixture was stirred 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, 10g), eluting with DCM to afford Intermediate 62 (140mg) containing
20% of 1,1-dimethylethyl (4-fluoro-3-cyclohexen-1-yl)carbamate. 1H NMR (400MHz
in CDC13,27°C, δppm)
Minor component: 55.11 (dm, 16Hz, 1H), 4.56 (br, 1H), 3.80 (br, 1H) 2.45-1.45 (m's,
6H excess), 1.43 (s, 9H). Major component: 54.43 (br, 1H), 3.58 (br, 1H), 2.45-1.45
(m's, 8H excess), 1.45 (s, 9H).

A solution of hydrogen chloride in dioxane (4M, 1.6ml) was added at 20°C to a stirred
solution of Intermediate 146 (140mg, 0.6mmol), in dioxane (1.6ml). After 3h, the
reaction mixture was concentrated in vacuo to afford Intermediate 147 (96.5mg)
containing 4-fluoro-3-cyclohexen-1-amme. lH NMR (400MHz in d6-DMSO, 27°C,
8ppm) Minor component: 58.22 (br, 3H excess), 5.18 (dm, 16Hz, 1H), 3.28-3.13 (m, 1H
excess), 2.41-1.53 (m's, 6H excess). Major component: 58.22 (br, 3H excess), 3.28-3.13
(m, 1H excess), 2.41-1.53 (m's, 8H excess). Impurities are also present.

























Intermediate 4 (0.043g) was dissolved in acetonitrile (2ml) then treated with phosphorous
oxychloride (0.101g) and stirred under nitrogen and heated at 90°C for 2h. The mixture
was concentrated in vacuo and the residue partitioned between DCM and saturated
aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo and
applied to an SPE cartridge (arninopropyl, lg), which was eluted with methanol.
Concentration in vacuo afforded Example 1 (0.032g). LCMS showed MH+ = 313; TRET =
3.13mm.

Similarly prepared, for example without limitation using the same or similar number of
moles of reagents and/or volumes of solvents, but with an extended reaction time (see
table) was:

Intermediate 10 was dissolved in acetonitrile (2ml) then treated with phosphorous
oxychloride (0.101g) and stirred under nitrogen at 90°C for 3.5h. The mixture was
concentrated in vacuo and the residue partitioned between DCM and saturated aqueous
sodium bicarbonate solution. The organic layer was concentrated in vacuo and the residue
applied to a SPE cartridge (silica, 5g), which was eluted with cyclohexane : Et2O (1:2).
Fractions containing desired material were combined and concentrated in vacuo to afford
Example 3 (0.034g). LCMS showed MH+ = 341; TRET = 3.39min.

A solution of Intermediate 4 (0.09g) in acetonitrile (5ml) was stirred under nitrogen and
treated with Lawesson's reagent (0.116g). The mixture was heated at 65°C for 16h, then
concentrated in vacuo. The residue was applied to an SPE cartridge (silica, 5g) and eluted
with a gradient of cyclohexane : Et2O (1:2 then 1:3, 1:4, 1:5, 0:1). Fractions containing
desired material were combined and concentrated in vacuo. Further purification was
achieved using mass directed autoprep HPLC to afford Example 4 (0.002g). LCMS
showed MH+ = 339; TRET = 3.23min.


A solution of Intermediate 5 (0.07g) in acetonitrile (3ml) was stirred under nitrogen and
treated with Lawesson's reagent (0.085g). The mixture was heated at 65°C for 136h, then
concentrated in vacuo. The residue was partitioned between DCM and water and the
organic layer concentrated in vacuo. Further purification was achieved using mass
directed autoprep HPLC to afford Example 5 (0.008g). LCMS showed MH+ = 407; TRET
= 2.98min.

Intermediate 10 was dissolved in acetonitrile (5ml) then treated with Lawesson's reagent
(0.125g) and heated under nitrogen at 65°C for 66h. Volatiles were removed in vacuo and
the residue was purified by mass directed autoprep HPLC to afford Example 6. LCMS
showed MH+ = 357; TRET = 3.59min.

A solution of Intermediate 6 (0.04g) in ethanol (1ml) was stirred over powdered 4A
molecular sieves (0.290g) and treated with Intermediate 9 (0.045g), followed by sodium
ethoxide (0.020g). The mixture was heated under reflux for 18h, then cooled and filtered.
Following concentration of the filtrate in vacuo, the residue was applied to an SPE

cartridge (silica, 5g) which was eluted with cyclohexane : Et2O (1:1). Fractions
containing desired material were combined and concentrated in vacuo to afford Example
7 (0.017g). LCMS showed MH+ = 339; TRET = 3.23min.

A solution of Intermediate 7 (0.06g) in ethanol (2ml) was treated with triethylamine
(0.101g), followed by methyl acetimidate hydrochloride (0.033g) and the mixture heated
under reflux (80°C) for 42h. Reaction was incomplete so a further portion of methyl
acetimidate hydrochloride (0.033 g) was added and stirring continued under reflux for 6
days. The mixture was concentrated in vacuo and the residue partitioned between DCM
and 2M aqueous HC1. The organic layer was concentrated in vacuo and purified by mass
directed autoprep to afford Example 8 (0.003g). LCMS showed MH+ = 326; TRET =
2.66min.

Intermediate 13 (0.016g) was dissolved in anhydrous acetonitrile (1ml).
4-Aminotetrahydropyran hydrochloride (Intermediate 21A, 0.008g) was then added,
followed by diisopropylethyl amine (0.05ml) and the mixture was stirred under nitrogen
at 75°C for 19h. A further portion of 4-aminotetrahydropyran (0.002g) was added and
stirring continued at 85°C for 16h. The mixture was concentrated in vacuo and partitioned
between DCM and water. The organic phase was concentrated in vacuo and applied to an
SPE cartridge (silica, lg), which was eluted sequentially with a gradient of EtOAc:
cyclohexane (i) 1:8, (ii) 1:4, (iii) 1:2, (iv) 1:1 and (v) 1:0. Fractions containing desired
material were combined and concentrated in vacuo to afford Example 9 (0.013g). LCMS
showed MH+ = 357; TRET = 2.89min.



Intermediate 13 (0.016g, 0.055 mmol) was dissolved in anhydrous acetonitrile (1ml).
Cyclobexyl amine (0.007ml, 0.061 mmol) was then added, followed by diisopropylethyl
amine (0.05ml, 0.29 mmol) and the mixture was stirred under nitrogen at 75 °C for 16h.
The mixture was concentrated in vacuo and partitioned between DCM and water. The
organic phase was concentrated in vacuo and applied to an SPE cartridge (silica, lg),
which was eluted sequentially with a gradient of EtOAc: cyclohexane (i) 1:16, (ii) 1:8,
(Hi) 1:4, (iv) 1:2 and (v) 1:1. Fractions containing desired material were combined and
concentrated in vacuo to afford Example 10 (0.015g). LCMS showed MH+ = 355; TRET =
3.59min.
Similarly prepared using the same or similar number of moles of reagents and volumes of
solvents was the following:

Intermediate 12 (0.026g, 0.1 mmol) was dissolved in ethanol (1.5ml) and treated with a
solution of isobutylamine (0.007g, 0.1 mmol), also in ethanol (1ml). The mixture was
then treated with diisopropylethyl amine (0.075 ml, 0.4 mmol, 4 mole equivalents) and
stirred at 75°C for 16h. The mixture was concentrated in vacuo and applied to an SPE
cartridge (silica, 0.5g) which was eluted sequentially with (i) chloroform, (ii) Et2O and
(iii) methanol. Fractions containing desired material were combined and concentrated in
vacuo to afford Example 12 (0.024g). LCMS showed MH+ = 301; TRET = 2.90min

Similarly prepared using the same or similar number of moles of reagents and volumes of
solvents were the following:



An alternative method of preparing Example 14 is now described:
An alternative method of preparing Example 17 is now described:
EDC (0.823g, 5.3mmol) and HOBT (0.614g, 4.55mmol) were added to Intermediate 17
(1.10g, 3.80mmol) in N,N'-dimethylformamide (10ml). The mixture was stirred for 1.5
hours then acetic hydrazide (0.421g, 5.7mmol) (commercially available e.g. from
Aldrich) was added and the reaction mixture stirred at 20 °C for 48 hours. The reaction
mixture was evaporated and the residue partitioned between chloroform and water. The
aqueous phase was extracted with chloroform and the combined organic phases were
washed with saturated aqueous sodium chloride solution then dried (Na2SO4) and
evaporated. Phosphorus oxychloride (10ml) was added to the residue and the mixture
heated at 120 °C for 0.5 hours. The reaction mixture was evaporated in vacuo and the
residue applied to an SPE cartridge (silica, 20g). The cartridge was eluted with
dichloromethane, cyclohexanerethyl acetate (2:1 then 1:1), ethyl acetate,
chloroform:methanol (19:1 followed by 9:1). Fractions containing the required
compounds were combined and evaporated in vacuo. The residue was then
chromatographed on the Biotage (silica, 50g) using cyclohexane:ethyl acetate (2:1 then
1:1), ethyl acetate followed by ethyl acetate:ethanol (19:1, 9:1 then 9:2). The residue was
partitioned between dichloromethane and aqueous sodium hydrogencarbonate solution.
The oreanic nhase was dried (Na2SO4) and evaporated in vacuo to give Example 14 as a


EDC (1.30g, 6.76mmol) and HOBT (0.782g, 5.80mmol) were added to Intermediate 17
(1.40g, 4.83mmol) in N,N'-dimethylformamide (20ml). The mixture was stirred for 0.5
hours then pivalic acid hydrazide (0.616g, 5.3mmol) (commercially available from
Fluorochem Ltd, Wesley Stree, Glossop, Derbyshire SKI 3 9RY, United Kingdom or can
be prepared according to the procedure by K. Ohmoto et al. in J. Med. Chem., 2001,
44(8), 1268) was added and the reaction mixture stirred at 20 °C for 18 hours. The
reaction mixture was evaporated and the residue partitioned between dichloromethane
and water. The organic phase was washed with water, saturated aqueous sodium
hydrogen carbonate solution followed by saturated aqueous sodium chloride solution then
evaporated in vacuo. Phosphorus oxychloride (10ml) was added to the residue and the
mixture heated at 120 °C for 3 hours. The reaction mixture was evaporated in vacuo and
the residue partitioned between dichloromethane and water. The organic phase was
washed with aqueous sodium hydrogen carbonate solution then dried and evaporated in
vacuo. The residue was applied to an SPE cartridge and eluted with cyclohexane: ethyl
acetate (3:1 followed by 7:3). The solvent was evaporated in vacuo to give Example 17

A solution of Intermediate 16 (0.05g, 0.157 mmol) in ethanol (2ml) was stirred over
powdered 4A molecular sieves (0.30g) and treated with a solution of Intermediate 9
(0.059g, 0.8 mmol) and sodium ethoxide (0.027g, 0.4 mmol) in ethanol (1ml). The
mixture was heated at reflux for 18h under nitrogen, then cooled and filtered. Following
concentration of the filtrate in vacuo, the residue was applied to an SPE cartridge (silica,
5g) which was eluted with cyclohexane : EtOAc (1:1). Fractions containing desired
material were combined and concentrated in vacuo to afford Example 28 (0.024g). LCMS
showed MH+ = 329; TRET = 2.86 min.
Similarly prepared using the same or similar number of moles of reagents and volumes of
solvents were the following:


A solution of Intermediate 16 (0.05g) in ethanol (2ml) was stirred over powdered 4A
molecular sieves (0.30g) and treated with a solution of Intermediate 23 (0.094g) and
sodium ethoxide (0.027g) in ethanol (1ml). The mixture was heated at reflux for 18h
under nitrogen, then cooled and filtered. Following concentration of the filtrate in vacuo,
the residue was applied to an SPE cartridge (silica, 5g) which was eluted with 2-5%
methanol in DCM. Fractions containing desired material were combined and
concentrated in vacuo, then applied to a further SPE cartridge (aminopropyl, 1g) which
was eluted with methanol to afford Example 30 (0.02g). LCMS showed MH+ = 372; TRET
= 2.10min.

A solution of Intermediate 16 (0.05g) in ethanol (2ml) was stirred over powdered 4A
molecular sieves (0.30g) and treated with a solution of Intermediate 24 (0.128g) and
sodium ethoxide (0.027g) in ethanol (1ml). The mixture was heated at reflux for 18h
under nitrogen, then cooled and filtered. Following concentration of the filtrate in vacuo,
the residue was applied to an SPE cartridge (silica, 5g) which was eluted with 2-5%
methanol in DCM. Fractions containing desired material were combined and

concentrated in vacuo to afford Example 31 (0.025g). LCMS showed MH+ = 415; TRET =
2.46 min.

A solution of Intermediate 20 (0.020g) in THF (0.2ml) was treated with Burgess reagent
(0.026g) and heated in a microwave at 120°C (100W) for 5min. The mixture was
concentrated by evaporation under a stream of nitrogen and the residue applied to an SPE
cartridge (silica, lg) which was eluted with 2% methanol in DCM to afford Example 32
as a white solid (0.014g). LCMS showed MH+ = 355; TRET = 2.78 min.

Intermediate 12 (0.03g) was dissolved in acetonitrile (2ml) and treated with DIPEA
(0.1ml) and Intermediate 25 (0.022g). The mixture was stirred at 85°C for 18h then
concentrated in vacuo and partitioned between DCM and water. The layers were
separated and the organic layer concentrated in vacuo, then purified by mass directed
autoprep HPLC to afford Example 33 (0.01g). LCMS showed MH+ = 370; TRET =
2.48rnin.


A solution of Intennediate 19 (0.05g, 0.133 mmol), TBTU (0.045g, 0.14 mmol) and
DIPEA (0.1ml, ca. 0.5 mmol) in DMF (1ml) is stirred at room temperature under nitrogen
for 5 min. A solution of Intermediate 26 (0.024g, 0.21 mmol) in DMF (1ml) is then added
and stirring continued for 18h. Reaction can be found to be incomplete after this time so a
further portion of Intermediate 26 (0.012g, 0.10 mmol) is added and stirring continued
under nitrogen for a further 18h. The mixture is concentrated in vacuo then the residue
applied to an SPE cartridge (aminopropyl, 2g), which is eluted with methanol (2x3ml).
Fractions containing desired material are concentrated in vacuo.
The partially purified intermediate is taken forward without further
characterisation and si dissolved in THF (0.5ml) then treated with Burgess reagent
(0.025g, ca. 0.1 mmol). The mixture is heated under microwave conditions at 120°C
(120W) for 5 min. The mixture is then concentrated in vacuo and purified by mass
directed autoprep HPLC to afford Example 34.
According to an alternative and more preferred embodiment, the reaction was performed
as follows. A solution of carboxylic acid Intermediate 26 (0.024g, 0.21 mmol), TBTU
(0.045g, 0.14 mmol) and DIPEA (0.1ml, ca. 0.5 mmol) in DMF (1ml) was stirred at room
temperature under nitrogen for 5 min. A solution of Intermediate 19 (0.05g, 0.133 mmol)
in DMF (1ml) was then added and stirring continued for 18h. Reaction was found to be
incomplete after this time so a further portion of Intermediate 26 (0.012g, 0.10 mmol)
was added and stirring continued under nitrogen for a further 18h. The mixture was
concentrated in vacuo then the residue applied to an SPE cartridge (aminopropyl, 2g),
which was eluted with methanol (2x3ml). Fractions containing desired material were
concentrated in vacuo. The partially purified intermediate was taken forward without
further characterisation and was dissolved in THF (0.5ml) then treated with Burgess
reagent (0.025g, ca. 0.1 mmol). The mixture was heated under microwave conditions at
120°C (120W) for 5 min. The mixture was then concentrated in vacuo and purified by
mass directed autoprep HPLC to afford Example 34 (0.006g). LCMS showed MH+ =
385; TRET = 2.65min.
Similarly prepared, via the original or alternative embodiment described above, and using
the same or similar number of moles of reagents and volumes of solvents, were the
following:



An alternative method of preparing Example 35 is now described:
A solution of Intermediate 27 (0.463g, 2.93mmol), TBTU (0.941g, 2.93mmol) and
DIPEA (1.53ml, 8.79mmol) in dry dimethylformamide (7ml) was stirred at room
temperature for 15min. A solution of Intermediate 19 (1.0g, 2.93mmol) in dry
dimethylformamide (5ml) was then added and stirring was continued for lh. The mixture
was concentrated in vacuo, and the residue was dissolved in methanol (5ml) and applied
equally to two SPE cartridges (aminopropyl, 10g). The cartridges were eluted with
methanol. The product-containing fractions were combined and evaporated to give a
yellow oil (1.56g) which was dissolved in dichloromethane (10ml) and applied to a SPE
cartridge (silica, 10g). The cartridge was eluted with chloroform-methano1-triethylamine
(9/0.2/0.1). Fractions containing the desired product were combined and evaporated to
give a pale yellow foam (1.17g). This product was suspended in dry tetrahydrofuran
(45ml) and treated with Burgess reagent (1.244g, 5.22mmol) at room temperature under
nitrogen. The resulting solution was heated at 70°C. After 2h, the reaction mixture was
evaporated and the residual oil was dissolved in dichloromethane (5ml) and applied to a
SPE cartridge (silica, 20g). The cartridge was eluted with chloroform-methano1-
triethylamine (9/0.2/0.1). Fractions containing the desired material were combined and
evaporated to give a cream solid. Further purification by passage through a SCX cartridge
(20g) eluting with methanol followed by 10% ammonia in methanol afforded Example 35



A solution of Intermediate 19 (0.05g, 0.133 mmol), TBTU (0.045g, 0.14 mmol) and
DIPEA (0.1ml, ca. 0.5 mmol) in DMF (1ml) is stirred at room temperature under nitrogen
for 5 min. A solution of Intermediate 30 (0.018g, 0.14 mmol) in DMF (1ml) is then added
and stirring continued for 18h. Reaction can be found to be incomplete after this time so a
further portion of Intermediate 30 (0.009g, 0.07 mmol) is added and stirring continued
under nitrogen for a further 18h. The mixture is concentrated in vacuo then the residue
applied to an SPE cartridge (aminopropyl, 2g), which is eluted with methanol (2x3ml).
Fractions containing desired material are concentrated in vacuo. The partially purified
intermediate is taken forward without further characterisation and is dissolved in THF
(0.5ml) then treated with Burgess reagent (0.025g, ca. 0.1 mmol). The mixture is heated
under microwave conditions at 120°C (120W) for 5 min. Reaction can appear incomplete
so a further portion of Burgess Reagent (0.012g, ca. 0.05 mmol) is added and the mixture
heated under microwave conditions at 140°C (120W) for a further 10 min. The mixture
is then concentrated in vacuo and purified by mass directed autoprep HPLC to afford
Example 38.
According to an alternative and more preferred embodiment, the reaction was performed
as follows. A solution of carboxylic acid Intermediate 30 (0.018g, 0.14 mmol), TBTU
(0.045g, 0.14 mmol) and DIPEA (0.1ml, ca. 0.5 mmol) in DMF (1ml) was stirred at room
temperature under nitrogen for 5 min. A solution of Intermediate 19 (0.05g, 0.133 mmol)
in DMF (1ml) was then added and stirring continued for 18h. Reaction was found to be
incomplete after this time so a further portion of Intermediate 30 (0.009g, 0.07 mmol)
was added and stirring continued under nitrogen for a further 18h. The mixture was
concentrated in vacuo then the residue applied to an SPE cartridge (aminopropyl, 2g),
which was eluted with methanol (2x3ml). Fractions containing desired material were
concentrated in vacuo. The partially purified intermediate was taken forward without
further characterisation and was dissolved in THF (0.5ml) then treated with Burgess
reagent (0.025g, ca. 0.1 mmol). The mixture was heated under microwave conditions at
120°C (120W) for 5 min. Reaction appeared incomplete so a further portion of Burgess
Reagent (0.012g, ca. 0.05 mmol) is added and the mixture heated under microwave
conditions at 140°C (120W) for a further 10 min. The mixture was then concentrated in
vacuo and purified by mass directed autoprep HPLC to afford Example 38 (0.006g).
LCMS showed MH+ = 399; TRET = 2.64min.

Similarly prepared, via the original or alternative embodiment described above, and using
the same or similar number of moles of reagents and volumes of solvents, were the
following:

An alternative method of preparing Example 38 is now described:
A mixture of Intermediate 30 (0.325g, 2.5mmol), TBTU (0.803g, 2.5mmol) and DDPEA
(1.75ml, 10.04mmol) in N,N-dimethylformamide (10ml) was stirred at 20 °C for 20
minutes. A suspension of Intermediate 19 (1.024g, 3.00mmol) in N,N-
dimethylformamide was added and the reaction mixture stirred for 18 hours. The solvent
was evaporated and the residue applied to SPE cartridges (2 x 50g, aminopropyl). The
cartridges were eluted with dichloromethane:memanol (0 - 100% methanol over 17
minutes at 25ml/min). Appropriate fractions were evaporated in vacuo and the residue
dissolved in tetrahydrofuran (10ml). Burgess Reagent (0.746g, 3.13mmol) was added
and the reaction mixture was heated at reflux for 2.5 hours. Additional Burgess Reagent
(0.284g) was added and heating continued for 1.5 hours. The solvent was evaporated in
vacuo. The residue was applied to an SPE cartridge (silica, lOOg) and eluted with
cyclohexane:ethyl acteate (gradient of 0 to 100% ethyl acetate over 25 minutes at
25ml/min) followed by ethyl acetate then ethyl acetate:methanol (4:1). Appropriate
fractions were combined and evaporated to give Example 38 as a white solid (0.503g).
LCMS showed MH+ = 399, TRET = 2.67min. 1H NMR (400MHz in CDC13, 27°C, δppm)


Intermediate 33 (0.055g, 0.14mmol) and Burgess reagent (0.037g, 0.16mmol) were
suspended in THF (2ml) and heated at reflux for 4 hours. Solvents were removed in
vacuo and the residue applied to an SPE cartridge (silica, 2g), which was eluted with
cyclohexane:ethyl acetate (1:2). Concentration in vacuo afforded Example 40A (0.03g).
LCMS showed MH+ = 374, TRET = 2.78min.

The compound of Example 41 was synthesised using the following route, reagents and
solvents:


In one embodiment, a suitable detailed procedure for the first two steps is given above in
"Intermediate 33" and "Example 40A". In one embodiment, a suitable detailed procedure
for synthesising Example 41 from Example 40A is as follows:
Example 40A (0.023g, 0.062mmol) and DBU (0.028g, 0.18mmol) were dissolved in
carbon tetrachloride/acetonitrile/pyridine (2:3:3, 1.6ml) and stirred at room temperature
under nitrogen for 48 hours. Solvents were removed in vacuo and the residue was
purified by mass directed autoprep HPLC to afford Example 41 (0.0017g). LCMS
showed MH+ = 372, TRET = 9.24min.


Intermediate 34 (0.095g, 0.27mmol) and Burgess reagent (0.071g, 0.30mmol) were
dissolved in THF (2ml) and heated at reflux for 4 hours. Solvents were removed in vacuo
and the residue applied to an SPE (silica, 5g), which was eluted with ethyl acetate to
afford Example 42 (0.045g). LCMS showed MH+ = 330, TRJET= 2.84min.

Example 43 was synthesised according to the following reaction scheme:


Detailed conditions which can be used for the first six reactions from Intermediate 1 to
Intermediate 40 are given in the "Intermediate" syntheses hereinabove for Intermediates
35,36, 37, 38, 39 and 40.

Example 43 can be made from Intermediate 40 using a similar process to mat described
for Example 1,2, 3, using a similar or the same number of moles of reagents and/or
volumes of solvents. LCMS showed MH+ = 343, TRET = 2.70min.

A solution of Tetrahydro-2-furoic acid = 2-(tetrahydrofuran)carboxylic acid
(commercially available from Sigma-Aldrich) (0.012ml, 0.12mmol), TBTU (0.039g,
0.12mmol) and DIPEA (0;084ml, 0.48mmol) in DMF (2ml) was stirred at room
temperature under nitrogen. Intermediate 19 (0.045g, 0.12mmol) was added and the
reaction stirred for 2 days. The mixture was concentrated in vacuo then the residue
applied to an SPE cartridge (aminopropyl, 5g), which was eluted with methanol.
Fractions containing the desired material were concentrated in vacuo. Half of the
partially purified material was dissolved in THF (0.1ml) and treated with Burgess reagent
(0.015g, 0.06mmol). The mixture was heated under microwave conditions at 120 °C
(100W) for 5 minutes. The mixture was then concentrated in vacuo and applied to an
SPE cartridge (silica, 0.5g). The cartridge was eluted with dichloromethane: methanol
(19:1), fractions containing the desired material were concentrated in vacuo. The sample
was then partitioned between dichloromethane and water, the organic phase was
evaporated to give Example 44 (0.0065g). LCMS showed MH+ =385, TRET = 2.69rnin.

Intermediate 86 (0.113g, 0.28mmol) and Burgess Reagent (0.133g, 0.56mmol) in THF
(lml) were heated in the microwave 5 minutes at 120 °C SmithCreator Microwave. The

sample was evaporated in vacuo and the residue purified by mass directed autoprep
HPLC...LCMS showed MH+ = 358; TRET = 2.57min

A solution of the Intermediate 19 (0.1g, 0.29mmol), diisopropylethylamine (0.3ml,
1.74rmnol) and methyl acetimidate hydrochloride (0.095g, 0.87mmol, commercially
available from Aldrich) in ethanol (3ml) was heated under reflux. After 17h, the reaction
mixture was evaporated to an oily residue which was partitioned between
dichloromethane (10ml) and water (2ml). The phases were separated and the organic
phase was dried over anhydrous sodium sulphate and evaporated to a waxy solid
(0.053g). Purification of a portion of this solid (0.025 g) by mass directed autoprep HPLC
afforded Example 46 (0.005g). LCMS showed MH+ = 328; TRET = 2.25min.

A mixture of Intermediate 41 (0.049mg, 0.14mmol), Intermediate 9 (0.051g, 0.68mmol),
sodium ethoxide (0.13ml, 21% solution in ethanol, commercially available from Aldrich)
and powdered 4A molecular sieves (0.3g) in ethanol (2ml) were heated at 80 °C for 16
hours under nitrogen. The mixture was cooled and filtered and the filtrate concentrated in
vacuo. The residue was applied to an SPE cartridge (silica, 5g) and eluted with
cyclohexane, cyclohexane: ethyl acetate (1:1) and then ethyl acetate. The desired
fractions were combined and evaporated to give Example 47 (0.005g). LCMS showed
MH+ = 370; TRET = 2.77min


Example 48 was prepared from Intermediate 41 and Intermediate 24 using an analogous
method to that for Example 47. LCMS showed MH+ = 455; TRET = 2.59mm.

Burgess reagent (0.189g, 0.79mmol) was added portionwise, over 3min, to a stirred
solution of Intermediate 42 (0.293g, 0.72mmol) in dry tetrahydrofuran (13ml) at room
temperature under nitrogen. The resulting solution was heated at 70°C under nitrogen for
4h. The reaction mixture was evaporated to give an off-white solid which was dissolved
in dichloromethane (5ml) and applied to a SPE cartridge (silica, lOg). The cartridge was
eluted sequentially with a gradient of ethyl acetate-petroleum ether (1:8,1:4,1:2,1:1,
1:0). Fractions containing the desired product were combined and evaporated to afford
Example 49 as a white crystalline solid (0.169g). LCMS showed MH+ = 392; TRET =
3.31min.



Example 50 was prepared from Intermediate 43 using an analogous method to that for
Example 49. LCMS showed MH+ = 392; TRET = 3.32min.

Example 51 was prepared from Intermediate 44 using an analogous method to that for
Example 49. LCMS showed MH+ = 406; TRET = 3.38min

Example 52 was prepared from Intermediate 45 using an analogous method to that for
Example 49. LCMS showed MH+ = 406; TRET = 3.38min.


Example 53 was prepared from Intermediate 46 using an analogous method to that for
Example 49. LCMS showed MH+ = 406; TRET = 3.37min.

Example 54 was prepared from Intermediate 47 using an analogous method to that for
Example 49. LCMS showed MH+ - 392; TRET = 3.29min.


Example 55 was prepared from Intermediate 48 using an analogous method to that for
Example 49. LCMS showed MH+ = 392; TRET = 3.29min.

Example 56 was prepared from Intermediate 49 using an analogous method to that for
Example 49. LCMS showed MH+ = 344; TRET = 2.95min.

A solution of lithium hydroxide (0.12g, 5.2mmol) in water (6ml) was added to a
suspension of Example 41 (0.48g, 1.3mmol) in methanol (20ml) and the resultant mixture
heated at 50 °C for 2 hours. The solvent was evaporated in vacuo and the residue
dissolved in water (50ml), cooled in an ice bath and acidified to pH 3 by the addition of
aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried in
vacuo at 40 °C to give Example 57 as a white solid (0.3g). LCMS showed MH+ = 358;
TRBT = 2.62min


A mixture of Example 57 (0.05g, 0.14mmol), HOBT (0.023g, 0.17mmol), EDC (0.038g,
0.2mmol) in DMF (2ml) were stirred at 20 °C for 20 minutes. isopropylamine (0.013ml,
0.15mmol) was added and the reaction mixture stirred overnight. The solvent was
concentrated in vacuo and the residue dissolved in DCM. The organic phase was washed
with water then aqueous sodium hydrogen carbonate solution. The aqueous phases were
extracted with DCM and the combined organic phases concentrated in vacuo. The
residue was applied to an SPE cartridge (aminopropyl, 2g) and eluted with MeOH,
appropriate fractions were combined and evaporated in vacuo. The residue was further
purified by chromatography on SPE (silica, 0.5g) eluting with cyclohexane-.ethyl acetate
(2:1 followed by 1:1) to give Example 58 as a white solid (0.012g). LCMS showed MH+
= 399; TRET = 2.78min
Similarly prepared using the same or similar numbers of moles of reagents and/or
volumes of solvents was the following:

Intermediate 53 (0.076g, 0.21mmol) in phosphorous oxychloride (3ml) was heated at 120
°C for 3 hours then evaporated in vacuo. The residue was partitioned between DCM and

water and the organic phase concentrated in vacuo. The residue was purified by mass
directed autoprep HPLC to afford Example 60 (0.027g). LCMS showed MH+ = 343; TRET
= 2.34min

Intermediate 54 (0.072g, 0.63mmol), Intermediate 12 (0.150g, 0.57mmol) and
diisopropylethylamine (0.51ml) in acetonitrile (3ml) were heated at 85 °C for 18 hours
then evaporated in vacuo. The residue was partitioned between DCM and water and the
organic phase concentrated in vacuo. The residue was purified by mass directed autoprep
HPLC to afford Example 61 (0.004g). LCMS showed MH+ = 343; TRET = 2.48min
Similarly prepared using the same or similar numbers of moles of reagents and/or
volumes of solvents were the following:


Intermediate 61 (0.266g, 0.56mmol) in phosphorous oxychloride (10ml) was heated at
120 °C for 1.5 hours then evaporated in vacuo. The residue was partitioned between
DCM and water and the organic phase concentrated in vacuo. The residue was purified
on an SPE cartridge (silica, 5g) eluting with cyclohexane: ethyl acetate (2:1,1:1 then 2:3)
to afford Example 65 (0.042g). LCMS showed MH+ = 385; TRET = 3.05min.

Intermediate 64 (0.05g, 0.1 lmol) and Burgess Reagent (0.053g, 0.22mol) in a mixture of
THF / DMF (1ml, 1:1) were heated under microwave conditions at 120 °C (120W) for 5
minutes. The reaction mixtures were heated at 150 °C for four 10 minutes intervals with
an additional portion of Burgess reagent (0.025g) being added after the first and third
period of additional microwave heating. The reaction mixture was concentrated in vacuo
and purified by SPE (silica, 0.5g) eluting with cyclohexane, cyclohexane: ethyl acetate
(2:3 then 1:4) then ethyl acetate. Fractions containing the desired material were
evaporated in vacuo to afford Example 66 (O.OlOg). LCMS showed MH+ = 413; TRET =
2.63min.

Intermediate 65 (0.05g, 0.13mmol) and Burgess Reagent (0.07g, 0.3mmol) in THF (2ml)
was heated at 80 °C for 7 hours. The reaction mixture was concentrated in vacuo and a
further portion of Burgess Reagent (0.07g, 0.3mmol) in THF (0.5ml) was added and the
reaction mixture refiuxed for 18 hours. The reaction was concentrated in vacuo and
partitioned between DCM and water. The phases were separated using a hydrophobic frit
(Whatman PTFE Filter Media with Polypropylene Housing 5µM pore size). The organic

phase was concentrated in vacuo and the residue purified by mass directed autoprep
HPLC to afford Example 67 (0.018g). LCMS showed MH+ = 369; TRET = 3.03min.
Similarly prepared using the same or similar numbers of moles of reagents and/or
volumes of solvents were the following:



Alternative Procedure:
Burgess Reagent (0.168g, 0.74mmol) was added to a solution of Intermediate 75 (0.141g,
0.33mmol) in tetrahydrofuran (2ml). The reaction mixture was heated at reflux for 1.5
hours then evaporated. The residue was applied to an SPE cartridge (silica, 10g) and
eluted with cyclohexane:ethyl acteate (gradient of 0 to 100% ethyl acetate over 15
minutes at 15ml/min) followed by ethyl acetate then ethyl acetate:methanol (4:1).
Appropriate fractions were combined and evaporated to give Example 77 as a white solid

Intermediate 79 (0.18mmol) and Burgess Reagent (0.14g, 0.6mmol) in THF (0.75ml) was
heated at 80 °C under an atmosphere of nitrogen for 16 hours. The reaction was
concentrated using a stream of nitrogen and the residue dissolved in DCM (8ml). The
solution was stirred with water and the phases separated using a hydrophobic frit
(Whatman). The organic phase was concentrated in vacuo and the material was purified
by mass directed auotprep HPLC to afford Example 81 (0.005g). LCMS showed MH4" =
440; TRET = 2.52min.


A mixture of Intermediate 16 (0.064g, 0.2mmol), Intermediate 80 (0.172g, lmmol), a
solution of sodium ethoxide in EtOH (0.19ml, 21% solution) and powdered 4A molecular
sieves (0.3 8g) in EtOH (2ml) were stirred at 82 °C under an atmosphere of nitrogen for
18 hours. The reaction mixture was filtered, the solvent was evaporated in vacuo and the
residue was applied to an SPE cartridge (silica, 2g). The cartridge was eluted with (i)
cyclohexane, (ii) cyclohexane: ethyl acetate (4:1, 3:2,1:1,2:3,1:4), (iii) EtOAc, (iv)
MeOH and (v) 10% aqueous NH3 solution in MeOH to afford Example 82 as a white
solid (0.038g). LCMS showed MH+ = 427; TRET = 2.10min.
Similarly prepared from Intermediate 16, using the same or similar numbers of moles of
reagents and/or volumes of solvents, were the following:


Examples 85 to 96 - various 5-{3-[substituted]-l,2,4-oxadiazol-5-yl}-1-ethyl-N-
(tetrahydro-2H-pyran-4-yI)-1H-pyrazolo[3,4-b]pyridin-4-amines
Examples 85 to 96 can be prepared from Intermediate 16 using a similar processes to
those described for any of Examples 28-31 or 82-84, using a similar or the same number
of moles of reagents and/or volumes of solvents.
Alternatively, Examples 85 to 90 and Examples 95 to 96 (all amides) can be prepared
from the corresponding carboxylic acid compound Intermediate 83, by activating the
carboxylic acid moiety (e.g. using a coupling agent such as EDC, HATU or more
preferably TBTU) and reacting the activated carboxylic acid with the appropriate amine
R10R11NH. This reaction, preferred reagents, and the structure of Intermediate 83 is
shown in the following scheme (Intermediate 83 has the same structure as Example 84
but the 1,2,4-oxadiazole side-chain Rx is -CH2-C(O)OH):

As shown in the scheme above, Intermediate 83 can be prepared by hydrolysis of the
corresponding t-butyl ester compound Intermediate 84 (wherein the 1,2,4-oxadiazole
side-chain R.X is -CH2-C(O)-0-tBu). Intermediate 84 can be prepared from Intermediate
17 and Intermediate 85 as shown in the scheme above. The preparation of Intermediate
85 has been shown earlier.

In an alternative embodiment, Examples 85 to 90 and Examples 95 to 96 can be prepared
from reaction of carboxylic acid Intermediate 83 with R10R11NH as shown above, but
the Intermediate 83 (wherein the 1,2,4-oxadiazole side-chain Rx is -CH2-C(O)OH)
might be preparable from Example 84, by hydrolysing the amide bond within Rx in
Example 84 to form the carboxylic acid Intermediate 83.
The example numbers and corresponding structures of Examples 85 to 96 are as follows:

N,N-Dimethylformamide (0.1ml) was added dropwise to a stirred mixture of Intermediate
83 (0.525g, 1.40mmol) and oxalyl chloride (0.18ml, 2.1mmol) in dichloromethane (15ml)
at 0 °C under an atmosphere of nitrogen. The resultant mixture was stirred at 0 °C for 1
hour.
An aliquot of the above solution (1.1ml) was added to a solution of the amine
(0.6mmol) in dichloromethane (0.5ml). The reaction mixture was allowed to stand at
room temperature for 2 hours then applied to an SPE cartridge (aminopropyl, 2g). The
cartridge was eluted with chloroform then ethyl acetate / methanol (9:1). Fractions
containing the product were concentrated and the residue purified by SPE cartridge
(silica, 5g) eluting with dichloromethane, ether, ethyl acetate then ethyl acetate /
methanol (9:1). The desired fractions were concentrated to afford the examples given
below.


A mixture of Intermediate 16 (0.059g, 0.2mmol), Intermediate 121 (0.161g, 1.54mmol), a
solution of sodium ethoxide in EtOH (0.21ml, 21% solution) and powdered 4A molecular
sieves (0.43g) in EtOH (1.5ml) were stirred at 82 °C under an atmosphere of nitrogen for
18 hours. The reaction mixture was filtered and the residue purified by mass directed
autoprep HPLC to afford Example 92 (0.007g). LCMS showed MH+ = 428; TRET =
2.46min.


A mixture of Intermediate 16 (0.098g, 0.31mmol), Intermediate 122 (0.24g, 0.93mmol), a
solution of sodium ethoxide in EtOH (0.21ml, 21 % solution) and powdered 4A molecular
sieves (0.43 g) in EtOH (1.5ml) were stirred at 82 °C under an atmosphere of nitrogen for
18 hours. The reaction mixture was filtered and the residue purified by mass directed
autoprep HPLC to afford Example 93 (0.079g). LCMS showed MH+ = 411; TRET =
3.80min.

General Procedure for Example 95 to 96:
N,N-Dimethylformamide (0.1ml) was added dropwise to a stirred mixture of Intermediate
83 (0.525g, 1.40mmol) and oxalyl chloride (0.18ml, 2.1mmol) in dichloromethane (15ml)
at 0 °C under an atmosphere of nitrogen. The resultant mixture was stirred at 0 °C for 1
hour.
An aliquot of the above solution (1.1ml) was added to a solution of the R10R11NH amine
(0.6mmol) in dichloromethane (0.5ml). The reaction mixture was allowed to stand at
room temperature for 2 hours then applied to an SPE cartridge (aminopropyl, 2g). The
cartridge was eluted with chloroform then ethyl acetate / methanol (9:1). Fractions
containing the product were concentrated and the residue purified by SPE cartridge
(silica, 5g) eluting with dichloromethane, ether, ethyl acetate then ethyl acetate /



Examples 97 to 125 -various 5-{5-[substituted]-l,3,4-oxadiazo1-2-yl}-1-ethyl-N-
(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amines
Examples 97 to 125 can be made using processes similar to those described for any of
Examples 9,14, 32-40,44-45,60-64, 65-66, and 67-81, using a similar or the same
number of moles of reagents and/or volumes of solvents.
ExajmjpjeJ7:1-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[5-(lH-l,2,3-triazo1-1-
ylmethyI)-l,3,4-oxadiazo1-2-yI]-1H-pyrazolo[3,4-6]pyridin-4-amine

General Procedure for preparation of Examples 97 to 125:
A mixture of diacyl hydrazide Intermediate (one of Intermediates 89-114) and Burgess
Reagent (2 equivalents) in N,N-dimethylformamide (1ml) was heated in a microwave for
10 minutes at 120 °C at 150 Watts. The resultant solution was concentrated in vacuo and
partitioned between chloroform and water. The organic phase was separated using a
hydrophobic frit (Whatman PTFE Filter Media with Polypropylene Housing 5pM pore
size) then concentrated. The residue was purified by mass directed auto-prep HPLC.
As either formic acid or trifluoroacetic acid are used in the solvents in the mass directed
auto-prep HPLC procedure (see "Machine Methods section hereinbefore), some of the
Examples were isolated as the formate salt or trifluoroacetate salt as shown below.
The example numbers and corresponding structures of Examples 97 to 125 are as
follows:





Examples 126 to 147-various 5-{4-[substituted]-oxazoI-2-yl}-1-ethyl-N-(tetrahydro-
2H-pyran-4-yl)-1H-pyrazoIo[3,4-b]pyridin-4-amines
Examples 126 to 147 (all amides) can be prepared by reacting Example 57 and the
appropriate amine to form the amide bond using a process similar to that described for
Example 58, except mat HATU is preferably used instead of EDC as coupling agent, and
using a similar or the same number of moles of reagents andVor volumes of solvents as in
Example 58.
Example 126: 2-[1-Ethv1-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-
6]pyridin-5-yl]-N-(phenylmethyl)-l,3-oxazole-4-carboxamide

General Procedure for Examples 126 to 147:
A mixture of Example 57 (0.014g, 0.04mmol), diisopropylethylamine (0.0017ml,
0.096mmol) and HATU (0.016g, 0.042mmol) in N,N-dimethylformamide (0.4ml) was
allowed to stand for 10 minutes. The resultant solution was added to the appropriate
amine R10R11NH (0.05mmol) and mixture agitated by sonication. After standing for 18
hours the solvent was removed in vacuo. The residue was applied to an SPE cartridge
(aminopropyl, 0.5g) and the cartridge eluted with chloroform (1.5ml) followed by ethyl
acetate : methanol (9:1,2ml). Appropriate fractions were evaporated in vacuo and the
residue purified by mass directed auto-prep HPLC
The example numbers and corresponding structures of Examples 126 to 147 are as
follows:





N,N-Dimethylformamide (0.1ml) was added dropwise to a stirred mixture of Intermediate
83 and oxalyl chloride (0.18ml, 2.1mmol) in dichloromethane (15ml) at 0 °C under an
atmosphere of nitrogen. The resultant mixture was stirred at 0 °C for 1 hour.
An aliquot of the above solution (1.1ml) was added to a solution of the amine
(0.6mmol) in dichloromethane (0.5ml). The reaction mixture was allowed to stand at
room temperature for 2 hours then applied to an SPE cartridge (aminopropyl, 2g). The
cartridge was eluted with chloroform then ethyl acetate / methanol (9:1). Fractions
containing the product were concentrated and the residue purified by SPE cartridge
(silica, 5g) eluting with dichloromethane, ether, ethyl acetate then ethyl acetate /
methanol (9:1). The desired fractions were concentrated to afford the examples given
below.



General Procedure for Examples 157 to 158:
A mixture of diacyl hydrazide Intermediate 104 or 105 and Burgess Reagent (2
equivalents) in N,N-dimethylformamide (lml) was heated in a microwave for 10 minutes
at 120 °C at 150 Watts. The resultant solution was concentrated in vacuo and partitioned
between chloroform and water. The organic phase was separated using a hydrophobic frit
(Whatman PTFE Filter Media with Polypropylene Housing 5yM pore size) then
concentrated. The residue was purified by mass directed auto-prep HPLC



General Procedure for Examples 159 to 165:
The appropriate carboxylic acid chloride R17C(O)Cl (0.12mmol) was added to a stirred
solution of amine Intermediate 118 (0.1mmol) and diisopropylethylamine (0.3mmol) in
chloroform (1ml) at room temperature. After stirring at room temperature for 16h, the
reaction mixture was applied to a SPE cartridge (aminopropyl, 2g) and the cartridge was
eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the
desired product were combined and blown down under nitrogen. The resulting residue
was further purified on a SPE cartidge (silica, 1g) eluting with a gradient of 30-100%
ethyl acetate in petroleum ether. Appropriate fractions were combined and the solvents
were evaporated to afford the product.



General Procedure for Examples 166 to 172:
The appropriate sulphonyl chloride R18S(O)2C1 (0.12mmol) was added to a stirred
solution of amine Intermediate 118 (0.1mmol) and pyridine (0.2mrnol) in chloroform
(1ml) at room temperature. After stirring at room temperature for 16h, the reaction
mixture was applied to a SPE cartridge (aminopropyl, 2g,) and the cartridge was eluted
sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired
product were combined and blown down under nitrogen. The resulting residue was
further purified on a SPE cartidge (silica, 1g) eluting with a gradient of 30-100% ethyl
acetate in petroleum ether. Appropriate fractions were combined and the solvents were
evaporated to afford the product.



A solution of Intermediate 119 (45mg, 0.1mmol) in dry dimethylformamide (2ml) was
added to sodium hydride (60% dispersion in mineral oil, 4.4mg, 0.11mmol), and the
resulting mixture was stirred at room temperature. After 16h, the reaction mixture was
diluted with water (2ml) and extracted with chloroform (3 x 5ml). The combined organic
extracts were dried over anhydrous sodium sulphate and evaporated to give the crude
product. Purification of the crude product on a SPE cartridge (silica, 2g) using a gradient
of ethyl acetate in petroleum ether afforded Example 173. LCMS showed MH+ =412,
TRET = 2.59min.


A solution of Intermediate 120 (46mg, 0.1mmol) in dry dimethylformamide (2ml) was
added to sodium hydride (60% dispersion in mineral oil, 4.4mg, 0.11mmol), and the
resulting mixture was stirred at room temperature. After 16h, the reaction mixture was
diluted with water (2ml) and extracted with chloroform (3 x 5ml). The combined organic
extracts were dried over anhydrous sodium sulphate and evaporated to give the crude
product. Purification of the crude product on a SPE cartridge (silica, 2g) using a gradient
of ethyl acetate in petroleum ether afforded Example 174. LCMS showed MH+ =426,
TRET = 2.66min.

Acetyl chloride (0.04mmol) was added to a stirred solution of Intermediate 125
(0.033mmol) and diisopropylethylamine (0.1mmol) in chloroform (1ml) at room
temperature. After stirring at room temperature for 1.5h, a further quantity of acetyl
chloride (0.04mmol) and diisopropylethylamine (0.1mmol) were added to the reaction
mixture. After 3.5h the reaction mixture was applied to a SPE cartridge (aminopropyl,
lg,) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol.
Fractions containing the desired product were combined and blown down under nitrogen,
the resulting residue was further purified on a SPE cartridge (silica, lg) eluting with a
gradient of 30-100% ethyl acetate in petroleum ether to afford Example 175 LCMS
showed MH+ = 454, TRET = 2.79min.

isovaleryl chloride (0.04mmol) was added to a stirred solution of Intermediate 125
(0.033mmol) and diisopropylemylamine (0.1mmol) in chloroform (1ml) at room
temperature. After stirring at room temperature for 1.5h, the reaction mixture was applied

to a SPE cartridge (arninopropyl, 1g,) and the cartridge was eluted sequentially with
chloroform, ethyl acetate and methanol. Fractions containing the desired product were
combined and blown down under nitrogen. The resulting residue was further purified on a
SPE cartridge (silica, lg) eluting with a gradient of 30-100% ethyl acetate in petroleum
ether to afford Example 176. LCMS showed MH+ = 496, TRET = 3.17min.

Methanesulphonyl chloride (1.16mmol) was added to a stirred solution of Intermediate
125 (0.033mmol) and pyridine (0.5ml) in chloroform (1ml) at room temperature. After
stirring at room temperature for 31h, the reaction mixture was applied to a SPE cartridge
(aminopropyl, 5g) and the cartridge was eluted sequentially with chloroform, ethyl
acetate and methanol. Fractions containing the desired product were evaporated in vacuo.
The resulting residue was further purified on a SPE cartridge (silica, 1g) eluting with a
gradient of 30-100% ethyl acetate in petroleum ether to afford Example 176. LCMS
showed MH+ = 490, TRET = 2.97min.

A mixture of Intermediate 16 (0.067g, 0.26mmol), amidoxime Intermediate 126 (0.255g,
1.06mmol), a solution of sodium ethoxide in EtOH (0.87ml, 21% solution) and powdered
4A molecular sieves (0.68g) in EtOH (2ml) were stirred at 82 °C under an atmosphere of
nitrogen for 12 hours. The reaction mixture was filtered and the solvent was evaporated
in vacuo. The residue was applied to an SPE cartridge (silica, 5g) and eluted with ethyl
acetate: cyclohexane (0 to 70% in 10% increments). Appropriate fractions were
combined and evaporated, the residue was purified further by mass directed auto prep
HPLC to give Example 178 (0.011g) LCMS showed MH+ = 495; TRBT = 3.2min.

Similarly prepared using the same or similar numbers of moles of reagents and/or
volumes of solvents were the following:



Propionic anhydride (0.015ml, 0.12mmol) was added to Intermediate 138 (0.030g,
O.lmmol) in glacial acetic acid (1.5ml). The reaction mixture was stirred at room
temperature for 2 hours then heated at 80 °C for 5 hours. The solvent was concentrated in
vacuo and the residue applied to an SPE cartridge (silica, 1g). The cartridge was eluted
with cyclohexane then cyclohexane:ethyl acetate (7:3). Appropriate fractions were
combined and evaporated to give Example 188 as a white solid (0.015g). LCMS showed
MH+ = 343; TRET - 2.92min

4-(Dimethylamino)phenylacetic acid (0.09g, 0.504mmol) and 1-(3-
dimemylarnmopropyl)-3-emylcarbodiimide hydrochloride (0.097g, 0.51mmol) in
dichloromethane (1ml) were stirred at room temperature for 3 hours. The reaction
mixture was concentrated then Intermediate 138 (0.07g, 0.23mmol) and diglyme (1ml)
were added. After stirring at 20 C for 18 hour glacial acetic acid (0.07ml) and additional
diglyme (0.5ml) were added and the mixture heated at 60 °C for 2 hours then at 75 °C for
4 hours. The reaction mixture was applied to an SPE cartridge (SCX, 2g) and the
cartridge eluted with methanol then 10% ammonia in methanol. The methanolic

ammonia fractions were evaporated in vacuo and the residue purified by mass directed
autoprep HPLC to afford Example 189 as a beige solid (0.004g). LCMS showed MH+ -
448; TRET = 3.24min.

Prepared from Intermediate 138 and 4-methoxyphenylacetic acid using a similar process
to that described for Example 189 using similar or the same number of moles of reagents
and/or volumes of solvents. LCMS showed MH+ = 435; TRET = 3.26rnin

Example 191 was prepared from Intermediate 139 using an analogous method to that for
Example 49. LCMS showed MH+ 386, TRET = 2.71min.


CLAIMS
A compound of formula (I) or a salt thereof:
wherein:
R1 is C1-3 alkyl, C1-2 fluoroalkyl or -(CH2)2OH;
R2 is a hydrogen atom (H), methyl or C1 fluoroalkyl;
R3 is unsubstituted branched C3-6alkyl, optionally substituted C3-8cycloalkyl, or an
optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc):

in which n1 and n2 independently are 1 or 2; and Y is O, S, SO2, or NR4; where R4 is a
hydrogen atom (H), C1-2alkyl, C1-2fluoroalkyl, C(O)NH2, C(O)-C1-2alkyl, or
C(O)-C1 fluoroalkyl;
wherein in R3 the unsubstituted branched C3-8alkyl is isobutyl, sec-butyl, t-butyl or 3-
methylbutan-2-yl;
wherein in R3 the C3-8cycloalkyl is optionally substituted with one or two substituents
independently being oxo (=O); OH; Cialkoxy; C1fluoroalkoxy; NHR21 wherein R21 is a
hydrogen atom (H); C1-2alkyl; C1fluoroalkyl; -CH2OH; -CH2NHR22 wherein R22 is H;
-C(O)OR23 wherein R23 is H; -C(O)NHR24 wherein R24 is H; -C(O)R25 wherein R25
is methyl; fluoro; hydroxyimino (=N-OH); or (C1-2alkoxy)imino (=N-OR26 where R26
is C1-2alkyl); and wherein any OH, alkoxy, fluoroalkoxy or NHR21 substituent is not
substituted at the R3 ring carbon attached (bonded) to the -NH- group of formula (I);

and wherein in R3 the heterocyclic group of sub-formula (aa), (bb) or (cc) is optionally
substituted with one or two substituents being oxo (=O);
and R3a is a hydrogen atom (H) or methyl;
provided that when R3a is methyl then R3 is tetrahydro-2H-pyran-4-yl, cyclohexyl (i.e.
unsubstituted), 3-hydroxy-cyclohexyl, 4-oxo-cyclohexyl or 4-(hydroxyimino)cyclohexyl;
and wherein Het is of sub-formula (i), (ii), (iii), (iv) or (v):

wherein:
W1, W2, W4 and W5 are N; and W3 is NRW;
X1, X3 and X4 are N or CRX; X2 is O, S or NRX; and X5 is CRX1RX2 or CRX3RX4;
Y1, Y2 and Y3 are CRY or N; Y4 is O, S or NRY; and Y$ is CRY1RY2;
Z1 and Z5 are O, S or NRZ; and Z2, Z3 and Z4 are N or CRZ;
wherein:
RW is a hydrogen atom (H);
Rx, Rx2, RY and RY2 independently are:
a hydrogen atom (H);
Ci-galkyl;
C3-6cycloalkyl optionally substituted by one or two C1-2alkyl groups and/or by one
oxo (=O) group;
-(CH2)n2a-C3-6cycloalkyl optionally substituted, in the -(CH2)n2a- moiety or in
the C3-6cycloalkyl moiety, by a C1-2alkyl group, or optionally substituted in
the C3-8cycloalkyl moiety by a -CH2C(O)NHC1-2alkyl group, wherein n2a is
1,2 or 3;

-(CH2)n3-S(O)2-R5, -CH(C1-2alkyl)-S(O)2-R5, -CMe2-S(O)2-R5, or
C~3-5cycloalkyl substituted at the connecting carbon atom by -S(O)2-R5,
wherein n3 is 1 or 2;
and R5 is C1-2alkyl, -NR15R16, phenyl, carbon-linked-pyridinyl or
benzyl (wherein the phenyl and benzyl are independently optionally
substituted on the aromatic ring by one or two substituents independently
being fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy
or OH, and wherein the pyridinyl is optionally substituted by one methyl,
methoxy or OH (including any tautomer thereof));
wherein R15 is H, C1-2alkyl, phenyl, benzyl (wherein the phenyl and
benzyl are independently optionally substituted on the aromatic ring by one or
two substituents independently being fluoro, chloro, C1-2alkyl, C1fluoroalkyl,
C1-2alkoxy or C1fluoroalkoxy), CH(Me)Ph, or carbon-linked-pyridinyl
optionally substituted by one methyl, methoxy or OH (including any tautomer
thereof);
and R16 is H or C1-2alkyl;
or wherein R15 and R16 together are -(CH2)n3a-X3a-(CH2)n3b- in which
n3a and n3b independently are 2 or 3 and X3a is a bond, -CH2-, O, or NR^a
wherein R8a is H or C1-2alkyl, acetyl, -S(O)2Me or phenyl, and wherein the
ring formed by NR15R16 is optionally substituted on a ring carbon by one or
two substituents independently being methyl or oxo (=O);
-(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7, -CMe2-NR6R7, or C~3-5cycloalkyl
substituted at the connecting carbon atom by -NR6R7, wherein n4 is 0,1, 2 or
3;
and R6 and R7 independently are H, C1-2alkyl, C3-6cycloalkyl,
-CH2-C3-6cycloalkyl, -C(O)R17, -S(O)2R18, phenyl, benzyl (wherein the
phenyl and benzyl are independently optionally substituted on the aromatic
ring by one or two substituents independently being fluoro, chloro, C1-2alkyl,
C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy), or carbon-linked-pyridinyl
optionally substituted by one methyl, methoxy or OH (including any tautomer
thereof);
and wherein R17 and R18 independently are C1-6alkyl, C3-6cycloalkyl,
optionally substituted 5-membered heteroaryl being furyl (furanyl) or 1,3-
oxazolyl or isoxazolyl or oxadiazolyl or thienyl or 1,3-thiazolyl or isothiazolyl
or pyrrolyl or imidazolyl or pyrazolyl (all independently optionally substituted
by one oxo and/or one or two methyl), or phenyl or benzyl (wherein the
phenyl and benzyl are independently optionally substituted on the aromatic
ring by one or two substituents independently being fluoro, chloro, C1-2alkyl,
C1fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy or OH), or carbon-linked-

pyridinyl optionally substituted by one methyl, methoxy or OH (including any
tautomer thereof);
or R6 and R7 together are -(CH2)n5-X5-(CH2)n6- in which n5 and n°
independently are 2 or 3 and X5 is a bond, -CH2-, O, or NR8 wherein R8 is H,
C1-2alkyl, acetyl, -S(O)2Me or phenyl, and wherein the ring formed by
NR6R7 is optionally substituted on a ring carbon by one or two substituents
independently being methyl or oxo (=O);
-(CH2)n7-0-R9; wherein n7 is 0,1, 2 or 3 and R9 is H, C1-6alkyl, C3-6cycloalkyl,
-CH2-C3-6cycloalkyl, -C(O)R17, phenyl, or benzyl (wherein the phenyl and
benzyl are independently optionally substituted on the aromatic ring by one or
two of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or
C1fluoroalkoxy); wherein n7 is 0 only when the -(CH2)n7-O-R9 is bonded to
a carbon atom in the Het ring; and wherein n7 is not 0 when Het is of sub-
formula (v) (i.e. n7 is not 0 for RX2 and for RY2);
-(CH2)n1 C(O)-NR10R11, -CH(C1-2alkyl)-C(O)-NR10R11,
-CMe2-C(O)-NR10R11, or C~3-5cycloalkyl substituted at the connecting
carbon atom by -C(O)-NR10R11, wherein n11 is 0,1 or 2;
and wherein R10 and R11 independently are H; C1-6alkyl;
C1fluoroalkyl; C2-4alkyl substituted by one OH or -OC1-2alkyl other than
at the connection point; C3-8cycloalkyl optionally substituted by one or two
methyl groups; -CH2-C3-6cycloalkyl optionally substituted by one methyl,
NH2 or NHMe group; -(CH2)n17-Het2; carbon-linked-pyridinyl optionally
substituted by one methyl, methoxy or OH (including any tautomer thereof);
phenyl; benzyl; or -CH(C1-2alkyl)Ph [wherein the phenyl, benzyl and
-CH(C1-2alkyl)Ph are independently optionally substituted on the aromatic
ring by one or two substituents independently being: fluoro, chloro,
C1-2alkyl, C1fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy, OH, -NR10aR10b
(wherein R10a is H or C1-2alkyl and R10b is H C1-2alkyl, -C(O)-C1-2alkyl
or -S(O)2-C1-2alkyl), -C(O)-NRl0cR10d (wherein R10c and R10d
independently are H or C1-2alkyl), or -S(O)2-R10e (wherein R10e is
C1-2alkyl, NH2, NHMe or NMe2)];
wherein n17 is 0, 1 or 2 and wherein Het2 is a 4-, 5- or 6- membered
saturated heterocyclic ring containing one O or S ring atom or one NR27 ring
group wherein R27 is H, C1-2alkyl, -C(O)Me, or -S(O)2Me, wherein the Het2
ring is optionally substituted on a ring carbon by one or two substituents
independently being methyl or oxo (=O);
and wherein when n17 is 2 then the Het2 ring can optionally contain one
additional ring N atom at the Het2 ring position bonded to the -(CH2)n17-

moiety; provided that, when Het2 contains one O or S or NR27 ring
atom/group and one additional ring N atom, then the O/S/NR27 ring
atom/group and the one additional ring N atom are not directly bonded to each
other, and are separated by more than one carbon atom;
or R10 and R11 together are -(CH2)n8-X6-(CH2)n9- in which n8 and n9
independently are 2 or 3 and X6 is a bond, -CH2-, O, or NR12 wherein R12 is
H, C1-2alkyl, acetyl, -S(O)2Me or phenyl, and wherein the ring formed by
NR10R11 is optionally substituted on a ring carbon by one or two substituents
independently being methyl or oxo (=O);
-(CH2)n12-C(O)-OR13 wherein n12 is 0,1 or 2; and wherein R13 is H, C1-2alkyl,
C3-6cycloalkyl, -CH2-C3-6cycloalkyl, phenyl, or benzyl (wherein the phenyl
and benzyl are independently optionally substituted on the aromatic ring by
one or two of (independently) fluoro, chloro, C1-2alkyl, C]fluoroalkyl,
C1-2alkoxy or C1fluoroalkoxy);
-(CH2)n13-C(O)-R13a wherein n13 is 0,1 or 2; and wherein R13a is a hydrogen
atom (H), C1-6alkyl, C1-2ffuoroalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl,
benzyl, or phenyl; wherein the phenyl and benzyl are independently optionally
substituted on the aromatic ring by one or two of (independently) fluoro,
chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
-(CH2)n14-Het1, -CHtC1-2alkyl)-Het1, -CMe2-Het1, or C~3-5cycloalkyl
substituted at the connecting carbon atom by Het1, wherein n14 is 0, 1 or 2
and wherein Het1 is a 4-, 5-, 6- or 7-membered saturated heterocyclic ring;
wherein said heterocyclic ring Het1 contains one O or S ring atom and/or
one NR14 ring group wherein R14 is H, C1-4alkyl, C3-6cycloalkyl, benzyl,
phenyl, -C(O)Rl9, or -S(O)2R19;
wherein R19, independent of any other R19, is C1-6alkyl, C3-6cycloalkyl,
thienyl, furyl (furanyl), or phenyl or benzyl; wherein the phenyl and benzyl
are independently optionally substituted by one or two of (independently)
fluoro, methyl or methoxy;
and wherein said heterocyclic ring Het1 is optionally substituted (at a
position or positions other than any NR14 position) by one or two oxo (=O)
and/or one C1-4alkyl substituents;
provided that, when the heterocyclic ring Het1 contains one O or S ring
atom and one NR14 ring group then: (a) the O/S ring atom and the NR14 ring
group are not directly bonded to each other, and (b) the O/S ring atom and the
NR14 ring group are separated by more than one carbon atom unless Het1
contains an -NR14-C(O)-O or -NR14-C(O)-S- moiety as part of the ring; or
-(CH2)n10-Ar, -CH(C1-2alkyl)-Ar, -CMe2-Ar, or C~3-5cycloalkyl substituted at the
connecting carbon atom by Ar, wherein n10 is 0, 1 or 2 and

(i) Ar is phenyl optionally substituted by one or two substituents
independently being fluoro, chloro, bromo, C1-2alkyl, C1-2fluoroalkyl,
C1-2alkoxy, C1-2fluoroalkoxy, OH, -NR1laR11b (wherein R1la is H or
C1-2alkyl and R1lb is H, C1-2alkyl, -C(O)-C1-2alkyl or -S(O)2-C1-2alkyl),
cyano, -C(O)-NR11CR11d (wherein R1lc and R1ld independently are H or
C1-2alkyl), -C(O)-OR1le wherein R1le is H or C1-2alkyl, or -S(O)2-R1lf
(wherein R1lf is C1-2alkyl, NH2, NHMe or NMe2); or the phenyl Ar is
optionally substituted at two adjacent Ar ring atoms by the two ends of a chain
which is: -(CH2)4-, -(CH2)3-, or -CH=CH-CH=CH-; or
(ii) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic
ring containing 1, 2, 3 or 4 heteroatoms selected from O, N or S; and wherein
when the heterocyclic aromatic ring Ar contains 2, 3 or 4 heteroatoms, one is
selected from O, N and S and the remaining heteroatom(s) are N; and wherein
the heterocyclic aromatic ring Ar is optionally substituted by one or two
groups independently being C1-4alkyl or OH (including any keto tautomer of
an OH-substituted aromatic ring), or the heterocyclic aromatic ring Ar is
optionally substituted at two adjacent Ar ring atoms by the two ends of a chain
which is: -(CH2)4-, -(CH2)3-, or -CH=CH-CH=CH-;
RX1 and RY1 independently are a hydrogen atom (H), C1-2alkyl or C1fluoroalkyl;
RX3 and RX4 together are -(CH2)n15-X7-(CH2)n16- wherein n15 and n16
independently are 1 or 2 and X7 is a bond, -CH2-, O, or NRX5 wherein RX5 is H,
C1-2alkyl, acetyl or -S(O)2Me; and
RZ is a hydrogen atom (H);
provided that:
when R3 is the heterocyclic group of sub-formula (bb), nl is 1, and Y is NR4, then R4 is
not C1-2alkyl or C1-2fluoroalkyl;
when R3 is the heterocyclic group of sub-formula (aa) and Y is NR4, then R4 is not
C(O)NH2, C(O)-C1-2alkyl or C(O)-C1fluoroalkyl;
provided that: when R3 is the heterocyclic group of sub-formula (cc), then NR3R3a is of
sub-formula (L), (m), (ml) or (m2), wherein the -NH- connection point of the NR3R3a
group to the 4-position of the pyrazolopyridine of formula (I) is underlined:


and provided that:
where R3 is optionally substituted C3-8cycloalkyl, then any OH, alkoxy, fluoroalkoxy,
-CH2OH, -CH2NHR22, -C(O)OR23, -C(O)NHR24, -C(O)R25 or fluoro substituent is at
the 3-, 4- or 5-position of the R3 cycloalkyl ring (wherein, in this connection, the 1-
position of the R3 cycloalkyl ring is deemed to be the connection point to the -NH- in
formula (I)).
2. A compound of formula (IA) or a salt thereof:

wherein:
R1 is C1-3alkyl, C1-2fluoroalkyl or -(CH2)2OH;
R2 is a hydrogen atom (H), methyl or C1fluoroalkyl;
R3 is unsubstituted branched C3-6alkyl, optionally substituted C3-8cycloalkyl, or an
optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc):

in which n1 and n2 independently are 1 or 2; and Y is O, S, SO2, or NR4; where R4 is a
hydrogen atom (H), C1-2alkyl, C1-2fluoroalkyl, C(O)NH2, C(O)-C1-2alkyl, or
C(O)-C1fluoroalkyl;

wherein in R3 the unsubstituted branched C3-6alkyl is isobutyl, sec-butyl, t-butyl or 3-
methylbutan-2-yl;
wherein in R3 the C3-8cycloalkyl is optionally substituted with one or two substituents
being oxo (=O), OH, C1alkoxy, C1fluoroalkoxy, or C1-2alkyl; and wherein any OH,
alkoxy or fluoroalkoxy substituent is not substituted at the R3 ring carbon attached
(bonded) to the -NH- group of formula (IA);
and wherein in R3 the heterocyclic group of sub-formula (aa), (bb) or (cc) is optionally
substituted with one or two substituents being oxo (=O);
and wherein Het is of sub-formula (i), (ii), (iii), (iv) or (v):

wherein:
W1, W2, W4 and W5 are N; and W3 is NRW;
X1, X3 and X4 are N or CRX; X2 is O, S or NRX ; and X5 is CRX1RX2;
Y1, Y2 and Y3 are CRY or N; Y4 is O, S or NRY ; and Y5 is CRY1RY2;
Z1 and Z5 are O, S or NRZ; and Z2, Z3 and Z4 are N or CRZ;
wherein:
RW is a hydrogen atom (H);
Rx, RX2, RY and RY2 independently are:
a hydrogen atom (H);
C1-8alkyl;
C3-6cycloalkyl optionally substituted by a C1-2alkyl group;
-(CH2)n2a-C3-6cycloalkyl optionally substituted, in the -(CH2)n2a- moiety or in
the C3-6cycloalkyl moiety, by a C1-2^alkyl group, wherein n2a is 1, 2 or 3;
-(CH2)n3-SO2-R5 wherein n3 is 1 or 2 and R5 is C1-3alkyl or -NH-C1-2alkyl or
phenyl;

-(CH2)n4-NR6R7 wherein n4 is 0,1, 2 or 3, and R6 and R7 independently are H,
C1-2galkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, -C(O)-C1-2alkyl, -SO2-C1-
2alkyl, phenyl, or benzyl (wherein the phenyl or benzyl are independently
optionally substituted on the aromatic ring by one of fluoro, chloro, C1-2alkyl,
C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy); or R6 and R7 together are
-(CH2)n5-X5-(CH2)n6- in which n5 and n6 independently are 2 or 3 and X5
is a bond, -CH2-, O, or NR8 wherein R8 is H or C1-2alkyl;
-(CH2)n7-0-R^; wherein n7 is 0, 1, 2 or 3 and R9 is H or C1-6alkyl; wherein n7 is
0 only when the -(CH2)n7-O-R9 is bonded to a carbon atom in the Het ring;
and wherein n7 is not 0 when Het is of sub-formula (v) (i.e. n7 is not 0 for
RX2andforRY2);
-C(O)-NR10R11 wherein R10 and R11 independently are H, C1-6alkyl,
C3-6cycloalkyl, -CH2-C3-8cycloalkyl, phenyl, or benzyl (wherein the phenyl
or benzyl are independently optionally substituted on the aromatic ring by one
of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy);
or R10 and R11 together are -(CH2)n8-X6-(CH2)n9- in which n8 and n9
independently are 2 or 3 and X6 is a bond, -CH2-, O, or NR12 wherein R12 is
HorC1-2alkyl;
-C(O)-OR13 wherein R13 is H, C1-6alkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl,
phenyl, or benzyl (wherein the phenyl or benzyl are independently optionally
substituted on the aromatic ring by one of fluoro, chloro, C1-2alkyl,
C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy);
-C(O)-Rl3a wherein R13a is hydrogen atom (H), C1-6alkyl, C1fluoroalkyl,
C3-6cycloalkyl, -CH2-C3-6cycloalkyl, benzyl, or phenyl; wherein the phenyl
or benzyl are independently optionally substituted on the aromatic ring by one
of fluoro, chloro, C1-2alkyl, C1 fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
a 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing one O ring atom or
one NR14 ring group wherein R14 is H or C1-2alkyl, said heterocyclic ring
being optionally substituted (at a position or positions other than any NR14
position) by one oxo (=O) and/or one C1-4alkyl substituent; or
-(CH2)n10-Ar wherein n10 is 0, 1 or 2 and
(i) Ar is phenyl optionally substituted by one or two substituents being fluoro,
chloro, C1-2alkyl, C1-2fluoroalkyl, C1-2alkoxy, C1fluoroalkoxy or cyano;
or
(ii) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic
ring containing 1, 2 or 3 heteroatoms selected from O, N or S; and wherein
when the heterocyclic aromatic ring Ar contains 2 or 3 heteroatoms, one is
selected from O, N and S and the remaining heteroatom(s) are N; and wherein

the heterocyclic aromatic ring Ar is optionally substituted by one or two
C1-4alkyl groups;
RX1 and RY1 independently are a hydrogen atom (H), C1-2alkyl or C1fluoroalkyl; and
RZ is a hydrogen atom (H);
provided that:
when R3 is the heterocyclic group of sub-formula (bb), n1 is 1, and Y is NR4, then R4 is
not C1-2alkyl or C1-2fluoroalkyl;
when R3 is the heterocyclic group of sub-formula (aa) and Y is NR4, then R4 is not
C(O)NH2, C(O)-C1-2alkyl or C(O)-C1fluoroalkyl;
provided that: when R3 is the heterocyclic group of sub-formula (cc), then NHR3 is of
sub-formula (L), (m) or (ml), wherein the -NH- connection point of the NHR3 group to
the 4-position of the pyrazolopyridine of formula (IA) is underlined:

and provided that:
where R3 is optionally substituted C3-8 cycloalkyl, then any OH, alkoxy or fluoroalkoxy
substituent is at the 3-, 4- or 5-position of the R3 cycloalkyl ring (wherein, in this
connection, the 1-position of the R3 cycloalkyl ring is deemed to be the connection point
to the -NH- in formula (IA)).
3. A compound or salt as claimed in claim 1, wherein R3a is a hydrogen atom (H).
4. A compound or salt as claimed in claim 1, 2 or 3, wherein R^ is a hydrogen atom
(H) or methyl.
5. A compound or salt as claimed in claim 1, 2, 3 or 4, wherein R1 is C2-3alkyl,
C2fluoroalkyl or -(CH2)2OH.
6. A compound or salt as claimed in any preceding claim, wherein R1 is ethyl,
n-propyl, C2fluoroalkyl or -CH2CH2OH.
7. A compound or salt as claimed in any preceding claim, wherein R1 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
unsubstituted branched C3-6alkyl, then R3 is (R)-3-methylbutan-2-yl or (S)-3-
methylbutan-2 -yl.
10. A compound or salt as claimed in any preceding claim, wherein R3 is optionally
substituted C3-8cycloalkyl or the optionally substituted heterocyclic group of sub-
formula (aa), (bb) or (cc).
11. A compound or salt as claimed in any preceding claim, wherein, where R3 is
optionally substituted C3-8cycloalkyl, then R3 is optionally substituted C6-8cycloalkyl.
12. A compound or salt as claimed in claim 11, wherein, where R3 is optionally
substituted C3-8cycloalkyl, then R3 is optionally substituted cyclohexyl.
13. A compound or salt as claimed in any preceding claim, wherein, where R3 is
optionally substituted C3-8cycloalkyl, 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
(C1-2alkoxy)imino (=N-OR26 where R26 is C1-2alkyl).
14. A compound or salt as claimed in any preceding claim, wherein, where R3 is
optionally substituted C3-8cycloalkyl, then the one or two optional substituents is or
independently are OH, oxo (=O) or hydroxyimino (=N-OH).
15. A compound or salt as claimed in any preceding claim, wherein, where R3 is
optionally substituted C3-8cycloalkyl, 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)).
16. A compound or salt as claimed in any preceding claim, wherein, where R3 is
optionally substituted C6cycloalkyl, then R3 is cyclohexyl (i.e. unsubstituted), 3-
hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-1-yl), 4-oxo-cyclohexyl (i.e. 4-
oxocyclohexan-1-yl), 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-1-
yl), 4-(C1-2alkoxyimino)cyclohexyl, 1-methylcyclohexyl or 3-methylcyclohexyl.

17. A compound or salt as claimed in any preceding claim, wherein R.4 is a hydrogen
atom (H), C1-2alkyl, C(O)NH2, C(O)-Me or C(O)-CF3.
18. A compound or salt as claimed in any preceding claim, wherein R.4 is a hydrogen
atom (H) or C(O)-Me.
19. A compound or salt as claimed in any preceding claim, wherein, where R.3 is the
heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is O.
20. A compound or salt as claimed in any preceding claim, wherein where R.3 is the
heterocyclic group of sub-formula (aa), (bb) or (cc), then Ry is the heterocyclic group of
sub-formula (bb) and n^ 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 unsubstiruted (wherein, where Y is
NR4, R4 is not classified as a substituent).
22. A compound or salt as claimed in any preceding claim, wherein
when R3 is the heterocyclic group of sub-formula (aa), then Y is not NR4, and
when R3 is the heterocyclic group of sub-formula (bb) and Y is NR4, then R4 is
not C1-2alkyl or C1-2fluoroalkyl.
23. A compound or salt as claimed in any preceding claim, wherein NHR3 or




A compound or salt as claimed in claim 23, wherein NHR3 or NR3R3a is of sub-
formula (c), (cl), (c 4), (c 5), (h), (i), (j), (k), (ml), (m.2), (n), (o), (o2), (o3), (p2), (p5),
(r),(s)or(tl).
25. A compound or salt as claimed in claim 23, wherein NHR3 or NR3R3a is of sub-
formula (c), (h), (k), (n), (o), (o2) or (s).
26. A compound or salt as claimed in claim 23, wherein NHR3 or NR3R3a is of sub-
formula (c), (h), (k), (n), (o) or (s).
27. A compound or salt as claimed in claim 23, wherein
NHR3 or NR3R3a is of sub-formula (h):

28. A compound or salt as claimed in claim 27, wherein R1 is ethyl.
29. A compound or salt as claimed in any preceding claim, wherein Het is of sub-
formula (i), (ii) or (v).
30. A compound or salt as claimed in claim 29, wherein Z1 and Z5 are O.
31. A compound or salt as claimed in claim 29 or 30, wherein Het is of sub-formula
(ia), (ib), (ic), (id), (ie), (if), (ig), (va), (vb) or (iia):


32. A compound or salt as claimed in claim 31, wherein Het is of sub-formula (ia),
(ib),(ic),(id),(ir),(ig),(va)or(iia).
33. A compound or salt as claimed in claim 31, wherein Het is of sub-formula (ia),
(ic) or (id).
34. A compound or salt as claimed in any preceding claim, wherein RW and RZ are a
hydrogen atom (H).
35. A compound or salt as claimed in any preceding claim, wherein for the Het group,
one of RX and RY (or RX2 and RY2) is as defined herein and the other of RX and RY
(or RX2 and RY2)
is a hydrogen atom (H).
36. A compound or salt as claimed in any preceding claim, wherein RX, RX2, RY
and RY2 independently are:
a hydrogen atom (H);
C1-8alkyl;
optionally substituted C3-6cycloalkyl;
optionally substituted -(CH2)n2a-C3-6 cycloalkyl;

-(CH2)n3-S(O)2-R5, -CH(Me)-S(O)2-R5, or C3cycloalkyl substituted at the
connecting carbon atom by -S(O)2-R5;
-(CH2)n4-NR6R7 or -CH(Me)-NR6R7;
-(CH2)n7-O-R9;
-(CH2)n11-C(O)-NR10R11 or-CH(Me)-C(O)-NR10R11;
-(CH2)n12-C(O)-ORl3;
-(CH2)n13-C(O)-Rl3a;
-(CH2)n14-Het1 or-CH(Me)-Het1; or
-(CH2)n10-Ar or -CH(Me)-Ar.
37. A compound or salt as claimed in any preceding claim, wherein one of RX and
RY, and for Het of sub-formula (v) one of RX2 and RY2, IS:
-(CH2)n4-NR6R7, -CH(Me)-NR6R7, -(CH2)n11-C(O)-NR10R11, -(CH2)n14-Het1, or
-(CH2)n10-Ar.
38. A compound or salt as claimed in any preceding claim, wherein RX, RX2, RY
and RY2 independently are:
C1-6alkyl;
optionally substituted C3-8cycloalkyl;
-(CH2)n2a-C3-8cycloalkyl optionally substituted by a C1-2alkyl group; wherein
n2a is 1;
-(CH2)n3-S(O)2-R5 or C3cycloalkyl substituted at the connecting carbon atom by
-S(O)2-Ph, wherein n3 is 1 and R5 is C1-2alkyl, -NR15R16, optionally substituted
phenyl or optionally substituted benzyl; wherein R16 is H or methyl and R15 is H,
C1-4alkyl or optionally substituted phenyl; or R15 and R16 together are
-(CH2)n3a-X3a.(CH2)n3b- wherein n3a and n3b are 2 and X3a is a bond, -CH2-, O, or
NR8a wherein R8a is C1-2alkyl or acetyl; and the ring formed by NR15R16 is not
substituted on a ring carbon or is substituted on a ring carbon by one methyl or oxo (=O)
substiruent;
-(CH2)n4-NR6R7, -CH(Me)-NR6R7 or -CMe2-NR6R7 wherein n4 is 0 (when the
-(CH2)n4-NR6R7 is bonded to a carbon atom in the Het ring) or wherein n4 is 1; and
wherein R6 is H or C1-4alkyl and R7 is H, C1-4alkyl, -C(O)R17 or -S(O)2R18; or R6

and R? together are -(CH2)n5-X5-(CH2)n6- in which n5 and n6 are 2 and X5 is a bond,
-CH2-, O, or NR8, and wherein the ring formed by NR6R7 is not substituted on a ring
carbon or is substituted on a ring carbon by one methyl or oxo (=O) substiruent;
-(CH2)n7-O-R9, wherein n7 is 1 or 2 and R9 is H, C1-4alkyl or phenyl;
-(CH2)nn-C(O)-NR10R11 ,-CH(Me)-C(O)-NR10R11 or
-CMe2-C(O)-NR10R11, wherein n11 is 0 or 1,
and R10 is H or C1-2alkyl,
and R11 is: H; C1-6alkyl; C3-6cycloalkyl optionally substituted by one or two
methyl groups; -CH2-C3-6cycloalkyl (unsubstituted); -(CH2)n17-Het2; optionally
substituted carbon-linked-pyridinyl; optionally substituted phenyl, optionally substituted
benzyl; or optionally substituted -CH(C1-2alkyl)Ph; wherein the phenyl, the benzyl and
the -CH(C1-2alkyl)Ph are independently optionally substituted on the aromatic ring by
one or two substituents independently being: fluoro, chloro, C1-2alkyl, C1fluoroalkyl,
C1-2alkoxy, C1fluoroalkoxy, -NR10aR10b (wherein R10a is H or methyl and R10b is H,
C1-2alkyl, -C(O)Me or -S(O)2Me), -C(O)-NR10cR10d (wherein R10c and R10d
independently are H or C1-2alkyl), or -S(O)2-R10e (wherein R10e is C1-2alkyl, NH2,
NHMe or NMe2); and wherein the carbon-linked-pyridinyl is preferably optionally
substituted by one OH (including any keto tautomer thereof);
or R10 and R11 together are -(CH2)n8-X6-(CH2)n9- in which n8 and n9 are 2
and X6 is a bond, -CH2-, O, or NR12; and wherein the ring formed by NR10R11 is not
substituted on a ring carbon or is substituted on a ring carbon by one methyl or oxo (=O)
substiruent;
-(CH2)n12-C(O)-OR13 , wherein n12 is 0 or 1, and R13 is H or C1-2alkyl;
-(CH2)n13-C(O)-R13a, n13 is 0 or 1, and R13a is C1-6alkyl, C1-2fluoroalkyl,
C1-2cycloalkyl, -CH2-C3-6cycloalkyl, benzyl, or phenyl (wherein the phenyl and benzyl
are independently optionally substituted on the aromatic ring by one of fluoro, chloro,
C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy);
-(CH2)n14-Het1, -CH(Me)-Het1, or -CMe2-Het1, wherein n14 is 0 or 1, and Het1
is 4-, 5- or 6-membered heterocyclic ring, and R14 is C1-2alkyl, C(O)R19 or S(O)2R19
wherein R19 is C1-4alkyl, C3-6cycloalkyl, 2-thienyl, furan-2-yl, phenyl (unsubstituted)
or benzyl (unsubstituted);
or

-(CH2)n10-Ar wherein n10 is 0 or 1.
39. A compound or salt as claimed in claim 33, or claim 34 or 38 as dependent on
claim 33, wherein, for the Het group, one of RX and RY is:
C1-8alkyl;
optionally substituted C3-6cycloalkyl;
-(CH2)n3-S(O)2-R5, -CH(C1-2alkyl)-S(O)2-R5, -CMe2-S(O)2-R5, or
C~3-5cycloalkyl substituted at the connecting carbon atom by -S(O)2-R5;
-(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7, -CMe2-NR6R7, or C~3-5cycloalkyl
substituted at the connecting carbon atom by -NR6R7;
-(CH2)n11-C(O)-NR10R11,-CH(C1-2alkyl)-C(O)-NR10R11,
-CMe2-C(O)-NR10R11, or C~3-5cycloalkyl substituted at the connecting
carbon atom by -C(O)-NR10R11;
-(CH2)n14-Het1, -CH(C1-2alkyl)-Hetl, -CMe2-Het1, or C~3-5cycloalkyl substituted
at the connecting carbon atom by Hetl;
-(CH2)n10-Ar, -CH(C1-2alkyl)-Ar, -CMe2-Ar, or C~3-5cycloalkyl substituted at the
connecting carbon atom by Ar;
(i) wherein Ar is optionally substituted phenyl, or (ii) wherein Ar is an
optionally substituted 5- or 6-membered heterocyclic aromatic ring;
and the other of RX and RY is a hydrogen atom (H).
40. A compound or salt as claimed in claim 39, wherein, for the Het group, one of RX
and RY is:
-(CH2)n4-NR6R7, -CH(C1-2alkyl)-NR6R7, -CMe2-NR6R7, or C~3-5cycloalkyl
substituted at the connecting carbon atom by -NR6R7;
-(CH2)n11-C(O)-NRl0R11, -CH(C1-2alkyl)-C(O)-NR10R11,
-CMe2-C(O)-NR10R11, or C~3-5cycloalkyl substituted at the connecting
carbon atom by -C1-2-NR10R11;
-(CH2)n14-Het1, -CH(C1-2alkyl)-Het1, -CMe2-Het1, or C~3-5cycloalkyl substituted
at the connecting carbon atom by Hetl; or
-(CH2)n10-Ar, -CH(C1-2alkyl)-Ar, -CMe2-Ar, or C~3-5cycloalkyl substituted at the
connecting carbon atom by Ar;
and wherein Ar is (ii) the optionally substituted 5- or 6-membered heterocyclic
aromatic ring;

and the other of RX and RY is a hydrogen atom (H).
41. A compound or salt as claimed in claim 40, wherein:




when RX or RY is -(CH2)n14-Het1, -CH(C1-2alkyl)-Het1, or -CMe2-Het1, then
the 4-, 5-, 6- or 7-membered optionally substituted saturated heterocyclic ring Het1 is:
tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,



Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic ring being
optionally substituted: furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, tetrazolyl, triazinyl, pyridazyl, pyrimidinyl,
pyrazolyl, isothiazolyl (1,2-thiazolyl), or isoxazolyl (1,2-oxazolyl);
wherein the Ar ring is optionally substituted by one or two independent C1-2alkyl
groups or by one OH group (including any keto tautoraer thereof).
42. A compound or salt as claimed in claim 40 or 41, wherein:
Rl is ethyl; and

NHR3 or NR3R3a is of sub-formula (h):

(h) .

43. A compound or salt as claimed in any preceding claim, which is:
N-Cyclopentyl-1-ethyl-5-(5-methyl-l,3,4-oxadiazo1-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine,
N-Cyclopentyl-1 -ethyl-5 - {5 -[(methylsulfonyl)methyl] -1,3,4-oxadiazo1-2-yl} -1 H-pyrazolo [3,4-
b]pyridin-4-amine,
N-Cyclopentyl-1-ethyl-5-(5-isopropyl-l,3,4-oxadiazo1-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine,





or a salt thereof.
45. A compound or salt as claimed in any of claims 1 to 42, which is:



or a salt thereof.
46. A compound or salt as claimed in any of claims 1 to 42, which is:











or a salt thereof.
47. A compound or salt as claimed in any of claims 1 to 42, which is:



or a salt thereof.
48. A compound or salt as claimed any preceding claim, which is the compound or a
pharmaceutically acceptable salt thereof.
49. A compound or salt as claimed in any preceding claim, which is in a particle-size-
reduced form, wherein the particle size (D50 value) of the size-reduced compound or salt
is 0.5 to 10 microns.
50. A compound or salt as claimed in any preceding claim, for use as an active
therapeutic substance in a mammal such as a human.
51. A pharmaceutical composition comprising a compound of formula (I) or (IA), as
defined in any of claims 1 to 49, or a pharmaceutically acceptable salt thereof, and one or
more pharmaceutically acceptable carriers and/or excipients.
52. A pharmaceutical composition as claimed in claim 51 which is suitable for and/or
adapted for inhaled administration.
53. A pharmaceutical composition as claimed in claim 51 which is suitable for and/or
adapted for oral administration.
54. A pharmaceutical composition as claimed in claim 51, 52 or 53, for the treatment
and/or prophylaxis of an inflammatory and/or allergic disease, or of cognitive impairment
in a neurological disorder, in a mammal such as a human.
55. The use of a compound of formula (I) or (IA), as defined in any of claims 1 to 49,
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 of cognitive
impairment in a neurological disorder, in a mammal such as a human.
56. A composition or the use as claimed in claim 54 or 55, wherein the composition
or medicament 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.
57. A composition or the use as claimed in claim 56, wherein the composition or
medicament is for the treatment and/or prophylaxis of chronic obstructive pulmonary
disease (COPD) in a mammal such as a human.
58. A composition or the use as claimed in any of claims 54 to 57, wherein the
composition or medicament is for oral administration and is a pharmaceutical
composition as defined in claim 53.
59. The use of a compound of formula (I) or a pharmaceutically acceptable salt
thereof, as defined in any of claims 1 to 49, in the manufacture of a medicament for the
treatment and/or prophylaxis of: asthma, chronic obstructive pulmonary disease (COPD),
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 in a neurological disorder, depression, or pain; in a
mammal such as a human.
60. A pharmaceutical composition as claimed in claim 51, 52 or 53, for use in the
treatment and/or prophylaxis of: asthma, chronic obstructive pulmonary disease (COPD),
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 in a neurological disorder, depression, or pain; in a
mammal such as a human.

The invention relates to a compound of formula (I) or a salt thereof: Formula (I) wherein: Rl is C1-4alkyl, C1-3fluo-
roalkyl or -(CH2)2OH; R2 is a hydrogen atom (H), methyl or C1fluoroalkyl; R3a is a hydrogen atom (H) or C1-3alkyl; R3 is optionally
substituted branched C3-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted mono-unsaturated-C5-7cycloalkenyl, op
tionally substituted phenyl, or an optionally substituted heterocyclic group of sub-formula (aa), or (bb) or (cc) in which nl and n2
independently are 1 or 2; and Y is O, S, SO2, or NR4; and wherein Het is of sub-formula (i), or (ii), or (iii), or (iv) or (v). The com-
pounds 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.

Documents:

1207-KOLNP-2005-CORRESPONDENCE.pdf

1207-KOLNP-2005-FORM 27-1.1.pdf

1207-KOLNP-2005-FORM 27.pdf

1207-KOLNP-2005-FORM-27.pdf

1207-kolnp-2005-granted-correspondence.pdf

1207-kolnp-2005-granted-description (complete).pdf

1207-kolnp-2005-granted-examination report.pdf

1207-kolnp-2005-granted-form 1.pdf

1207-kolnp-2005-granted-form 13.pdf

1207-kolnp-2005-granted-form 18.pdf

1207-kolnp-2005-granted-form 3.pdf

1207-kolnp-2005-granted-form 5.pdf

1207-kolnp-2005-granted-gpa.pdf

1207-kolnp-2005-granted-reply to examination report.pdf

1207-kolnp-2005-granted-specification.pdf

1207-kolnp-2005granted-abstract.pdf

1207-kolnp-2005granted-assignment.pdf

1207-kolnp-2005granted-claims.pdf


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Patent Number 228089
Indian Patent Application Number 1207/KOLNP/2005
PG Journal Number 05/2009
Publication Date 30-Jan-2009
Grant Date 28-Jan-2009
Date of Filing 22-Jun-2005
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GREEEFORD, MIDDLESEX
Inventors:
# Inventor's Name Inventor's Address
1 EDLIN CHRISTOPHER DAVID GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
2 HAMBLIN JULIE NICOLE GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
3 JOHNSON MARTIN REDPATH GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
4 JONES PAUL SPENCER GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
5 LINDVALL MIKA KRISTIAN GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
6 MITCHELL CHARLOTTE JANE GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
7 REDGRAVE ALISON JUDITH GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
8 ALLEN DAVID GEORGE GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
9 COE DIANE MARY GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
10 COOK CAROLINE MARY GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
11 COOPER ANTHONY WILLIAM JAMES GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
12 DOWLE MICHAEL DENNIS GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/EP2003/014867
PCT International Filing date 2003-12-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0230165.3 2002-12-24 U.K.
2 0230045.7 2002-12-23 U.K.
3 0307998.5 2003-04-07 U.K.