Benzamide compounds

专利摘要:

公开号:AU2005278966A1
申请号:U2005278966
申请日:2005-08-31
公开日:2006-03-09
发明作者:David Michael Andrews；Keith Hopkinson Gibson；Mark Andrew Graham；Zbigniew Stanley Matusiak；Elaine Sophie Elizabeth Stokes；Michael James Waring
申请人:AstraZeneca AB；
IPC主号:C07D401-06

专利说明:
WO 2006/024841 PCT/GB2005/003355 1 BENZAMIDE COMPOUNDS This invention concerns certain novel benzamide compounds, or pharmaceutically acceptable salts or pro-drug forms thereof, which are potent inhibitors of the enzyme histone 5 deacetylase (HDAC). The invention also concerns processes for the manufacture of these novel benzamide compounds, to pharmaceutical compositions containing them and to their use in therapeutic methods, for example in the manufacture of medicaments to inhibit HDAC in a warm-blooded animal, such as man. HDAC activity has been associated with a number of disease states, such as cancer o10 (Marks et al., Nature Reviews, 1, 194-202, (2001)), cystic fibrosis (Li, S. et al, J Biol. Chemn., 274, 7803-7815, (1999)), Huntingdons chorea (Steffan, J. S. et al., Nature, 413, 739-743, (2001)) and sickle cell anaemia (Gabbianelli, M. et al., Blood, 95, 3555-3561, (2000)). Accordingly, the invention also extends to methods of treating any of the aforementioned diseases using the benzamide compounds of the present invention, as well as to the use of 15 these benzamide compounds in the manufacture of a medicament for the treatment of such disease states. In the eukaryotic cell, DNA is routinely compacted to prevent transcription factor accessibility. When the cell is activated this compacted DNA is made available to DNA binding proteins, thereby allowing the induction of gene transcription (Beato, M., J. Med. 20 Chem., 74, 711-724 (1996); Wolffe, A. P., Nature, 387, 16-17 (1997)). Nuclear DNA is known to associate with proteins known as histones to form a complex that is known as chromatin. The core histones, termed H2A, H2B, H3 and H4, are surrounded by 146 base pairs of DNA to form the fundamental unit of chromatin, which is known as the nucleosome. The N-terminal tails of the core histones contain lysine residues that are sites for post 25 transcriptional acetylation. Acetylation of the terminal amino group on the lysine side chain neutralizes the potential of the side chain to form a positive charge, and is thought to impact on chromatin structure. Histone Deacetylases (HDACs) are zinc-containing enzymes which catalyse the removal of acetyl groups from the E-amino termini of lysine residues clustered near the amino 30 terminus ofnucleosomal histones. HDACs may be divided into two classes, the first (HDAC 1, 2, 3 and 8) represented by yeast Rpd3-like proteins, and the second (HDAC 4, 5, 6, 7, 9 and WO 2006/024841 PCT/GB2005/003355 2 10) represented by yeast Hdal-like proteins. The reversible process of acetylation is known to be important in transcriptional regulation and cell-cycle progression. In addition, HDAC deregulation has been associated with several cancers and HDAC inhibitors, such as Trichostatin A (a natural product isolated from Streptomyces hygroscopicus), have been 5 shown to exhibit significant cell growth inhibition and anti-tumour effects (Meinke, P. T., Current Medicinal Chemistry, 8, 211-235 (2001)). Yoshida et al, (Exper. Cell Res., 177, 122 131 (1988)) teach that Trichostatin A causes the arrest of rat fibroblasts at the G1 and G2 phases of the cell cycle, thereby implicating the role of HDAC in the regulation of the cell cycle. Furthermore, Trichostatin A has been shown to induce terminal differentiation, inhibit lo cell growth, and prevent the formation of tumours in mice (Finnin et al., Nature, 401, 188-193 (1999)). It is known from International Patent Publication Numbers WO 03/087057 and WO 03/092686, that certain benzamide derivatives are inhibitors of HDAC. One particular compound disclosed in WO 03/087057 is N-(2-aminophenyl)-4-pyridin-2-yi-benzamide. s15 However, there is no specific disclosure in either of these documents ofbenzamide derivatives, which possess a further substituted-pyridin-2-yl ring moiety at the 4-position of the benzamide ring. We have now found that certain benzamide derivatives possessing an optionally substituted 3-cyanopyridin-2-yl group in the 4-position of the benzamide ring are potent inhibitors of the HDAC enzyme. 20 According to the present invention there is provided a compound of formula (I): Rio R1 b RIcR 4 Rib NN- Ra N H R IN
(R
2 )m 0 (R3
)
n (I) wherein: WO 2006/024841 PCT/GB2005/003355 3 Ri a is selected from hydrogen, amino, nitro, (1-3C)alkyl, N-(1-3C)alkylamino, N,N-di-(1 3C)alkylamino, phenyl, or piperazinyl; and wherein: (i) if Ra is N-(1-3C)alkylamino or N,N-di-(1-3C)alkylamino group, the (1 5 3C)alkyl moiety is optionally substituted by hydroxy or (1-3C)alkoxy; (ii) if Ra is phenyl, it is optionally substituted by halo, amino, K.(1-3)alkylamino, or N,N-di-(1-3C)alkylamino; and (iii) if Ra is piperazinyl, it is optionally substituted by halo, amino, (1-3C)alkyl, N (1-3)alkylamino, or N,N-di-(1-3C)alkylamino; 10 Rib is selected from: (i) hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-6C)alkyl, hydroxy(1 6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyl, (1-6C)alkoxy, 15 (1-6C)alkanoyloxy, N-(1-6C)alkylamino, N,N-di-[(1 -6C)alkyl]amino, N-[(3 6C)cycloalkyl]amino, N,N-di-[(3-6C)cycloalkyl]amino, N-[(3 6C)cycloalkyl(1-6C)alkyl] amino, N,N-di-[(3-6C)cycloalkyl(1-6C)alkyl]amino, N-[(3-6C)cycloalkyl]-N-[(l -6C)alkyl] amino, N-[(3-6C)cycloalkyl(1-6C)alkyl] N-[(1-6C)alkyl]amino, N-(1-6C)alkanoylamino, N,N-di-[(1 20 6C)alkanoyl]amino, N-[(1-6C)alkoxy(1-6C)alkyl]amino, N,N-di-[(1 6C)alkoxy(1-6C)alkyl] amino, N-[(1-6C)alkoxy(1-6C)alkyl]-N-[(1 6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (1 6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1 6C)alkoxycarbonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1 25 6C)alkyl]sulphamoyl, aryl, aryl-(1-6C)alkyl, a carbon linked heterocyclyl group, or a heterocyclyl-(1-6C)alkyl group wherein the heterocyclyl moiety is carbon-linked to the alkyl group; or (ii) a group of sub-formula II: WO 2006/024841 PCT/GB2005/003355 4
R
7 RSN-[CRaRb]a-X-[CReRdb (II) wherein:
X
1 is selected from a direct bond, -0- or-C(O)-; 5 integer a is 0, 1, 2, 3 or 4, with the proviso that ifX 1 is -0-, integer a is at least 1; integer b is 0, 1, 2, 3 or 4; each Ra, Rb, R e and Rd group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl; 10 R 7 and R are independently selected from hydrogen, (1-6C)alkyl, hydroxy(1 6C)alkyl, halo(1-6C)alkyl, (2-6C)alkenyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyl, aryl, aryl(1-6C)alkyl, heterocyclyl; 15 a heterocyclyl-(1-6C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from a substituted or unsubstituted thienyl, pyrimidinyl, pyridazinyl, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, or indolyl group, or from one the following particular substituent groups: 1,3-dimethyl-1H 20 pyrazol-5-yl, 3,5-dimethyl-l1H-pyrazol-4-yl, and 1-methyl-lH-imidazol-4-yl; a group of sub-formula III:
R
9 RIoN-[CReR]e-X 2 -[ CRRh d (III) wherein: 25 X 2 is selected from a direct bond, -0- or -C(O)-; integer c is 1, 2 or 3; integer d is 0, 1, 2 or 3; WO 2006/024841 PCT/GB2005/003355 5 each Re, R, R and Rh group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl;
R
9 and R 1 0 are independently selected from hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, halo(1-6C)alkyl, (3-6C)cycloalkyl, (3 5 6C)cycloalkyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, or R 9 and R 1 o are linked so that, together with the nitrogen atom to which they are attached, they form a 4-, 5-, 6- or 7-membered non-aromatic heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 9 and R i0 are attached, one or 10 two further heteroatoms selected from N, O or S, and wherein said heterocyclic ring is optionally substituted by hydroxy, halo, (1 4C)alkyl, carbamoyl, or -[CH 2 ]eNR R2 (wherein integer e is 0, 1 or 2, and R 11 and R 12 are independently selected from hydrogen, (1 6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-6C)alkyl); 15 or R 7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 10-membered heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 7 and R 8 are attached, one or two further nitrogen atoms; or (iii) a group of the sub-formula IV: 20 Q1_X3_y1_ (IV) wherein:
Y
1 is a direct bond or -[CR 13
R
14 x-where integer x is 1 to 4 and R 13 and R 14 are independently selected from hydrogen, halo and (1-4C)alkyl; 25 X 3 is selected from -0-, -S-, -SO-, -SO2-, -C(O)-, -OC(O)- and -C(O)O-, with the proviso that Y 1 is not a direct bond if X 3 is -C(O)-;
Q
1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyl, aryl, aryl-(1 6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, or RsR 16N-(1-6C)alkyl WO 2006/024841 PCT/GB2005/003355 6 (wherein R 1 5 and R 16 are each independently selected from hydrogen, (1 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-6C)alkyl); 5 and wherein any heterocyclyl ring within a R b substituent group (apart from those for which particular substituents are expressly stated above, such as heterocyclyl rings formed when R 9 and R 1 0 are linked) is optionally substituted on carbon by one or more Z 1 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, 10 carbamoyl, mercapto, sulphamoyl, (1-6C)alkyl, hydroxy(1-6C)alkyl, (2 6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkanoyl, (1-6C)alkanoyloxy, (1-6C)alkoxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl, halo(1-6C)alkyl, N-[(1 6C)alkyl]amino, N,N-di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di [(1-6C)alkyl]carbamoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1 15 6C)alkylsulphonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1 6C)alkyl]sulphamoyl, aryl, aryl-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1 6C)alkyl, (b) a group of the sub-formula V:
R"R
1 'N-[CRiR j ]rf-X 4 -[CRkR]g 20 (V) wherein
X
4 is selected from a direct bond, -0- or-C(O)-; integer f is 0, 1, 2 or 3, with the proviso that integer f is at least 1 if X 4 is -0O-; 25 integer g is 0, 1 or 2; each R i , Ri, Rk and R 1 group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl;
R
17 and R 18 are each independently selected from hydrogen, (1 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3- WO 2006/024841 PCT/GB2005/003355 7 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-6C)alkyl; or (c) a group of the sub-formula VI: Q2_X 5_ Y 2_ 5 (VI) wherein: Y2 is a direct bond or -[CR 9
R
2 ]y- wherein integer y is 1 to 4 and R 19 and R 20 are independently selected from hydrogen, halo and (1-4C)alkyl;
X
5 is selected from -0-, -S-, -SO-, -S02-, -C(O)-, -OC(O)- or -C(O)O-; and 10 Q 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyl, aryl, aryl-(1 6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, R 21
R
22 N-(1-6C)alkyl (wherein R 21 and R 22 are each independently selected from hydrogen, (1 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 15 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-6C)alkyl); and wherein if any heterocyclyl group within a Rib substituent group contains an unsubstituted nitrogen atom, then, unless any particular substituents are expressly stated in the definition above (e.g. such as when R 9 and R 1 0 are linked to form a heterocyclic ring together 20 with the nitrogen atom to which they are attached), the nitrogen atom may be optionally substituted by one or more Z 2 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) trifluoromethyl, carboxy, carbamoyl, (1-6C)alkyl, hydroxy(1-6C)alkyl, (2 6C)alkenyl, (1-6C)alkanoyl, (1-6C)alkoxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl, 25 halo(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl, N,N-di-[(1 -6C)alkyl]amino (1-6C)alkyl, (1-6C)alkylsulphonyl, aryl, aryl-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl; or (b) a group of the formula VII: WO 2006/024841 PCT/GB2005/003355 8 R23R24N-[CR m Rn]h (VII) wherein integer h is 0, 1, 2, or 3; 5 each R m and R n group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl;
R
23 and R 24 are each independently selected from hydrogen, (1 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 10 6C)cycloalkenyl(1-6C)alkyl; or (c) a group of the formula VIII: Q3-X6-Y3 (VIII) wherein y 3 is a direct bond or -[CR 2 5
R
2 6 ]z- wherein z is 1 to 4 and R 25 and R 26 15is are independently selected from hydrogen, halo and (1-4C)alkyl;
X
6 is selected from -0-, -S-, -SO-, -SO 2 -, -C(O)-, -OC(0)- or -C(O)O- if Y 3 is
-[CR
23
R
24 ]-, and if Y 3 is a direct bond, X 6 is selected from -S-, -SO-, -SO2-, C(O)-, and -OC(O)-; and
Q
3 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycioalkyl(1 20 6C)alkyl, aryl, aryl-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl or R27R28N-(1-6C)alkyl (wherein R 27 and R 28 are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1 6C)alkanoyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3 6C)cycloalkenyl, or (3-6C)cycloalkenyl(1-6C)alkyl); 25 and wherein any heterocyclyl group within a Z ' or Z 2 substituent group optionally bears one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-6C)alkyl, hydroxy(1-6C)alkyl, halo(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, WO 2006/024841 PCT/GB2005/003355 9 (1-6C)alkoxy, (1-6C)alkanoyl, (1-6C)alkanoyloxy, N-[(1 -6C)alkyl]amino, and N,N-di-[(1 6C)alkyl]amino; and wherein any non-aromatic heterocyclyl group within a Rb substituent (including optional substituent groups Z 1 and Z 2 ) optionally bears 1 or 2 oxo substituents; 5 and wherein any alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, or cycloalkenyl group within a Rib substituent group (including optional substituent groups Z' and Z 2 ) is, unless particular substituents are expressly stated above, optionally substituted by one or more Z 3 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, mercapto, (1-6C)alkoxy, trifluoromethyl, or -NR 29
R
3 0 wherein lo each of R 29 and R 30 is independently selected from hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl; and wherein any aryl group within a Rlb substituent group (including optional substituent groups Z 1 and Z 2 ) is optionally substituted by one or more Z 4 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from hialo, nitro, cyano, 15 hydroxy, amino, (1-6C)alkyl, hydroxy(1-6C)alkyl, halo(1-6C)alkyl, (1-6C)alkoxy, (1 6C)alkanoyl, N-[(1-6C)alkyl]amino, N,N-di-[(1-6C)alkyl]amino, carbamoyl, N-(1 6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl; Ric is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-3C)alkyl, (2 20 3C)alkenyl, (2-3C)alkynyl, (1-3C)alkoxy, (1-3C)alkanoyl, (1-3C)alkanoyloxy, N-(1 3C)alkylamino, N,N-di-[(1-3C)alkyl]amino, (1-3C)alkanoylamino, N-(1-3C)alkylcarbamoyl, N,N-di-(1-3C)alkylcarbamoyl, (1-3C) alkylthio, (1-3C)alkylsulphinyl, (1-3C)alkylsulphonyl, (1-3C)alkoxycarbonyl, N-(1-3C)alkylsulphamoyl, and N,N-di-(1-3C)alkylsulphamoyl; with the proviso that at least one of R 1 a, RIb and Ric is hydrogen; 25 mis0,1,2,3or4; R2 is halo; n is 0, 1, 2, 3 or 4;
R
3 is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-3C)alkyl, (2-3C)alkenyl, (2- WO 2006/024841 PCT/GB2005/003355 10 3C)alkynyl, (1-3C)alkoxy, (1-3C)alkanoyl, (1-3C)alkanoyloxy, N-(1-3C)alkylamino, N,N-di [(1-3C)alkyl]amino, (1-3C)alkanoylamino, N-(1-3C)alkylcarbamoyl, N,N-Di(1 3C)alkylcarbamoyl, (1-3C) alkylthio, (1-3C)alkylsulphinyl, (1-3C)alkylsulphonyl, (1 3C)alkoxycarbonyl, N-(1-3C)alkylsulphamoyl, and N,N-di-(1-3C)alkylsulphamoyl; and 5R is amino or hydroxy; or a pharmaceutically acceptable salt thereof. It is to be understood that, insofar as certain of the compounds of Fuinula (I) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic 10 form which possesses the above-mentioned activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter. 15 It is to be understood that certain compounds of Formula (I) defined above may exhibit the phenomenon of tautomerism. In particular, tautomerism may affect any heterocyclic groups that bear 1 or 2 oxo substituents. It is to be understood that the present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric 20 form utilised within the formulae drawings or named in the Examples. Where optional substituents are selected from "one or more" substituent groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. Furthermore, where reference is made to a specified group within a R l b substituent 25 group being optionally substituted by one or more specified substituent groups, then such a reference is to be understood as referring to the possibility of the specified group being optionally substituted if it forms the R l b substituent group per se or if it is present as a moiety within a Rlb substituent group. For instance, the reference to any alkyl group within a Rib substituent group (including optional substituent groups Z 1 and Z 2 ) being optionally 30 substituted by one or more Z 3 substituent groups is to be understood as including, for example, R l b being an alkyl group per se which is optionally substituted by one or more of the WO 2006/024841 PCT/GB2005/003355 11 specified Z 3 substituent groups, as well as the possibility of an alkyl moiety of a group such as a N,N-di-[(1-6C)alkyl]amino optionally bearing one or more Z 3 substituent groups. In this specification the generic term "(1-6C)alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3 5 6C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and also cycloalkyl-alkyl groups having 4 to 6 carbon atoms, such as cyclopropylmethyl, 2 cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, and cyclopentylmethyl. However, references to individual alkyl groups such as "propyl" are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as "isopropyl" are io specific for the branched-chain version only and references to individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (1-6C)alkoxy includes (3-6C)cycloalkyloxy groups and cycloalkyl-alkoxy groups having 4 to 6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, 15 cyclohexyloxy, cyclopropylmethoxy, 2-cyclopropylethoxy, cyclobutylmethoxy, 2 cyclobutylethoxy and cyclopentylmethoxy; (1-6C)alkylamino includes (3 6C)cycloalkylamino groups and N-(cycloalkylalkyl)amino groups having 4 to 6 carbon atoms, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino, cyclopropylmethylamino, 2-cyclopropylethylamino, 20 cyclobutylmethylamino, 2-cyclobutylethylamino and cyclopentylmethylamino; and N,N-di [(1-6Calkyl]amino includes N,N-di-[(3-6C)cycloalkyl]amino groups and N,N-di [cycloalkylalkyl]amino groups in which the cycloalkylalkyl moiety has 4 to 6 carbon atoms, for example dimethylamino, diethylamino, dipropylamino, N-cyclopropyl-N-methylamino, N cyclobutyl-N-methylamino, N-cyclohexyl-N-ethylamino, N-cyclopropylmethyl-N 25 methylamino, N-(2-cyclopropylethyl)-N-methylamino and N-cyclopentylmethyl-N methylamino. A person skilled in the art will appreciate that the terms "(1-4C)alkyl", "(1-3C)alkyl" and "(1-2C)alkyl" are used herein refer to any of the alkyl groups defined above that posses 1 to 4, 1 to 3 and 1 to 2 carbon atoms respectively. The same convention applies to other terms 30 used herein, such as, for example, "(1-4C)alkoxy", "(1-3C)alkoxy" and "(1-2C)alkoxy". The term "halo" refers to fluoro, chloro, bromo and iodo.
WO 2006/024841 PCT/GB2005/003355 12 The term "heterocyclyl" refers to a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and wherein a CH 2 group can optionally be replaced by a C(O), and wherein a ring sulphur 5 atom may be optionally oxidised to form the S-oxide(s). Preferably a "heterocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 4, 5 or 6 atoms, or a saturated, partially saturated or unsaturated, bicyclic ring containing 6, 7, 8, 9, or 10 atoms, wherein at least one atom of the ring is chosen from nitrogen, sulphur or oxygen, and the ring system may, unless otherwise specified, be carbon or nitrogen linked, and wherein a ring io sulphur atom may be optionally oxidised to form S-oxide(s). Examples and suitable values of the term "heterocyclyl" are azetidinyl, thiazolidinyl, pyrrolidinyl, 1,3-benzodioxolyl, 1,2,4 oxadiazolyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, pyrrolyl, pyrazolyl, oxadiazolyl, tetrazolyl, oxazolyl, thienopyrimidinyl, thienopyridinyl, thieno[3,2d]pyrimidinyl, is 1,3,5-triazinyl, purinyl, 1,2,3,4-tetrahydroquinolinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, indazolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, napthyridinyl, benzotriazolyl, pyrrolothienyl, imidazothienyl, isoxazolyl, imidazolyl, thiadiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridinyl, quinolyl, quinazolinyl, 1-isoquinolinyl, 20 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 7-azabicyclo[2.2.1]heptyl, 2 azabicyclo[2.2.2]octyl, and hexahydropyrrolo[3,4-c]pyrrolyl. Particular examples of 4-, 5- or 6-membered monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, thienyl, pyridazinyl, 25 and thiazolyl. Particular examples of bicyclic heterocyclic ring systems containing 6, 7, 8, 9, or 10 atoms include 3-azabicyclo[3.1.0]hexyl, hexahydropyrrolo[3,4-c]pyrrolyl, 7 azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, especially 3-azabicyclo[3.1.0]hex-3-yl, hexahydropyrrolo[3,4-c]pyrrol-2-yl, 7-azabicyclo[2.2.1]hept-7-yl, and 2-azabicyclo[2.2.2]oct 2-yl. 30 Where a heterocyclyl group includes one or more nitrogen atoms, these may carry a hydrogen atom or a substituent group such as a (1-6C)alkyl group if required to fulfil the WO 2006/024841 PCT/GB2005/003355 13 bonding requirements of nitrogen, or they may be linked to the rest of the structure by way of the nitrogen atom. A nitrogen atom within a heterocyclyl group may be oxidized to give the corresponding N oxide. An "aryl" group is, for example, phenyl, indenyl, indanyl, naphthyl, 5 tetrahydronaphthyl or fluorenyl, preferably phenyl. Within this specification composite terms are used to describe groups comprising more that one functionality such as aryl(1-6C)alkyl and heterocyclyl(1-6C)alkyl. These composite terms are to be given their ordinary meanings and will be understood by a person skilled in the art. For example, the terms aryl(1-6C)alkyl and heterocyclyl-(1-6C)alkyl refer to 10 substituent groups wherein the aryl and heterocyclyl moieties respectively are linked via a (1 6C)alkyl chain. For instance, such terms encompass substituent groups wbere the aryl and heterocyclyl moieties are linked via a methylene or ethylene linker. Suitable examples of such groups include [aryl]methyl, [heterocyclyl]methyl, 1-[aryl]ethyl, 1-[heterocyclyl]ethyl, 2-[aryl]ethyl, and 2-[heterocyclyl]ethyl. The same convention also applies to other composite 15 terms used herein, such as (1-6C)alkoxy(1-6C)alkyl and (3-6C)cycloalkyl(1-6C)alkyl. A suitable value for a carbon-linked heterocyclyl-alkyl group (i.e. a heterocyclyl-alkyl group wherein the heterocyclyl moiety is carbon-linked to the alkyl group) include a carbon linked azetidinylalkyl, pyrrolidinylalkyl, piperidinylalkyl, piperazinylalkyl, morpholinylalkyl, homopiperazinylalkyl, homopiperidinylalkyl, pyrrolylalkyl, oxazolylalkyl, thiazolylalkyl, 20 imidazolylalkyl, isoxazolylalkyl, isothiazolylalkyl, oxadiazolylalkyl, triazolylalkyl, pyridinylalkyl, pyridazinylalkyl, pyrimidinylalkyl, pyrazolylalkyl, pyrazinylalkyl, oxindolylalkyl, tetrahydrofuranylalkyl, furanylalkyl, tetrahydropyranylalkyl, pyranylalkyl, and indolylalkyl groups. Suitable values for any of the groups R la , R ic , or R 3 , or groups within a R i , R 1 c, or R 25 substituent group, are as follows: for (1-3C)alkyl: methyl, ethyl, propyl, and isopropyl; for (2-3C)alkenyl: vinyl, isopropenyl, and allyl; for (2-3C)alkynyl: ethynyl, and 2-propynyl; for (1-3C)alkanoyl: acetyl and propionyl; 30 for (1-3C)alkanoyloxy: acetoxy and propionyloxy; for (1-3C)alkoxy: methoxy, ethoxy, and propoxy; WO 2006/024841 PCT/GB2005/003355 14 for N-(1-3C)alkylamino: methylamino, ethylamino, propylamino, and isopropylamino; for N,N-di-[(1-3C)alkyl]amino: dimethylamino, diethylamnino, N-ethyl-N-methylamino and diisopropylamino; 5 for (1-3C)alkanoylamino: acetamido and propionamido; for N-(1-3C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for N,N-di-(1-3C)alkylcarbamoyl: N,N-dimethylcarbamoyl, N-ethyl N-methylcarbamoyl and N,N-diethylcarbamoyl; 10 for (1-3C)alkylthio: methylthio, ethylthio and propylthio; for (1-3C)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (1-3C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (1-3C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl; 15 for N-(1-3C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl; and for N,N-di-(1-3C)alkylsulphamoyl: N,N-dimethylsulphamoyl. lb I Suitable values for Rb, or optional substituents within a Rib substituent group, are as follows: for halogeno fluoro, chloro, bromo and iodo; 20 for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl and 2-cyclopropylethyl; for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, and cyclobutyl; 25 for (1-2C)alkyl: methyl and ethyl; for (2-6C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-6C)alkynyl: ethynyl, 2-propynyl and but-2-yny; WO 2006/024841 PCT/GB2005/003355 15 for (3-6C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; for (3-6C)cycloalkyl-(1-6C)alkyl: cyclopropylmethyl, cyclobutylmethyl, cyclopentyl methyl, 2-cyclopropylethyl and 2-cyclobutylpropyl; 5 for (3-6C)cycloalkenyl: cyclopropenyl and cyclobutenyl; for (3-6C)cycloalkenyl(1-6C)alkyl: cyclopropenylmethyl and cyclobutenylmethyl; for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (1-6C)alkoxy(1-6C)alkyl: methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, and 3-methoxypropyl; 10 for (1-6C)alkanoyloxy: acetoxy and propionyloxy; for halo(1-6C)alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl, 1-chloroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, and trifluoromethyl; 15 for hydroxy-(1-6C)alkyl group: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for N-(1-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; 20 for N,N-di-[(1-6C)alkyl] amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino; for N-[(3-6C)cycloalkyl]amino: cyclopropylamino, cyclobutylamino and cyclopentylamino; for N,N-di-[(3-6C)cycloalkyl] amino: di-cyclopropylamino; 25 for N-[(3-6C)cycloalkyl-(1-6C)alkyl] amino: cyclopropylmethylamino and cyclobutylmethylamino; WO 2006/024841 PCT/GB2005/003355 16 for N,N-di-[(3-6C)cycloalkyl-(1-6C)alkyl] amino: dicyclopropylmethylamino; for N-[(3-6C)cycloalkyl]-N-[(1-6C)alkyl]amino: N-cyclopropyl-N-methylamino and N 5 cyclopropyl-N-butylamino; for N-[(3-6C)cycloalkyl-(1-6C)alkyl]-N-[(1-6C)alkyl]amino: N-cyclopropylmethyl-N-methylamino and N cyclobutylmethyl-N-methylamino; for N-(1-6C)alkanoylamino: acetamido and propionamido; o10 for N,N-di-[(1 -6C)alkanoyl] amino: diacetylamino; for N-[(1-6C)alkoxy(1-6C)alkyl]amino: methoxymethylamino and 2-methoxyethylamino; for N,N-di-[(1-6C)alkoxy(1-6C)alkyl] amino: di-methoxymethylamino and di-(2 methoxyethyl)amino; 15 for N-[(1-6C)alkoxy(1-6C)alkyl]-N-[(1-6C)alkyl] amino: N-(2-methoxyethyl)-N-methylamino, N-(2 methoxyethyl)-N-ethylamino and N-(2 methoxyethyl)-N-isopropylamino; for (1-6C)alkylthio: methylthio, ethylthio and propylthio; 20 for (1-6C)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (1-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and 25 N-propylcarbamoyl; WO 2006/024841 PCT/GB2005/003355 17 for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl N-methylcarbamoyl and N,N-diethylcarbamoyl; for N-(1-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl; for N,N-di-[(1-6C)alkyl] sulphamoyl: N,N-dimethylsulphamoyl; 5 for a hydroxy-substituted (1-6C)alkyl group: hydroxymethyl, 2-hydroxyethyl, 1 hydroxyethyl and 3-hydroxypropyl; for a halo-substituted (1-6C)alkyl group: chloromethyl, 2-fluoroethyl, 2-chloroethyl, 1-chloroethyl, 2,2-difluoroethyl, 2,2,2 10 trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, and trifluoromethyl; for a mercapto-substituted (1-6C)alkyl group: mercaptomethyl, 2-mercaptoethyl, 1 mercaptoethyl and 3-mercaptopropyl; 15 for a (1-6C)alkoxy-substituted (1-6C)alkyl group: methoxymethyl, ethoxymethyl, 1 methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; for a cyano-substituted (1-6C)alkyl group: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 20 3-cyanopropyl; for an amino-substituted (1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl and 5 aminopropyl; for aryl: phenyl; 25 for aryl-(1-6C)alkyl: benzyl and 2-phenylethyl, 2-phenylpropyl and 3 phenylpropyl; for heterocyclyl-(1-6C)alkyl: azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, WO 2006/024841 PCT/GB2005/003355 18 morpholinylhnethyl, 1-azetidinylethyl, 1 pyrrolidinylethyl, 1-piperidinylethyl, 1 piperazinylethyl, 1-morpholinylethyl. Particular examples of R l b when it is a group of the sub-formula II: 5 R 7 RSN-[CRaRb]a -X 1 -[C RcRd b (II) include (methylamino)methyl, (ethylamino)methyl, 1-(ethylamino)ethyl, (propylamino)methyl, (isopropylamino)methyl, (cyclopropylamnino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (cyclopentylamino)methyl, (1 o10 methylpropylamino)methyl, (2-methylpropylamino)methyl, (allylamino)methyl, (di ethylamino)methyl, [(ethyl)(methyl)amino]methyl, [(isopropyl)(methyl)amino]methyl, [(propyl)(methyl)amino]methyl, [(butyl)(methyl)amino]methyl, [(cyclopropylmethyl)amino]methyl, [(cyclobutylmethyl)(methyl)amino]methyl, [(2 methoxyethyl)(methyl)amino]methyl, [(isopropyl)(2-methoxyethyl)amino]methyl, [(2 15 methoxyethyl)amino]methyl, [(ethyl)(2-methoxyethyl)amino]methyl, [(2-methoxy- 1 methylethyl)amino]methyl, [(3-methoxypropyl)amino]methyl, [(3 isopropoxypropyl)amino]methyl, [(2-ethoxyethyl)amino]methyl, [(2 isopropoxyethyl)amino]methyl, [(3-ethoxypropyl)amino]methyl, [(2 propoxyethyl)amino]methyl, [(2-methoxy-2-methylpropyl)amino]methyl, [bis(2 20 methoxyethyl)amino]methyl, [(2-hydroxyethyl)(ethyl)amino]methyl, [(2 hydroxyethyl)(methyl)amino]methyl, { [2-(di-methylamino)ethyl] amino} methyl, {[2-(di ethylamino)ethyl] amino }methyl, { [2-(di-methylamino)ethyl][methyl]amino}methyl, {[2-(di ethylamino)ethyl] [methyl] amino}methyl, { [2-(di-methylamino)- 1 (methyl)ethyl] amino}methyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, 1 25 piperidinylethyl, piperazinylmethyl, 7-azabicyclo[2.2.1]heptylmethyl, 2 azabicyclo[2.2.2]octylmethyl, {[2-(pyrrolidin-1-yl)ethyl]amino}methyl, {[2-(piperidin-1 yl)ethyl]amino}methyl, (3-fluoropyrrolidin-1-yl)methyl, (4-fluoropiperidin-1-yl)methyl, (3 hydroxypyrrolidin-1-yl)methyl, (3-hydroxypiperidin-1-yl)methyl, (4-hydroxypiperidin-1 yl)methyl, (4-trifluoromethylpiperidin-1-yl)methyl, [2,5-dimethylpyrrolidin-1-yl]methyl, (4 30 methylpiperidin-1-yl)methyl, (4-hydroxymethylpiperidin-1-yl)methyl, (3,3-dimethylpiperidin 1-yl)methyl, [6-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]methyl, (3- WO 2006/024841 PCT/GB2005/003355 19 methylaminopyrrolidin-1-yl)methyl, [3-(dimethylamino)pyrrolidin-1-yl]methyl, [3 (diethylamino)pyrrolidin-1-yl]methyl, (3-phenylpyrrolidin-1-yl)methyl, (3-phenylpiperidin-1 yl)methyl, (4-phenylpiperidin-1-yl)methyl, [3-(4-fluorophenyl)piperidin-1-yl]methyl, (3 pyridin-2-ylpyrrolidin-1-yl)methyl, (4-morpholin-4-ylpiperidin-1-yl)methyl, [4-(2 5 oxopyrrolidin-1-yl)piperidin-1-yl]methyl, (4-pyrrolidin-1-ylpiperidin-1-yl)methyl, (4-pyridin 4-ylpiperidin-1-yl)methyl, [(4-methylpiperazin-1-yl)piperidin-1-yl]methyl, [4-(morpholin-4 ylcarbonyl)piperidin-1-yl]methyl, (4-methylpiperazin-1-yl)methyl, (4-ethylpiperazin-1 yl)methyl, [4-(2-hydroxyethyl)piperazin-1-yl]methyl, (4-isopropylpiperazin-1-yl)methyl, {4 [2-(dimethylamino)ethyl]piperazin-1-yl}methyl, (4-allylpiperazin-1-yl)methyl, (4 10 acetylpiperazin-1-yl)methyl, (5-butyrylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl, [4-(2 methoxyethyl)piperazin-1-yl]methyl, [4-(methylsulfonyl)piperazin-1-yl]methyl, [4 (ethylsulfonyl)piperazin-1-yl]methyl, [4-(2-cyanophenyl)piperazin-1-yl]methyl, [4-(pyridin 2-yl)piperazin-1-yl]methyl, [4-(3-cyanopyridin-2-yl)piperazin-1-yl]methyl, [4-(3 cyanopyrazin-2-yl)piperazin-1-yl]methyl, (4-pyrimidin-2-ylpiperazin-1-yl)methyl, (4-pyrazin 15 2-ylpiperazin-1-yl)methyl, [4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl, [4 (cyclopropylcarbonyl)piperazin-1-yl]methyl, { [(1,3-dimethyl- 1H-pyrazol-5 yl)methyl] amino}methyl, {[2-(3,5-dimethyl- 1H-pyrazol-4-yl)ethyl] amino} methyl, [methyl(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5-methylpyrazin-2 yl)methyl]amino}methyl, [6-(trifluoromethyl)pyridin-3-yl]methyl} amino)methyl, [(4-methyl 20 1,3-thiazol-2-yl)methyl]amino}methyl, [2-(1-methyl-l1H-imidazol-4-yl)ethyl]amino}methyl, [(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5-methyl-2-furyl)methyl]amino} methyl, (tetrahydro-2H-pyran-4-ylmethyl)amino]methyl, (tetrahydro-2H-pyran-4-ylamino)methyl, { [2-(2-methyl- 1H-indol-3-yl)ethyl]amino}methyl, (2-methoxybenzyl)amino]methyl, [(3 methoxybenzyl)amino]methyl, { [2-(isopropylamino)ethoxy]methyl, [2 25 (ethylamino)ethoxy]methyl, and [2-(methylamino)ethoxy]methyl. Suitably, the -[CRaRb]a-XI-[CReRd b- moiety of formula II is group selected from methylene, ethylene, methoxymethyl, and ethoxymethyl, particularly methylene and ethoxymethyl. A suitable value for X 1 is selected from a direct bond, -0- or -C(0)-, particularly a 3o direct bond or -0-. A suitable value for integer a is 0, 1 or 2, with the proviso that if X 1 is -0- then integer WO 2006/024841 PCT/GB2005/003355 20 a is at least 1. In particular, integer a is 1 or 2. A suitable value for integer b is 0, 1, 2, 3 or 4, particularly 0 or 1. A suitable value for each Ra, Rb, Rc and Rd group present is hydrogen, halo, hydroxy or (1-4C)alkyl, particularly hydrogen or (1-4C)alkyl, and especially hydrogen or methyl. 5 A suitable value for X 2 is a direct bond, -0- or -C(0)-, particularly a direct bond. A suitable value for integer c is 1, 2 or 3, particularly 1 or 2, and especially 2. A suitable value for integer d is 0, 1, 2 or 3, particularly 0. A suitable value for each Re, R', R9 and R h group present is hydrogen, halo, hydroxy or (1-4C)alkyl, particularly hydrogen. 10 Suitable values for a heterocyclic ring formed when R 9 and R 1 0 are linked include an unsubstituted azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl ring, particularly an azetidin- 1 -yl, pyrrolidin-1-yl, piperidin-1-yl, or piperazin- 1 -yl ring, and especially a pyrrolidin-1-yl or piperidin-1-yl ring. Suitable values for a heterocyclic ring formed when R 7 and R 8 are linked include a s15 substituted or unsubstituted azetidin-l-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-l-yl, 3 azabicyclo[3.1.0]hex-3-yl, hexahydropyrrolo[3,4-c]pyrrol-2-yl, 7-azabicyclo[2.2.1]hept-7-yl, or 2-azabicyclo[2.2.2]oct-2-yl ring. When either of R 7 and R 8 is a carbon-linked heterocyclyl(1-6C)alkyl or heterocyclyl(1 2C)alkyl group (i.e. a heterocyclyl-alkyl group wherein the heterocyclyl moiety is carbon 20 linked to the alkyl group) then it is suitably selected from a substituted or unsubstituted thienylalkyl, pyrimidinylalkyl, pyridazinylalkyl, furanylalkyl, tetrahydrofuranylalkyl, pyranylalkyl, tetrahydropyranylalkyl, pyridinylalkyl, pyrazinylalkyl, thiazolylalkyl, or indolylalkyl group, or from one the following particular substituent groups: 1,3-dimethyl-lH pyrazol-5-ylalkyl, 3,5-dimethyl-l1H-pyrazol-4-ylalkyl, and 1-methyl-lH-imidazol-4-ylalkyl. 25 Particular examples of either of R 7 and R 8 when they are a heterocyclyl-(1-6C)alkyl or heterocyclyl(1-2C)alkyl group wherein the heterocyclyl moiety is carbon-linked to the alkyl group include { [(1,3-dimethyl- 1H-pyrazol-5-yl)methyl]amino}methyl, {[2-(3,5-dimethyl 1H-pyrazol-4-yl)ethyl]amino}methyl, [methyl(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5 methylpyrazin-2-yl)methyl]amino } methyl, [6-(trifluoromethyl)pyridin-3- WO 2006/024841 PCT/GB2005/003355 21 yl]methyl}amino)methyl, [(4-methyl-1,3-thiazol-2-yl)methyl]amino}methyl, [2-(1-methyl 1H-imidazol-4-yl)ethyl]amino}methyl, [(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5 methyl-2-furyl)methyl]amino}methyl, (tetrahydro-2H-pyran-4-ylmethyl)amino]methyl. Suitably, Y 1 is a direct bond or -[CR 13
R
1 4 ]x- where integer x is 1 to 2 and R1 3 and R 1 4 5 are independently selected from hydrogen and (1-4C)alkyl, particularly hydrogen. Suitably, X 3 is selected from -0- and -C(0)-. Suitably, Q 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl. A suitable value for X 4 is a direct bond, -0- or -C(0)-, particularly a direct bond. 10 A suitable value for integer f is 0, 1, 2 or 3, particularly 0, 1 or 2. A suitable value for integer g is 0, 1 or 2, particularly 0. A suitable value for each R i , RI, Rk and R 1 group present is hydrogen, halo, hydroxy or (1-4C)alkyl, particularly hydrogen. Suitably Y 2 is a direct bond. 15 A suitable value for X 5 is -0-, -S-, -SO-, -SO 2 -, -C(O)-, -OC(O)- or -C(O)O-, particularly -C(O)-; and Suitably Q 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, heterocyclyl, or heterocyclyl-(1-6C)alkyl group, particularly a (1-6C)alkyl, (3 6C)cycloalkyl, or a heterocyclyl group. 20 A suitable value for integer h is 0, 1, 2, or 3, particularly 0, 1 or 2. A suitable value for each R m and R n group present is hydrogen, halo, hydroxy or (1 4C)alkyl, particularly hydrogen. Suitably R 23 and R 24 are each independently selected from hydrogen or (1-6C)alkyl. Suitably, Y 3 is a direct bond or -[CR 25
R
26 ]z- wherein z is 1 to 2 and R 25 and R 26 are 25 independently selected from hydrogen and (1-4C)alkyl, particularly hydrogen. Suitably, X 6 is -C(O)- if Y 3 is -[CR 23 R24 z-, and ifY 3 is a direct bond, X6 is selected from -SO 2 - and -C(O)-. A particularly suitable value for X 6 is -C(O)- or -SO 2
-.
WO 2006/024841 PCT/GB2005/003355 22 Suitably, Q 3 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, heterocyclyl, or heterocyclyl-(1-6C)alkyl group, particularly a (1-6C)alkyl, (3 6C)cycloalkyl, or a heterocyclyl group A suitable value for m is 0, 1, 2 or 3, particularly 0. A suitable value for R 2 , when present, is fluoro or chloro, particularly fluoro. 5 A suitable value for n is 0, 1, 2 or 3, particularly 0. A suitable value for R 3 , when present, is hydroxy, fluoro or chloro, particularly fluoro. A suitable value for R 4 is amino. Particular novel compounds of the invention include, for example, benzamide derivatives of the Formula (I), or pharmaceutically-acceptable salts thereof, wherein, unless l0 otherwise stated, each of R a , R b, R i c, integer m, R 2 , integer n, R 3 , and R 4 has any of the meanings defined hereinbefore or in paragraphs (1) to (29) hereinafter: (1) Ria is selected from hydrogen, amino, nitro, (1-3C)alkyl, N-(1-3C)alkylamino, N,N-di (1-3C)alkylamino, phenyl, or piperazinyl; 15is and wherein: (i) if R l a is N-(1-3C)alkylamino or N,N-di-(1-3C)alkylamino group, the (1 3C)alkyl moiety is optionally substituted by hydroxy; (ii) if R l a is phenyl, it is optionally substituted by halo; and (iii) if Ra is piperazinyl, it is optionally substituted by (1-3C)alkyl; 20 (2) R 1 " a is selected from hydrogen, amino, nitro, (1-3C)alkyl, N-(1-3C)alkylamino, phenyl, piperazinyl, wherein: (i) if R l a is N-(1-3C)alkylamino, the (1-3C)alkyl moiety is optionally substituted by hydroxy; 25 (ii) if R 1 a is phenyl it is optionally substituted by halo; and (iii) if Ria is piperazinyl it is optionally substituted by (1-3C)alkyl; WO 2006/024841 PCT/GB2005/003355 23 (3) Ria is selected from hydrogen, amino, nitro, (1-2C)alkyl, N-(1-2C)alkylamino, phenyl, or piperazinyl, wherein (i) if R l a is N-(1-2C)alkylamino, the (1-2C)alkyl moiety is opticnally substituted by hydroxy; 5 (ii) if R l a is phenyl it is optionally substituted by fluoro; and (iii) if Ria is piperazinyl it is optionally substituted by (1-2C)alkyl; (4) Ria is selected from hydrogen, amino, nitro, (1-2C)alkyl, or N-(1-2C)alkylamino, wherein if Ria is N-(1-2C)alkylamino, the (1-2C)alkyl moiety is substituted by hydroxy; 10 (5) R " is selected from hydrogen, amino, methyl, 2-hydroxyethylamino, and 4 methylpiperazinyl; (6) R a is selected from hydrogen, methyl, or 2-hydroxyethylamino; 15 (7) Ria is hydrogen; (8) R 1 a is methyl; 20 (9) R a is 2-hydroxyethylamino; 10) Rib is selected from: (i) hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1 25 4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-2C)alkyl, (1-4C)alkoxy, (1-4C)alkanoyloxy, N-(1-4C)alkylamino, N,N-di-[(1 -4C)alkyl]amino, N-[(3- WO 2006/024841 PCT/GB2005/003355 24 6C)cycloalkyl]amino, N,N-di-[(3-6C)cycloalkyl]amino, N-[(3 6C)cycloalkyl(1-2C)alkyl]amino, N,N-di-[(3-6C)cycloalkyl(1-2C)alkyl] amino, N-[(3-6C)cycloalkyl]-N-[(1-2C)alkyl]amino, N-[(3-6C)cycloalkyl(1-2C)alkyl] N-[(1-4C)alkyl]amino, N-(1-4C)alkanoylamino, N,N-di-[(1 5 4C)alkanoyl]amino, N-[(1-4C)alkoxy(1-4C)alkyl]amino, N,N-di-[(1 4C)alkoxy(1-4C)alkyl] amino, N-[(1-4C)alkoxy(1-4C)alkyl]-N-[(1 4C)alkyl]amino, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, (1 4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1 4C)alkoxycarbonyl, N-(1-4C)alkylsulphamoyl, N,N-di-[(1 10 4C)alkyl]sulphamoyl, aryl, aryl-(1-2C)alkyl, a carbon linked heterocyclyl group, or a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon-linked to the alkyl group; or (ii) a group of sub-formula II:
R
7 RSN-[CRaRb]a-X - [
CR
R d
]
b 15 (II) wherein:
X
1 is selected from a direct bond, -0- or-C(O)-; integer a is 1, 2, or 3; integer b is 0, 1, or 2; 20 each Ra, R b, R5 and Rd group present is independently selectect from hydrogen, or (1-2C)alkyl;
R
7 and R 8 are independently selected from hydrogen, (1-6C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-2C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3 25 6C)cycloalkenyl, (3-6C)cycloalkenyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group, and is either selected from a substituted or unsubstituted thienyl, pyrimidinyl, pyridazinyl, furanyl, tetrahydrofuranyl, WO 2006/024841 PCT/GB2005/003355 25 pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, or indolyl group, or from one the following particular substituent groups: 1,3-dimethyl-1H-pyrazol 5-yl, 3,5-dimethyl-1H-pyrazol-4-yl, and 1-methyl-l1H-imidazol-4-yl; a group of sub-formula III: 5 R 9 RION-[CReR]c-X 2 -[ CRRh]d (III) wherein:
X
2 is selected from a direct bond, -0- or-C(O)-; integer c is 1, 2 or 3; 10 integer d is 0, 1, or 2; each Re, R!, R9 and Rh group present is independently selected from hydrogen or (1-2C)alkyl;
R
9 and R 1 0 are independently selected from hydrogen, (1-4C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (1 15 4C)alkoxy(1-4C)alkyl, or R 9 and R 1 0 are linked so that, together with the nitrogen atom to which they are attached, they form a 4-, 5-, 6- or 7-membered non-aromatic heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 9 and R 1 0 are attached, one or two further heteroatoms selected from N, O or S, and wherein said heterocyclic ring 20 is optionally substituted by hydroxy, halo, (1-4C)alkyl, carbamoyl, or -[CH 2 ]e- NR"R1 2 (wherein integer e is 0, 1 or 2, and R 11 and R 12 are independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1 2C)alkyl); or R 7 and R 8 are linked so that, together with the nitrogen atom to which they 25 are attached, they form a 4 to 10-membered heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 7 and R 8 are attached, one or two further nitrogen atoms; or WO 2006/024841 PCT/GB2005/003355 26 (iii) a group of the sub-formula IV:
Q
1
-X
3
_Y
1 _ (IV) wherein: 5 Y 1 is a direct bond or -[CR 1 3
R
14 ]x-where integer x is 1 to 4 and R 13 and R 14 are independently selected from hydrogen, halo and (1-4C)alkyl:
X
3 is selected from -0-, -S-, -SO-, -SO2-, -C(0)-, -OC(O)- and -C(O)O-, with the proviso that Y 1 is not a direct bond if X 3 is -C(O)-; and
Q
1 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 10 4C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-2C)alkyl, aryl, aryl-(1 2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, or Rs 15
R
16 N-(1-2C)alkyl (wherein R 15 and R 16 are each independently selected from hydrogen, (1 4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3 15 6C)cycloalkenyl(1-2C)alkyl); and wherein any heterocyclyl ring within a Rb substituent group (apart from those for which particular substituents are expressly stated above, such as heterocyclyl rings formed when R 9 and R 1 0 are linked) is optionally substituted on carbon by one or more Z 1 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: 20 (a) halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, (2 4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkanoyloxy, (1-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl, halo(1-4C)alkyl, N-[(1 4C)alkyl]amino, N,N-di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl, N,N-di 25 [(1-4C)alkyl]carbamoyl, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1 4C)alkylsulphonyl, N-(1-4C)alkylsulphamoyl, N,N-di-[(1 4C)alkyl]sulphamoyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1 2C)alkyl, (b) a group of the sub-formula V: WO 2006/024841 PCT/GB2005/003355 27 RR"17 N- [CR iR j -X 4 - [C R k R (V) wherein
X
4 is selected from a direct bond, or -0-; 5 integer fis 0, 1, or 2, with the proviso that integer fis at least 1 ifX 4 is -0-; integer g is 0, or 1; each R i , R, Rk and R' group present is independently selected from hydrogen or (1-2C)alkyl;
R
17 and R 18 are each independently selected from hydrogen, (1-4C)alkyl, (1 10 4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3-6C)cycloalkenyl(1 2C)alkyl; or (c) a group of the sub-formula VI: Q 2-X 5
-Y
2 15 (VI) wherein:
Y
2 is a direct bond or -[CR 19
R
2 0 ]y- wherein integer y is 1 or 2 and R 19 and R 2 0 are independently selected from hydrogen or (1-2C)alkyl;
X
5 is selected from -0- or -C(0)-; and 20 Q 2 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-2C)alkyl, aryl, aryl-(1 2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, R 21
R
22 N-( .. 2C)alkyl (wherein R 21 and R 22 are each independently selected from hydrogen, (1 4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3 25 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-2C)alkyl); and wherein if any heterocyclyl group within a Rb substituent group contains an WO 2006/024841 PCT/GB2005/003355 28 unsubstituted nitrogen atom, then, unless any particular substituents are expressly stated in the definition above (e.g. such as when R 9 and R 1 0 are linked to form a heterocyclic ring together with the nitrogen atom to which they are attached), the nitrogen atom may be optionally substituted by one or more Z 2 substituent groups (for example 1, 2 or 3), which may be the 5 same or different, selected from: (a) trifluoromethyl, carboxy, carbamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, (2 4C)alkenyl, (1-4C)alkanoyl, (1-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl, halo(1-4C)alkyl, N-(1-4C)alkylamino-(1-2C)alkyl, N,N-di-[(1-4C)alkyl]amino (1-2C)alkyl, (1-4C)alkylsulphonyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, o10 heterocyclyl-(1-2C)alkyl; or (b) a group of the formula VII:
R
23
R
24 N-[CRmR1h (VII) wherein 15 integer h is 0, 1, 2 or 3; each Rm and R n group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl;
R
23 and R 24 are each independently selected from hydrogen, (1 4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3 20 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-2C)alkyl; or (c) a group of the formula VIII: Q3_X6-Y3_ (VIII) 25 wherein Y 3 is a direct bond or -[CR 25
R
26 ]z- wherein z is 1 to 3 and R 25 and R 26 are independently selected from hydrogen or (1-2C)alkyl;
X
6 is selected from -0- or -C(0)-, if Y 3 is -[CR 2 3
R
24 ]z-, and if Y 3 is a direct bond, X 6 is selected from -SO 2 - or -C(O)-; and WO 2006/024841 PCT/GB2005/003355 29
Q
3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl or
R
27
R
28 N-(1-2C)alkyl (wherein R 27 and R 28 are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1 5 4C)alkanoyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (3 6C)cycloalkenyl, or (3-6C)cycloalkenyl(1-2C)alkyl); and wherein any heterocyclyl group within a Z ' or Z 2 substituent group optionally bears one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, o10 sulphamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkanoyloxy, N-[(1 -4C)alkyl]amino, and N,N-di-[(1 4C)alkyl]amino; and wherein any non-aromatic heterocyclyl group within a Rib substituent (including optional substituent groups Z 1 and Z 2 ) optionally bears 1 or 2 oxo substituents; 5is and wherein any alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, or cycloalkenyl group within a Rib substituent group (including optional substituent groups Z 1 and Z 2 ) is, unless particular substituents are expressly stated above, optionally substituted by one or more Z 3 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, mercapto, (1-4C)alkoxy, trifluoromethyl, or -NR 29
R
30 wherein 20 each of R 29 and R 3 0 is independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl; and wherein any aryl group within a Rib substituent group (including optional substituent groups Z 1 and Z 2 ) is optionally substituted by one or more Z 4 si'bstituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, nitro, cyano, 25 hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, (1-4C)alkoxy, (1 4C)alkanoyl, N-[(1-4C)alkyl]amino, N,N-di-[(1-4C)alkyl]amino, carbamoyl, N-(1 4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl; WO 2006/024841 PCT/GB2005/003355 30 11) Rlb is selected from: (i) hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1 4C)alkyl, N-(1-4C)alkylamino, or N,N-di-[(1 -4C)alkyl]amino; or 5 (ii) a group of sub-formula II: RTR'N-[CRaR b]a-X
I
-[CR
o R d b (II) wherein: X' is selected from a direct bond, -0- or -C(O)-; 10 integer a is 1, 2, or 3; integer b is 0, 1, or 2; each R a, , R Rc and Rd group present is independently selected from hydrogen, or (1-2C)alkyl;
R
7 and R 8 are independently selected from hydrogen, (1-6C)alkyl, hydroxy(1 15 4C)alkyl, halo(1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-2C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3 6C)cycloalkenyl, (3-6C)cycloalkenyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon 20 linked to the alkyl group and is either selected from a substituted or unsubstituted furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, or indolyl group, or from one the following particular substituent groups: 1,3-dimethyl-lH-pyrazol-5-yl, 3,5-dimethyl-lH-pyrazol-4 yl, and 1-methyl- 1H-imidazol-4-yl; 25 a group of sub-formula III:
R
9 RION-[CReR]c-X 2 -[ CRR]d
(III)
WO 2006/024841 PCT/GB2005/003355 31 wherein: X2 is selected from a direct bond, -0- or -C(O)-; integer c is 1, 2 or 3; integer d is 0, 1, or 2; 5 each Re, R! , R9 and Rh group present is independently selected from hydrogen or (1-2C)alkyl;
R
9 and R 10 are independently selected from hydrogen, (1-4C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalky1(1-2C)alkyl, (1 4C)alkoxy(1-4C)alkyl, or R 9 and R 10 are linked so that, together with the 10 nitrogen atom to which they are attached, they form a 4-, 5-, 6- or 7-membered non-aromatic heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 9 and R 1 0 are attached, one or two further heteroatoms selected from N, O or S, and wherein said heterocyclic ring is optionally substituted by hydroxy, halo, (1-4C)alkyl, carbamoyl, or -[CH 2 ]e 15 NR 1 " R1 2 (wherein integer e is 0, 1 or 2, and R 1 and R 12 are independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1 2C)alkyl); or R 7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 10-membered heterocyclic ring, said heterocyclic 20 ring optionally comprising, in addition to the nitrogen atom to which R 7 and R are attached, one or two further nitrogen atoms; or and wherein any heterocyclyl ring within a Rb substituent group (apart from those for which particular substituents are expressly stated above, such as heterocyclyl rings formed when R 9 and R 1 0 are linked) is optionally substituted on carbon by one or more Z' 25 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, (2 4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkanoyloxy, (1-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl, halo(1-4C)alkyl, N-[(1- WO 2006/024841 PCT/GB2005/003355 32 4C)alkyl] amino, N,N-di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl, N,N-di [(1-4C)alkyl]carbamoyl, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1 4C)alkylsulphonyl, N-(1-4C)alkylsulphamoyl, NN-di-[(1 4C)alkyl]sulphamoyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1 5 2C)alkyl, (b) a group of the sub-formula V: R17R 1N-[CRiRJ]f-X4- CRkR]g (vT) wherein 10 X 4 is selected from a direct bond, or -0-; integer f is 0, 1, or 2, with the proviso that integer f is at least 1 if X 4 is -0-; integer g is 0, or 1; each R i , R, Rk and R' group present is independently selected from hydrogen or (1-2C)alkyl; 15 R 17 and R 18 are each independently selected from hydrogen, (1-4C)alkyl, (1 4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3-6C)cycloalkenyl(1 2C)alkyl; or (c) a group of the sub-formula VI: 20 Q2-Xs-Y2 (VI) wherein:
Y
2 is a direct bond or -[CR 9
R
2 0 ]y- wherein integer y is 1 or 2 and R 19 and R 20 are independently selected from hydrogen or (1-2C)alkyl; 25 X 5 is selected from -0- or -C(0)-; and
Q
2 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-2C)alkyl, aryl, aryl-(1- WO 2006/024841 PCT/GB2005/003355 33 2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, R 21
R
22 N-(1-2C)alkyl (wherein R 21 and R 22 are each independently selected from hydrogen, (1 4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3 5 6C)cycloalkenyl(1-2C)alkyl); and wherein if any heterocyclyl group within a Rb substituent group contains an unsubstituted nitrogen atom, then, unless any particular substituents are expressly stated in the definition above (e.g. such as when R 9 and R 10 are linked to form a heterocyclic ring together with the nitrogen atom to which they are attached), the nitrogen atom may be optionally io substituted by one or more Z 2 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) trifluoromethyl, carboxy, carbamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, (2 4C)alkenyl, (1-4C)alkanoyl, (1-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl, halo(1-4C)alkyl, N-(1-4C)alkylamino-(1-2C)alkyl, N,N-di-[(1-4C)alkyl]amino 15 (1-2C)alkyl, (1-4C)alkylsulphonyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl; or (b) a group of the formula VII: R23R24N-[CR m R]h (VII) 20 wherein integer h is 0, 1, or 2; each R m and R n group present is independently selected from hydrogen or (1 2C)alkyl;
R
23 and R 24 are each independently selected from hydrogen, (1-4C)alkyl, (1 25 4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3-6C)cycloalkenyl(1 2C)alkyl; or WO 2006/024841 PCT/GB2005/003355 34 (c) a group of the formula VIII: Q3_X6_y3 (VIII) wherein Y 3 is a direct bond or -[CR 25
R
26 ]z- wherein z is 1 to 2 and R 2 5 and R 26 5 are independently selected from hydrogen or (1-2C)alkyl;
X
6 is selected from -0- or -C(O)-, if Y 3 is -[CR 23
R
2 4 ]z-, and if Y 3 is a direct bond, X 6 is selected from -SO 2 - or -C(O)-; and
Q
3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl or 10 R 27
R
28 N-(1 -2C)alkyl (wherein R 2 7 and R 28 are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1 -4C)alkyl, (1 4C)alkanoyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (3 6C)cycloalkenyl, or (3-6C)cycloalkenyl(1-2C)alkyl); and wherein any heterocyclyl group within a Z ' or Z 2 substituent group optionally 15 bears one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkanoyloxy, N-[(1-4C)alkyl]amino, and N,N-di-[(1 4C)alkyl]amino; 20 and wherein any non-aromatic heterocyclyl group within a Rb substituent (including optional substituent groups Z' and Z 2 ) optionally bears 1 or 2 oxo substituents; and wherein any alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, or cycloalkenyl group within a Rib substituent group (including optional substituent groups Z and Z 2 ) is, unless particular substituents are expressly stated above, optionally substituted by 25 one or more Z 3 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, mercapto, (1-4C)alkoxy, trifluoromethyl, or -NR 29
R
3 0 wherein each of R 29 and R 3 0 is independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl; WO 2006/024841 PCT/GB2005/003355 35 and wherein any aryl group within a Rb substituent group (including optional substituent groups Z 1 and Z 2 ) is optionally substituted by one or more Z 4 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, (1-4C)alkoxy, (1 5 4C)alkanoyl, N-[(1 -4C)alkyl]amino, N,N-di-[(1-4C)alkyl]amino, carbamoyl, N-(1 4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl; 12) Rb is selected from: (i) hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, 10 amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1 4C)alkyl, N-(1-4C)alkylamino, or N,N-di-[(1-4C)alkyl]amino; or (ii) a group of sub-formula II:
R
7 RSN-[CRaRb a-Xl-[CRRd]b (II) 15 wherein:
X
1 is selected from a direct bond, -0- or -C(O)-; integer a is 1, 2, or 3; integer b is 0, 1, or 2; each Ra, Rb , Rc and Rd group present is independently selected from hydrogen 20 or (1-2C)alkyl;
R
7 and R are independently selected from hydrogen, (1-6C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-2C)alkyl, (1-4C)alkoxy(1-4C)alkyl; an aryl group which is unsubstituted or substituted with one to three 25 substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; an aryl(1-2C)alkyl group the aryl moiety of which is unsubstituted or substituted with one to three substituents selected from the group consisting of WO 2006/024841 PCT/GB2005/003355 36 halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 4C)alkyl, and (1-4C)alkoxy; a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms selected from N, 0 or S, and which is unsubstituted or substituted with one to 5 three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1 -4C)alkyl, halo(1 -4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from the group consisting of a 10 furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, indolyl group, each of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy, or the heterocyclyl moiety is selected from 1,3-dimethyl-1H 15 pyrazol-5-yl, 3,5-dimethyl-l1H-pyrazol-4-yl, and 1-methyl-lH-imidazol-4-yl; a group of sub-formula III:
R
9 RioN-[CReR]c-X 2 -[ CRgRhd (III) wherein: 20 X 2 is selected from a direct bond, -0- or -C(O)-; integer c is 1, 2 or 3; integer d is 0, 1, or 2; each Re, R , R and Rh group present is independently selected from hydrogen or (1-2C)alkyl; 25 R 9 and R 1 0 are independently selected from hydrogen, (1-4C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (1 4C)alkoxy(1-4C)alkyl, or R 9 and R 1 0 are linked so that, together with the nitrogen atom to which they are attached, they form a 4-, 5-, 6- or 7-membered non-aromatic heterocyclic ring, said heterocyclic ring optionally comprising, in WO 2006/024841 PCT/GB2005/003355 37 addition to the nitrogen atom to which R 9 and R 1 0 are attached, one or two further heteroatoms selected from N, O or S, and wherein said heterocyclic ring is optionally substituted by one to three substituents selected from the group consisting of hydroxy, halo, (1-4C)alkyl, carbamoyl, or -[CH 2 ]NeR 11
R
12 5 (wherein integer e is 0, 1 or 2, and R 1 1 and R 1 2 are independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl); or R7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 10-membered heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R7 and R8 10 are attached, one or two further nitrogen atoms, and wherein said heterocyclylic ring is optionally substituted on carbon by one to three substituents selected from: (a) halo, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, (2 15is 4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkanoyl, halo(1-4C)alkyl, N-[(1-4C)alkyl] amino, N,N-di-[(1 -4C)alkyl] amino, an aryl group which is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1 4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; 20 an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms 25 selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl mioiety is optionally 30 substituted with one to three substituents selected from the group consisting of WO 2006/024841 PCT/GB2005/003355 38 halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 4C)alkyl, and (1-4C)alkoxy; or (b) a group of the sub-formula V:
R
1
R
18
N-[CR
iR
]
f
-X
4-[
CR
kR ]g 5 (0V) wherein
X
4 is selected from a direct bond, or -0-; integer fis 0, 1, or 2, with the proviso that integer fis at least 1 ifX 4 is -0-; integer g is 0, or 1; 10 each R i , R, Rk and R 1 group present is hydrogen;
R
17 and R 18 are each independently selected from hydrogen, (1-4C)alkyl, (1 4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkanoyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-2C)alkyl, (3-6C)cycloalkenyl, or (3-6C)cycloalkenyl(1 2C)alkyl; or 15is (c) a group of the sub-formula VI:
Q
2
-X
5
-Y
2 (VI) wherein:
Y
2 is a direct bond or -[CR 1 9
R
2 0 ]y- wherein integer y is 1 or 2 and R 19 and R 2 0 20 are independently selected from hydrogen or (1-2C)alkyl;
X
5 is selected from -0- or -C(0)-; and
Q
2 is selected from an aryl group which is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1 25 4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; an aryl-(1 -2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, WO 2006/024841 PCT/GB2005/003355 39 hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms selected from N, 0 or S, and which is unsubstituted or substituted with one to 5 three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1 -4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of 10 halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 4C)alkyl, and (1-4C)alkoxy; and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: 15 (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl, halo(1-4C)alkyl, an aryl group which is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, 20 and (1-4C)alkoxy; an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; 25 a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms selected from N, 0 or S, and which is unsubstituted or substituted with one to three substituents selected frc . the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; WO 2006/024841 PCT/GB2005/003355 40 a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; 5 (b) a group of the formula VII: R23R24N-[CR m Rn]h (VII) wherein integer h is 0, 1, or 2; 10 each R m and R n group present is hydrogen; R2 3 and R 24 are each independently selected from hydrogen or (1 4C)alkyl; or (c) a group of the formula VIII: Q3X6_y3. 15 (VIII) wherein y 3 is a direct bond or -[CR 25
R
2 6 ]z- wherein z is 1 to 2 and R 25 and R 26 are independently selected from hydrogen or (1-2C)alkyl;
X
6 is selected from -0- or -C(0)-, if Y 3 is -[CR 23
R
2 4 ]z-, and if VY 3 is a direct bond, X 6 is selected from -S-, -SO-, -SO 2 - or -C(O)-; and 20 Q 3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl; an aryl group which is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1 4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; 25 an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1- WO 2006/024841 PCT/GB2005/003355 41 4C)alkoxy; a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, 5 hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 10 4C)alkyl, and (1-4C)alkoxy; and wherein any non-aromatic heterocyclyl group within a Rb substituent group optionally bears 1 or 2 oxo substituents; 13) Rb is selected from: s15 (i) hydrogen, halo, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, N-(1-4C)alkylamino, or N,N-di-[(1-4C)alkyl]amino; or (ii) a group of sub-formula II:
R
7 RSN-[CRaRb a-Xl-
[
CRRd]b (II) 20 wherein:
X
1 is selected from a direct bond, or -0-; integer a is 1, 2 or 3; integer b is 0, 1 or 2; each Ra, R b, Rc and Rd group present is independently selected from hydrogen 25 or (1-2C)alkyl;
R
7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 4C)alkyl; halo(1-4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3- WO 2006/024841 PCT/GB2005/003355 42 6C)cycloalkyl(1-2C)alkyl; (1-4C)alkoxy(1-4C)alkyl; an aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; 5 an aryl(1-2C)alkyl group the aryl moiety of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 4C)alkyl, and (1-4C)alkoxy; a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms 10 selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon 15 linked to the alkyl group and is either selected from the group consisting of a furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, indolyl group, each of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, (1 20 4C)alkoxy, or the heterocyclyl moiety is selected from 1,3-dimethyl-1H pyrazol-5-yl, 3,5-dimethyl-l1H-pyrazol-4-yl, and 1-methyl-l1H-imidazol-4-yl; a group of sub-formula III:
R
9 RIoN-[CReRf]c-X 2 -[ CRgRh d (III) 25 wherein:
X
2 is selected from a direct bond, -0- or -C(O)-; integer c is 1, 2 or 3; integer d is 0, 1 or 2; WO 2006/024841 PCT/GB2005/003355 43 each Re, R , R9 and Rh group present is independently selected from hydrogen or (1-2C)alkyl;
R
9 and R 1 0 are independently selected from hydrogen, (1-4C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (1 5 4C)alkoxy(1-4C)alkyl, or R 9 and R 1 0 are linked so that, together with the nitrogen atom to which they are attached, they form a 4-, 5-, 6- or 7-membered non-aromatic heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 9 and R 10 are attached, one or two further heteroatoms selected from N, O or S, and wherein said heterocyclic ring 10 is optionally substituted by one to three substituents selected from the group consisting of hydroxy, halo, or (1-4C)alkyl; or R 7 and R a are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 1 0-membered heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 7 and R 8 15 are attached, one or two further nitrogen atoms, and wherein said heterocyclylic ring is optionally substituted on carbon by one to three substituents selected from: (a) halo, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, (2 20 4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkanoyl, halo(1-4C)alkyl, N-[(1 -4C)alkyl]amino, N,N-di-[(1-4C)alkyl]amino, an aryl group which is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1 4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; 25 an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms 30 selected from N, O or S, and which is unsubstituted or substituted with one to WO 2006/024841 PCT/GB2005/003355 44 three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 -4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is optionally 5 substituted with one to three substituents selected from the goup consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 4C)alkyl, and (1-4C)alkoxy; (b) a group of the sub-formula V:
R
17
RRN-
[
CR
iR j ]f
-
X
4-[ CRkR]g 10 (V) wherein
X
4 is selected from a direct bond, or -0-; integer fis 0, 1, or 2, with the proviso that integer fis at least 1 ifX 4 is -0-; integer g is 0, or 1; 15 each R i , Ri, Rk and R 1 group present is hydrogen;
R
1 7 and R 18 are each independently selected from hydrogen, (1-4C)alkyl, (3 6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; or (c) a group of the sub-formula VI: Q2-X 5 -y2_ 20 (VI) wherein:
Y
2 is a direct bond or -[CR1 9
R
2 0 ]y- wherein integer y is 1 or 2 and R 19 and R20 are independently selected from hydrogen or (1-2C)alkyl;
X
5 is selected from -0- or -C(0)-; and 25 Q 2 is selected from a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to WO 2006/024841 PCT/GB2005/003355 45 three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is optionally 5 substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 4C)alkyl, and (1-4C)alkoxy; and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 10 3), which may be the same or different, selected from: (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl, halo(1-4C)alkyl; an aryl group which is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, 15 hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, 20 halo(1-4C)alkyl, and (1-4C)alkoxy; a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, 25 hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; WO 2006/024841 PCT/GB2005/003355 46 (b) a group of the formula VII:
R
23
R
2 4 N-[CRmRIh (VII) wherein 5 integer h is 0, 1, or 2; each R m and R n group present is hydrogen;
R
23 and R 2 4 are each independently selected from hydrogen or (1-4C)alkyl; or (c) a group of the formula VIII: Q3_-X-Y3 10 (VIII) wherein Y 3 is a direct bond or -[CR 25
R
26 ]z- wherein z is 1 to 2 and R 25 and R 26 are independently selected from hydrogen or (1-2C)alkyl;
X
6 is selected from -0- or -C(0)-, if Y 3 is -[CR 23
R
24 ]z-, and if Y 3 is a direct bond, X 6 is selected from -S-, -SO-, -SO 2 - or -C(O)-; and 15 Q 3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, a 4, 5, 6 or 7-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, 20 hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 25 4C)alkyl, and (1-4C)alkoxy; and wherein any non-aromatic heterocyclyl group within a Rb substituent group optionally bears 1 or 2 oxo substituents; WO 2006/024841 PCT/GB2005/003355 47 14) R b is selected from: (i) hydrogen, cyano, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl; or (ii) a group of sub-formula II:
R
7 RSN-[CRaRb] a-X-[CRcRd]b 5 (II) wherein:
X
1 is selected from a direct bond, or -0-; integer a is 1, 2, or 3; integer b is 0, 1, or 2; 10 each Ra, R b, R and Rd group present is independently selected from hydrogen or (1-2C)alkyl;
R
7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3-6C)cycloalkyl(1-2C)alkyl; (1 4C)alkoxy(1-4C)alkyl; 15is an aryl(1-2C)alkyl group the aryl moiety of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to 20 three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from the group consisting of a furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, 25 thiazolyl, indolyl group, each of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, halo(1-4C)alkyl or (1-4C)alkoxy, or the heterocyclyl moiety is selected from 1,3-dimethyl-1H-pyrazol-5-yl, 3,5- WO 2006/024841 PCT/GB2005/003355 48 dimethyl-l1H-pyrazol-4-yl, and 1-methyl-1H-imidazol-4-yl; a group of sub-formula III:
R
9 RIoN-[CReR]c
-
X
2- [ CRgRh]d (III) 5 wherein:
X
2 is selected from a direct bond, or -0-; integer c is 1, 2 or 3; integer d is 0, 1, or 2; each Re, R t , R9 and R" group present is independently selected from hydrogen 10 or (1-2C)alkyl;
R
9 and R 1 0 are independently selected from hydrogen, (1-4C)alkyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, or R 9 and R I0 are linked so that, together with the nitrogen atom to which they are attached, they form a 4, 5-, or 6-membered non-aromatic heterocyclic ring, said heterocyclic ring optionally 15is comprising, in addition to the nitrogen atom to which R 9 and R 10 are attached, one or two further heteroatoms selected from N, O or S, and wherein said heterocyclic ring is optionally substituted by one to three substituents selected from the group consisting of hydroxy, halo, or (1-4C)alkyl; or R 7 and R 8 are linked so that, together with the nitrogen atom to which they 20 are attached, they form a 4 to 8-membered heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 7 and R 8 are attached, one or two further nitrogen atoms, and wherein said heterocyclylic ring is optionally substituted on carbon by one to three substituents selected from: 25 (a) halo, cyano, hydroxy, trifluoromethyl, amino, (1-4C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, N-[(1-4C)alkyl]amino, N,N-di-[(1 4C)alkyl]amino, an aryl group which is optionally substituted with one to three WO 2006/024841 PCT/GB2005/003355 49 substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of 5 halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unlsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1 o10 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S and is optionally substituted with one to three substituents selected from the group consisting of halo, 15 cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; (b) a group of the sub-formula VI: Q2-X 5
-Y
2 (VI) wherein: 20 y 2 is a direct bond or -[CR 19
R
2 0 ]y- wherein integer y is 1 or 2 and R 1 9 and R 2 0 are independently selected from hydrogen or (1-2C)alkyl;
X
5 is selected from -0- or -C(0)-; and
Q
2 is selected from a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms 25 selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or WO 2006/024841 PCT/GB2005/003355 50 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and is optionally substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1 4C)alkyl, or (1-4C)alkoxy; 5 and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl; 10 an aryl group which is optionally substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of 15 halo, cyano, hydroxy, amino, (1-4C)alkyl,orl-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1 20 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and is optionally substituted with one to three substituents selected from the group consisting of halo, 25 cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; (b) a group of the formula VII:
R
23
R
24 N-[CRmRn]h (VII) wherein WO 2006/024841 PCT/GB2005/003355 51 integer h is 0, 1, or 2; each R m and R n group present is hydrogen;
R
23 and R 24 are each independently selected from hydrogen or (1 4C)alkyl; or 5 (c) a group of the formula VIII: Q3_X6_y3 (VIII) wherein Y 3 is a direct bond or -[CR 25
R
26 ]z- wherein z is 1 to 2 and R 25 and R 26 are independently selected from hydrogen or (1-2C)alkyl; 10 X 6 is selected from -0- or -C(0)-, if Y 3 is -[CR 23
R
2 4 ]z-, and if Y 3 is a direct bond, X 6 is selected from -S-, -SO-, -SO 2 - or -C(O)-; and
Q
3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms 15 selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or 20 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and is optionally substituted with halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1 -4C)alkyl, and (1-4C)alkoxy; and wherein any non-aromatic heterocyclyl group within a Rb substituent group optionally bears 1 or 2 oxo substituents; 25 15) Rib is selected from: (i) hydrogen, amino, (1-4C)alkyl; or WO 2006/024841 PCT/GB2005/003355 52 (ii) a group of sub-formula II:
R
7
R
8 N-[CRaRb]a-XI -[CRcRd]b (II) wherein: 5 X 1 is selected from a direct bond, or -0-; integer a is 1, 2 or 3; integer b is 0, 1 or 2; each Ra, Rb Rc and Rd group present is independently selected from hydrogen or (1-2C)alkyl; 10 R 7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3-6C)cycloalkyl(1-2C)alkyl; (1 4C)alkoxy(1-4C)alkyl; a phenyl(1-2C)alkyl group, the phenyl moiety of which is munsubstituted or substituted with one to three substituents selected from the group consisting of 15 halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, and pyridinyl, and wherein each heterocyclic group is unsubstituted or substituted 20 with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group, and is either selected from the group consisting of a furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, 25 thiazolyl, indolyl group, each of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, halo(1-4C)alkyl or (1-4C)alkoxy, or the heterocyclyl moiety is selected from 1,3-dimethyl-lH-pyrazol-5-yl, 3,5 dimethyl-lH-pyrazol-4-yl, and 1-methyl-lH-imidazol-4-yl; WO 2006/024841 PCT/GB2005/003355 53 a group of sub-formula III:
R
9 RION-[CReRf]c-X 2 -[ CRgRh d (III) wherein: 5 X 2 is selected from a direct bond, or -0-; integer c is 1, 2 or 3; integer d is 0, 1, or 2; each Re, R, R and Rh group present is independently selected from hydrogen or (1-2C)alkyl; 10 R 9 and R 1 0 are independently selected from hydrogen, (1-4C)alkyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, or R 9 and R 10 are linked so that, together with the nitrogen atom to which they are attached, they form a 4, 5-, or 6-membered non-aromatic heterocyclic ring, selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, 15 and wherein said heterocyclic ring is optionally substituted by hydroxy, halo, or (1-4C)alkyl; or R 7 and R8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 8-membered heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 3 20 azabicyclo[3.1.0]hexyl, hexahydropyrrolo[3,4-c]pyrrolyl, 7 azabicyclo[2.2.1]heptyl, and 2-azabicyclo[2.2.2]octyl, and wherein said heterocyclylic ring is optionally substituted on carbon by one to three substituents selected from: (a) halo, cyano, hydroxy, trifluoromethyl, amino, (1-4C)alkyl, hydroxy(1 25 4C)alkyl, halo(1-4C)alkyl, N-[(1-4C)alkyl]amino, N,N-di-[(1 4C)alkyl]amino; a phenyl group which is optionally substituted with cne to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; WO 2006/024841 PCT/GB2005/003355 54 a phenyl-(1-2C)alkyl wherein the phenyl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1 4C)alkoxy; 5 a 4, 5, or 6-membered heterocyclyl group selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, and pyridinyl, and which is unsubstituted or substituted with one to three substituents selected from the group 10 consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, 15 imidazolyl, pyranyl, and pyridinyl, and is optionally substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; (b) a group of the sub-formula VI: Q2-X5_-y2 20 (VI) wherein:
Y
2 is a direct bond or -[CR 1 9
R
20 ]y- wherein integer y is 1 or 2 and R 19 and R 2 0 are independently selected from hydrogen or (1-2C)alkyl;
X
5 is selected from -0- or -C(0)-; and 25 Q 2 is selected from a 4, 5, or 6-membered heterocyclyl group selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, and pyridinyl, and which is unsubstituted or substituted with one to three substituents selected WO 2006/024841 PCT/GB2005/003355 55 from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, 5 tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, and pyridinyl, and is optionally substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is o10 optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) (1-4C)alkyl, hydroxy(1 -4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl; a phenyl group which is optionally substituted with one to three 15 substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a phenyl-(1-2C)alkyl wherein the aryl moiety is optionally substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; 20 a 4, 5, or 6-membered heterocyclyl group selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, pyranyl, and pyridinyl, and wherein said heterocyclyl group is unsubstituted or substituted with one to three 25 substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, 30 pyrimidinyl, imidazolyl, pyranyl, and pyridinyl, and is optionally WO 2006/024841 PCT/GB2005/003355 56 substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1 4C)alkoxy groups; (b) a group of the formula VII: 5 R 23
R
24 N-[CRmRn]h (VII) wherein integer h is 0, 1, or 2; each R m and R n group present is hydrogen; 10 R23and R 24 are each independently selected from hydrogen or (1 4C)alkyl; or (c) a group of the formula VIII: Q3-X_y3_ (VIII) 15 wherein Y 3 is a direct bond or -[CR 25
R
6 ]z- wherein z is 1 to 2 and R 25 and R 26 are independently selected from hydrogen or (1-2C)alkyl;
X
6 is selected from -0- or -C(0)-, if Y 3 is -[CR 23
R
24 ]z-, and ifY 3 is a direct bond, X 6 is selected from -SO 2 - or -C(O)-; and
Q
3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, 20 a 4, 5, or 6-membered heterocyclyl group selected from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyrimidinyl, imidazolyl, pyranyl, and pyridinyl, said heterocyclyl group being unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, 25 cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is selected WO 2006/024841 PCT/GB2005/003355 57 from azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyrimidinyl, imidazolyl, pyranyl, and pyridinyl, and is optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, 5 hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, and (1 4C)alkoxy; and wherein any non-aromatic heterocyclyl group within a Rb substituent group optionally bears 1 or 2 oxo substituents; o10 16) Rlb is selected from: (i) hydrogen, amino, (1-4C)alkyl; or (ii) a group of sub-formula II:
R
7 RN-[CRaRb a-Xl-[CRcRdb (II) 15 wherein:
X
1 is selected from a direct bond or -0-; integer a is 1, or 2; integer b is 0, 1, or 2; each Ra, Rb, RC and Rd group present is independently selected from hydrogen 20 or (1-2C)alkyl;
R
7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3-6C)cycloalkyl(1-2C)alkyl; (1 4C)alkoxy(1-4C)alkyl; a phenyl(1-2C)alkyl group, the phenyl moiety of which is unsubstituted or 25 substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group selected from azetidinyl, WO 2006/024841 PCT/GB2005/003355 58 pyrrolidinyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, and pyridinyl, and wherein each heterocyclic group is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, 5 cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from the group consisting of a furanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, indolyl group, each of which is unsubstituted or substituted with one to three 10 substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, halo(1 -4C)alkyl or (1-4C)alkoxy, or the heterocyclyl moiety is selected from 1,3-dimethyl-l1H-pyrazol-5-yl, 3,5-dimethyl-1H-pyrazol-4-yl, and 1-methyl- 1H-imidazol-4-yl; a group of sub-formula III: 15 R 9 RION-[CReR]c-X 2 -[ CRRh d (III) wherein:
X
2 is selected from a direct bond; integer c is 1, or 2; 20 integer d is 0, 1, or 2; each Re, R', R and Rh group present is independently selected from hydrogen or (1-2C)alkyl;
R
9 and R 1 0 are independently selected from hydrogen, (1-4C)alkyl, or R 9 and R1o are linked so that, together with the nitrogen atom to which they are 25 attached, they form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring; or R 7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 8-membered heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 3- WO 2006/024841 PCT/GB2005/003355 59 azabicyclo[3.1.0]hexyl, hexahydropyrrolo[3,4-c]pyrrolyl, 7 azabicyclo[2.2.1]heptyl, and 2-azabicyclo[2.2.2]octyl, and wherein said heterocyclylic ring is optionally substituted on carbon by one to three substituents selected from: 5 (a) halo, cyano, hydroxy, trifluoromethyl, amino, (1-4C)alkyl, hydroxy(1 4C)alkyl, N-[(1 -4C)alkyl]amino, N,N-di-[(1-4C)alkyl]amino; a phenyl group which is optionally substituted with one or two substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy groups; 10 a pyrrolidinyl, morpholinyl, piperazinyl or pyridinyl ring, each of which is optionally substituted with one or two (1-4C)alkyl groups; or (b) a group of the sub-formula VI: Q2_Xs-Y2_ (VI) 15 wherein: Y2 is a direct bond or -[CR 1 9
R
2 0 ]y- wherein integer y is 1 or 2 and R 19 and R 2 are independently selected from hydrogen or (1-2C)alkyl;
X
5 is selected from -C(O)-; and Q2 is morpholinyl; 20 and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl; 25 a phenyl group which is optionally substituted with one or two substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; WO 2006/024841 PCT/GB2005/003355 60 a 4, 5, or 6-membered heterocyclyl group selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazinyl, pyrimidinyl, and pyridinyl, and wherein said ring is unsubstituted or substituted with one or two substituents selected from the group consisting of halo, cyano, 5 hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; (b) a group of the formula VII: R23R24N-[CR m RI]h (VII) wherein 10 integer h is 0, 1 or 2; each R m and R" group present is hydrogen; R2 3 and R 24 are each independently selected from hydrogen or (1 4C)alkyl; or (c) a group of the formula VIII: 15
Q
3
-X
6
-Y
3 (VIII) wherein V 3 is a direct bond or -[CR 25
R
26 ]z- wherein z is 1 and R 2 5 and R 26 are both hydrogen;
X
6 is selected from -C(O)-, if Y 3 is -[CR 2 3
R
24 ]z-, and if Y 3 is a direct bond, X 6 20 is selected from -SO 2 - or -C(O)-; and
Q
3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl or pyrrolidinyl, and wherein any non-aromatic heterocyclyl group within a Rb substituent group optionally bears 1 or 2 oxo substituents; 25 17) R b is selected from: (i) hydrogen, amino, (1-4C)alkyl; or (ii) a group of sub-formula II: WO 2006/024841 PCT/GB2005/003355 61
R
7
R
8
N
-
[CRaRb]a-X
-
[C
R e Rd b (II) wherein:
X
1 is selected from a direct bond or -0-; 5 integer a is 1, or 2; integer b is 0, 1, or 2; each Ra, Rb, R e and Rd group present is independently selected from hydrogen or (1-2C)alkyl;
R
7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 10 4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3-6C)cycloalkyl(1-2C)alkyl; (1 4C)alkoxy(1-4C)alkyl; a phenyl(1-2C)alkyl group, the phenyl moiety of which is optionally substituted with one or two (1-4C)alkoxy groups; tetrahydropyranyl; 15 a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from the group consisting of a furan-2-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, pyridin-2-yl, pyridin-3 yl, pyridin-4-yl, pyrazin-2-yl, thiazol-2-yl, and indol-3-yl, and wherein each of said heterocyclyl moieties is unsubstituted or substituted with one or two 20 substituents selected from the group consisting of halo, (1-4C)alkyl, or halo(1 4C)alkyl, or the heterocyclyl moiety is selected from 1,3-dimethyl-1H-pyrazol-5-yl, 3,5 dimethyl-l1H-pyrazol-4-yl, and 1-methyl-l1H-imidazol-4-yl; a group of sub-formula III: 25 R 9 RIoN-[CReRf]c-X 2 -[ CRgRh d (III) wherein: WO 2006/024841 PCT/GB2005/003355 62
X
2 is selected from a direct bond; integer c is 1 or 2; integer d is 0 or 1; each Re, R!, R g and Rh group present is independently selected from hydrogen 5 or (1-2C)alkyl;
R
9 and R 10 are independently selected from hydrogen, (1-4C)alkyl, or R 9 and R1o are linked so that, together with the nitrogen atom to which they are attached, they form a pyrrolidinyl or piperidinyl ring; or R 7 and R 8 are linked so that, together with the nitrogen atom to which they 10 are attached, they form a 4 to 8-membered heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 3 azabicyclo[3.1.0]hexyl, hexahydropyrrolo[3,4-c]pyrrolyl, 7 azabicyclo[2.2.1]heptyl, and 2-azabicyclo[2.2.2]octyl, and wherein said heterocyclylic ring is optionally substituted on carbon by one or two 15 substituents selected from: (a) halo, hydroxy, trifluoromethyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, N-[(1 4C)alkyl]amino, N,N-di-[(1 -4C)alkyl] amino; a phenyl group which is optionally substituted with one or two halo atoms; a heterocyclyl group which is selected from pyrrolidinyl, morpholinyl, 20 piperazinyl or pyridinyl, each of which is optionally substituted with one or two (1-4C)alkyl groups; or (b) a group of the sub-formula VI:
Q
2
-X
5
-Y
2 (VI) 25 wherein: y 2 is a direct bond;
X
5 is selected from -C(O)-; and WO 2006/024841 PCT/GB2005/003355 63
Q
2 is morpholinyl; and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: 5 (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl; a phenyl group which is optionally substituted with one or two cyano groups; a heterocyclyl group selected from pyrrolidinyl, pyrazinyl, pyrimidinyl 10 and pyridinyl, and wherein said heterocyclyl group is unsubstituted or substituted with one or two cyano groups; (b) a group of the formula VII: R23R24N-[CR m Rn]h (VII) 15 wherein integer h is 0, 1 or 2; each R m and R n group present is hydrogen;
R
23 and R 24 are each independently selected from hydrogen or (1-4C)alkyl; or (c) a group of the formula VIII: 20 Q3-X-Y3 (VIII) wherein y 3 is a direct bond or -[C 25
R
26 ]z- wherein z is 1 and R 25 and R 26 are both hydrogen;
X
6 is -C(O)-, if Y 3 is -[CR 23
R
24 ]z-, and if Y 3 is a direct bond, X 6 is selected 25 from -SO 2 - or -C(O)-; and
Q
3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl or pyrrolidinyl, and wherein any non-aromatic heterocyclyl group within a Rb substituent group WO 2006/024841 PCT/GB2005/003355 64 optionally bears 1 or 2 oxo substituents; 18) Rlb is selected from: (i) hydrogen, amino, (1-4C)alkyl; or 5 (ii) a group of sub-formula II:
R
7 RSN-[CRaRb a- Xc - [
CR
cR d
]
b (II) wherein:
X
1 is selected from a direct bond or -0-; 10 integer a is 1 or 2; integer b is 0, 1 or 2; each Ra, Rb, Rc and Rd group present is independently selected from hydrogen or (1-2C)alkyl;
R
7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 15 4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3-6C)cycloalkyl(1-2C)alkyl; (1 4C)alkoxy(1-4C)alkyl; a phenyl(1-2C)alkyl group, the phenyl moiety of which is optionally substituted with one or two (1-4C)alkoxy groups; tetrahydropyranyl; 20 a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from the group consisting of a furan-2-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2 yl, thiazol-2-yl, indol-3-yl group, each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of halo, (1 25 4C)alkyl or halo(1-4C)alkyl; WO 2006/024841 PCT/GB2005/003355 65 a group of sub-formula III:
R
9 RION-[CReR]c-X 2 -[ CRRh]c (III) wherein: 5 X 2 is selected from a direct bond; integer c is 1, or 2; integer d is 0, or 1; each Re, R f , R9 and Rh group present is independently selected from hydrogen or (1-2C)alkyl; 10 R 9 and R 1 i0 are independently selected from hydrogen, (1-4C)alkyl, or R 9 and
R
I
o are linked so that, together with the nitrogen atom to which they are attached, they form a pyrrolidinyl or piperidinyl ring; or R 7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 8-membered heterocyclic ring selected from the 15 group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 3 azabicyclo[3.1.0]hexyl, hexahydropyrrolo[3,4-c]pyrrolyl, 7 azabicyclo[2.2.1]heptyl, and 2-azabicyclo[2.2.2]octyl, and wherein said heterocyclylic ring is optionally substituted on carbon by one or two substituents selected from: 20 (a) halo, hydroxy, trifluoromethyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, N-[(1 4C)alkyl]amino, N,N-di-[(1 -4C)alkyl]amino; a phenyl group which is optionally substituted with one or two halo atoms; a pyrrolidinyl, morpholinyl, piperazinyl or pyridinyl, each of which is 25 optionally substituted with one or two (1-4C)alkyl groups, (b) a group of the sub-formula VI: WO 2006/024841 PCT/GB2005/003355 66 Q2_Xs-Y2_ (VI) wherein:
Y
2 is a direct bond; 5 X 5 is selected from -C(O)-; and Q2 is morpholinyl; and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: 10 (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl; a phenyl group which is optionally substituted with one or two cyano groups; a heterocyclyl group selected from pyrrolidinyl, pyrazinyl, pyrimidinyl 15 and pyridinyl, and wherein said heterocyclyl group is unsubstituted or substituted with one or two cyano groups; (b) a group of the formula VII: R23R24N-[CR m Rn]h (VII) 20 wherein integer h is 0, 1, or 2; each R m and R n group present is hydrogen;
R
2 3 and R 24 are each independently selected from hydrogen or (1-4C)alkyl; or (c) a group of the fonnula VIII: 25 Q 3
-X
6
-Y
3 (VIII) WO 2006/024841 PCT/GB2005/003355 67 wherein Y 3 is a direct bond or -[CR 25
R
26 ]z- wherein z is 1 and R 25 and
R
26 are both hydrogen;
X
6 is -C(O)-, if Y 3 is -[CR 2 3
R
24 ]z-, and if Y 3 is a direct bond, X 6 is selected from -SO 2 - or -C(O)-; and 5 Q 3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl or pyrrolidinyl, and wherein any non-aromatic heterocyclyl group within a Rib substituent group optionally bears 1 or 2 oxo substituents; (19) Rb is selected from hydrogen, cyano, amino, methyl, hydroxymethyl, 1-hydroxyethyl, i0 (methylamino)methyl, (ethylamino)methyl, 1-(ethylamino)ethyl, (propylamino)methyl, (isopropylamino)methyl, (cyclopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (cyclopentylamino)methyl, (1-methylpropylamino)methyl, (2 methylpropylamino)methyl, (allylamino)methyl, (di-ethylamino)methyl, [(ethyl)(methyl)amino]methyl, [(isopropyl)(methyl)amino]methyl, 15 [(propyl)(methyl)amino]methyl, [(butyl)(methyl)amino]methyl, [(cyclopropylmethyl)amino]methyl, [(cyclobutylmethyl)(methyl)amino]methyl, [(2 methoxyethyl)(methyl)amino]methyl, [(isopropyl)(2-methoxyethyl)amino]methyl, [(2 methoxyethyl)amino]methyl, [(ethyl)(2-methoxyethyl)amino]methyl, [(2-methoxy-1 methylethyl)amino]methyl, [(3-methoxypropyl)amino]methyl, [(3 20 isopropoxypropyl)amino]methyl, [(2-ethoxyethyl)amino]methyl, [(2 isopropoxyethyl)amino]methyl, [(3-ethoxypropyl)amino]methyl, [(2 propoxyethyl)amino]methyl, [(2-methoxy-2-methylpropyl)amino]methyl, [bis(2 methoxyethyl)amino]methyl, [(2-hydroxyethyl)(ethyl)amino]methyl, [(2 hydroxyethyl)(methyl)amino]methyl, { [2-(di-methylamino)ethyl]amino} methyl, {[2-(di 25 ethylamino)ethyl] amino}methyl, { [2-(di-methylamino)ethyl][methyl]amino}methyl, {[2-(di ethylamino)ethyl] [methyl] amino}methyl, { [2-(di-methylamino)- 1 (methyl)ethyl]amino}methyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, 1 piperidinylethyl, piperazinylmethyl, 7-azabicyclo[2.2.1]heptylmethyl, 2 azabicyclo[2.2.2]octylmethyl, {[2-(pyrrolidin-1-yl)ethyl]amino}methyl, {[2-(piperidin-1 30 yl)ethyl]amino}methyl, (3-fluoropyrrolidin-1-yl)methyl, (4-fluoropiperidin-1-yl)methyl, (3- WO 2006/024841 PCT/GB2005/003355 68 hydroxypyrrolidin-1-yl)methyl, (3-hydroxypiperidin-1-yl)methyl, (4-hydroxypiperidin-1 yl)methyl, (4-trifluoromethylpiperidin-1-yl)methyl, [2,5-dimethylpyrrolidin-1-yl]methyl, (4 methylpiperidin-1-yl)methyl, (4-hydroxymethylpiperidin-1-yl)methyl, (3,3-dimethylpiperidin 1-yl)methyl, [6-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]methyl, (3 5 methylaminopyrrolidin-1-yl)methyl, [3-(dimethylamino)pyrrolidin-1-yl]methyl, [3 (diethylamino)pyrrolidin-1-yl]methyl, (3-phenylpyrrolidin-1-yl)methyl, (3-phenylpiperidin-1 yl)methyl, (4-phenylpiperidin-1-yl)methyl, [3-(4-fluorophenyl)piperidin-1-yl]methyl, (3 pyridin-2-ylpyrrolidin-1-yl)methyl, (4-morpholin-4-ylpiperidin-1-yl)methyl, [4-(2 oxopyrrolidin-1-yl)piperidin-1-yl]methyl, (4-pyrrolidin-1-ylpiperidin-1-yl)methyl, (4-pyridin 10 4-ylpiperidin-1-yl)methyl, [(4-methylpiperazin-1-yl)piperidin-1-yl]methyl, [4-(morpholin-4 ylcarbonyl)piperidin-1-yl]methyl, (4-methylpiperazin-1-yl)methyl, (4-ethylpiperazin-1 yl)methyl, [4-(2-hydroxyethyl)piperazin-1-yl]methyl, (4-isopropylpiperazin-1-yl)methyl, {4 [2-(dimethylamino)ethyl]piperazin-1-yl} methyl, (4-allylpiperazin-1-yl)methyl, (4 acetylpiperazin-1-yl)methyl, (5-butyrylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl, [4-(2 15 methoxyethyl)piperazin-1-yl]methyl, [4-(methylsulfonyl)piperazin-1-yl]methyl, [4 (ethylsulfonyl)piperazin-1-yl]methyl, [4-(2-cyanophenyl)piperazin-1-yl]methyl, [4-(pyridin 2-yl)piperazin-1-yl]methyl, [4-(3-cyanopyridin-2-yl)piperazin-1-yl]methyl, [4-(3 cyanopyrazin-2-yl)piperazin-1-yl]methyl, (4-pyrimidin-2-ylpiperazin-1-yl)methyl, (4-pyrazin 2-ylpiperazin-1-yl)methyl, [4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl, [4 20 (cyclopropylcarbonyl)piperazin-1-yl]methyl, { [(1,3-dimethyl-l1H-pyrazol-5 yl)methyl] amino}methyl, {[2-(3,5-dimethyl- 1H-pyrazol-4-yl)ethyl] amino}methyl, [methyl(tetrahydrofuran-2-ylnethyl)amino]methyl, [(5-methylpyrazin-2 yl)methyl] amino } methyl, [6-(trifluoromethyl)pyridin-3-yl]methyl} amino)methyl, [(4-methyl 1,3-thiazol-2-yl)methyl]amino } methyl, [2-(1-methyl-1H-imidazol-4-yl)ethyl]amino}methyl, 25 [(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5-methyl-2-furyl)methyl]amino} methyl, (tetrahydro-2H-pyran-4-ylmethyl)amino]methyl, (tetrahydro-2H-pyran-4-ylamino)methyl, { [2-(2-methyl- 1H-indol-3-yl)ethyl] amino} methyl, (2-methoxybenzyl)amino]methyl, [(3 methoxybenzyl)amino]methyl, { [2-(isopropylamino)ethoxy]methyl, [2 (ethylamino)ethoxy]methyl, and [2-(methylamino)ethoxy]methyl; 30 (20) Rlb is selected from hydrogen, amino, methyl, azetidinylmethyl, pyrrolidinylmethyl, WO 2006/024841 PCT/GB2005/003355 69 piperidinylmethyl, 1-piperidinylethyl, piperazinylmethyl, 7-azabicyclo[2.2.1]heptylmethyl, 2 azabicyclo[2.2.2]octylmethyl, (3-fluoropyrrolidin-1-yl)methyl, (4-hydroxypiperidin-1 yl)methyl, (4-trifluoromethylpiperidin-1-yl)methyl, [2,5-dimethylpyrrolidin-1-yl]methyl, (4 methylpiperidin-1-yl)methyl, (4-hydroxymethylpiperidin-1-yl)methyl, (3,3-dimethylpiperidin 5 1-yl)methyl, (3-methylaminopyrrolidin-1-yl)methyl, [3-(dimethylamino)pyrrolidin-1 yl]methyl, (3-phenylpyrrolidin-1-yl)methyl, (3-phenylpiperidin-1-yl)methyl, (4 phenylpiperidin-1-yl)methyl, [3-(4-fluorophenyl)piperidin-1-yl]methyl, (3-pyridin-2 ylpyrrolidin-1-yl)methyl, (4-morpholin-4-ylpiperidin-1-yl)methyl, [4-(2-oxopyrrolidin-1 yl)piperidin-1-yl]methyl, (4-pyrrolidin-1-ylpiperidin-1-yl)methyl, (4-pyridin-4-ylpiperidin-1 10 yl)methyl, [(4-methylpiperazin-1-yl)piperidin-1-yl]methyl, (4-methylpiperazin-1-yl)methyl, (4-ethylpiperazin-1-yl)methyl, [4-(2-hydroxyethyl)piperazin-1-yl]methyl, (4 isopropylpiperazin-1-yl)methyl, {4-[2-(dimethylamino)ethyl]piperazin-1-yl}methyl, (4 allylpiperazin-1-yl)methyl, (4-acetylpiperazin-1-yl)methyl, (5-butyrylhexahydropyrrolo[3,4 c]pyrrol-2(1H)-yl)methyl, [4-(2-methoxyethyl)piperazin-1-yl]methyl, [4 15 (methylsulfonyl)piperazin-1-yl]methyl, [4-(ethylsulfonyl)piperazin-1-yl]mnthyl, [4-(2 cyanophenyl)piperazin-1-yl]methyl, [4-(pyridin-2-yl)piperazin-1-yl]methyl, [4-(3 cyanopyridin-2-yl)piperazin-1-yl]methyl, [4-(3-cyanopyrazin-2-yl)piperazin-1-yl]methyl, (4 pyrimidin-2-ylpiperazin-1-yl)methyl, (4-pyrazin-2-ylpiperazin-1-yl)methyl, { [2-(2-methyl 1H-indol-3-yl)ethyl]amino}methyl, (methylamino)methyl, (ethylamino)methyl, 1 20 (ethylamino)ethyl, (propylamino)methyl, (isopropylamino)methyl, (cyclopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (cyclopentylamino)methyl, (1-methylpropylamino)methyl, (2-methylpropylamino)methyl, (allylamino)methyl, (di-ethylamino)methyl, [(ethyl)(methyl)amino]methyl, [(isopropyl)(methyl)amino]methyl, [(propyl)(methyl)amino]methyl, 25 [(cyclopropylmethyl)amino]methyl, [(cyclobutylmethyl)(methyl)amino]methyl, [(2 methoxyethyl)(methyl)amino]methyl, [(isopropyl)(2-methoxyethyl)amino]methyl, [(2 methoxyethyl)amino]methyl, [(ethyl)(2-methoxyethyl)amino]methyl, { [2-(di methylamino)ethyl]amino}methyl, {[2-(di-ethylamino)ethyl]amino}methyl, ([2-(di methylamino)ethyl][methyl] amino }methyl, { [2-(di-ethylamino)ethyl] [methyl] amino}methyl, 30 { [2-(di-methylamino)- 1 -(methyl)ethyl]amino}methyl, [(1-methylpropyl)amino]methyl, { [2 (pyrrolidin- 1 -yl)ethyl]amino}methyl, {[2-(piperidin-1-yl)ethyl]amino}methyl, {[2 (isopropylamino)ethoxy]methyl, and [2-(ethylamino)ethoxy]methyl, WO 2006/024841 PCT/GB2005/003355 70 [(butyl)(methyl)amino]methyl, [(2-methoxy- 1-methylethyl)amino]methyl, [(3 methoxypropyl)amino]methyl, [(3-isopropoxypropyl)amino]methyl, [(2 ethoxyethyl)amino]methyl, [(2-isopropoxyethyl)amino]methyl, [(3 ethoxypropyl)amino]methyl, [(2-propoxyethyl)amino]methyl, [(2-methoxy-2 5 methylpropyl)amino]methyl, [bis(2-methoxyethyl)amino]methyl, (2 methoxybenzyl)amino]methyl, [(3-methoxybenzyl)amino]methyl, [methyl(tetrahydrofuran-2 ylmethyl)amino]methyl, [(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5-methyl-2 furyl)methyl] amino} methyl, (tetrahydro-2H-pyran-4-ylmethyl)amino]methyl, (tetrahydro-2H pyran-4-ylamino)methyl, or [3-(diethylamino)pyrrolidin-1-yl]methyl. 10 (21) Ric is selected from hydrogen, amino, (1-3C)alkyl, N-(1-3C)alkylamino, and N,N-di [(1-3 C)alkyl]amino; (22) Ric is selected from hydrogen, (1-3C)alkyl and N,N-di-[(1-3C)alkyl]amino; 15 (23) Ric is selected from hydrogen, (1-2C)alkyl and N,N-di-[(1-2C)alkyl]amino; (24) Ric is selected from hydrogen, methyl and di-methylamino; 20 (25) RiC is di-methylamino; (26) Ric is hydrogen; (27) m is 0; 25 (28) n is 0; WO 2006/024841 PCT/GB2005/003355 71 (29) R 4 is amino. A particularly preferred group of compounds of the invention have the general structural formula VIII below: RRo RIO N Rib Rla N H NH2 N 0 5 VIII wherein R 1 l , Rlb and Ric have any one of the definitions set out herein, with the proviso that at least one of Ria, Rlb and Ric is hydrogen. In the compounds of formula VIII above, Ria is suitably as defined in any one of paragraphs (1) to (9) above, and is particularly as defined in any one of paragraphs (4) to (9) o10 above. Rlb is suitably as defined in any one of paragraphs (10) to (20) above, and is particularly as defined in any one of paragraphs (16) to (20) above. Rio is suitably as defined in any one of paragraphs (21) to (26) above, and is particularly as defined in any one of paragraphs (24) to (26) above. A further particular sub group of preferred compounds of the present invention has the 15is general formula IX shown below:
R
1 b ,N N NH 2 R1 a |H IX wherein Ria and Rlb have any one of the definitions set out hereinbefore.
WO 2006/024841 PCT/GB2005/003355 72 In the compounds of formula IX above, Ria is suitably as defined in any one of paragraphs (1) to (9) above. In particular, Rla is hydrogen or (1-3C)alkyl, especially hydrogen or methyl. RIb is suitably as defined in any one of paragraphs (10) to (20) above, and is particularly as defined in any one of paragraphs (16) to (20) above. 5 A further particular group of preferred compounds has the general formula X shown below: Rib wherein R is as hereinbefore defined. lb N " NH2 /N wherein R lb is as hereinbefore defined. 10 Suitably Rlb is as defined in any one of paragraphs (10) to (20) above, and is particularly as defined in any one of paragraphs (16) to (20) above. Suitably Rlb is a group of sub-formula II as defined in any one of paragraphs (10) to (18) above, and especially as defined in paragraphs (16) and (18) above. A particular sub-group of compounds of formula X above has the general formula XI 15 shown below R7 CN R8 N H NH2 /N XI wherein R 7 and R 8 have any one of the definitions set out herein.
WO 2006/024841 PCT/GB2005/003355 73 Suitably, R 7 and R 8 are as defined in anyone of paragraphs (10) to (18) above, and are particularly as defined in paragraphs (16) and (18) above. A further particular sub-group of compounds of formula (X) above has the general formula (XII) shown below 5 XII wherein R 7 , R 8 , integer a and integer b have any one of the definitions set out hereinbefore. In the compounds of formula XII above, R7 and R 8 are as defined in anyone of paragraphs (10) to (18) above. Suitably, R7 and R 8 are selected from hydrogen or (1 o10 6C)alkyl, and especially hydrogen or (1-4C)alkyl. Integer a is preferably 1 or 2. Integer b is preferably 1 or 2. In a further preferred group of compounds formula (I), m is 0, n is 0, R 4 is amino, Rlb is hydrogen, Ric is hydrogen and Ria has any one of the definitions set out herein (and, in 15is particular, is as defined in any one of paragraphs (1) to (9) above). In a further preferred group of compounds formula (I), m is 0, n is 0, R 4 is amino, RIb is hydrogen, Ria is selected from hydrogen or (1-3C)alkyl and RIc has any one of the definitions set out herein (and, in particular, is as defined in any one of paragraphs (21) to (26) above). 20 Particular novel compounds of the invention include any one of the following:
N-(
2 -aminophenyl)-4-(3-cyanopyridin-2-yl)benzamide; N-(2-aminophenyl)-4- { 3 -cyano-6-[(2-hydroxyethyl)amino]-4-methylpyridin-2-yl}benzamide; N-(2-aminophenyl)-4-[3-cyano-5-(piperidin-1-ylmethyl)pyridin-2-yl]benzamide; WO 2006/024841 PCT1GB20051003355 74 N-(2-aminophenyl)-4- {3-cyano-5-[(4-methylpiperidin- 1 -yl)methyl]pyridin-2-ylfbenzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(diethylamino)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4-[3-cyano-4-methyl-6-(4-methylpiperazin- 1-yl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4-[3-cyano-5-(pyrrolidin- 1-ylmethyl)pyridin-2-yl]benzamide; 5 N-(2-aminophenyl)-4- {3-cyano-5-[(3-phenylpyrrolidin- 1 -yl)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- {3 -cyano-5-[(4-isopropylpiperazin- 1 -yl)methyl]pyridin-2 ylfbenzamide; N-(2-aminophenyl)-4-[3-cyano-5-(piperazin- 1-ylmethyl)pyridin-2-yl]benzamide; N-(2-amninophenyl)-4- {3-cyano-5-[(4-methiylpiperazin- 1 -yl)methyl]pyridin-2-yllbenzamide; 10 N-(2-arninophenyl)-4- {3-cyano-5-[(4-ethylpiperazin- 1 -yl)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- {3 -cyano-5-[(3-pyridin-2-ylpyrrolidin- 1 -yl)methyl]pyridin-2 yllbenzamide;I N-(2-aminophenyl)-4-(3-cyano-5- { [(2R,5R)-2,5-dimethylpyrrolidin- 1 -yl]methyllpyridin-2 yl)benzamide; 15 N-(2-aminophenyl)-4- {3-cyano-5-[(4-hydroxypiperidin- 1 -yl)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4-(3-cyano-5- f [4-(trifluorornethyl)piperidin- 1 -yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(4-morpholin-4-ylpiperidin- 1 -yl)methyl]pyridin-2 yl}benzamnide; 20 N-(2-amninophenyl)-4- {3-cyano.-5-[(3 ,3-dimethylpiperidin- 1-yl)methyl]pyridin-2 yl}benzamtide; N-(2-aminophenyl)-4-[5-(azetidin- 1 -ylmethyl)-3-cyanopyridin-2-yl]benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[4-(2-oxopyrrolidin- 1 -yl)piperidin- 1 -yl]methyl}pyridin-2 yl)belizamide; 25 N-(2-aminophenyl)-4- {3-cyano-5-[(4-pyrrolidin- 1-ylpiperidin- 1-yl)methyl]pyridin-2 yl}benzamide; WO 2006/024841 PCT1GB20051003355 75 N-(2-amninophenyl)-4-(3-cyano-5- {[(cyclobutylmethyl)(methyl)amino]methyllpyridin-2 yl)belizamnide; N-(2-amninophenyl)-4-(3 -cyano-5- f{[(2-methoxyetliyl)(methyl) amino Imethyllpyridil-2 yl)benzamide; s N-(2-amiriophenyl)-4-(3-cyanio-5- {[(3S)-3-(dimethylamnino)pyrrolidin- 1 -yl]metliyllpyridin-2 yl)benzamnide; N-(2-aminophenyl)-4-(3-cyano-5- f{[(isopropyl)(2-rnethoxyethyl)amino]methyllpyridin-2 yl)benzamide; N-(2-amiuophenyl)-4- f{3-cyano-5-[(4-pyridin-4-.ylpiperidin- 1 -yl)methyl]pyridin-2 10 yllbenzamide; N-(2-aminophenyl)-4-[5-(7-azabicyclo [2.2.1 ]hept-7-ylmethyl)-3-cyanopyridin-2 yl]benzaiide; N-(2-aminophenyl)-4-(3-cyano-5- {[(cyclopropylmethyl)amino]methyllpyridin-2 yl)benzatnide; 15 N-(2-aminophenyl)-4-[5-(2-azabicyclo[2.2.2]oct-2-ylmethyl)-3 -cyanopyridin-2-yl]benzamnide; N-(2-amninophenyl)-4-[3-cyano-6-methyl-5 -(1 -piperidin- 1-ylethyl)pyridin-.2-yl]benzamnide; N-(2-aminophenyl)-4-(3-cyano-5- {[4-(4-methylpiperazin- 1 -yl)piperidin- 1 -yllmethyllpyridin 2-yl)benzamide; N-(2-arninophenyl)-4-(3-cyano-5- {[isopropyl(methyl)aminojmethyllpyridin-2-yl)benzamide; 20 N-(2-aminophenyl)-4-(3-cyano-5- { [ethyl(2-methoxyethyl)aminojmethyllpyridin-2 yl)benzamide; N-(2-amninophenyl)-4-(3-cyano-5- {[methy1(propy1)amilio]methy1}pyridin-2-y1)benzamide; 4- {5-[(4-allylpiperazin- 1-yl)methiyl]-3-cyanopyridin-2-yl} -N-(2-aminophenyl)benzainide; N-(2-amninophenyl)-4-(3-cyano-5- {[4-(2-methoxyethyl)piperazin- 1-yl]methyllpyridin-2 25 yl)benzamide; N-(2-aminophenyl)-4- [3 -cyano-5 -( {[2-(dimethylamino)ethyl] amino Imethyl)pyridin-2 yl]benzarnide; WO 2006/024841 PCT1GB20051003355 76 N-(2-aminophenyl)-4-[3 -cyano-5 -( {[2-(diethylamino)ethyl] amino Imethyl)p;yridin-2 yl]benzamnide; N-(2-aminophenyl)-4-(3-cyano-5- { [(2-pyrrolidin- 1-ylethyl)amino]methyllpyridin-2 yl)benzamide; 5 N-(2-aminophenyl)-4-(3 -cyano-5- {[(2-piperidin- 1-ylethyl)amino]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [4-(3-cyanopyridin-2-yl)piperazin- 1-yl]methiyllpyridin-2 yl)benzamide; N-(2-aininophenyl)-4-[3-cyano-5-( {4- [2-(dimethylamnino)ethyl]piperazin- 1 10 yl} methyl)pyridin-2-yl]benzamnide; N-(2-aminophenyl)-4- {3-cyanio-5 -[(4-pyridin-2-ylpiperazin- 1-yl)methyl]pyridin-2 yllbenzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[[2-(dimethylamino) ethyl] (methyl) amino]methyllpyridin 2-yl)benzamide; is N-(2-aminophenyl)-4-(3 -cyano-5- { [[2-(diethylamino)ethyl](methyl)amnino]methyllpyridin-2 yl)benzarnide; N-(2-aminophenyl)-4- {3-cyano-5-[(propylamnino)methyl]pyridin-2-yllbenzamnide; N-(2-aminophenyl)-4- {5-[(butylamino)rnethyl]-3-cyanopyridin-2-yllbenzamide; N-(2-aminophenyl)-4- { 5- [(sec-butylamino)methyl]-3-cyanopyridin-2-yl} benzamide; 20 N-(2-aminophenyl)-4- {3-cyano-5 -[(cyclobutylamino)methylljpyridin-2-yllbenzarnide; N-(2-ai-ninophenyl)-4- {3-cyano-5-[(isopropylamino)methylljpyridin-2-yllbenzarnide; N-(2-aminophenyl)-4- { 3-cyano-5- [(isobutylamino)methyl]pyridin-2-yl} benzamide; 4- {5-[(allylamino)methyl]-3-cyanopyridin-2-yl} -N-(2-aminophenyl)benzanide; N-(2-aminophenyl)-4- {3-cyano-.5-[(cyclopentylamino)methyl]pyridin-2-yllbenzamide; 25 N-(2-aminophenyl)-4- {3-cyano-5-[(ethylamino)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(4-pyrazin-2-ylpiperazin- 1-yl)methyl]pyridin-2 yllbenzamide; WO 2006/024841 PCT1GB20051003355 77 N-(2-aminophenyl)-4-[3 -cyano-5-( {[2-(dimethylamino)- 1 m-ethylethyl] amino) methyl)pyridin-2-yllbenzamide; N-(2-amninophenyl)-4-(3-cyano-5- {[3-(methylamino)pyrrolidin- 1-yl]methylfpyridin-2 yl)benzamide; 5 N-(2-amninophenyl)-4-(3-cyano-5- { [4-(2-cyaniopheniyl)piperazin- 1-yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f [4-(3 -cyanopyrazin-2-yl)piperazin- 1-yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4- {3-.cyano-5-[l1-(ethylamiino)ethyl]-6-methylpyridin-2-yllbenzamide; 10 N-(2-aminophenyl)-4- {3-cyano-5-[(methylamino)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4-(3-cyanio-5- f [(3R)-3-hydroxypyrrolidin- 1-yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3 -cyano-5- {[(3R)-3 -fluoropyrrolidin- 1 -yl]methyllpyridin-2 yl)benzamide; 15 N-(2-aminophenyl)-4-(3-eyano-5. f [(2-hydroxyethyl)(methyl)amino]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3 -cyano-5- f{[4-(ethylsulfonyl)piperazin- 1-y1]methy1jpyridin-2 yl)benzamide; N-(2-aminophenyl)-4- f{3-cyano-5-[(4-pyimidin-2-ylpiperazin- 1-yl)rnethyl]pyridini-2 20 yllbenzamide; 4-( 5 -amino-3-cyano-6-methylpyridin-2-yl)-N-(2-aminophenyl)benzamide; N-(2-aminophenyl)-4-[3 -cyano-5-( { [(1R)-l1-methyipropyl] aminolmethyl)pyridin-2 yl]benzamide; N-(2-amninophenyl)-4-[3-cyano-5-( {[(1 S)-l1-methyipropyl] amiliolmethyl)pyridin-2 25 yl]benzamide; N-(2-amninophenyl)-4-(3 -cyanio-5- {[ 4 -(methylsulfonyl)piperazin- 1-yl]methyllpyridin-2 yl)benzamide; WO 2006/024841 PCT1GB20051003355 78 N-(2-aminophenyl)-4-[3-cyano-5-( {[2-(2-methyl- 1H-indol-3-yl) ethyl] aminolmethyl)pyridin 2-yllbenzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[2-(isopropylamino)ethoxylmethyl}pyridifl-2 yl)benzamide; 5 N-(2-aminophenyl)-4-(3-cyano- 5 - { [2-(ethylamnino)ethoxy]methyl}pyridil-2-y1)beflzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[2-(methylamino)ethoxy]methy}pyridifl-2-yl)beflzaride; N-2aiohnl--3cai--ehlyii--lbnaie N-2annpey)4[-yn--dmtyaioprdn2y~eznie N-2aiohnl--3cao6(tyamn)4mtyprdn2y~eziie 10 N-2aiohnl--3cao46-iehlyii--lbnaie N-2aiohnl--3cao6mtyprdi--lbnaie N-(2-amninophenyl)-4-(3-cyano-5- {[4-(2-oxo-2-pyrrolidin- 1-ylethyl)piperazin- 1 yl]methyllpyridin-2-yl)benzamlide; N-(2-aminophenyl)-4-(3-cyano-5- {[4-(2-hydroxyetliyl)piperazin- 1-yl]methyllpyridin-2 15 yl)benzamide; N-(2-aminophenyl)-4-(3 -cyano-5- {[(1R,5S)-6-(hydroxymethyl)-3-azabiCYClo [3. 1 .]hex-3 yllmnethyl}pyridin-2-yl)benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(4-hydroxymethylpiperidil- 1 -yl)methyl]pyridin-2 yl}benzamide; 20 4- f{5-[(4-acetylpiperazin- 1 -yl)methyl]-3-cyanopyridin-2-yl} -N-(2-aminophenyl)benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(3-hydroxypiperidifl-1I-yl)methyl]pyridin-2-yllbenzamide; N-(2-amninophenyl)-4- {5- [(5-butyrylhexahydropyrrolo[3 ,4-clpyrrol-2(TH-yl)methyl]- 3 cyanopyridin-2-yl~benzamide; N-(2-aminophenyl)-4-(3-CYalo-5- f [(2-hydroxyethyl)(etliyl)amino]methyl} pyridin-2 25 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano- 5 - {[(2-methoxyethy1)amino~methy11pyridifl-2-y1)beflzaiide; N-(2-.aminophenyl)-4-(3-cyano- 5 - { [ethyl(methyl)amino]methyl}pyridil-2-Yl)beflzamide; WO 2006/024841 PCT1GB20051003355 79 N-(2-aminophenyl)-4- {3-cyano-5-[(3-phenylpiperidin- 1 -yl)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- f{3 -cyano-5-[(4-phenylpiperidin- 1 -yl)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[3-(4-fluorophenyl)piperidin- 1-yl]methyllpyridin-2 yl)benzamide; 5 N-(2-aminophenyl)-4-(3 -cyano-5- {[4-(morpholin-4-ylcarbonyl)piperidin- 1 yl]methyllpyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[3 -(diethylamnino)pyrrolidin- 1-yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(5- f [butyl(methyl)amino]methyl} -3 -cyanopyridin-2-yl)benzamnide; 10 N-(2-aminophenyl)-4-(3.-cyano-6-nitropyridin-2-yl)benzamide; N-(2-arninophenyl)-4-[3 -cyano-6-(4-fluoropheniyl)pyridin-2-yl]benzamide; 4-(6-amino-3,5-dicyanopyridin-2-yl)-N-(2-aminophenyl)benzamide; N-(2--aminophenyl)-4-(3-cyano-5- f [4-(cyclopropylcarbonyl)piperazin- 1-yl]methyllpyridin-2 yl)benzamide; 15 N-(2-aminophenyl)-4- {3-cyano-5-[(methylamnino)methyl]pyridin-2-yl}benzamide; N-(2-aminophenyl)-4-[3-cyano-5-( {[(1 ,3-dimethyl- 1H-pyrazol-5 yl)methyl] amino) methyl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4-[3-cyano-5-( { [2-(3 ,5-dimethyl- 1H-pyrazol-4 yl) ethyl] amino Imethyl)pyridin-2-yl]benzamide; 20 N-(2-aminophenyl)-4-(3-cyano-5- {[(2-methoxy-l1-methylethyl)amino]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f [(3 -methoxypropyl)amino]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f [(2-methoxybenzyl)amino]methyllpyridin-2 25 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[(3-methoxybenzyl)amino]methyllpyridin-2 yl)benzamide; WO 2006/024841 PCT/GB2005/003355 80 N-(2-aminophenyl)-4-(3-cyano-5- { [(3-isopropoxypropyl)amino]methyl}pyridin-2 yl)benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[({[6-(trifluoromethyl)pyridin-3 yl]methyl} amino)methyl]pyridin-2-yl}benzamide; 5 N-(2-aminophenyl)-4-[3-cyano-5-({ [(4-methyl-1,3-thiazol-2 yl)methyl] amino} methyl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4-[3-cyano-5-( { [2-(1 -methyl- 1H-imidazol-4 yl)ethyl] amino}methyl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [(tetrahydrofuran-2-ylmethyl)amino]methyl}pyridin-2 10 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [(2-ethoxyethyl)amino]methyl} pyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [(2-isopropoxyethyl)amino]methyl}pyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[(3-ethoxypropyl)amino]methyl}pyridin-2-yl)benzamide; 15 N-(2-amninophenyl)-4-(3-cyano-5- { [(2-propoxyethyl)amino]methyl} pyridin-2-yl)benzamide; N-(2-aminophenyl)-4-[3-cyano-5-({[(5-methyl-2-furyl)methyl] amino}methyl)pyridin-2 yl]benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl} pyridin 2-yl)benzamide; 20 N-(2-aminophenyl)-4- {3-cyano-5-[(tetrahydro-2H-pyran-4-ylamino)methyl]pyridin-2 yl}benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[(2-methoxy-2-methylpropyl)amino]methyl}pyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [methyl(tetrahydrofuran-2 25 ylmethyl)amino]methyl}pyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(5- { [bis(2-methoxyethyl)amino]methyl} -3-cyanopyridin-2 yl)benzamide; WO 2006/024841 PCT/GB2005/003355 81 or a pharmaceutically acceptable salt thereof. A suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, an acid-addition salt of a compound of the Formula (I), for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, 5 trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt. A further suitable pharmaceutically acceptable salt of a compound of the Formula (I) is, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I). 10 The compounds of the invention may be administered in the form of a pro-drug that is a compound that is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group 15 can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I) and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I). Accordingly, the present invention includes those compounds of the Formula (I) as 20 defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a 25 synthetically-produced compound or a metabolically-produced compound. A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. 30 Various forms of pro-drug have been described, for example in the following documents : a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic WO 2006/024841 PCT/GB2005/003355 82 Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113 5 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium o10 Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987. A suitable pharmnnaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula (I) containing a carboxy group is, for example, 15is a pharmaceutically-acceptable ester, which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as 20 cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters. A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) 25 that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether, which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters 30 (including phosphoramidic cyclic esters). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups WO 2006/024841 PCT/GB2005/003355 83 such as ethoxycarbonyl, N,N-[di-(1-4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1-4C)alkylpiperazin-1-ylmethyl. Suitable 5 pharmaceutically-acceptable ether forming groups for a hydroxy group include c~ acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1-4C)alkylamine such as o10 methylamine, a di-(1-4C)alkylamine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) 15 that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (1-10OC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, 20 N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1-4C)alkylpiperazin-l1-ylmethyl. The in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in vivo effects of a compound of the 25 Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug). Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein R a , Rb, Ric, R 2 , R 3
,R
4 integer m and integer n are, unless otherwise specified, as hereinbefore defined), said process comprising the steps of: 30 (a) the reaction of a compound of the formula (A) WO 2006/024841 PCT/GB2005/003355 84 x R4 H N
(R
2 )m O (R3 n (A) wherein X is a reactive group, with a compound of the formula (B) RR' CN RIa' N ML z (B) wherein Rla' is a group Rl a as hereinbefore defined or a precursor thereof, R1b' is a group R l b as hereinbefore defined or a precursor thereof, 10 Ric' is a group Ri c as hereinbefore defined or a precursor thereof, M is a metal, L is a ligand, and integer z is 0 to 3; and wherein if any one of said groups R a' , Rlb' or Rlc' is a precursor for a R la, Rlb or 15 Ric group respectively, then said process thereafter comprises a step of converting the compound formed by the reaction of a compound of the formula (A) with a compound of the formula (B) to a compound of formula (I) (by converting the precursor of any one of groups la Ibla l R a , Rib or Ric group to the appropriate R a , Rib or Ric group); or (b) The reaction of a compound of the formula (C) WO 2006/024841 PCT/GB2005/003355 85 LzM R4 H N
(R
2 )m (R3
)
n (C) wherein M, L and integer z are as defined above, with a compound of the formula (D) 5 RIc ' Rb' CN Rla' N x (D) wherein R a' , R1b' and Ric ' are as defined above and X is a reactive group; and wherein if any one of said groups Ria', R1b' or R l c' is a precursor for a R l a, Rlb or io Ric group respectively, then said process comprises an additional step thereafter of converting the compound formed by the reaction of a compound of the formula (C) with a compound of the formula (D) to a compound of formula (I) (by converting the precursor of any one of groups Ria, Rib or Ric group to the appropriate R a, Rib or Ric group); or (c) the reaction, in the presence of 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4 15 methylmorpholinium chloride, of a compound of the formula (E) WO 2006/024841 PCT/GB2005/003355 86 0 HKO HN O 4
H
2 N (R3)n (E) with a compound of the formula (F) Ric ' Rib' CN CN N/ Rla' OH
(R
2 )m O 5 (F) wherein R l a' , Rib' and Rio' are as defined above, and wherein if any one of said groups
R
l a' , Rib' or Ric' is a precursor for a Ria, Rlb or Ric group respectively, then said process comprises an additional step thereafter of converting the compound formed by the reaction of a compound of the formula (E) with a compound of the formula (F) to 10 a compound of formula (I) (by converting the precursor of any one of groups R a , RIb or Ric group to the appropriate R l a , Rib or Ric group); and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); and/or ii) removing any protecting groups. s15 A suitable base for process (a), (b) or (c) is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, WO 2006/024841 PCT/GB2005/003355 87 potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal hydride, for example sodium hydride, or an alkali metal hydrogencarbonate such as sodium hydrogencarbonate, or a metal alkoxide such as sodium ethoxide. 5 A suitable reactive group X is, for example, a halo or a sulphonyloxy group, for example a chloro, bromo, iodo, methanesulphonyloxy, trifluromethanesulphonyloxy or toluene-4-sulphonyloxy group. The reactions are conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alkanol or ester such as methanol, ethanol, isopropanol or ethyl o10 acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N dimethylacetamnide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reactions are conveniently carried out at a temperature in the range, for example, 10 to 250 0 C, preferably in 15 the range 40 to 80 0 C; Metal M may be any metal that is known in the literature to form organometallic compounds that undergo catalytic cross coupling reactions. Examples of suitable metals include boron, tin, zinc, and magnesium. A suitable value for integer z is dependent on the metal M, but is usually in the range 20 0-3. Suitable values for the ligand L, when present, include, for example, a hydroxy, a halo, (1-4C)alkoxy or (1-6C)alkyl ligand, for example a hydroxy, bromo, chloro, fluoro, iodo, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand or, where integer z is 2 and M is boron, the two ligands present may be linked such 25 that, together with the boron atom to which they are attached, they form a ring. Suitably, the group MLz is a group of the formula -BL 1
L
2 , where B is boron and L 1 and L 2 are as defined for ligand L above. In particular, the ligands L 1 and L 2 may be linked such that, together with the boron atom to which they are attached, they form a ring. For example, L 1 and L 2 together may define an oxy-(2-4C)alkylene-oxy group, for example an 30 oxyethyleneoxy, pinacolato (-O-C(CH 3
)
2
C(CH
3
)
2 -O-) or oxypropyleneoxy group such that, WO 2006/024841 PCT/GB2005/003355 88 together with the boron atom to which they are attached, they form a cyclic boronic acid ester group. A suitable catalyst for process (a) or (b) includes, for example, a metallic catalyst such as a palladium(0), palladium(II), nickel(0) or nickel(II) catalyst, for example 5 tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride, palladium(II) bromide, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II) bromide, bis(triphenylphosphine)nickel(II) chloride or dichloro[1-1'-bis(diphenylphosphino)ferrocene]palladium(II). In addition, a free radical initiator may conveniently be added, for example an azo compound such as o10 azo(bisisobutyronitrile). It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of 15is the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, reductive amination of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro 20 group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halo group. Particular examples of modifications include the reduction of a nitro group to an amino group by for 25 example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those 30 skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green and P.G.M. Wuts, Protective Groups in Organic WO 2006/024841 PCT/GB2005/003355 89 Synthesis, John Wiley and Sons, 1999). Thus, if reactants include groups such as amino, formyl, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl 5 group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an aryhnlmethexycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an o10 aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for 15 example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for 20 example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. 25 Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, 30 for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation WO 2006/024841 PCT/GB2005/003355 90 over a catalyst such as palladium-on-carbon. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. Where any one of groups R la' , R1b' or Rlc' is a precursor for a R la , Rlb or Rc group 5 respectively, it may be converted into a compound of formula (I) by converting the precursor of any one of groups R a , Rlb or Rio to the appropriate R la , R b or Ric group using standard chemical techniques that are well known to those skilled in the art. Examples of possible R l a Rib' or RIc' precursor groups (particularly Rib' precursor groups) include hydroxy or alcohol containing groups (e.g. -CH 2 OH), aldehyde-containing groups (e.g. -CHO), carboxylic acid o10 containing groups (e.g. -(CH 2 )0- 3 -COOH), ester containing groups (e.g. -(CH 2 )0-3-COORz, where Rz is (1-4C)alkyl), amide containing groups (e.g. -CONH 2 ), a group -CH 2 -X where X is a reactive group as hereinbefore defined, or an activated ester group, such as a pentafluorphenoxy ester or an acyl chloride. A person skilled in the art will appreciate how to select the most appropriate precursor group for conversion into the desired Ria, RIb or Ric 15is substituent groups. For example, a compound of the present invention having the formula (XI) shown below (i.e. a compound of formula (I) in which R 1 a and R 1 c are both hydrogen; R b is a group of the formula R 7
RN-CH
2 -; integer m is 0; integer n is 0; and R 4 is amino) R7 CN 'N R N H NH2 N 20 (XI) is suitably prepared by a process (process (d)) comprising the reaction, in the presence of a suitable base, of a compound of formula (G) (wherein the aniline may be protected and RIb' is a precursor for the R 7 R8N-CH 2 - group in the compound of formula (VI) above, said precursor having the formula -CH 2 -X, wherein X is a reactive group as hereinbefore defined), WO 2006/024841 PCT/GB2005/003355 91 RIb ' CN N (G) with a compound of formula (H);
R
7
R
8 N H 5 (H) and thereafter, if necessary, removing any protecting groups. Alternatively, a compound of general structural formula (XI) above may be prepared by a process (process (e)) which comprises the reaction, in the presence of a suitable reducing agent and a suitable acid, of a compound of formula (G) (wherein the aniline may be io protected and R1b' is a precursor for the R 8
RN-CH
2 - group in the compound of formula (VI) above, said precursor having the formula -CHO (formyl)): Rb' NH2 N (G) with a compound of formula (H);
R
7
R
8 N 15 H
(H)
WO 2006/024841 PCT/GB2005/003355 92 and thereafter, if necessary, removing any protecting groups. A suitable base for process (d) is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an 5 alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal hydride, for example sodium hydride, or an alkali earth metal hydrogencarbonate such as sodium hydrogencarbonate, or a metal alkoxide such as sodium ethoxide. 10 A suitable reducing agent for process (e) includes, for example, an inorganic borohydride salt such as, sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. A suitable acid for process (e), includes a Bronsted acid such as, for example formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulphuric acid, paratoluene sulfonic 15is acid or camphor sulfonic acid; or a Lewis acid of formula MXz, wherein M is a metal, X is a reactive group as hereindefined and z is in the range of 1-6 and the value of z will depend on the metal M. Typical examples of suitable Lewis acids include boron trifluoride, scandium(III) trifluoromethanesulfonate, tin(VI) chloride, titanium(IV) isopropoxide or zinc(II) chloride. 20 The present invention also provides a particular process (process (g)) for preparing a particular sub-group of compounds of formula (D) for use in process (b) above which have the formula (D') shown below, R7 CN
R
8 N X 25 (D') (i.e. compounds of formula D above wherein R l a' and Ric' are both hydrogen and RI b ' is a group R 7
R
8
N-CH
2 - where R7 and R 8 are any substituent group as hereinbefore defined except hydrogen, said process comprising the steps of: WO 2006/024841 PCT/GB2005/003355 93 (i) reacting, in a suitable solvent, a substituted acrolein of formula (J), wherein R 50 so is a suitable leaving group, R5o 0 with formaldehyde and a compound of formula (H) R7N R 8 I 5 H (H) to form a compound of formula (L); R5o R7N
R
8 0 (L) 10 (ii) reacting, in a suitable solvent and in the presence of a suitable base, the compound of formula (L) prepared in step (i) above with 2-cyanoacetamide to form a compound of formula (M) as a metal salt; N CN R8 0 15 (M) (iii) converting compound (M) to compounds of formula (D') and thereafter, if necessary, removing any protecting groups. The compounds of formula (D') prepared above are then used in process (b) above to form a compound of formula VI above. 20 In step (iii) of process (g), above, any suitable method known in the art for converting WO 2006/024841 PCT/GB2005/003355 94 compound (M) to a compound of formula (D') may be used. This conversion involves the substitution of the -0- group of compound (M) with a reactive group X as hereinbefore defined (e.g. a halogen). For example, compound (M) may be converted into a compound of formula (D') in which X is chloro by a chlorination reaction. Such a reaction may involve the 5 neutralisation of the compound of formula (M) followed by chlorination with phosphorus oxychloride. Suitably R 50 is a substituted amino group, particularly a (1-6C)alkyl amino group (e.g. dimethylamino) a substituted-(1-6C)alkyl (e.g. benzyl) amino group. 3 (dimethylamino)acrolein is especially preferred. 10 A suitable solvent for steps (i) and (ii) of process (g) is an alcohol such as ethanol. A suitable base for step (ii) is any of those mentioned for processes (a) to (c) above, particularly an alkaline metal alkoxide such as sodium ethoxide. Biological Assays 15 The following assays can be used to measure the effects of the compounds of the present invention as HDAC inhibitors, as inhibitors in vitro of recombinant human HDAC1 produced in Hi5 insect cells, and as inducers in vitro & in vivo of Histone H3 acetylation in whole cells and tumours. They also assess the ability of such compounds to inhibit proliferation of human tumour cells. 20 (a) In Vitro Enzyme Assay of recombinant HDAC1 HDAC inhibitors were screened against recombinant human HDAC1 produced in Hi5 insect cells. The enzyme was cloned with a FLAG tag at the C-terminal of the gene and affinity purified using Anti-FLAG M2 agarose from SIGMA (A2220). The deacetylase assays were carried out in a 50 RI reaction. HDAC1 (75 ng of 25 enzyme) diluted in 15pgl of reaction buffer (25 mM TrisHCl (pH 8), 137 mM NaC1, 2.7 mM KC1, 1 mM MgC1 2 ) was mixed with either buffer alone (10 pl) or buffer containing compound (10 pl) for 30 minutes at ambient temperature. The 25 pM acetylated histone H4 peptide (KI 174 Biomol) diluted in 25gl of buffer was then added to the reaction and incubated for one hour at ambient temperature. The reaction was stopped by addition of an equal volume (50 30o pl) Fluor de Lys developer (Biomol) containing Trichostatin A at 2 gM. The reaction was WO 2006/024841 PCT/GB2005/003355 95 allowed to develop for 30 minutes at ambient temperature and then fluorescence measured at an excitation wavelength of 360 nM and an emission wavelength of 465 nM. The IC 50 values for HDAC enzyme inhibitors were determined by performing dose response curves with individual compounds and determining the concentration of inhibitor producing fifty percent 5 decrease in the maximal signal (diluent control). (b) In Vitro Assay of inhibition of proliferation in whole cells Inhibition of proliferation in whole cells was assayed using the Promega cell titer 96 aqueous proliferation assay (Promega #G5421). The HCT1 16 cells were seeded in 96 well plates at lxi03 cells/well, and allowed to adhere overnight. They were treated with inhibitors lo for 72 hours. The 20 pl of the tetrazolium dye MTS was added to each well and the plates were reincubated for 3 hours. Absorbance was then measured on a 96 well plate reader at 490 nM. The IC 50 values for HDAC inhibitors were determined by performing dose response curves with individual compounds and determining the concentration of inhibitor producing fifty percent decrease in maximal signal (diluent control). 15 Although the pharmacological properties of the compounds of the formula (I) vary with structural change as expected, in general activity possessed by compounds of the Formula (I), may be demonstrated at the following concentrations or doses in one or more of the above tests (a)-(b): Test (a):- IC 50 in the range, for example, < 0.060gM; 20 Test (b):- IC 50 in the range, for example, <0.80pM. The following table discloses various biological data for a representative selection of compounds of the present invention. Comparative test data is also provided for N-(2 aminophenyl)-4-pyridin-2-ylbenzamide (Comparator).
WO 2006/024841 PCT/GB2005/003355 96 EXAMPLE Test (a) IC 50 so (RM) Test (b) IC 50 (FtM) (COMPOUND NO.) 1 0.013 0.289 2(10) 0.003 0.211 2 (12) 0.006 0.218 5 (15) 0.012 0.287 Comparator 0.089 2.33 According to a further aspect of the invention there is provided a phannaceutical composition, which comprises a compound of the formula (I), or a pharmaceutically 5 acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier. The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical o10 administration as an ointment or cream or for rectal administration as a suppository. In general the above compositions may be prepared in a conventional manner using conventional excipients. The compound of formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg/m 2 body area of the animal, i.e. approximately 15 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be 20 determined by the practitioner who is treating any particular patient. We have found that the compounds defined in the present invention, or a WO 2006/024841 PCT/GB2005/003355 97 pharmaceutically acceptable salt thereof, are effective cell cycle inhibitors (anti-cell proliferation agents), which property is believed to arise from their HDAC inhibitory properties. We also believe that the compounds of the present invention may be involved in the inhibition of angiogenesis, activation of apoptosis and differentiation. Accordingly the s compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by HDAC enzymes, i.e. the compounds may be used to produce a HDAC inhibitory effect in a warm-blooded animal in need of such treatment. Thus, the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of HDAC enzymes, i.e. the o10 compounds may be used to produce an anti-proliferative effect mediated alone or in part by the inhibition of HDACs. According to one aspect of the present invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy. 15 Thus according to a further aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament. According to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the 20 manufacture of a medicament for use in the production of a HDAC inhibitory effect in a warm-blooded animal such as man. According to a further feature of this aspect of the invention there is provided a method for producing a HDAC inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a 25 compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore. According to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of a cell cycle inhibitory 30 (anti-cell-proliferation) effect in a warm-blooded animal such as man.
WO 2006/024841 PCT/GB2005/003355 98 According to a further feature of this aspect of the invention there is provided a method for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a phannrmaceutically acceptable salt 5 thereof, as defined hereinbefore. According to an additional feature of this aspect of the invention there is provided a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore. 10 According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancer. According to an additional feature of this aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined 15 hereinbefore, for use in the treatment of cancer. According to an additional feature of this aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the manufacture of a medicament for the treatment of cancer. In a further aspect of the present invention there is provided the use of a compound of 20 the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in lung cancer, colorectal cancer, breast cancer, prostate cancer, lymphoma and/or leukaemia. In a further aspect of the present invention there is provided a method of treating lung cancer, colorectal cancer, breast cancer, prostate cancer, lymphoma or leukaemia, in a 25 warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore. Cancers that are amenable to treatment with the present invention include oesophageal cancer, myeloma, hepatocellular, pancreatic and cervical cancer, Ewings tumour, 30 neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate WO 2006/024841 PCT/GB2005/003355 99 cancer, bladder cancer, melanoma, lung cancer [including non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)], gastric cancer, head and neck cancer, brain cancer, renal cancer, lymphoma and leukaemia. There is further provided is a compound of the formula (I), or a pharmaceutically 5 acceptable salt thereof, as defined hereinbefore, for use in a method of treating inflammatory diseases, autoimmune diseases and allergic/atopic diseases. In particular a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, is provided for use in a method of treating inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro o10 intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis), multiple sclerosis, atherosclerosis, spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis, arthritis connected to ulcerative colitis), AIDS-related neuropathies, systemic lupus erythematosus, astluna, chronic obstructive lung diseases, bronchitis, pleuritis, adult respiratory distress 15 syndrome, sepsis, and acute and chronic hepatitis (either viral, bacterial or toxic). Further provided is a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use as a medicament in the treatment of inflammatory diseases, autoimmune diseases and allergic/atopic diseases in a warm-blooded animal such as man. 20 In particular a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, is provided for use as a medicament in the treatment of inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis), 25 multiple sclerosis, atherosclerosis, spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis, arthritis connected to ulcerative colitis), AIDS-related neuropathies, systemic lupus erythematosus, asthma, chronic obstructive lung diseases, bronchitis, pleuritis, adult respiratory distress syndrome, sepsis, and acute and chronic hepatitis (either viral, bacterial or toxic).
WO 2006/024841 PCT/GB2005/003355 100 Further provided is the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of inflammatory diseases, autoimmune diseases and allergic/atopic diseases in a warm-blooded animal such as man. 5 As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged. The HDAC inhibitory activity defined hereinbefore may be applied as a sole therapy o10 or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of 15 such conjoint treatment in addition to the cell cycle inhibitory treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, 20 nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca 25 alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example 30 fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and WO 2006/024841 PCT/GB2005/003355 101 buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5c-reductase such as finasteride; (iii) Agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors 5 like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 ar'tibody trastuzumab [Herceptin T M ] and the anti-erbbl antibody cetuximab [C225]), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase o10 inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3 morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7 bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro 4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example 15 inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent 20 Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin cavP3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, 25 W002/04434 and W002/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug 30 therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial WO 2006/024841 PCT/GB2005/003355 102 nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such 5 as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies; (x) Cell cycle inhibitors including for example CDK inhibitiors (eg flavopiridol) and other o10 inhibitors of cell cycle checkpoints (eg checkpoint kinase); inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation (eg mitotic kinesins); and other histone deacetylase inhibitors; and (xi) differentiation agents (for example retinoic acid and vitamin D). According to this aspect of the invention there is provided a pharmaceutical 15is composition comprising a compound of the formula (1) as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer. In addition to their use in therapeutic medicine, the compounds of formula (1) and their pharmaceutically acceptable salts thereof, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the 20 effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. The invention will now be illustrated in the following Examples in which, generally: (i) operations were carried out at ambient temperature, i.e. in the range 17 to 25oC and under an atmosphere of an inert gas such as argon unless otherwise stated; 25 (ii) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, WO 2006/024841 PCT/GB2005/003355 103 Germany or using proprietory pre-packed normal phase silica catridges, for example Redisep(TM) disposable chromatography cartridges obtained from Presearch Ltd., Hitchin, UK, or high pressure liquid chromatography (HPLC) was performed on C18 reverse phase silica, for example on a Dynamax C-18 60A preparative reversed-phase column; 5 (iv) yields, where present, are not necessarily the maximum attainable; (v) in general, the structures of the end-products of the Formula (I) were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical io shift values were measured on the delta scale [roton magnetic resonance spectra were determined using a Jeol JNM EX 400 spectrometer operating at a field strength of 400 MHz, Varian Gemini 2000 spectrometer operating at a field strength of 300MHz or a Bruker AM300 spectrometer operating at a field strength of 300MHz - measurements were taken at ambient temperature unless otherwise specified; 15 (vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis; (vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula (I) were determined after crystallisation from a conventional 20 organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; (viii) the following abbreviations have been used: DMF N,N-dimethylformamide DMSOdimethylsulphoxide THF tetrahydrofuran WO 2006/024841 PCT/GB2005/003355 104 (ix) the abbreviation sm is used to refer to the starting material; all starting materials were commercially available unless otherwise stated (by reference to a preparative method described herein or by reference to a published reference). 5 EXAMPLE 1 N-(2-aminophenyl)-4-(3-cyanopyridin-2-yl)benzamide /N N NH2 H2 N 10 N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyanopyridin-2-yl)benzamide (210 mg; prepared as described in Method 1 below), 1,4-dioxane (6.8 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (6.8 ml) were stirred at ambient temperature for 20 hours. The resultant precipitate was collected by filtration and washed with diethyl ether (3 x), suspended in water, basified with a 2M aqueous solution of sodium hydroxide and extracted 15 with dichloromethane. The organic extract was dried over sodium sulfate to afford the title compound as a cream solid (130 mg, 82 %); NMR Spectrum: (DMSO-d 6 ) 4.94 (br s, 2H), 6.60 (min, 1H), 6.78 (min, 1H), 6.98 (min, 1H), 7.19 (d, 1H), 7.65 (min, 1H), 7.98 (d, 2H), 8.14 (d, 2H), 8.46 (min, 1H), 8.98 (min, 1H), 9.77 (s, 1H); Mass Spectrum: M+H 315. 20 WO 2006/024841 PCT/GB2005/003355 105 EXAMPLE 2 Using an analogous procedure to that described in Example 1, the appropriate N-(2-t butoxycarbonylaminophenyl)-4-(3-cyanopyridin-2-yl)benzamide starting material was reacted to give the compounds shown in Table 1. 5 Table 1 0 X N H
H
2 N Compound X Analytical Data SM 1 -N NMR Spectrum: (DMSO-d 6 ) Method 2.41 (s, 3H), 4.94 (br s, 2H), 2 6.60 (m, 1H), 6.78 (d, 1H), N 6.98 (m, 1H), 7.19 (d, 1H), 7.95 (d, 2H), 8.14 (d, 2H) 8.30 (d, 1H), 8.82 (d, 1H), 9.77 (s, 1H); Mass Spectrum:
M+H
+ 329. 2 N NMR Spectrum: (DMSO-d 6 ) Method N 3.23 (s, 6H), 4.92 (br s, 2H), 3 6.60 (m, 1H), 6.78 (m, 1H), 6.89 (d, 1H), 6.97 (m, 1H), N 7.19 (m, 1H), 7.86 (d, 2H), 8.06 (d, 2H), 8.33 (d, 1H), 9.75 (s, 1H); Mass Spectrum:
M+H
+
358.
WO 2006/024841 PCT/GB2005/003355 106 Compound X Analytical Data SM 3 NMR Spectrum: (DMSO-d 6 ) Method 1.15 (t, 3H), 2.35 (s, 3H), 4 3.35 (m, 2H), 4.92 (br s, 2H), N N 6.45 (s, 1H), 6.60 (m, 1H), H 6.78 (m, 1H), 6.97 (m, 1H), 7.19 (m, 1H), 7.56 (m, 1H), 7.86 (d, 2H), 8.06 (d, 2H), 9.70 (s, 1H); Mass Spectrum:
M+H
+ 372. 4 NMR Spectrum: (DMSO-d 6 ) Method /-N 2.35 (s, 3H), 3.30-3.60 (m, 5 4H), 6.51 (s, 1H), 6.63 (m, H N N 1H), 6.79 (d, 1H), 6.97 (m, H 1H), 7.19 (d, 1H), 7.57 (m, 1H), 7.86 (d, 2H), 8.06 (d, 2H), 9.73 (s, 1H); Mass Spectrum: M+H + 388. 5 NMR Spectrum: (DMSO-d 6 ) Method 2.54 (s, 3H), 2.59 (s, 3H), 6 4.94 (br s, 2H), 6.60 (m, 1H), N 6.78 (d, 1H), 6.97 (m, 1H), 7.19 (d, 1H), 7.45 (s, 1H), 7.91 (d, 2H), 8.12 (d, 2H), 9.77 (s, 1H); Mass Spectrum: M+H 343.
WO 2006/024841 PCT/GB2005/003355 107 Compound X Analytical Data SM 6 NMR Spectrum: (DMSO-d 6 ) Method kN 1.39 (m, 2H), 1.51 (m, 4H), 8 N 2.40 (m, 4H), 3.58 (s, 2H), 4.94 (br s, 2H), 6.60 (m, 1H), 6.78 (m, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.98 (d, 2H), 8.14 (d, 2H), 8.30 (d, 1H), 8.86 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H 412. 7 NMR Spectrum: (DMSO-d 6 ) Method S 2.21 (s, 3H), 2.40 (m, 4H), 7 2.44 (s, 3H), 3.70 (m, 4H), N N 4.92 (br s, 2H), 6.60 (m, 1H), N 6.78 (d, 1H), 6.93 (s, IH), 6.97 (m, 1H), 7.19 (d, 1H), 7.88 (d, 2H), 8.07 (d, 2H), 9.70 (s, 1H); Mass Spectrum:
M+H
+ 427. 8 _>N NMR Spectrum: (DMSO-d 6 Method 343K) 1.74 (m, 4H), 2.53 (m, 9 N 4H), 3.76 (s, 2H), 4.80 (br s, 2H), 6.62 (m, 1H), 6.81 (in, 1H), 6.98 (m, 1H), 7.25 (m, 1H), 7.99 (d, 2H), 8.14 (d, 2H), 8.28 (d, 1H), 8.88 (d, 1H), 9.63 (s, 1H); Mass Spectnm: M+H 398.
WO 2006/024841 PCT/GB2005/003355 108 Compound X Analytical Data SM 9 N NMR Spectrum: (DMSO-d 6 ) Method 1.80 (m, 1H), 2.27 (m, 1H), 10 N 2.51 (m, 1H), 2.76 (m, 2H), 2.99 (t, 1H), 3.34 (m, 1H), 3.80 (s, 2H), 4.93 (br s, 2H), 6.60 (m, 1H), 6.79 (d, 1H), 6.98 (m, 1H), 7.18 (m, 2H), 7.29 (m, 4H), 7.98 (d, 2H), 8.14 (d, 2H), 8.37 (d, 1H), 8.92 (d, 1H), 9.77 (s, 1H); Mass Spectrum: M+H + 474. 10 N ,N NMR Spectrum: (DMSO-d 6 ) Method 2.05 (min, 1H), 2.24 (m, 1H), 11 NI 2.68 (m, 2H), 2.84 (m, 1H), 3.04 (t, 1H), 3.52 (m, 1H), 3.80 (s, 2H), 4.93 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.98 (m, 1H), 7.19 (m, 2H), 7.31 (d, 1H), 7.69 (m, 1H), 7.98 (d, 2H), 8.14 (d, 2H), 8.37 (d, 1H), 8.48 (m, 1H), 8.91 (d, 1H), 9.77 (s, 1H); Mass Spectrum: M+H
+
475.
WO 2006/024841 PCT/GB2005/003355 109 Compound X Analytical Data SM 11 H < N NMR Spectrum: (DMSO-d 6 ) Method ' 11.27 (s, 2H), 1.34 (m, 1H), 12 HOH N2.38 (d, 2H), 2.91 (d, 2H), 3.24 (m, 2H), 3.71 (s, 2H), 4.37 (t, 1H), 4.93 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.98 (d, 2H), 8.14 (d, 2H), 8.27 (d, 1H), 8.84 (d, 1H), 9.77 (s, 1H); Mass Spectrum: M+H 440. 12 N MR Spectrum: (DMSO-d 6 ) Method 0.97 (d, 6H), 1.8 (m, 2H), 13 1.98 (m, 2H), 3.00 (m, 2H), '"N -3.80 (dd, 2H), 4.92 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.31 (d, 1H), 8.90 (d, 1H), 9.77 (s, 1H); Mass Spectrum:
M+H
+
426.
WO 2006/024841 PCT/GB2005/003355 110 Compound X Analytical Data SM 13 /N NMR Spectrum: (DMSO-d 6 ) Method N 1.63 (m, 1H), 1.87 (m, 1H), 14 N 2.08 (s, 6H), 2.13 (d, 1H), -N 2.33 (m, 1H), 2.61 (m, 1H), 2.66-2.76 (m, 2H), 3.70 (dd, 2H), 4.94 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.31 (d, 1H), 8.87 (d, 1H), 9.77 (s, 1H); Mass Spectrum: M+H 441.
WO 2006/024841 PCT/GB2005/003355 111 EXAMPLE 3 Using an analogous procedure to that described in example 1, the appropriate n-(2-t butoxycarbonylaminophenyl)-4-(3-cyanopyridin-2-yl)benzamide starting material was reacted to give the compounds shown in table 2 below. 5 Table 2 X0 x N H
H
2 N Compound X Analytical Data SM 1 sN NMR Spectrum: (DMSO-d 6 ) 4.95 Method (br s, 2H), 6.60 (m, 1H), 6.80 (d, 16 O .l 1H), 6.98 (m, 1H), 7.20 (d, 1H), N N 8.02 (d, 2H), 8.20 (d, 2H), 9.36 0 (d, 1H), 9.69 (d, 1H), 9.80 (s, 1H); Mass Spectrum: M-H- 358. 2 N NMR Spectrum: (DMSO-d 6 ) 4.93 Method (br s, 2H), 6.60 (m, 1H), 6.80 (d, 17 1H), 6.99 (m, 1H), 7.2 (d, 1H), 7.40 (m, 2H), 8.08 (d, 2H), 8.17 (d, 2H), 8.22 (d, 1H), 8.32 (m, 2H), 8.52 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H
+
409.
WO 2006/024841 PCT/GB2005/003355 112 Compound X Analytical Data SM 3 N <N NMR Spectrum: (DMSO-d 6 ) 4.92 Method (br s, 2H), 6.60 (m, 1H), 6.79 (d, 18 1H), 6.98 (m, 1H), 7.19 (d, 1H), H2, H 2 N N 7.90 (d, 2H), 8.05 (br s, 2H), 8.11 (d, 2H), 8.60 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H 355. EXAMPLE 4 N-(2-aminophenyl)-4-(3-cyano-5- {[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1 yl]methyl}pyridin-2-yl)benzamide 0rN N N N
NH
2 /N 5 N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.3 g, prepared as described in Method 15 below) and 1-(pyrrolidinocarbonylmethyl)piperazine (0.14 g) were dissolved in dichloromethane (10 ml). Sodium triacetoxyborohydride (0.15 g) was added, and the mixture stirred for 3 hours before being washed with water (10 ml). The lo organic residues were separated and purified using flash column chromatography eluting with ethyl acetate, followed by (6-8%) MeOH in dichloromethane to give t-butyl (2-{[4-(3-cyano 5- { [4-(2-oxo-2-pyrrolidin- 1 -ylethyl)piperazin- 1 -yl]methyl}pyridin-2 yl)benzoyl]amino}phenyl)carbamate (300 mg) as a pale yellow oil. The oil was dissolved in methanol (10 ml), and a 4M solution of hydrogen chloride in 1,4-dioxan (10 ml) added and 15 the solution stirred at ambient temperature for 2 hours. The solvent was evaporated, methanol (5 ml) added and the resulting solution absorbed onto an SCX-2 column, which was then washed with methanol (2 column volumes) and the product eluted with a 2M solution of ammonia in methanol (2 column volumes). The ammonia/methanol was evaporated to give a foam. This was treated with diethyl ether (20 ml), stirred and filtered to give the product as a WO 2006/024841 PCT/GB2005/003355 113' white solid (195 mg, 57%); NMR Spectrum: (DMSO-d 6 373K) 1.82 (m, 4H), 2.50 (m, 8H), 3.11 (s, 2H), 3.40 (m, 4H), 3.66 (s, 2H), 4.74 (br s, 2H), 6.64 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.24 (d, 1H), 8.87 (d, 1H), 9.49 (br s, 1H); Mass Spectrum: M+H 524. 5 EXAMPLE 5 Using an analogous procedure to that described in Example 4, the appropriate amine starting material was reacted with N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5 formnylpyridin-2-yl)benzamide to give the compounds shown in Table 3 below. Table 3 0 X NP H 10
H
2 Compound X Analytical Data SM 1 NMR Spectrum: (DMSO-d 6 373K) N CN 1.09 (t, 6H), 2.64 (q, 4H), 3.79 (s, 2H), 4.77 (br s, 2H), 6.64 (mn, 1H), N 6.82 (m, 1H), 6.98 (m, 1H), 7.28 (m, 1H), 7.99 (d, 2H), 8.14 (d, 2H), 8.27 (s, 1H), 8.90 (s, 1H), 9.49 (br s, 1H); Mass Spectrum: M+H 400. 2 NMR Spectrum: (DMSO-d 6 373K) NCN 2.43 (m, 4H), 2.80 (m, 4H), 3.66 (s, HN / 2H), 4.73 (br s, 2H), 6.66 (m, 1H), N 6.84 (m, 1H), 7.01 (mn, 1H), 7.30 (m, 1H), 8.02 (d, 2H), 8.16 (d, 2H), 8.27 (d, 1H), 8.88 (d, 1H), 9.49 (br s, 1H); Mass Spectrum: M+H
+
413.
WO 2006/024841 PCT/GB2005/003355 114 Compound X Analytical Data SM 3 NMR Spectrum: (DMSO-d6 373K) N /CN 0.99 (d, 6H), 2.50 (m, 8H), 2.67(m, N 1H), 3.66 (s, 2H), 4.72 (br s, 2H), 6.64 (m, 1H), 6.82 (m, 1H11), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.24 (d, 1H), 8.87 (d, 1H), 9.49 (br s, 1H); Mass Spectrum: M+Hi 455. 4 NMR Spectrum: (DMSO-d 6 373K) N CN 2.22 (s, 3H), 2.50 (mn, 8H11), 3.66 (s, IN2H), 4.72 (br s, 2H), 6.64 (m, 1H), N 6.82 (mn, 1H), 6.98 (m, 1H), 7.28 (inm, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.23 (d, 1H), 8.87 (d, IH), 9.49 (br s, 1H); Mass Spectrum: M+H + 427. 5 NMR Spectrum: (DMSO-d 6 373K) r N "NCN 2.50 (m, 10H), 3.55 (t, 2H), 3.68 (s, N N 2H), 3.98 (br s, 1H), 4.72 (br s, 2H), N 6.64 (m, 1H), 6.82 (m, 1H11), 6.98 (m, HO 1H), 7.28 (m, 1H), 7.99 (d, 2H), 8.14 (d, 2H), 8.24 (d, 1H), 8.87 (d, 1H), 9.49 (br s, 1H); Mass Spectrum: M+H 457.
WO 2006/024841 PCT/GB2005/003355 115 Compound X Analytical Data SM 6 NMR Spectrum: (DMSO-d 6 373K) N CN 0.99 (t, 3H), 2.41 (q, 2H), 2.50 (m, N /8H), 3.68 (s, 2H), 4.72 (br s, 2H), N 6.65 (m, 1H), 6.84 (m, 1H), 7.01 (m, 1H), 7.29 (m, 1H), 8.02 (d, 2H), 8.15 (d, 2H), 8.25 (d, 1H), 8.89 (d, 1H), 9.51 (br s, 1H); Mass Spectrum:
M+H
+ 441. 7 NMR Spectrum: (DMSO-d 6 373K) N ON 1.99 (s, 3H), 2.50 (m, 4H), 3.49 (m, O N 4H), 3.70 (s, 2H11), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.28 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.28 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum:
M+H
+ 455. 8 NMR Spectrum: (DMSO-d 6 373K) N CN 2.55 (s, 3H), 2.99 (m, 2H), 3.31 (s, 3H), 3.67 (t, 2H), 4.10 (s, 2H), 6.64 N (m, 1H), 6.83 (m, 1H), 6.99 (m, 1H), O 7.28 (m, 1H), 8.02 (d, 2H), 8.16 (d, 2H), 8.48 (d, 1H), 9.00 (d, 1H), 9.53 (br s, 1H); Mass Spectrum: M+H + 416.
WO 2006/024841 PCT/GB2005/003355 116 Compound X Analytical Data SM 9 NMR Spectrum: (DMSO-d 6 ) 2.12 N- CN (m, 2H), 3.45 (m, 4H), 3.92 (s, 2H), 4.92 (br s, 2H), 6.62 (m, 1H), 6.80 N (m, 1H), 7.00 (m, 1H), 7.20 (m, 1H), 7.99 (d, 2H), 8.18 (d, 2H), 8.39 (s, 1H), 8.92 (s, 1H), 9.81 (br s, 1H); Mass Spectrum: M+H + 384. 10 NMR Spectrum: (DMSO-d 6 ) 1.20 (m, 6H), 3.10 (m, 101H), 4.16 (br s, CN 1H), 5.12 (br s, 1H), 6.62 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.22 (m, N 1H), 8.02 (d, 2H), 8.18 (d, 2H), 8.62 O (m, 1H), 9.08 (m, 1H), 9.88 (br s, 1H); Mass Spectrum: M+H + 444. 11 NMR Spectrum: (DMSO-d 6 373K) NCN 1.08 (t, 3H), 2.67 (m, 4H), 3.57 (t, 2H), 3.83 (s, 2H), 4.12 (br s, 1H), N 4.72 (br s, 2H), 6.64 (m, 1H), 6.82 OH (m, 1H), 6.98 (m, 1H), 7.28 (m, IH), 8.00 (d, 2H), 8.13 (d, 2H), 8.31 (d, 1H), 8.90 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 416. 12 HN CN NMR Spectrum: (DMSO-d 6 373K) 2.80 (t, 2H), 3.29 (s, 3H), 3.48 (t, N 2H), 3.93 (s, 2H), 4.70 (br s, 2H), /O 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.31 (d, IH), 8.90 (d, 1H), 9.49 (br s, 1H); Mass Spectrum:
M+H
+
402.
WO 2006/024841 PCT/GB2005/003355 117 Compound X Analytical Data SM 13 NMR Spectrum: (DMSO-d6 373K) NCN 1.09 (t, 3H11), 2.28 (s, 3H), 2.55(m, 2H), 3.72 (s, 2H), 4.72 (br s, 2H), N 6.64 (m, 1H), 6.82 (mn, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.27 (s, 1H), 8.89 (s, 1H), 9.49 (br s, 1H); Mass Spectrum: M+H 386. 14 NMR Spectrum: (DMSO-d6 373K) OCN 1.08 (t, 3H), 2.67(q, 2H), 2.73 (t, 2H), 3.26 (s, 3H), 3.51 (t, 2H), 3.82 N (s, 2H), 4.78 (br s, 2H), 6.63 (m, O 1H), 6.84 (m, 1H), 6.99 (m, 1H), 7.30 (m, 1H), 8.02 (d, 2H), 8.18 (d, 2H), 8.29 (d, 1H), 8.90(d, 1H), 9.54 (br s, 1H); Mass Spectrum: M+H + 430. 15 NMR Spectrum: (DMSO-d6 373K) 1.09 (d, 6H11), 2.21 (s, 3H), 2.92 (m, N CN 1H), 3.72 (s, 2H), 4.77 (br s, 2H), 6.68 (m, 1H), 6.86 (m, 1H), 7.00(m, N 1H), 7.30 (m, 1H), 8.01 (d, 2H), 8.18 (d, 2H), 8.28 (s, 1H), 8.89 (s, 1H), 9.54 (br s, 1H); Mass Spectrum: M+H 400.
WO 2006/024841 PCT/GB2005/003355 118 Compound X Analytical Data SM 16 NMR Spectrum: (DMSO-d6 373K) N CN 0.92 (t, 3H), 1.52 (m, 2H), 2.26 (s, I 3H), 2.44 (t, 2H), 3.68 (s, 2H), 4.73 N (br s, 2H), 6.64 (m, 1H), 6.82 (m, 1H), 6.99(m, 1H), 7.28 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.23 (d, 1H), 8.88 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 400. 17 NMR Spectrum: (DMSO-d, 373K) -N
C
N 2.66 (m, 4H), 3.72 (m, 4H), 3.74 (s, NN N.NN 2H), 4.72 (br s, 2H), 6.63 (m, 1H), CN O""'N 6.82 (mn, 111), 6.88 (mn, 111), 6.98 (in, 1H), 7.27 (m, 1H), 7.97 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.30 (d, 1H), 8.38 (m, 1H), 8.90 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 515.
WO 2006/024841 PCT/GB2005/003355 119 EXAMPLE 6 Using an analogous procedure to that described in Example 4, the appropriate amine starting material was reacted with N-(2-t-butoxycarbonylaminophenyl)-4-( 3 -cyano-5 5 formylpyridin-2-yl)benzamide to give the compounds shown in Table 4 below. Table 4 CN ONO - 0 Rib
H
2 N 10 COMPOUND RB ANALYTICAL DATA SM 1 NMR SPECTRUM: (DMSO-D6) 0.89 (D, 3H), 1.15 (M, 2H), 1.32 (M, 1H), ,- N 1.58 (D, 2H), 2.00 (T, 2H), 2.79 (D, 2H), 3.59 (S, 2H), 4.94 (BR S, 2H),
H
3 C 6.60 (M, 1H), 6.78 (D, 1H), 6.98 (M, 1H), 7.19 (D, 1H), 7.98 (D, 2H), 8.14 (D, 2H), 8.30 (S, 1H), 8.86 (S, 1H), 9.77 (BR S, 1H); MASS SPECTRUM: M+H 426.
WO 2006/024841 PCT/GB2005/003355 120 2 NMR SPECTRUM: (DMSO-D6 373K) 1.74 (M, 2H), 1.91 (M, 2H), N 2.37 (M, 2H), 2.56 (M, 2H), 3.64 (S, 2H), 4.70 (M, 1H), 4.93 (BR S, 2H), F 6.61 (M, 1H), 6.78 (M, 1H), 6.98 (M, 1H), 7.19 (D, 1H), 7.99 (D, 2H), 8.14 (D, 2H), 8.33 (D, 1H), 8.90 (S, 1H), 9.81 (BR S, 1H); MASS SPECTRUM:
M+H
+ 430. 3 NMR SPECTRUM: (DMSO-D6) 1.42 (M, 2H), 1.73 (M, 2H), 2.15 (M, 2H), N 2.71 (M, 2H), 3.49 (M, 1H), 3.62 (S, 2H), 4.55 (D, 1H), 4.95 (BR S, 2H), HO 6.61 (M, 1H), 6.80 (D, 1H), 7.00 (M, 1H), 7.21 (D, 1H), 8.00 (D, 2H), 8.15 (D, 2H), 8.32 (S, 1H), 8.88 (S, 1H), 9.78 (BR S, 1H); MASS SPECTRUM:
M+H
+ 428. 4 NMR SPECTRUM: (DMSO-D6) 1.18 (M, 2H), 1.36 (M, 1H), 1.65 (D. 2H), N 2.02 (M, 2H), 2.85 (D, 2H), 3.27 (M, HO 2H), 3.62 (S, 2H), 4.40 (M, 1H), 4.95 (BR S, 2H), 6.62 (M, 1H), 6.80 (D, 1H), 7.00 (M, 1H), 7.21 (D, 1H), 8.00 (D, 2H), 8.15 (D, 2H); 8.32 (S, 1H), 8.88 (S, 1H), 9.79 (BR S, 1H); MASS SPECTRUM: M+H
+
442.
WO 2006/024841 PCT/GB2005/003355 121 5 NMR SPECTRUM: (DMSO-D6) 1.52 N (M, 2H), 1.81 (D, 2H), 2.09 (T, 2H), F 2.31 (M, 1H), 2.94 (D, 2H), 3.67 (S, F F 2H), 4.95 (BR S, 2H), 6.62 (M, 1H), 6.80 (M, 1H), 6.99 (M, 1H), 7.21 (D, 1H), 8.00 (D, 2H), 8.15 (D, 2H), 8.36 (D, 1H), 8.90 (D, 1H), 9.79 (D, 1H); MASS SPECTRUM: M+H + 480. 6 NMR SPECTRUM: (DMSO-D6) 0.94 (S, 6H), 1.22 (M, 2H), 1.57 (M, 2H), N 2.08 (M, 2H), 2.37 (M, 2H), 3.56 (S, 2H), 4.95 (BR S, 2H), 6.62 (M, 1H), 6.80 (D, 1H), 6.99 (M, 1H), 7.21 (D, 1H), 8.01 (D, 2H), 8.16 (D, 2H), 8.31 (S, 1H), 8.89 (S, 1H), 9.79 (BR S, 1H); MASS SPECTRUM: M+H 440. 7 NMR SPECTRUM: (DMSO-D6) 1.38-1.48 (M, 2H), 1.76 (D, 2H), 2.02 (T, 2H), 2.12 (M, 1H), 2.46 (M, 4H), N 2.87 (D, 2H), 3.56 (M, 4H), 3.62 (S, o 2H), 4.95 (BR S, 2H), 6.62 (M, 1H), 6.80 (M, 1H), 6.99 (M, 1H), 7.21 (D, 1H), 8.00 (D, 2H), 8.15 (D, 2H), 8.32 (D, 1H), 8.88 (D, 1H), 9.79 (BR S, 1H); MASS SPECTRUM: M+H
+
497.
WO 2006/024841 PCT/GB2005/003355 122 8 NMR SPECTRUM: (DMSO-D6, 373K) 1.61 (M, 2H), 1.80 (M, 2H), N 1.93 (M, 2H), 2.21 (T, 2H), 2.30 (M, N 2H), 3.00 (M, 4H), 3.33 (T, 2H), 3.78 (M, 3H), 6.64 (M, 1H), 6.83 (M, 1H), 0 6.98 (M, 1H), 7.28 (D, 1H), 8.00 (D, 2H), 8.15 (D, 2H), 8.30 (D, 1i), 8.89 (D, 1H), 9.51 (BR S, 1H); MASS SPECTRUM: M+H + 495. 9 NMR SPECTRUM: (DMSO-D6, 373K) 1.60 (M, 2H), 1.75 (M, 4H), N 1.86 (M, 2H), 2.15 (DDD, 2H), 2.40 (M, 1H), 2.73 (M, 4H), 2.87 (M, 2H), N 3.64 (S, 2H), 4.70 (BR S, 2H), 6.63 (M, 1H), 6.82 (M, 1H), 6.97 (M, 1H), 7.28 (D, 1H), 8.00 (M, 2H), 8.14 (D, 2H), 8.26 (D, 1H), 8.85 (D, 1H), 9.48 (BR S, 1H); MASS SPECTRUM:
M+H
+ 481. 10 NMR SPECTRUM: (DMSO-D6, HO ,373K) 1.23 (M, 1H), 1.40 (M, 1H), 1.77 (M, 2H), 2.07 (M, 1H), 2.18 (M, 1H), 2.68 (M, 1H), 2.83 (M, 1H), 2.89 (M, 2H), 3.59 (M, 1H), 3.72 (BR S, 2H), 6.64 (M, 1H), 6.82 (M, 1H), 6.99 (M, 1H), 7.28 (D, 1H), 8.00 (D, 2H), 8.14 (D, 2H), 8.28 (D, 1H), 8.87 (D, 1H), 9.51 (BR S, 1H); MASS SPECTRUM: M+H 428.
WO 2006/024841 PCT/GB2005/003355 123 11 NMR SPECTRUM: (DMSO-D6, 373K) 1.68 (M, 2H), 1.85 (M, 2H), N 2.06 (M, 2H), 2.21 (S, 3H), 2.56 (M, 3H), 3.63 (S, 2H), 4.70 (BR S, 2H), 6.63 (M, 1H), 6.82 (M, 1H), 6.98 (M, 1H), 7.28 (M, 1H), 8.00 (M, 2H), 8.14 (D, 2H), 8.22 (D, 1H), 8.85 (D, 1H), 9.49 (BR S, 1H); MASS SPECTRUM:
M+H
+ 426. 12 NMR SPECTRUM: (DMSO-D6, 373K) 1.53 (M, 1H), 1.77 (M, 2H), N 1.91 (M, 1H), 2.34 (M, 1H), 2.95 (M, 4H), 3.81 (BR S, 2H), 6.63 (M, 1H), 6.82 (M, 1H), 6.98 (M, 1H), 7.19 (M, 1H), 7.28 (M, 5H), 8.00 (D, 2H), 8.14 (D, 2H), 8.33 (S, 1H), 8.92 (S, 1H), 9.51 (BR S, 1H); MASS SPECTRUM:
M+H
+ 488. 13 NMR SPECTRUM: (DMSO-D6, N 373K) 1.82 (M, 4H), 2.36 (M, 1H), 2.60 (M, 1H), 2.90 (M, 3H), 3.71 (S, 2H), 6.63 (M, 1H), 6.82 (M, 1H), 6.99 (M, 1H), 7.19 (M, 1H), 7.28 (M, 5H), 8.00 (D, 2H), 8.14 (D, 2H), 8.33 (S, 1H), 8.93 (S, 1H), 9.51 (BR S, 1H); MASS SPECTRUM: M+H 488.
WO 2006/024841 PCT/GB2005/003355 124 14 NMR SPECTRUM: (DMSO-D6, 373K) 1.78 (M, 4H), 2.26 (DDD, 2H), 2.59 (M, 1H), 2.96 (M, 2H), 3.72 (S, 2H), 6.64 (M, 1H), 6.82 (M, 1H), 6.99 N...(M, 1H), 7.27 (M, 3H), 8.00 (D, 2H), 8.14 (D, 2H), 8.28 (D, 1H), 8.47 (M, 2H), 8.91 (S, 1H), 9.50 (BR S, 1H); MASS SPECTRUM: M+H + 489. 15 NMR SPECTRUM: (DMSO-D6, N 373K) 1.47 (M, 1H), 1.73 (M, 2H), 1.88 (M, 1H), 2.25 (M, 2H), 2.89 (M, 3H), 3.75 (S, 2H), 6.63 (M, 1H), 6.82 (M, 1H), 6.99 (M, 1H), 7.07 (M, 2H), 7.29 (M, 3H), 8.00 (D, 2H), 8.14 (D, 2H), 8.30 (D, 1H), 8.90 (D, 1H), 9.51 (BR S, 1H); MASS SPECTRUM: M+H 506. 16 NMR Spectrum: (DMSO-d 6 , 373K) 2.17 (s, 6H), 2.38 (t, 2H), 2.66 (t, 2H), N 3.87 (s, 2H), 4.72 (br s, 2H), 6.63 (m, H 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (d, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.29 (d, 1H), 8.87 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H
+
415.
WO 2006/024841 PCT/GB2005/003355 125 17 NMR Spectrum: (DMSO-d 6 , 373K) -DN 1.68 (m, 4H), 2.48 (mn, 4H), 2.56 (t, N N2H), 2.69 (t, 2H), 3.88 (s, 2H), 4.72 H (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.29 (d, 1H), 8.87 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 441. EXAMPLE 7 N-(2-aminophenyl)-4-(3-cyano-6-methylpyridin-2-yl)benzamnide
NNH
2 N NH2
N
WO 2006/024841 PCT/GB2005/003355 126 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (ii) chloride (32 mg, 0.044 mmol) was added to a mixture of n-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)benzamide (389 mg, 0.887 mmol; prepared as described in international patent publication number wo03/087057, method 13, page 60), 2-chloro-6 5 methyl-3-pyridinecarbonitrile (135 mg, 0.887 mmol) and saturated aqueous sodium hydrogen carbonate solution (2 ml) in 1,2-dimethoxyethane (4 ml). the mixture was heated in a microwave at 100 0 c for 30 minutes. the mixture was allowed to cool, then partitioned between dichloromethane (30 ml) and water (20 ml). the aqueous layer was extracted with further dichloromethane (2 x 30 ml). combined organics were dried over magnesium sulfate then o10 evaporated, the residue was purified by flash chromatography (eluting with 99:1->97:3 dichloromethane:methanol) to afford the title compound as a yellow gum which crystallised on trituration (80 mg, 27%). Nmr spectrum: (cdcl 3 ) 2.72 (s, 3h), 3.88 (br s, 2h), 6.86 (m, 2h), 7.11 (m, lh), 7.28 (d, lh), 7.37 (d, lh), 8.05 (m, 6h); mass spectrum: m+h+ 329. 15 EXAMPLE 8 N-(2-aminophenyl)-4- {3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2-yl}benzamide N / N H NH 2 NN 20 t-Butyl {2-[(4-{3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2 yl}benzoyl)amino]phenyl}carbamate (586 mg, 1.06 mmol; prepared as described in Method 19) was dissolved in ethyl acetate (7 ml) and 3M aqueous hydrochloric acid (7 ml) was added. The resulting suspension was stirred for 6 hours at ambient temperature then 3M aqueous hydrochloric acid (1.75 ml) added. The suspension was stirred for a further 2 hours then 3M WO 2006/024841 PCT/GB2005/003355 127 aqueous hydrochloric acid (3.5 ml) was added and stirred for 30 minutes. The suspension was poured into water (50 ml) and washed with ethyl acetate (3 x 15 ml). The resulting aqueous solution was basified using a 2M aqueous solution of sodium hydroxide. A pale yellow precipitate crashed out which was filtered and washed with water. The pale yellow solid was 5 dried in a vacuum oven at 50 0 C overnight (294 mg, 62 %); NMR Spectrum: (CDC1 3 ) 0.99 (d, 6H), 2.48 (m, 8H), 2.60 (m, 1H11) 3.56 (s, 2H), 3.79 (br s, 2H), 6.80 (m, 2H), 7.03 (m, 1H), 7.32 (d, 1H), 7.81 (br s, 1H), 7.99 (s, 4H), 8.04 (s, 1H), 8.74 (s, 1H); Mass Spectrum: M+H 455. o10 EXAMPLE 9 N-(2-aminophenyl)-4- {3-cyano-5-[(ethylamino)methyl]pyridin-2-yl}benzamide N N H
NH
2 N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.80 g, 1.8 mmol; prepared as described in Method 15 below) and ethylamine (1.4 ml of a 15is 1.0M solution in THF, 1.4 mmol) were dissolved in dichloromethane (15 ml). Titanium (IV) isopropoxide (1.55 g, 1.62 ml, 5.4 mmol) was added and the mixture stirred at ambient temperature for 1 hour. Sodium borohydride (342 mg) and methanol (3 ml) were then added and the mixture stirred for a further 30 minutes. Water (20 ml) then a saturated aqueous sodium bicarbonate solution (30 ml) was added and the product extracted with 20 dichloromethane (3 x 30 ml). The organic residues were concentrated and the residue purified using flash column chromatography eluting with ethyl acetate, followed by 2M
NH
3 /MeOH (3-5%) in ethyl acetate to give t-butyl {2-[(4-{3-cyano-5 [(ethylamino)methyl]pyridin-2-yl}benzoyl)amino]phenyl} carbamate (508 mg) as a white solid. This was dissolved in methanol (4 ml), a 4M solution of hydrogen chloride in 1,4- WO 2006/024841 PCT/GB2005/003355 128 dioxan (10 ml, 40 mmol) was added and the solution then stirred at ambient temperature for 2 hours. The solvent was evaporated, methanol (5 ml) was added and the resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (2 column volumes) and then eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the 5 product as a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title compound as a white solid (359 mg, 53 %); NMR Spectrum: (DMSO-d 6 373K) 1.08 (t, 3H), 2.62 (q, 2H), 3.67 (s, 2H), 4.73 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (mn, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.88 (d, 1H), 9.50 (br s, 1H11); Mass Spectrum:
M+H
+ 372. 10 WO 2006/024841 PCT/GB2005/003355 129 EXAMPLE 10 Using an analogous procedure to that described in example 1, the appropriate n-(2-t butoxycarbonylaminophenyl)-4-(3-cyanopyridin-2-yl)benzamide starting material was reacted to give the compounds shown in table 5 below. 5 TABLE 5 0 X x N H
H
2 N Analytical Data SM Compound X 1 N NMR Spectrum: (DMSO-d 6 ) Method N 1.57 (m, 1H), 2.01 (m, 1H), 23 N 2.38 (m, 1H), 2.44 (m, 1H), HO 2.63 (m, 1H), 2.72 (m, 1H), 3.71 (dd, 2H), 4.20 (m, iH), 4.72 (d, 1H), 4.94 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.34 (d, 1H), 8.88 (d, 1H), 9.78 (s, 1H); Mass Spectrum:
M+H
+
414.
WO 2006/024841 PCT/GB2005/003355 130 . N NMR Spectrum: (DMSO-d 6 ) Method 2 1.90 (m, 1H), 2.16 (m, 1H), 24 N 2.40 (m, 1H), 2.75 (m, 3H), F 3.77 (s, 2H), 4.94 (br s, 2H), 5.21 (m, 1H), 6.60 (m, 1H), 6.78 (d, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.34 (d, 1H), 8.89 (d, 1H), 9.79 (s, 1H); Mass Spectrum: M+H + 416. 3 NMR Spectrum: (DMSO-d 6 ) Method 0.84 (m, 1H), 1.16 (m, 1H), 25 N 1.57 (m, 1H), 2.01 (m, 1H), 2.29 (s, 3H), 2.43 (m, 1H), N-N 2.66 (m, 2H), 3.73 (s, 2H), 4.93 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.34 (d, 1H), 8.88 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H + 427. 4 NMR Spectrum: (DMSO-d 6 ) Method N 2.43 (s, 3H), 4.90 (br s, 2H), 26 ~/N
H
2 N 5.79 (s, 2H), 6.60 (in, 1H), 6.79 (d, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.31 (s, 1H), 7.86 (d, 2H), 8.06 (d, 2H), 9.70 (s, 1H); Mass Spectrum:
M+I
+
344.
WO 2006/024841 PCT/GB2005/003355 131 NMR Spectrum: (DMSO-d 6 ) Method 5 N 4.67 (s, 2H), 4.96 (br s, 2H), 29 HO 5.57 (br s, 1H), 6.61 (m, 1H), N 6.80 (m, 1H), 6.99 (m, 1H), 7.20 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.33 (s, 1H), 8.91 (s, 1H), 9.78 (br s, 1H); Mass Spectrum: M+H 345. 6 NMR Spectrum: (DMSO-d 6 ) Method N 0.92 (t, 6H), 1.63 (m, 1H), 14a N 1.88 (m, 2H), 2.37 (m, 1H), N 2.50 (m, 6H), 2.66 (m, 1H), 3.69 (m, 2H), 4.95 (br s, 2H), 6.60 (m, 1H), 6.78 (m, 1H), 6.98 (m, 1H), 7.19 (m, 1H), 7.98 (d, 2H), 8.14 (d, 2H), 8.31 (d, 1H), 8.87 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H 469. 7 NMR Spectrum: (DMSO-d 6 ) Method N 0.87 (t, 3H), 1.30 (m, 2H), 14b N I l1.46 (m, 2H), 2.16 (s, 3H), N 2.38 (t, 2H), 3.60 (s, 2H), 4.96 (br s, 2H), 6.60 (m, 1H), 6.79 (m, 1H), 6.98 (m, 1H), 7.19 (m, 1H), 7.98 (d, 2H), 8.14 (d, 2H), 8.30 (d, 1H), 8.86 (d, 1H), 9.79 (s, 1H); Mass Spectrum: M+H
+
414.
WO 2006/024841 PCT/GB2005/003355 132 8 NMR Spectrum: (DMSO-d 6 ) Method 2.09 (s, 3H), 2.69 (br s, 1H), 14c 3.56 (s, 2H), 3.63 (s, 3H), N N 3.80 (s, 2H), 4.95 (br s, 2H), -N N5.97 (s, 1H), 6.60 (m, 1H), N-N N 6.80 (d, 1H), 7.00 (m, 1H), 7.20 (d, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.32 (s, 1H), 8.90 (s, 1H), 9.78 (br s, 1i); Mass Spectrum: M+H + 452. 9 NMR Spectrum: (DMSO-d 6 ) Method 2.07 (s, 6H), 2.50 (m, 6H), 14d N__ N , 3.84 (s, 2H), 4.93 (br s, 2H), N6.60 (m, 1H), 6.80 (d, 1H), 7.00 (m, 1H), 7.20 (d, 1H), 7.97 (d, 2H), 8.14 (d, 2H), 8.32 (d, 1H), 8.89 (d, 1H), 9.78 (br s, 1H); Mass Spectrum: M+H 466. 10 NMR Spectrum: (DMSO-d 6 ) Method N N 4.95 (br s, 2H), 6.60 (m, 1H), 8 N 6.80 (d, 1H), 7.00 (m, 1I), 7.20 (d, 1H), 8.04 (d, 2H), 8.18 (d, 2H), 9.12 (d, 1H), 9.40 (d, 1H), 9.80 (br s, 1H); Mass Spectrum: M+H
+
340.
WO 2006/024841 PCT/GB2005/003355 133 EXAMPLE 11 Using an analogous procedure to that described in Example 4, the appropriate amine starting material was reacted with N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5 5 formylpyridin-2-yl)benzamide to give the compounds shown in Table 6 below. Table 6 0 X N H
H
2 N Analytical Data Compound X SM 1 NMR Spectrum: (DMSO-d 6 CN 373K) 1.48 (m, 4H), 1.92 (m, N 4H), 3.49 (br s, 2H), 3.87 (br s, LN. 2H), 4.75 (br s, 2H), 6.66 (m, 1H), 6.84 (m, 1H), 7.01 (m, 1H), 7.30 (m, 1H), 8.02 (d, 2H), 8.17 (d, 2H), 8.43 (br s, IH), 9.01 (s, 1H), 9.53 (br s, 1H); Mass Spectrum: M+H 424.
WO 2006/024841 PCT/GB2005/003355 134 Analytical Data Compound X SM 2 NMR Spectrum: (DMSO-d 6 N C N 373K) 0.38 (m, 2H), 0.60 (m, 2H), 1.11 (m, 1H), 2.86 (d, 2H), N 4.27 (s, 2H), 6.64 (m, 1H), 6.82 (m, 1H), 6.99 (m, 1H), 7.28 (m, 1H), 8.02 (d, 2H), 8.16 (d, 2H), 8.56 (d, 1H), 9.06 (d, 1H), 9.52 (br s, 1H); Mass Spectrum: M+H 398. 3NMR Spectrum: (DMSO-d 6 CN 373K) 1.55 (m, 4H), 1.67 (m, N O N 3H), 1.99 (m, 2H), 2.66 (m, 1H), 2.78 (m, 2H), 3.87 (s, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.13 (d, 2H), 8.28 (s, 1H), 8.91 (s, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H-t 438. 4 NMR Spectrum: (DMSO-d 6 C N 373K) 1.53 (m, 2H), 1.79 (in, NNI N 2H), 2.12 (m, 2H), 2.32 (m, 4H), 2.62 (m, 8H), 2.91 (m, 2H), 3.66 (s, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.24 (d, 1H), 8.87 (d, 1H), 9.51 (br s, 1H); Mass Spectrum: M+H
+
510.
WO 2006/024841 PCT/GB2005/003355 135 Analytical Data Compound X SM 5 NMR Spectrum: (DMSO-d 6 373K) 0.97 (t, 6H), 2.52 (m, 6H), N 2.65 (t, 2H), 3.89 (s, 2H), 4.73 NN CN H (br s, 2H), 6.63 (m, 1H), 6.82 (m, N 1H), 6.98 (m, 1H), 7.27 (mn, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.29 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 443. 6NMR Spectrum: (DMSO-d 6 373K) 1.39 (m, 2H), 1 50 (m, ON N CN 4H), 2.35 (m, 4H), 2.40 (t, 2H), H 2.66 (t, 2H), 3.88 (s, 2H), 4.73 N (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 455. 7 NMR Spectrum: (DMSO-d 6 373K) 2.20 (s, 6H), 2.27 (s, 3H), NCN 2.46 (t, 2H), 2.58 (t, 2H), 3.70 (s, 2H), 4.72 (br s, 2H), 6.63 (m, N 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.28 (m, 1H), 8.00 (d, 2h-1), 8.14 (d, 2H), 8.26 (d, 1H), 8.87 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H
+
429.
WO 2006/024841 PCT/GB2005/003355 136 Analytical Data Compound X SM 8 NMR Spectrum: (DMSO-d 6 HO CN 373K) 2.29 (s, 3H), 2.61 (t, 2H), 3.59 (t, 2H), 3.75 (s, 2H), 4.11 N (br s, 1H), 4.73 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.28 (m, 1H), 8.00 (d, 2H), 8.13 (d, 2H), 8.30 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 402. 9 NMR Spectrum: (DMSO-d 6 N.CN 373K) 1.26 (t, 3H), 2.57 (m, 4H), O M3.06 (q, 2H), 3.26 (m, 4H), 3.74 o (s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 505. 10 NMR Spectrum: (DMSO-d 6 373K) 0.97 (t, 6H), 2.28 (s, 3H), N 2.55 (m, 8H), 3.70 (s, 2H), 4.72 CN (br s, 2H), 6.63 (m, 1H), 6.82 (m, N 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.13 (d, 2H), 8.27 (d, 1H), 8.87 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H
+
457.
WO 2006/024841 PCT/GB2005/003355 137 Analytical Data Compound X SM 11 NMR Spectrum: (DMSO-d 6 373K) 1.03 (d, 3H), 2.11 (m, N N 1H), 2.18 (s, 6H), 2.30 (m, 1H), H 2.76 (1i, 1H), 3.91 (d, 2H), 4.72 N (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.30 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 429. 12 NMR Spectrum: (DMSO-d 6 CN 373K) 2.55 (m, 4H), 2.87 (s, O N- 3H), 3.14 (m 4H), 3.74 (s, 2H), s- N 6.63 (m, 1H), 6.82 (m, 1H), 6.98 0 0 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.87 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 491. 13 NMR Spectrum: (DMSO-d 6 373K) 2.36 (s, 3H), 2.84 (m, / .NN 4H), 3.90 (s, 2H), 4.72 (br s, H 2H), 6.63 (m, 1H), 6.82 (m, 1H), N 6.94 (m, 3H), 7.23 (m, 1H), 7.28 (m, 1H), 7.40 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.23 (d, 1H), 8.85 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H1 501.
WO 2006/024841 PCT/GB2005/003355 138 Analytical Data Compound X SM 14 NMR Spectrum: (DMSO-d 6 N CN 373K) 2.50 (m, 8H), 3.04 (m, N 2H), 3.68 (s, 2H), 4.72 (br s, 2H), 5.20 (m, 2H), 5.83 (mn, 1H), 6.64 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (min, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.24 (d, IH), 8.87 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 453. 15 NMR Spectrum: (DMSO-d 6 CN 373K) 2.50 (m, 10H), 3.26 (s, N .~ OC ,N 3H), 3.47 (t, 2H), 3.66 (s, 2H), 4.72 (br s, 2H), 6.64 (m, IH), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.24 (d, 1H), 8.86 (d, IH), 9.50 (br s, 1H); Mass Spectrum: M+H+ 471. 16 NMR Spectrum: (DMSO-d 6 CN 373K) 2.22 (s, 6H), 2.43 (s, 4H), NNO ^ 2.50 (m, 8H), 3.63 (s, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (min, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.24 (d, 1H), 8.87 (d, 1H), 9.49 (br s, 1H); Mass Spectrum: M+TI+ 484.
WO 2006/024841 PCT/GB2005/003355 139 Analytical Data Compound X SM 17 NMR Spectrum: (DMSO-d 6 CN 373K) 2.58 (m, 4H), 3.56 (m, O ^4H), 3.72 (s, 2H), 4.73 (br s, N 2H), 6.62 (m, 2H), 6.77 (d, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.50 (m, 1H), 5.00 (d, 2H), 8.10 (m, 1H), 8.14 (d, 2H), 8.30 (d, 1H), 8.90 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 490. 18 NMR Spectrum: (DMSO-d 6 N 373K) 2.57 (m, 4H), 3.72 (s, S N 2H), 3.80 (m, 4H), 4.72 (br s, NN 2H), 6.59 (in, 1H), 6.62 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.30 (d, 1H), 8.33 (d, 2H), 8.90 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 491. 19 NMR Spectrum: (DMSO-d 6 CN 373K) 2.61 (im, 4H), 3.63 (m, N 4H), 3.73 (s, 2H), 4.72 (br s, (N N N 2H), 6.64 (m, 1H), 6.82 (m, 1H), N 6.98 (m, 1H), 7.27 (m, 1H), 7.82 (d, 1H), 8.01 (d, 2H), 8.05 (m, 1H), 8.14 (d, 2H), 8.26 (d, 1H), 8.31 (d, 1H), 8.90 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 491.
WO 2006/024841 PCT/GB2005/003355 140 Analytical Data Compound X SM 20 NMR Spectrum: (DMSO-d 6 ON NCN 373K) 2.70 (m, 4H), 3.24 (m, N 4H), 3.75 (s, 2H), 4.72 (br s, N,12H), 6.64 (m, 1H), 6.82 (m, 1H), 6.88 (m, 1H), 7.07 (m, 1H), 7.17 (m, 1H), 7.27 (m, 1H), 7.57 (m, 1H), 7.63 (min, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.31 (d, 1H), 8.91 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 514. 21 NMR Spectrum: (DMSO-d 6 CN 373K) 2.68 (m, 4H), 3.76 (s, N 0 C 2H), 3.82 (m, 4H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.01 (d, 2H), 8.08 (m, 1H), 8.14 (d, 2H), 8.31 (d, 1H), 8.40 (d, 1H), 8.90 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 516. NMR Spectrum: (DMSO-d 6 22 CAS 22 -- CN 373K) 1.70 (m, 4H), 2.27 (m, CAS N 63214 N 2H), 2.44 (m, 1H), 2.63 (m, 1H), 63214 o 3.48 (m, 4H), 3.57 (m, 4H), 3.72 57-3 (br s, 2H), 4.73 (br s, 2H), 6.63 WO20 (m, 1H), 6.82 (m, 1H), 6.98 (m, 04018 1H), 7.27 (m, 1H), 8.00 (d, 2H), 480 8.14 (d, 2H), 8.28 (s, 1H), 8.87 (s, 1H), 9.51 (br s, 1H); Mass Spectrum: M+H
+
525.
WO 2006/024841 PCT/GB2005/003355 141 Analytical Data Compound X SM NMR Spectrum: (DMSO-d 6 23 CN 373K) 0.69 (m, 2H), 0.76 (in, N ^ N 2H), 1.89 (m, 1H), 2.95 (m, 4H), o 3.60 (m, 4H), 3.71 (s, 2H), 4.71 (br s, 2H11), 6.63 (in, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.28 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 481. EXAMPLE 12 Using an analogous procedure to that described in Example 9, the appropriate amine starting material was reacted with N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5 5 formylpyridin-2-yl)benzamide to give the compounds shown in Table 7 below. Table 7 0 H
H
2 10 WO 2006/024841 PCT/GB2005/003355 142 Analytical Data Compound X SM 1 NMR Spectrum: (DMSO-d 6 N CN 373K) 1.07 (d, 6H), 2.06 (br s, H 1H), 2.80 (m, 1H), 3.86 (s, 2H), N 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.29 (d, 1H), 8.88 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 386. 2 N CN NMR Spectrum: (DMSO-d 6 H 373K) 0.92 (d, 6H), 1.73 (m, 1H), 2.17 (br s, 1H), 2.42 (d, 2H), 3.86 (s, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.29 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum:
M+H
+
400.
WO 2006/024841 PCT/GB2005/003355 143 Analytical Data Compound X SM 3 NCN NMR Spectrum: (DMSO-d 6 H 373K) 3.24 (m, 2H), 3.86 (s, N 2H), 4.72 (br s, 2H), 5.08 (m, 1H), 5.21 (m, 1H), 5.90 (m, 1H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.29 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 384. 4 .NMR Spectrum: (DMSO-d 6 NCN 373K) 0.30 (m, 2H), 0.42 (m, H 2H), 2.14 (m, 1H), 3.89 (s, 2H), N 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 384.
WO 2006/024841 PCT/GB2005/003355 144 Analytical Data Compound X SM 5 NMR Spectrum: (DMSO-d 6 N CN 373K) 1.40 (m, 2H), 1.51 (m, H 2H), 1.67 (m, 2H), 1.77 (m, N 2H), 2.14 (br s, 1H), 3.08 (m, 1H), 3.84 (s, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum:
M+H
+ 412. 6 C NMR Spectrum: (DMSO-d 6 N N 373K) 0.88 (t, 3H), 1.04 (d, H 3H), 1.36 (m, 1H), 1.49 (m, 1H), 2.04 (br s, 1H), 2.59 (m, 1H), 3.88 (d, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d. 2H), 8.29 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum:
M+H
+
400.
WO 2006/024841 PCT/GB2005/003355 145 Analytical Data Compound X SM NMR Spectrum: (DMSO-d 6 7 N ~
C
N 373K) 0.88 (t, 3H), 1.04 (d, H H 3H), 1.36 (m, 1H), 1.49 (m, N 1H), 2.04 (br s, 1H), 2.59 (m, 1H), 3.88 (d, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.29 (d, 1H), 8.89 (d, 1H), 9.50 (br s, 1H); Mass Spectrum:
M+H
+ 400. 8 N CN NMR Spectrum: (DMSO-d 6 373K) 2.37 (s, 3H), 3.81 (s, N 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.27 (d, 1H), 8.87 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H + 358. 9 N CN NMR Spectrum: (DMSO-d 6 373K) 0.91 (t, 3H), 1.50 (m, N 2H), 2.57 (t, 2H), 3.87 (s, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.88 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M-H
+
384.
WO 2006/024841 PCT/GB2005/003355 146 Analytical Data Compound X SM 10 Nc N NMR Spectrum: (DMSO-d 6 373K) 0.92 (t, 3H), 1.39 (m, 2H), 1.49 (m, 2H), 2.60 (t, 2H), 3.87 (s, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (m, 2H), 8.13 (m, 2H), 8.28 (d, 1H), 8.88 (d, 1H), 9.50 (br s, 1H); Mass Spectrum:
M+H
+ 400. 11NMR Spectrum: (DMSO-d 6 CN N 373K) 0.91 (t, 3H), 1.08 (d, 3H), 1.37 (m, 1H), 1.52 (m, 1H), 2.62 (m, 1H), 3.89 (m, 2H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.30 (d, 1H), 8.90 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+IH + 400. 12 NMR Spectrum: (DMSO-d 6 CN N 373K) 1.73 (m, 4H), 2.23 (m, 2H), 3.30 (m, 1H), 3.82 (s, 2H), N 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.88 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H
+
398.
WO 2006/024841 PCT/GB2005/003355 147 EXAMPLE 13 Using an analogous procedure to that described in Example 9, the appropriate amine starting material was reacted with N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5-(1-oxo 5 ethyl)-6-methylpyridin-2-yl)benzamide prepared in Method 27 to give the compounds shown in Table 8 below. Table 8 0 X NP
H
2 N Compound X Analytical Data SM SN NMR Spectrum: (DMSO-d 6 1 N 373K) 1.05 (t, 3H), 1.33 (d, 3H), Method CN 2.43 (m, 1H), 2.55 (m, 1H), 2.69 27 (s, 3H), 4.08 (q, 1H), 4.72 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), N 6.98 (m, 1H), 7.28 (m, 1H), 7.98 (d, 2H), 8.12 (d, 2H), 8.30 (s, 1H), 9.48 (br s, 1H); Mass Spectrum: M+H + 400. 2NMR Spectrum: (DMSO-d 6 ~2 373K) 0.86 (mn, 2H), 1.44 (In, Method 10H), 2.45 (m, 1H), 2.73 (s, 3H), 27 N 3.82 (m, 1H), 4.72 (br s, 2H), CN 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.28 (m, 1H), 8.00 (d, , 2H), 8.12 (d, 2H), 8.19 (br s, N 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 440.
WO 2006/024841 PCT/GB2005/003355 148 Compound X Analytical Data SM OH NMR Spectrum: (DMSO-d 6 ) 3 * CN 1.42 (d, 3H), 2.66 (s, 3H), 4.72 Method (br s, 2H), 5.02 (q, 1H), 5.19 (br 27 s, 1H), 6.63 (m, 1H), 6.82 (m, N 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.98 (d, 2H), 8.12 (d, 2H), 8.24 (s, 1H), 9.48 (br s, 1H); Mass Spectrum: M+H 373 * During the isolation of Example 13/2, Example 13/3 was isolated as a by-product. EXAMPLE 14 N-(2-Aminophenyl)-4-(3-cyano-5- { [2-(ethylamino)ethoxy]methyl}pyridin-2-yl)benzamide H N O CN N" N H, H2 NN 5 t-Butyl (2- { [4-(3-cyano-5- {[2-(ethylamino)ethoxy]methyl}pyridin-2 yl)benzoyl]amino}phenyl)carbamate (466 mg, 0.90 mmol, prepared as described in Method 28), 1,4-dioxane (3.4 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (3.4 ml) were stirred at ambient temperature for 4 hours. io The resulting precipitate was collected by filtration, washed with diethyl ether (3 x) and dissolved in methanol. The solution was absorbed onto an SCX-2 column and the column washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes). The ammonia/methanol solution was concentrated under reduced pressure to give the title compound (320 mg, 86 %); NMR 15 Spectrum: (DMSO-d 6 ) 1.02 (t, 3H), 2.56 (m, 4H), 3.51 (m, 2H), 3.76 (s, 2H), 4.44 (m, 1H), 4.95 (br s, 1H), 6.62 (m, 1H), 6.80 (d, 1H), 7.00 (m, 1H), 7.22 (d, 1H), 8.00 (d, 2H), 8.16 (d, 2H), 8.39 (s, 1H), 8.92 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H
+
416.
WO 2006/024841 PCT/GB2005/003355 149 EXAMPLE 15 N-(2-aminophenyl)-4-(3-cyano-5- { [2-(methylamino)ethoxy]methyl}pyridin-2-yl)benzamide H /N O CN N NH, H N 5 t-Butyl (2- {[4-(3-cyano-5- {[2-(methylamino)ethoxy]methyl}pyridin-2 yl)benzoyl]amino}phenyl)carbamate (465 mg, 0.93 mmol, prepared as described in Method 30), 1,4-dioxane (3.5 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (3.5 ml) were stirred at ambient temperature for 4 hours. The resulting precipitate was collected by filtration, washed with diethyl ether (3 x) and io dissolved in methanol. The solution was absorbed onto an SCX-2 column and the column washed with methanol (3 column volumes) and eluted with a 2M solution of ammonia in methanol (3 column volumes). The ammonia/methanol solution was concentrated under reduced pressure and the residue purified by reverse phase HPLC. The product trifluoroacetate was re-dissolved in methanol and absorbed onto an SCX-2 column and the 15 column washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammunonia in methanol (3 column volumes). The ammonia/methanol solution was concentrated under reduced pressure to give the title compound (200 mg, 54 %); NMR Spectrum: (DMSO-d 6 ) 2.24 (s, 3H), 2.51 (min, 2H), 3.55 (min, 2H), 3.69 (s, 2H), 4.47 (m, 1H), 4.95 (br s, 2H), 6.62 (min, 1H), 6.81 (d, 1H), 6.99 (min, 1H), 7.21 (d, 1H), 8.01 (d, 2H), 8.15 (d, 20 2H), 8.40 (s, 1H), 8.91 (s, 1H), 9.79 (s, 1H); Mass Spectrum: M+H
+
402.
WO 2006/024841 PCT/GB2005/003355 150 EXAMPLE 16 N-(2-aminophenyl)-4-(3-cyano-5- { [2-(isopropylamino)ethoxy]methyl}pyridin-2 yl)benzamide H N o CN N NH2
H
2 -yN 5 t-Butyl (2- { [4-(3-cyano-5- { [2-(isopropylamino)ethoxy]methyl}pyridin-2 yl)benzoyl]amino}phenyl)carbamate (170 mg, 0.32 mmol, prepared as described in Method 31), 1,4-dioxane (1.5 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (1.2 ml) were stirred at ambient temperature for 21 hours. o10 The resulting precipitate was collected by filtration, washed with diethyl ether (3 x) and dissolved in methanol. The solution was absorbed onto an SCX-2 column and the column washed with methanol (3 column volumes). The product was eluted with a 2M solution of ammonia in methanol (3 column volumes). The ammonia/methanol solution was concentrated under reduced pressure and the residue purified by reverse phase HPLC. The 15is isolated trifluoroacetate salt of the product was re-dissolved in methanol and absorbed onto an SCX-2 column and the column washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes). The ammonia/methanol solution was concentrated under reduced pressure to give the title compound (83 mg, 61 %); NMR Spectrum: (DMSO-d 6 ) 1.03 (d, 6H), 2.55 (mn, 2H), 2.93 (inm, 20 1H), 3.41 (m, 2H), 3.75 (s, 2H), 4.39 (br s, 1H), 4.95 (br s, 2H), 6.62 (mn, 1H), 6.80 (d, 1H), 6.99 (min, 1H), 7.21 (d, 1H), 8.00 (d, 2H), 8.15 (d, 2H), 8.41 (s, 1H), 8.94 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H 430.
WO 2006/024841 PCT/GB2005/003355 151 EXAMPLE 17 N-(2-aminophenyl)-4-(3-cyano-5- {[(2-methoxy-1-methylethyl)amino]methyl}pyridin-2 yl)benzamide 0/N NZ N NH 2 N 5 N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.20 g, 0.45 mmol; prepared as described in Method 15 below) and 2-amino-1 methoxypropane (56 mg, 0.75 mmol) were dissolved in dichloromethane (5 ml). Titanium (IV) isopropoxide ( 0.27 ml, 0.90 mmol) was added and the mixture stirred at ambient temperature for 2 hours. Sodium borohydride (68 mg) and methanol (0.5 ml) were then added o10 and the mixture stirred for a further 2 hours. The solution was absorbed onto an SCX-2 column and the product eluted with a 2M solution of ammonia in methanol. Concentration of the solvent gave the product as a gum. This was dissolved in dichlorometh.e (5 ml) and trifluoroacetic acid (1 ml) was added and the solution then stirred at ambient temperature for 4 hours. The resulting solution was absorbed onto an SCX-2 column which was washed with 15 methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the product as a gum. This was stirred in diethyl ether to give the title compound as a white solid (66 mg, 57 %). NMR Spectrum: (DMSO-d6) 1.02 (d, 3H), 2.50 (br s, 1H), 2.82 (m, 1H), 3.24 (m, 2H), 3.26 (s, 3H), 3.91 (mn, 2H), 4.95 (br s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H), 8.39 20 (s, 1H), 8.92 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H+ 416.
WO 2006/024841 PCT/GB2005/003355 152 EXAMPLE 18 Using an analogous procedure to that described in Example 17, the appropriate amine starting material was reacted with N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5 fonnrmylpyridin-2-yl)benzamide prepared in Method 15 to give the compounds shown in Table 5 9 below. Table 9 H NH2 H2 N Compound X Analytical Data SM 1 N NMR Spectrum: (DMSO N d 6 ) 1.68 (m, 2H), 2.51 (s, N 1H), 2.57 (t, 2H), 3.23 (s, 3H), 3.40 (t, 2H), 3.84 (s, 2H), 4.95 (br s, 2H), 6.62 (mn, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.15 (d, 2H), 8.37 (s, 1H), 8.91 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H 416.
WO 2006/024841 PCT/GB2005/003355 153 2 / N NMR Spectrum:
(DMSO
N d 6 ); 2.48 (s, 3H), 3.57 (br s, H H 1H), 3.88 (s, 2H), 3.91 (s, Nr N 2H), 4.94 (br s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H), 8.40 (s, 1H), 8.47 (s, 1H), 8.59 (s, 1H), 8.92 (s, 1H), 9.79 (s, 1H); Mass Spectrum:
M+H
+ 450. 3 NMR Spectrum: (DMSO sN d 6 ); 2.85 (br m, 1H), 3.71 NH (s, 2H), 3.79 (s, 3H), 3.88 N -(s, 2H), 4.95 (br s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.96 (m, 3H), 7.23 (m, 2H), 7'.37 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H), 8.38 (s, 1H), 8.92 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H + 464. 4 /N NMR Spectrum: (DMSO H d 6 ); 3.76 (s, SH), 3.87 (s, H N 2H), 4.95 (br s, 2H), 6.62 o (m, 1H), 6.81 (m, 2H), 6.98 (m, 3H), 7.24 (m, 2H), 7.99 (d, 2H), 8.16 (d, 2H), 8.38 (s, 1H), 8.92 (s, 1H), 9.79 (s, 1H); Mass Spectrum:
M+H
+
464.
WO 2006/024841 PCT/GB2005/003355 154 5 N NMR Spectrum: (DMSO oNNd 6 ); 1.07 (d, 6H), 1.65 (m, '"N 2H), 2.50 (br s, 1H), 2.57 (t, 2H), 3.42 (t, 2H), 3.50 (m, 1H), 3.84 (s, 2H), 4.95 (br s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H), 8.36 (s, Iv), 8.91 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H + 444. 6 NN NMR Spectrum: (DMSO H d 6 ); 3.27 (s, 1H), 3.88 (s, CF N N 2H), 3.89 (s, 2H), 4.95 (br s, 2H), 6.62 (m, 1H), 6.81 (d, 1H), 7.00 (m, 1H), 7.21 (d, 1H), 7.87 (d, 1H), 7.99 (d, 2H), 8.08 (d, 1H), 8.16 (d, 2H), 8.41 (s, 1H), 8.76 (s, 1H), 8.94 (s, 1H), 9.79 (s, 1H); Mass Spectrum:
M+H
+
503.
WO 2006/024841 PCT/GB2005/003355 155 7 /N
NM
R Spectrum: (DM SO N d 6 ); 2.33 (s, 3H), 3.40 (br s, N 1H), 3.93 (s, 2H), 3.99 (s, 2H), 4.95 (br s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.14 (s, 1H), 7.21 (d, 1H), 8.00 (d, 2H), 8.16 (d, 2H), 8.40 (s, 1H), 8.94 (s, 1H), 9.79 (s, 1H); Mass Spectrum: M+H 455. 8 N NMR Spectrum: (DMSO N d 6 ); 2.61 (t, 2H), 2.68 (br s, H 1H), 2.75 (t, 2H), 3.58 (s, N 3H), 3.87 (s, 2H), 4.95 (br s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.85 (s, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.43 (s, 1H), 8.00 (d, 2H), 8.15 (d, 2H), 8.35 (s, 1H), 8.91 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H
+
452.
WO 2006/024841 PCT/GB2005/003355 156 EXAMPLE 19 N-(2-aminophenyl)-4-(3-cyano-5- {[(tetrahydro-2h-pyran-4-ylmethyl)amino]methyl}pyridin 2-yl)benzamide N NNH NH2 HH 5 N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.20 g, 0.45 mmol; prepared as described in Method 15 below) and 4 aminomethyltetrahydropyridine (81 mg, 0.7 mmol) were dissolved in dichloromethane (6 ml). Titanium (IV) isopropoxide (0.27 ml, 0.9 mmol) was added and the mixture stirred at ambient temperature for 2 hours. Sodium borohydride (70 mg) and methanol (0.6 ml) were then added io and the mixture stirred for a further 16 hours. Water (4 ml) and a saturated aqueous sodium bicarbonate solution (2 ml) were added and stirred for 10 minutes. The product was extracted with dichloromethane (3 x 10 ml) and the organic residues concentrated. The residue was purified using chromatography eluting with 10 % methanol in ethyl acetate, and concentration of the solvent gave product as a gum. This was dissolved in dichloromethane (6 ml), 15 trifluoroacetic acid (1.2 ml) added and the solution then stirred at ambient temperature for 2 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated to give the product as a gum. This was re precipitated by stirring in diethyl ether (3 ml) to give the title compound as a foam (73 mg, 37 20 %). NMR Spectrum: (DMSO-d6) 1.18 (m, 2H), 1.66 (m, 3H), 2.46 (d, 2H), 3.29 (m, 2H), 3.85 (m, 4H), 4.95 (s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 7.00 (m, 1H), 7.21 (d, 1H), 8.00 (d, 2H), 8.16 (d, 2H), 8.39 (s, 1H), 8.39 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H+ 442.
WO 2006/024841 PCT/GB2005/003355 157 EXAMPLE 20 Using an analogous procedure to that described in Example 19, the appropriate amine starting material was reacted with N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5 fonnylpyridin-2-yl)benzamide prepared in Method 15 to give the compounds shown in Table 5 10 below. TABLE 10 H NH H 2 N 0 SM Compound X Analytical Data 1 NMR Spectrum: (DMSO O ,,N d 6 ) 1.37 (m, 2H), 1.87 (d, H 2H), 2.81 (m, 1H), 3.31 (m, N 2H), 3.88 (d, 2H), 4.00 (s, 2H), 4.95 (br s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 7.00 (m, 1H), 7.21 (d, 1H), 8.00 (d, 2H), 8.16 (d, 2H), 8.44 (s, 1H), 8.96 (s, 1H), 9.79 (s, 1H); Mass Spectrum: M+Na
+
450.
WO 2006/024841 PCT/GB2005/003355 158 2 N NMR Spectrum: (DMSO O N d 6 ) 1.17 (s, 6H), 2.73 (br s, N 2H), 3.13 (s, 3H), 4.08 (br s, 2H), 4.95 (br s, 2H), 6.62 (mn, 1H), 6.81 (d, 1H), 7.00 (min, 1H), 7.21 (d, 1H), 8.01 (d, 2H), 8.17 (d, 2H), 8.49 (s, 1H), 8.99 (s, 1H), 9.80 (s, 1H); Mass Spectrum:
M+H
+ 430. Example 21 N-(2-amrninophenyl)-4-(3-cyano-5- {[methyl(tetrahydrofuran-2 ylmethyl)amino]methyl}pyridin-2-yl)benzamide /N N
NH
2 5 N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formnylpyridin-2-yl)benzamide (0.20 g, 0.45 mmnol; prepared as described in Method 15 below), N methyltetrahydrofurfurylamine (81 mg, 0.7 mmol) and acetic acid (26 1Al, 0.45 mmol) were dissolved in tetrahydrofuran (5 ml). The mixture was stirred at ambient temperature for 1 10 hour. Sodium triacetoxyborohydride (144 mg, 0.7 mmol) was then added and the mixture stirred for a further 3 hours. The mixture was concentrated and the residue purified by flash chromatography eluting with 100 % ethyl acetate. Concentration of the solvent gave product as a gum. This was dissolved in dichloromethane (6 ml), trifluoroacetic acid (1.2 ml) was added and the solution then stirred at ambient temperature for 2 hours. The resulting solution WO 2006/024841 PCT/GB2005/003355 159 was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated to give the product as a gum. This was re-precipitated by stirring in diethyl ether (3 ml) to give the title compound as a foam/gum (43 mg, 22 %). NMR Spectrum: (DMSO-d 6 , 5 373K) 1H NMR 1.53 (m, 1H), 1.82 (m, 2H), 1.98 (m, 1H), 2.37 (s, 3H), 2.64 (m, 2H), 3.00 (br s, 2H), 3.66 (q, 1H), 3.77 (q, 1H), 3.84 (m, 2H), 4.04 (m, 1H), 6.63 (m, 1H), 6.82 (d, 1H), 6.98 (m, 1H), 7.27 (d, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.29 (s, 1H), 8.89 (s, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H 442. lo EXAMPLE 22 N-(2-aminophenyl)-4-(5- {[bis(2-methoxyethyl)ainamino]methyl}-3-cyanopyridin-2 yl)benzamide Using an analogous procedure to that described in Example 21, the appropriate amine starting material was reacted with N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5 15 formylpyridin-2-yl)benzamide prepared in Method 15 to give the compound shown in Table 11 below. Table 11 H NH2 YN
O
WO 2006/024841 PCT/GB2005/003355 160 SM Compound X Analytical Data 1 NMR Spectrum: (DMSO N d 6 , 373K) 2.83 (t, 4H), N 3.26 (br m, 8H), 3.49 (t, N 4H), 3.94 (s, 2H11), 6.64 (m, O 1H), 6.82 (m, 1H), 6.99 (m, 1H), 7.27 (min, 1I), 8.00 (d, 2H), 8.14 (d, 2H), 8.31 (d, 1H), 8.89 (d, 1H), 9.51 (br s, 1H); Mass Spectrum: M+H + 460. EXAMPLE 23 N-(2-aminophenyl)-4-(3-cyano-5- {[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)benzamide N 00
NH
2 5 t-Butyl [2-({4-[3-cyano-5-(hydroxymethyl)pyridin-2 yl]benzoyl}amino)phenyl]carbamate (0.2 g, 0.45 mmol, prepared a described in Method 29) was dissolved with stirring in tetrahydrofuran (5 ml). N,N-Diisopropylethylamine (0.24 ml, 1.35 mmol) was added and the mixture cooled to 0 oC in an ice bath. Methanesulfonyl o10 chloride (46 p1, 0.6 mmol) was added and the solution stirred for 30 minutes at low temperature to form the mesylate.
WO 2006/024841 PCT/GB2005/003355 161 The mixture was allowed to warm to ambient temperature and a solution of 2 ethoxyethylamine (625 mg, 7.0 mnol) in tetrahydrofuran (2 ml) was added. The mixture was then stirred at ambient temperature for 16 hours. The solution was concentrated under reduced pressure and the residue purified by flash chromatography eluting with 10 % 5 methanol/ethyl acetate to give product as a gum. The residue was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (1.2 ml) added then the solution then stirred at ambient temperature for 2 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then 10 concentrated to give the product as a gum. The gum was re-precipitated by stirring in diethyl ether (3 ml) to give the title compound as a solid (86 mg, 46 %). NMR Spectrum: (DMSO d 6 ) 1.12 (t, 3H11), 2.45 (br s, 1H), 2.68 (t, 2H), 3.44 (m, 4H), 3.87 (s, 2H), 4.95 (s, 2H), 6.62 (m, 1H), 6.80 (d, 1H11), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H11), 8.38 (s, 1H), 8.91 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H + 416. 15 EXAMPLE 24 Using an analogous procedure to that described in Example 23, the appropriate amine starting material was reacted with t-butyl [2-({4-[3-cyano-5-(hydroxymethyl)pyridin-2 yl]benzoyl} amino)phenyl]carbamate (0.2 g, 0.45 mmol, prepared as descriled in Method 29) 20 to give the compounds shown in Table 12 below. Table 12 H NH H22 0 25 WO 2006/024841 PCT/GB2005/003355 162 Compound X Analytical Data SM 1 N NMR Spectrum: (DMSO-d 6 ) H j 1.10 (d, 6H), 2.68 (t, 2H), 3.46 N (t, 2H), 3.55 (m, 1H), 3.89 (s, 2H), 4.95 (s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H), 8.39 (d, 1H), 8.92 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H + 430. 2 N NMR Spectrum: (DMSO-d 6 ) H 1.10 (t, 3H), 1.68 (m, 2H), 2.58 N (t, 2H), 2.63 (br s, 1H), 3.41 (m, 4H), 3.85 (s, 2H), 4.95 (s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H), 8.37 (d, 1H), 8.92 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H + 430. 3 N NMR Spectrum: (DMSO-d 6 ) H 0.88 (t, 3H), 1.52 (m, 2H), 2.55 N (br s, 1H), 2.70 (t, 2H), 3.34 (t, 2H), 3.47 (t, 2H), 3.89 (s, 2H), 4.95 (s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.99 (d, 2H), 8.16 (d, 2H), 8.38 (d, 1H), 8.92 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H
+
430.
WO 2006/024841 PCT/GB2005/003355 163 4 N NMR Spectrum: (DMSO-d 6 ) N 1.55 (m, 1H), 1.81 (m, 2H), N 1.93 (m, 1H), 2.60 (d, 2H), 3.63 (m, 1H), 3.76 (m, 1H), 3.91 (m, 3H), 4.95 (br s, 2H1), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 8.00 (d, 2H), 8.16 (d, 2H), 8.39 (s, 1H), 8.92 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H + 428. 5 -N NMR Spectrum: (DMSO-d 6 ) N 2.22 (s, 3H), 2.97 (br s, 1H), N 3.67 (s, 2H), 3.85 (s, 2H), 4.95 (s, 2H), 5.96 (m, 1H), 6.12 (d, 1H), 6.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 1H), 7.21 (d, 1H), 7.98 (d, 2H), 8.16 (d, 2H), 8.34 (d, 1H), 8.89 (d, 1H), 9.78 (s, 1H); Mass Spectrum: M+H
+
438.
WO 2006/024841 PCT/GB2005/003355 164 METHOD SECTION METHOD 1 N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyanopyridin-2-yl)benzamide. N-(2-t-butoxycarbonylaminophenyl)-4-( 4
,
4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 5 benzamide (400 mg, 0.913 mmol; prepared as described in international patent publication number wo03/087057, method 13, page 60), 2-bromonicotinonitrile (167 mg, 0.913 nmmnol), tetrakis(triphenylphosphine)palladium[0] (50 mg, 0.043 mmol), 1,2-dimethoxyethane (4 ml) and a saturated aqueous solution of sodium hydrogen carbonate (2 ml) were stirred at 100 0 c under an atmosphere of nitrogen in a microwave for 130 mins. the mixture was allowed to o10 cool before being partitioned between dichloromethane and water, the organics were separated, dried over sodium sulfate, filtered and evaporated, the crude product was purified by chromatography on silica eluting with 60:40 ethyl acetate : isohexane to afford the title compound as a white solid (214 mg, 57 %); nmr spectrum: (dmso-d 6 ) 1.45 (s, 9h), 7.18 (in, 2h), 7.57 (m, lh), 7.66 (dd, lh), 8.01 (d, 2h), 8.13 (d, 2h), 8.47 (dd, lh), 8.73 (s, lh), 8.98 (d, 15 lh), 9.97 (s, lh); mass spectrum: mn+h 415. METHODS 2- 7 Using an analogous procedure to that described in Method 1, the N-(2-t butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl) benzamide 20 starting material was reacted with the appropriate bromo- or choro-pyridine to give the compounds described in Table 13 below.
WO 2006/024841 PCT/GB2005/003355 165 Table 13 - 0 X N HN 0 0 Method X Analytical Data SM 2 , N NMR Spectrum: (DMSO-d 6 ) CAS 65996-18-1 1.45 (s, 9H), 2.42 (s, 3H), Baldwin, JJ; et al. N 7.18 (m, 2H), 7.56 (m, 2H), Journal of 7.97 (d, 2H), 8.11 (d, 2H), Organic 8.30 (d, 1H), 8.70 (s, 1H), Chemistry (1978), 8.83 (d, 1H), 9.93 (s, 1H); 43(12), 2529-35. Mass Spectrum: M+H + 429. 3 N NMR Spectrum: (DMSO-d 6 ) N 1.45 (s, 9H), 3.23 (s, 6H), 6.91 (d, 1H), 7.17 (m, 2H), 7.55 (m, 2H), 7.89 (d, 2H), N 8.05 (d, 2H), 8.34 (d, 1H), 8.67 (s, 1H), 9.91 (s, 1H); Mass Spectrum: M+H + 458. 4 NMR Spectrum: (DMSO-d 6 ) CAS 51561-60-5 1.15 (t, 3H), 1.45 (s, 9H), Lamm, Gunther; 2.35 (s, 3H), 3.35 (m, 2H), et al. Ger Offen N H 6.46 (s, 1H), 7.17 (m, 2H), (1993), 7.56 (m, 3H), 7.90 (d, 2H), DE4142192 8.05 (d, 2H11), 8.67 (s, 1H), 9.89 (s, 1H); Mass Spectrum:
M+H
+
472.
WO 2006/024841 PCT/GB2005/003355 166 Method X Analytical Data SM 5 N NMR Spectrum: (DMSO-d 6 ) CAS 56331-50-1 "' 1.45 (s, 9H), 2.36 (s, 3H), Lamm, Gunther; HO t N N 3.44 (m, 2H), 3.55 (m, 2H), et al. Brit (1975) H 4.70 (t, 1H), 6.51 (s, 1H), GB1405308. 7.17 (m, 2H), 7.56 (m, 3H), 7.90 (d, 2H), 8.05 (d, 2H), 8.67 (s, 1H), 9.89 (s, 1H); Mass Spectrum: M+H 488. 6 N NMR Spectrum: (DMSO-d 6 ) 1.45 (s, 9H), 2.54 (s, 3H), 2.59 (s, 3H), 7.17 (m, 2H), N 7.45 (s, 1H), 7.56 (m, 2H), 7.95 (d, 2H), 8.10 (d, 2H), 8.68 (s, 1H), 9.93 (s, 1H); Mass Spectrum: M+Na + 465. 7-N NMR Spectrum: (DMSO-d 6 ) 1.54 (s, 9H), 2.21 (s, 3H), N2 N 2.39 (m, 4H), 2.43 (s, 3H), -N 3.70 (m, 4H), 6.95 (s, 1H), 7.18 (m, 2H), 7.56 (m, 2H), 7.91 (d, 2H), 8.06 (d, 2H), 8.66 (s, 1H), 9.89 (s, 1H); Mass Spectrum: M+H 527. 8 N -N NMR Spectrum: (DMSO-d 6 ) CAS No. 1.44 (s, 9H), 7.17 (m, 2H), 172208-08-1. N 7.56 (t, 2H), 8.08 (d, 2H), National academy 8.16 (d, 2H), 8.71 (br s, 1H), of science letters 9.12 (d, 1H), 9.40 (d, 1H), 1995, 18, 15 9.98 (br s, 1H); WO 2006/024841 PCT/GB2005/003355 167 Method 8 T-butyl [2-({4-[3-cyano-5-(piperidin-1-ylmethyl)pyridin-2 yl]benzoyl} amino)phenyl]carbamate N 0 ONHN O N O 5 A solution ofN-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2 yl)benzamide (400 mg, 0.905 mmol, prepared as described in Method 15) in dichloromethane (5 ml) was added over 20 min to a stirred mixture of piperidine ( 0.1 ml, 1.00 mmol) sodium triacetoxyborohydride (212 mg, 1.0 mmnol), powdered 3A molecular sieve (500 mg) and o10 dichloromethane (15 ml) at -20 0 C under nitrogen. The reaction mixture was stirred for 16 hours at ambient temperature before being filtered and washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica eluting with ethyl acetate to afford the title compound as a cream solid (252 mg, 55 %); NMR Spectrum: (DMSO-d 6 ) 1.40 (m, 2H), 1.45 (s, 9H), 1.46 is (m, 4H), 2.39 (m 4H), 3.58 (s, 2H), 7.17 (m, 2H), 7.56 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.31 (d, 1H), 8.69 (s, 1H), 8.87 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H 512. Methods 9 - 14d Using an analogous procedure to that described in Method 8 above, the appropriate 20 amine starting material was reacted to give the compounds described in Table 14 below.
WO 2006/024841 PCT/GB2005/003355 168 Table 14 CN N H HN O 0 Method Rib Analytical Data SM 9 NMR Spectrum: (DMSO-d 6 ) N 1.45 (s, 9H), 1.72 (m, 4H), 2.50 (min, 4H), 3.73 (s, 2H), 7.18 (m, 2H), 7.56 (m 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.33 (d, 1H), 8.69 (s, 1H), 8.87 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H + 498. 10 NMR Spectrum: (DMSO-1 6 ) 1.45 (s, 9H), 1.81 (m, 1H), 2.27 (m, 1H), 2.51 (m, 1H), 2.75 (m, 2H), 2.99 (m, 1H), 3.34 (m, 1H), 3.80 (s, 2H), 7.18 (m, 3H), 7.29 (m, 4H), 7.56 (m, 2H), 8.02 (d, 2H), 8.13 (d, 2H), 8.38 (d, 1H), 8.68 (s, 1H), 8.93 (d, 1H), 9.95 (s, 1H); Mass Spectrum: M+H + 574.
WO 2006/024841 PCT/GB2005/003355 169 Method Rb Analytical Data SM 11 N NMR Spectrum: (DMSO-d 6 ) N 1.45 (s, 9H), 2.05 (m, 1H), 2.24 (m, 1H), 2.67 (m, 2H), 2.84 (m, 1H), 3.04 (m, 1H), 3.52 (m, 1H), 3.81 (s, 2H), 7.18 (m, 3H), 7.33 (m, 1H), 7.55 (m, 2H), 7.69 (m, 1H), 8.02 (d, 2H), 8.12 (d, 2H), 8.37 (d, 1H), 8.48 (m, 1H), 8.69 (s, 1H), 8.91 (d, 1H), 9.94 (s, 1H4); Mass Spectrum: M+H + 575. 12 NMR Spectrum: (DMSO-d 6 ) CAS H 1.27 (m, 2H), 1.34 (m, 1H), 185561 1N 1.45 (s, 9H), 2.39 (m, 2H), 91-5 " H 2.91 (d, 2H), 3.24 (m, 2H), Brighty, H 3.71 (s, 2H), 4.37 (t, 1H), 7.18 Katherine (m, 2H), 7.57 (m, 2H), 8.01 (d, E. et al; 2H), 8.12 (d, 2H), 8.27 (d, 1H), Syn Lett 8.69 (s, 1H), 8.84 (d, 1IH), 9.94 (1996), (s, 1H); Mass Spectrum: M+H + (11), 540. 1097 1099.
WO 2006/024841 PCT/GB2005/003355 170 Method Rlb Analytical Data SM 13 NMR Spectrum: (DMSO-d 6 ) 0.97 (d, 6H), 1.35 (m, 2H), N 1.54 (s, 9H) 1.99 (m, 2H), 3.00 (m, 2H), 3.80 (dd, 2H), 7.18 (m, 2H), 7.57 (in, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.33 (d, 1H), 8.69 (s, 1H), 8.91 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H 526. 14 NMR Spectrum: (DMSO-d 6 ) 1.45 (s, 9H), 1.63 (m, 1H), 1.87 (m, 1H), 2.08 (s, 6H), -N 2.13 (d, 1H), 2.33 (m, 1H), 2.61 (m, 1H), 2.73 (m, 2H), 3.70 (dd, 2H), 7.18 (m, 2H), 7.57 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.32 (d, 1H), 8.69 (s, 1H), 8.87 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H 541. 14a NMR Spectrum: (DMSO-d 6 ) N 0.93 (t, 6H), 1.45 (s, 9H), 1.64 (m, 1H), 1.89 (m, 2H), 2.38 N (m, 1H), 2.50 (m, 6H), 2.67 (m, 1H), 3.70 (dd, 2H), 7.19 (m, 2H), 7.55 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.32 (d, 1H), 8.71 (s, 1H), 8.88 (d, 1H), 9.96 (s, 1H); Mass Spectrum: M+H + 569.
WO 2006/024841 PCT/GB2005/003355 171 Method Rib Analytical Data SM 14b NMR Spectrum: (DMSO-d 6 ) N 0.87 (t, 3H), 1.30 (m, 2H), 1.44 (m, 11H), 2.16 (s, 3H), 2.37 (t, 2H), 3.60 (s, 2H), 7.18 (m, 2H), 7.55 (in, 2H), 8.02 (d, 2H), 8.12 (d, 2H), 8.31 (d, 1H), 8.71 (s, 1H), 8.87 (d, 1H), 9.96 (s, 1H); Mass Spectrum: M+H 514. 14c N Mass Spectrum: M + H + 552. N- N
N
14d N ..
Mass Spectrum: M+H+ 566.
NN"
N Method 15 N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5,tetramethyl-1,3,2,-dioxaborolan-2-yl) 5 benzamide (1.2 g, 2.74 mmol; prepared as described in international patent publication number wo03/087057, method 13, page 60), 2-chloro-3-cyano-5-formylpyridine [repared as described in de 4429465 al (1996)] (456 mg, 2.74 mmol), 1,1' bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex 112 mg, 0.137 mmol), 1,2-dimethoxyethane (12 ml) and a saturated aqueous solution of sodium WO 2006/024841 PCT/GB2005/003355 172 hydrogen carbonate (6 ml) were stirred at 60 oc under an atmosphere of nitrogen for 7.5 hours. the mixture was allowed to cool before being partitioned between dichloromethane and water. the organics were separated, dried over sodium sulfate, filtered and evaporated, the crude product was purified by chromatography on silica eluting with 30:70 to 40:60 ethyl acetate: 5 isohexane to afford the title compound as a cream solid (615 mg, 51 %); nmr spectrum: (dmso-d 6 ) 1.45 (s, 9h), 7.18 (min, 2h), 7.56 (min, 2h), 8.10 (d, 2h), 8.17 (d, 2h), 8.70 (s, lh), 8.90 (d, lh), 9.39 (d, lh), 9.97 (s, lh), 10.18 (s, lh); mass spectrum: m+na+ 465. Methods 16 -18 10 The starting materials for the above were synthesised from N-(2-t butoxycarbonylaminophenyl)-4-(4,4,5,5,tetramethyl-1,3,2,-dioxaborolan-2-yl) benzamide (prepared as described in International Patent Publication Number WO03/G7057, Method 13, page 60) and the appropriate 2-chloro-pyridine using the procedure outlined in Method 15 above to give the compounds shown in Table 15 below. 15 Table 15 - 0 X HN boc Method X Analytical Data SM 16 CN Mass Spectrum: M-H- 458. 0 2 N N 17 CN Mass Spectrum: M+H + 409.
F
WO 2006/024841 PCT/GB2005/003355 173 Method X Analytical Data SM 18 NC CN Mass Spectrum: M-H- 453.
H
2 N N Method 19 t-Butyl {2-[(4- {3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2 yl}benzoyl)amino]phenyl} carbamate N N 0 N NO /N 5 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) chloride (58 mg, 0.072 mmol) was added to a mixture of N-(2-t-butoxycarbonylaminophenyl)-4-(4.4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)benzamide (626 mg, 1.43 mmol prepared as described in International Patent Publication Number W003/087057, Method 13, page 60), 2-chloro-5-[(4 o10 isopropylpiperazin-1-yl)methyl]nicotinonitrile (398 mg, 1.43 mmol; see Method 20), saturated aqueous sodium hydrogen carbonate solution (5 ml) and 1,2-dimethoxyethane (10 ml). The mixture was heated at 80 oC for 1 hour then allowed to cool to room temperature and partitioned between dichloromethane (75 ml) and water (50 ml). The aqueous layer was extracted with further dichloromethane (2 x 75 ml). The combined organics were dried over 15is magnesium sulfate, filtered and then evaporated to dryness. The residue was purified by flash chromatography on silica, eluting with methanol (5-10 %) in dichloromethane to afford the title compound as a yellow gum which crystallised on trituration with diethyl ether, (652 mg, 82 %).
WO 2006/024841 PCT/GB2005/003355 174 NMR Spectrum: (DMSO-d 6 373K) 0.97 (d, 6H), 1.46 (s, 9H), 2.45 (m, 8H), 2.62 (m, 1H), 3.62 (s, 2H), 7.17 (m, 1H), 7.22 (m, 1H), 7.57 (m, 2H), 8.02 (d, 2H), 8.13 (d, 2H), 8.33 (d, 1H), 8.71 (br s, 1H), 8.89 (d, 1H), 9.95 (br s, 1H); Mass Spectrum: M+H 555. 5 Method 20 2-Chloro-5-[(4-isopropylpiperazin-1-yl)methyl]nicotinonitrile N N N Cl A 4.0 M solution of hydrogen chloride in dioxane (1.33 ml, 5.31 mmol) was added to a stirred suspension of sodium 3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2-olate o10 (1.5 g, 5.31 mmol; see Method 21) in acetonitrile (15 ml). The mixture was heated to 40 oC and phosphorous oxychloride (2.48 ml, 26.6 mmol) added then the mixture was heated at 80 oC for 18 hours. After cooling to room temperature, isopropyl alcohol (8 ml) was added and the mixture stirred for 10 minutes. The mixture was diluted with water (50 ml) and basified with a solution of sodium hydroxide (1M) to pH 8. The product was extracted with 15 dichloromethane (2 x 100 ml), the extracts dried over magnesium sulfate, filtered and concentrated to yield the title compound as a brown oil (1.2 g, 81 %). NMR Spectrum: (DMSO-d6) 0.94 (d, 6H), 2.42 (m, 8H), 2.61 (m, 1H), 3.55 (s, 2H), 8.35 (s, 1H), 8.51 (s, 1H); Mass spectrum: M+IH + 279. 20 WO 2006/024841 PCT/GB2005/003355 175 Method 21 Sodium 3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2-olate N N N 0 Na+ 2-Cyanoacetamide (5.36 g, 63.7 mmol) was added to a solution of (2E)-3 5 (dimethylamino)-2-[(4-isopropylpiperazin-1-yl)methyl]acrylaldehyde (6.10 g, 25.5 mmol; see Method 22) in ethanol (150 ml), followed by drop wise addition of sodium ethoxide (21% solution in ethanol, 28.6 ml, 76.5 mmol) over 5 minutes. The solution was heated at reflux for 17 hours, then cooled to room temperature. The yellow solid was filtered and the filtrate concentrated in vacuo. The residue was triturated with diethyl ether and the solid obtained o10 dried to yield the title compound (8.74g, used without further purification). NMR Spectrum: (DMSO-d6) 0.93 (d, 6H), 2.26 (min, 4H), 2.37 (min, 4H), 2.55 (min, 1H), 3.09 (s, 2H), 7.24 (d, 1H), 7.74 (d, 1H); Mass spectrum: M+H + 261. Method 22 15is (2E)-3-(Dimethylamino)-2-[(4-isopropylpiperazin-1-yl)methyl]acrylaldehyde N N 1-Isopropylpiperazine (4.4 ml, 30.6 mmol) was added to a solution of 3 (dimethylamino)acrolein (2.82 g, 25.5 mmol) in ethanol (100 ml), followed by formaldehyde (37% solution in water, 2.3 ml, 30.6 nimol) and acetic acid (100 pl). The mixture was stirred 20 at 50 0 C for 3.5 hours, then room temperature for 15 hours. The solution was concentrated in vacuo, re-dissolved in ethanol (25 ml) and then formaldehyde (2.3 ml) and acetic acid (100 WO 2006/024841 PCT/GB2005/003355 176 pl) were added. The mixture was stirred at 60 0 C for 4 hours then concentrated in vacuo to yield the title compound as a pale yellow oil (6.10 g, 90 %). NMR Spectrum: (CDC1 3 ) 1.02 (d, 6H), 2.51 (m, 8H), 2.67 (m, 1H), 3.19 (s, 2H), 3.24 (s, 6H), 6.61 (s, 1H), 8.92 (s, 1H); Mass spectrum: M+H + 240. 5 WO 2006/024841 PCT/GB2005/003355 177 Method 23-25 Using an analogous procedure to that described in method 8, the appropriate amine starting material was reacted with n-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5 formylpyridin-2-yl)benzamide to give the compounds shown in table 16 below. 5 Table 16 CN ONO Rib HN >-0 0 Method Rib Analytical Data SM 23 NMR Spectrum: (DMSO-d 6 ) 23 N1.45 (s, 9H), 1.58 (m, 1H), 2.02 (m, 1H), 2.38 (m, 1H), HO 2.45 (m, 1H), 2.66 (m, 1H), 2.73 (m, 1H), 3.72 (dd, 2H), 4.20 (m, 1H), 4.70 (d, 1H), 7.18 (m, 2H), 7.57 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.34 (d, 1H), 8.70 (s, 1H), 8.88 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H 514.
WO 2006/024841 PCT/GB2005/003355 178 24 ,/ NMR Spectrum: (DMSO-d 6 ) CAS136725-55-8 N 1.45 (s, 9H), 1.90 (m, 1H), Giardina, G, et al; 2.15 (m, 1H), 2.42 (m, 1H), F 2.65 (m, 1H), 2.80 (m, 2H), Synlett (1995), 3.78 (s, 2H), 5.22 (m, 1H), (1),5557 7.18 (m, 2H), 7.57 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.36 (d, 1H), 8.69 (s, 1H), 8.90 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H 516. 25 , NMR Spectrum: (DMSO-d 6 ) N 1.38 (s, 9H), 1.45 (s, 9H), 1.71 (m, 1H), 2.00 (m, 2H), -NBoc 2.38 (m, 1H), 2.57 (mn, 2H), 2.72 (in, 1H), 2.76 (s, 3H), 3.71 (dd, 2H), 7.18 (m, 2H), 7.57 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.35 (d, 1H), 8.69 (s, 1H), 8.89 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H 627.
WO 2006/024841 PCT/GB2005/003355 179 Method 26 Using an analogous procedure to that described in Method 15, N-(2-t butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (prepared as described in International Patent Publication Number W003/087057, Method 13, 5 page 60) was reacted with the appropriate 2-chloro-pyridine to give the compound shown in Table 17 below. Table 17
N-
HN boc Method X Analytical Data SM Mass Spectrum: M-H CAS57183-29 26 442.
H
2 N CN 6 Perez Medina, LA et N al; JACS (1947), 69, 2574-2579. 10 WO 2006/024841 PCT/GB2005/003355 180 Method 27 N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-(1-oxo-ethyl)-6-methylpyridin-2 yl)benzamide 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) chloride (33 mng, 0.045 5 mmol) was added to a mixture of N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5,tetramethyl 1,3,2,-dioxaborolan-2-yl) benzamide (393 mg, 0.896 mmol prepared as described in International Patent Publication Number W003/087057, Method 13, page 60), 5-acetyl-2 chloro-6-methylnicitinonitrile (174 mg, 0.896 mmol) and saturated aqueous sodium hydrogen carbonate solution (2 ml) in 1,2-dimethoxyethane (4 ml). The mixture was heated in a io microwave at 80'C for 1 hour. The mixture was allowed to cool, then partitioned between dichloromethane (30 ml) and water (20 ml). The aqueous layer was extracted with further dichloromethane (2 x 30 ml). The combined organics fractions were dried over magnesium sulfate, filtered then evaporated. The residue was purified by flash chromatography (eluting with 30:70-+50:50 ethyl acetate:isohexane) to afford the title compound as a white solid (220 15is mg, 52 %). NMR Spectrum: (CDC1 3 ) 1.53 (s, 9H), 2.67 (s, 3H), 2.92 (s, 3H), 7.02 (s, 1H), 7.19 (m, 3H), 7.77 (m, 1H), 8.11 (m, 4H), 8.36 (s, 1H), 9.46 (br s, 1H); Mass spectrum: M+Na + 493. Method 28 20 t-Butyl (2- {[4-(3-cyano-5- {[2-(ethylamino)ethoxy]methyl}pyridin-2 yl)benzoyl]amino}phenyl)carbamate H N o CN O N HN -O NN 0 WO 2006/024841 PCT/GB2005/003355 181 t-Butyl [2-({4-[3-cyano-5-(hydroxymethyl)pyridin-2 yl]benzoyl}amino)phenyl]carbamate (1.01 g, 2.27 mmol, prepared as described in Method 29) was dissolved with stirring in dichloromethane (50 ml). Methanesulfonyl chloride (0.44 ml, 5.69 mmol) was added followed by triethylamine (0.8 ml, 5.74 mmol) and the solution 5 stirred for 3 hours at ambient temperature to form the mesylate. Sodium hydride (300 mg of a 60 % dispersion in mineral oil, 7.49 mmol) was added to a stirred solution of 2-(ethylamino)ethanol (0.66 ml, 6.81 mmol) in DMF (20 ml) and the solution stirred for 1 hour at ambient temperature. The solution of the mesylate in dichloromethane was then added and the resulting solution was stirred for 24 hours at ambient o10 temperature. The solution was concentrated under reduced pressure and the residue treated with water. This was extracted with ethyl acetate, the combined organic extracts washed with brine then dried over magnesium sulphate and filtered. The resulting solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 2 % methanol/dichloromethane to give t-butyl (2-{[4-(3-cyano-5-{[2 15 (ethylamino)ethoxy]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate (466 mg, 40 %); NMR Spectrum: (DMSO-d 6 ) 1.02 (t, 3H), 1.47 (s, 9H), 2.56 (m, 4H), 3.51 (m, 2H), 3.76 (s, 2H), 4.44 (m, 1H), 7.21 (m, 2H), 7.59 (m, 2H), 8.03 (d, 2H), 8.14 (d, 2H), 8.40 (s, 1H), 8.71 (br s, 1H), 8.93 (s, 1H), 9.96 (s, 1H); Mass Spectrum: M+H + 516. 20 Method 29 T-butyl [2-( {4-[3-cyano-5-(hydroxymethyl)pyridin-2-yl]benzoyl} amino)phenyl]carbamate CN HO o N HN00O H N 00 O/ N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formnylpyridin-2-yl)benzamide (1.14 g, 2.57 mmol, prepared as described in Method 15) was dissolved in methanol (50 ml). 25 Sodium borohydride (194 mg, 5.14 mmol) was added and the solution stirred for 1 hour at WO 2006/024841 PCT/GB2005/003355 182 ambient temperature. The solution was concentrated under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and dichloromethane. The aqueous layer was further extracted with dichloromethane and the combined organic extracts washed with brine then dried over magnesium sulphate and filtered. The 5 solution was concentrated under reduced pressure to give t-butyl [2-({4-[3-cyano-5 (hydroxymethyl)pyridin-2-yl]benzoyl} amino)phenyl]carbamate (1.11 g, 97 %); NMR Spectrum: (DMSO-d 6 ) 1.46 (s, 9H), 4.67 (d, 2H), 5.58 (t, 1H), 7.20 (m, 2H), 7.59 (m, 2H), 8.05 (d, 2H), 8.13 (d, 2H), 8.35 (s, 1H), 8.70 (br s, 1H), 8.93 (s, 1H), 9.96 (br s, 1H); Mass Spectrum: M+H + 445. 10 Method 30 t-Butyl (2- {[4-(3-cyano-5- { [2-(methylamino)ethoxy]methyl}pyridin-2 yl)benzoyl] amino}phenyl)carbamate H /N O C N O N HN 0 /oN 15 t-Butyl [2-({4-[3-cyano-5-(hydroxymethyl)pyridin-2 yl]benzoyl}amino)phenyl]carbamate (1.01 g, 2.27 mmol, prepared a described in Method 29) was dissolved with stirring in dichloromethane (50 ml). Methanesulfonyl chloride (0.44 ml, 5.69 mmol) was added followed by triethylamine (0.8 ml, 5.74 mmol) and the solution stirred for 3 hours at ambient temperature to form the mesylate. 20 Sodium hydride (545 mg of a 60 % dispersion in mineral oil, 13.62 imnol) was added to a stirred solution of 2-(methylamino)ethanol (1.10 ml, 13.62 mmol) in DMF (20 ml) and the solution stirred for 1 hour at ambient temperature. The solution of the 'mesylate' in dichloromethane was added and the resulting solution was stirred for 24 hours at ambient temperature. The solution was concentrated under reduced pressure and the residue treated WO 2006/024841 PCT/GB2005/003355 183 with water. This was extracted with ethyl acetate, the combined extracts washed with brine, dried over magnesium sulphate and filtered. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 2 % methanol/dichloromethane to give t-butyl (2- { [4-(3-cyano-5- { [2 5 (methylamino)ethoxy]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate (465 mg, 41 %); NMR Spectrum: (DMSO-d 6 ) 1.46 (s, 9H), 2.24 (s, 3H), 2.51 (min, 2H), 3.56 (min, 2H), 3.69 (s, 2H), 4.46 (min, 1H), 7.19 (min, 2H), 7.58 (min, 2H), 8.04 (d, 2H), 8.14 (d, 2H), 8.40 (s, 1H), 8.71 (br s, 1H), 8.92 (s, 1H), 9.96 (s, 1H); Mass Spectrum: M+H + 502. o10 Method 31 t-Butyl (2- { [4-(3-cyano-5- {[2-(isopropylamino)ethoxy]methyl}pyridin-2 yl)benzoyl]amino}phenyl)carbamate H N O CN0 N HN O - N H 0 6YN 00 OX t-Butyl [2-({4-[3-cyano-5-(hydroxymethyl)pyridin-2 15 yl]benzoyl}amino)phenyl]carbamate ( 555 mg, 1.25 rmmol) was stirred and dissolved in DMF (20 ml). Methanesulfonyl chloride (0.19 ml, 2.46 mmol) was added followed by triethylamine (0.38 ml, 2.73 mmol) and the solution stirred for 2 hours at ambient temperature. Sodium hydride (166 mg of a 60 % dispersion in mineral oil, 4.15 mmol) was added to 20 a stirred solution of iso-propylaminoethanol (0.43 ml, 3.74 mmol) in DMF (10 ml) and the solution stirred for 1 hour at ambient temperature. The solution of the 'mesylate' in DMF was added and the resulting solution was stirred for 24 hours at ambient temperature. The reaction was poured into water (300 ml) and the resulting precipitate filtered then washed with water (X 3). The resulting solution was absorbed onto an SCX-2 column, which was washed with WO 2006/024841 PCT/GB2005/003355 184 methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated to give the product, t-butyl (2-{[4-(3-cyano 5- { [2-(isopropylamino)ethoxy]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate as a foam (170 mg, 26 %); NMR Spectrum: (DMSO-d 6 ) 1.03 (d, 6H), 1.45 (s, 9H), 2.54 (mn, 2H), 5 2.91 (m, 1H), 3.41 (in, 2H), 3.75 (s, 2H), 4.37 (m, 1H), 7.20 (m, 2H), 7.58 (m, 2H), 8.04 (d, 2H), 8.13 (d, 2H), 8.41 (s, 1H), 8.71 (br s, 1H), 8.94 (s, 1H), 9.96 (s, 1H); Mass Spectrum: M+H 530.

权利要求:
Claims (23)
[1] 1. A compound of formula (I): RIC Rib RlR4 R l b N R 4 NN (R 2 )m O (R3 )n (I) 5 wherein: R a is selected from hydrogen, amino, nitro, (1-3C)alkyl, N-(1-3C)alkylamino, N,N-di-(1 3C)alkylamino, phenyl, or piperazinyl; and wherein: (i) if Ra is N-(1-3C)alkylamino or N,N-di-(1-3C)alkylamino group, the (1 10 3C)alkyl moiety is optionally substituted by hydroxy or (1-3C)alkoxy; (ii) if R a is phenyl, it is optionally substituted by halo, amino, N-(1-3)alkylamino, or N,N-di-(1-3C)alkylamino; and (iii) if Ria is piperazinyl, it is optionally substituted by halo, amino, (1-3C)alkyl, N (1-3)alkylamino, or N,N-di-(1 -3C)alkylamino; 15 Rb is selected from: (i) hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-6C)alkyl, hydroxy(1 6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyl, (1-6C)alkoxy, 20 (1-6C)alkanoyloxy, N-(1-6C)alkylamino, N,N-di-[(1-6C)alkyl]amino, N-[(3 6C)cycloalkyl]amino, N,N-di-[(3-6C)cycloalkyl]amino, N-[(3 6C)cycloalkyl(1-6C)alkyl] amino, N,N-di-[(3-6C)cycloalkyl(1-6C)alkyl]amino, WO 2006/024841 PCT/GB2005/003355 186 N-[(3-6C)cycloalkyl]-N-[(1-6C)alkyl]amino, N-[(3-6C)cycloalkyl(1-6C)alkyl] N-[(1-6C)alkyl] amino, N-(1-6C)alkanoylamino, N,N-di-[(1 6C)alkanoyl]amino, N-[(1-6C)alkoxy(1 -6C)alkyl]amino, N,N-di-[(1 6C)alkoxy(1-6C)alkyl]amino, N-[(1-6C)alkoxy(1-6C)alkyl]-N-[(1 5 6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (1 6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1 6C)alkoxycarbonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1 6C)alkyl]sulphamoyl, aryl, aryl-(1-6C)alkyl, a carbon linked heterocyclyl group, or a heterocyclyl-(1-6C)alkyl group wherein the heterocyclyl moiety is 10 carbon-linked to the alkyl group; or (ii) a group of sub-formula II: R 7 RSN - [CRaRb] a- X 1 -[C RCRd] b (II) wherein: 15 X 1 is selected from a direct bond, -0- or -C(O)-; integer a is 0, 1, 2, 3 or 4, with the proviso that if X 1 is -0-, integer a is at least 1; integer b is 0, 1, 2, 3 or 4; each Ra, Rb, Rc and Rd group present is independently selected from hydrogen, 20 halo, hydroxy or (1-4C)alkyl; R7 and R 8 are independently selected from hydrogen, (1-6C)alkyl, hydroxy( 1 6C)alkyl, halo(1-6C)alkyl, (2-6C)alkenyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyl, aryl, aryl(1-6C)alkyl, 25 heterocyclyl; a heterocyclyl-(1-6C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from a substituted or unsubstituted thienyl, pyrimidinyl, pyridazinyl, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, or indolyl group, WO 2006/024841 PCT/GB2005/003355 187 or from one the following particular substituent groups: 1,3-dimethyl-l1H pyrazol-5-yl, 3,5-dimethyl-l1H-pyrazol-4-yl, and 1-methyl-l1H-imidazol-4-yl; a group of sub-formula III: R9RioN- [C R eR f] c -X 2- [ CRgRhd 5 (II1) wherein: X 2 is selected from a direct bond, -0- or-C(O)-; integer c is 1, 2 or 3; integer d is 0, 1, 2 or 3; 10 each Re, R, R and Rh group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl; R 9 and R 1 0 are independently selected from hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, halo(1-6C)alkyl, (3-6C)cycloalkyl, (3 6C)cycloalkyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, or R 9 and R 1 0 are 15 linked so that, together with the nitrogen atom to which they are attached, they form a 4-, 5-, 6- or 7-membered non-aromatic heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 9 and R 1 0 are attached, one or two further heteroatoms selected from N, O or S, and wherein said 20 heterocyclic ring is optionally substituted by hydroxy, halo, (1 4C)alkyl, carbamoyl, or -[CH 2 ]e_ 11R 12 (wherein integer e is 0, 1 or 2, and R 1 1 and R 1 2 are independently selected from hydrogen, (1 6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-6C)alkyl); or R 7 and R are linked so that, together with the nitrogen atom to which they 25 are attached, they form a 4 to 10-membered heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 7 and R 8 are attached, one or two further nitrogen atoms; or (iii) a group of the sub-formula IV: WO 2006/024841 PCT/GB2005/003355 188 QIX3_YI _ (IV) wherein: Y' is a direct bond or -[CR 13 R 1 4 ] x-where integer x is 1 to 4 and R 1 3 and R 1 4 ae 5 independently selected from hydrogen, halo and (1-4C)alkyl; X 3 is selected from -0-, -S-, -SO-, -SO2-, -C(O)-, -OC(O)- and -C(O)O-, with the proviso that Y' is not a direct bond if X 3 is -C(O)-and Q 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyl, aryl, aryl-(1 10 6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, or R 1 5 R 16 N-(1-6C)alkyl (wherein R 15 and R 16 are each independently selected from hydrogen, (1 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-6C)alkyl); 15 and wherein any heterocyclyl ring within a Rib substituent group (apart from those for which particular substituents are expressly stated above, such as heterocyclyl rings formed when R 9 and R 10 are linked) is optionally substituted on carbon by one or more Z I substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, 20 carbamoyl, mercapto, sulphamoyl, (1-6C)alkyl, hydroxy(1-6C)alkyl, (2 6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkanoyl, (1-6C)alkanoyloxy, (1-6C)alkoxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl, halo(1-6C)alkyl, N-[(1 6C)alkyl]amino, N,N-di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di [(1-6C)alkyl]carbamoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1 25 6C)alkylsulphonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1 6C)alkyl]sulphamoyl, aryl, aryl-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1 6C)alkyl, (b) a group of the sub-formula V: WO 2006/024841 PCT/GB2005/003355 189 R 7 R 1 RN-[CRiR]f-X 4 -[CRkR]g (V) wherein X 4 is selected from a direct bond, -0- or -C(O)-; 5 integer fis 0, 1, 2 or 3, with the proviso that integer fis at least 1 ifX 4 is -O-; integer g is 0, 1 or 2; each Ri, RI, Rk and R group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl; 10 R 17 and R 18 are each independently selected from hydrogen, (1 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-6C)alkyl; or (c) a group of the sub-formula VI: s15 Q 2 -X 5 _-Y2 (VI) wherein: y2 is a direct bond or -[CR 9 R 2 0 ]y- wherein integer y is 1 to 4 and R' 9 and R 20 are independently selected from hydrogen, halo and (1-4C)alkyl; 20 X 5 is selected from -0-, -S-, -SO-, -SO 2 -, -C(O)-, -OC(O)- or -C(O)O-; and Q2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl(1-6C)alkyI, aryl, aryl-(1 6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, R 21 R 2 2 N-(1-6C)alkyl (wherein R 21 and R 2 2 are each independently selected from hydrogen, (1 25 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-6C)alkyl); WO 2006/024841 PCT/GB2005/003355 190 and wherein if any heterocyclyl group within a Rb substituent group contains an unsubstituted nitrogen atom, then, unless any particular substituents are expressly stated in the definition above (e.g. such as when R 9 and R 10 are linked to form a heterocyclic ring together with the nitrogen atom to which they are attached), the nitrogen atom may be optionally s substituted by one or more Z 2 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: (a) trifluoromethyl, carboxy, carbamoyl, (1-6C)alkyl, hydroxy(1-6C)alkyl, (2 6C)alkenyl, (1-6C)alkanoyl, (1-6C)alkoxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl, halo(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]amino 10 (1-6C)alkyl, (1-6C)alkylsulphonyl, aryl, aryl-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl; or (b) a group of the formula VII: R 23 R 24 N-[CRmRnh_ (VII) s15 wherein integer h is 0, 1, 2, or 3; each Rm and R n group present is independently selected from hydrogen, halo, hydroxy or (1-4C)alkyl; R 23 and R 24 are each independently selected from hydrogen, (1 20 6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkanoyl, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3-6C)cycloalkenyl, or (3 6C)cycloalkenyl(1-6C)alkyl; or (c) a group of the formula VIII: Q 3 -X 6 _-Y 3 25 (VIII) wherein Y 3 is a direct bond or -[CR 25 R 26 ]z- wherein z is 1 to 4 and R 25 and R 26 are independently selected from hydrogen, halo and (1-4C)alkyl; X 6 is selected from -0-, -S-, -SO-, -SO 2 -, -C(O)-, -OC(O)- c; .. C(O)O- if y 3 is WO 2006/024841 PCT/GB2005/003355 191 -[CR 23 R 24 1]z-, and if Y 3 is a direct bond, X 6 is selected from -S-, -SO-, -SO 2 -, C(O)-, and -OC(O)-; and Q 3 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 6C)alkyl, aryl, aryl-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl or 5 R 2 7 R 28 N-(1-6C)alkyl (wherein R 27 and R 28 are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1 6C)alkanoyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl, (3 6C)cycloalkenyl, or (3-6C)cycloalkenyl(1-6C)alkyl); and wherein any heterocyclyl group within a Z' or Z 2 substituent group optionally o10 bears one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-6C)alkyl, hydroxy(1-6C)alkyl, halo(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkanoyl, (1-6C)alkanoyloxy, N-[(1-6C)alkyl]amino, and N,N-di-[( 1 6C)alkyl]amino; 15 and wherein any non-aromatic heterocyclyl group within a Rb substituent (including optional substituent groups Z 1 and Z 2 ) optionally bears 1 or 2 oxo substituents; and wherein any alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, or cycloalkenyl group within a Rb substituent group (including optional substituent groups ZI and Z 2 ) is, unless particular substituents are expressly stated above, optionally substituted by 20 one or more Z 3 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, cyano, mercapto, (1-6C)alkoxy, trifluoromethyl, or -NR 29 R 3 0 wherein each of R 29 and R 3 0 is independently selected from hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (3 6C)cycloalkyl, (3-6C)cycloalkyl(1-6C)alkyl; and wherein any aryl group within a Rlb substituent group (including optional 25 substituent groups Z' and Z 2 ) is optionally substituted by one or more Z 4 substituent groups (for example 1, 2 or 3), which may be the same or different, selected from halo, nitro, cyano, hydroxy, amino, (1-6C)alkyl, hydroxy(1-6C)alkyl, halo(1-6C)alkyl, (1-6C)alkoxy, (1 6C)alkanoyl, N-[(1-6C)alkyl]amino, N,N-di-[(1-6C)alkyl]amino, carbamoyl, N-(1 6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl; 30 Ric is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, WO 2006/024841 PCT/GB2005/003355 192 amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-3C)alkyl, (2-3C)alkenyl, (2 3C)alkynyl, (1-3C)alkoxy, (1-3C)alkanoyl, (1-3C)alkanoyloxy, N-(1-3C)alkylamino, N,N-di [(1-3C)alkyl]amino, (1-3C)alkanoylamino, N-(1-3C)alkylcarbamoyl, N,N-di-(1 3C)alkylcarbamoyl, (1-3C) alkylthio, (1-3C)alkylsulphinyl, (1-3C)alkylsulphonyl, (1 5 3C)alkoxycarbonyl, N-(1-3C)alkylsulphamoyl, and N,N-di-(1-3C)alkylsulphamoyl; with the proviso that at least one of R a , R b and Rc is hydrogen; mis 0, 1,2,3 or4; R is halo; n is 0, 1, 2, 3 or 4; 10 R 3 is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1 3C)alkoxy, (1-3C)alkanoyl, (1-3C)alkanoyloxy, N-(1-3C)alkylamino, N,N-di-[(1 3C)alkyl]amino, (1-3C)alkanoylamino, N-(1-3C)alkylcarbamoyl, N,N-Di(1 3C)alkylcarbamoyl, (1-3C) alkylthio, (1-3C)alkylsulphinyl, (1-3C)alkylsulphonyl, (1 15 3C)alkoxycarbonyl, N-(1-3C)alkylsulphamoyl, and N,N-di-(1-3C)alkylsulphaimoyl; and R 4 is amino or hydroxy; or a pharmaceutically acceptable salt thereof.
[2] 2. A compound according to claim 1, wherein said compound has the general structural 20 formula VIII: RIOc Rib RIa N H NH 2 N VIII Vill WO 2006/024841 PCT/GB2005/003355 193 wherein R l a, Rib and RIc are as defined in claim 1.
[3] 3. A compound according to claim 1 or claim 2, wherein Ra is selected from hydrogen, amino, nitro, (1-3C)alkyl, N-(1-3C)alkylamino, phenyl, or piperazinyl, and wherein: 5 (i) if Ria is N-(1-3C)alkylamino, the (1-3C)alkyl moiety is optionally substituted by hydroxy; (ii) if R l a is phenyl it is optionally substituted by halo; and (iii) if R l a is piperazinyl it is optionally substituted by (1-3C)alkyl. 10
[4] 4. A compound according to any one of claims 1 to 3, wherein RIb is selected from: (i) hydrogen, cyano, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl; or (ii) a group of sub-formula II: RR 8 N-[CRaRb] a - XI - [C R e Rd] b (II) 15 wherein: X 1 is selected from a direct bond, or -0-; integer a is 1, 2, or 3; integer b is 0, 1, or 2; each Ra, Rb, Rc and Rd group present is independently selected from hydrogen 20 or (1-2C)alkyl; R 7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3-6C)cycloalkyl(1-2C)alkyl; (1 4C)alkoxy(1-4C)alkyl; an aryl group which is unsubstituted or substituted with one to three 25 substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; WO 2006/024841 PCT/GB2005/003355 194 an aryl(1-2C)alkyl group the aryl moiety of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms 5 selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from the group consisting of a 10 furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyridinyl, pyrazinyl, thiazolyl, indolyl group, each of which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, halo(1-4C)alkyl or (1-4C)alkexy, or the heterocyclyl moiety is selected from 1,3-dimethyl-lH-pyrazol-5-yl, 3,5 15 dimethyl-lH-pyrazol-4-yl, and 1-methyl-lH-imidazol-4-yl; a group of sub-formula III: R 9 RoN-[CReR]c-X 2 -[ CRgRh]d (III) wherein: 20 X 2 is selected from a direct bond, or -0-; integer c is 1, 2 or 3; integer d is 0, 1, or 2; each Re, R', R9 and Rh group present is independently selected from hydrogen or (1-2C)alkyl; 25 R 9 and Rio are independently selected from hydrogen, (1 4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, or R 9 and R 1 io are linked so that, together with the nitrogen atom to which they are attached, they form a 4, 5-, or 6-membered non aromatic heterocyclic ring, said heterocyclic ring optionally WO 2006/024841 PCT/GB2005/003355 195 comprising, in addition to the nitrogen atom to which R 9 and R 1 0 are attached, one or two further heteroatoms selected from N, O or S, and wherein said heterocyclic ring is optionally substituted by hydroxy, halo, or (1-4C)alkyl; 5 or R 7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 8-membered heterocyclic ring, said heterocyclic ring optionally comprising, in addition to the nitrogen atom to which R 7 and R 8 are attached, one or two further nitrogen atoms, and wherein said heterocyclylic ring is optionally substituted on carbon by one to three 10 substituents selected from: (a) halo, cyano, hydroxy, trifluoromethyl, amino, (1-4C)alkyl, hydroxy(1 4C)alkyl, halo(1-4C)alkyl, N-[(1-4C)alkyl]amino, N,N-di-[(1 4C)alkyl]amino, an aryl group which is optionally substituted with halo, cyano, 15 hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; an aryl-(1 -2C)alkyl wherein the aryl moiety is optionally substituted with halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or 20 substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or 6-membered heterocyclyl group comprising up to three 25 heteroatoms selected from N, O or S and is optionally substituted with halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; (b) a group of the sub-formula VI: Q2-X-Y2 (VI) WO 2006/024841 PCT/GB2005/003355 196 wherein: Y2 is a direct bond or -[CR 9 R 2 0 ]y- wherein integer y is 1 or 2 and R 19 and R 2 0 are both hydrogen or (1-2C)alkyl; X 5 is selected from -0- or -C(O)-; and s Q 2 is selected from a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, 10 amino, (1-4C)alkyl, or (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and is optionally substituted with one to three substituents selected 15 from the group consisting of halo, cyano, hydroxy, amino, (1 4C)alkyl, or (1-4C)alkoxy; and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: 20 (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-4C)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl; an aryl group which is optionally substituted with halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; an aryl-(1-2C)alkyl wherein the aryl moiety is optionally substituted 25 with halo, cyano, hydroxy, amino, (1-4C)alkyl,orl-4C)alkoxy; a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is unsubstituted or substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1- WO 2006/024841 PCT/GB2005/003355 197 4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and is optionally substituted with 5 halo, cyano, hydroxy, amino, (1-4C)alkyl, or (1-4C)alkoxy; (b) a group of the formula VII: R23R24N-[CR m Rn]h (VII) wherein 10 integer h is 0, 1, or 2; each R m and R n group present is hydrogen; R23and R 24 are each independently selected from hydrogen or (1-4C)alkyl; or (c) a group of the formula VIII: 15 3-X6-y3 (VIII) wherein Y 3 is a direct bond or -[CR 25 R 26 ]z- wherein z is 1 to 2 and R 25 and R 26 are independently selected from hydrogen or (1-2C)alkyl; X 6 is selected from -0- or -C(O)-, if Y 3 is -[CR 2 3 R 24 ]z-, and if VY 3 is a 20 direct bond, X 6 is selected from -S-, -SO-, -SO 2 - or -C(O)-; and Q 3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1 2C)alkyl, a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and which is 25 unsubstituted or substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1- WO 2006/024841 PCT/GB2005/003355 198 4C)alkyl, (1-4C)alkoxy; a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is a 4, 5, or 6-membered heterocyclyl group comprising up to three heteroatoms selected from N, O or S, and is 5 optionally substituted with halo, nitro, cyano, hydroxy, amino, (1-4C)alkyl, hydroxy(1-4C)alkyl, halo(1-4C)alkyl, (1 4C)alkoxy; and wherein any non-aromatic heterocyclyl group within a Rib substituent group optionally bears 1 or 2 oxo substituents. 10
[5] 5. A compound according to any one of claims 1 to 3, wherein Rb is selected from: (i) hydrogen, amino, (1-4C)alkyl; or (ii) a group of sub-formula II: R 7 RSN-[CRaRb]a-XI-[CRCRd]b 15 (II) wherein: X 1 is selected from a direct bond or -0-; integer a is 1, or 2; integer b is 0, 1, or 2; 20 each R , R b , Rc and R group present is independently selected from hydrogen or (1-2C)alkyl; R7 and R 8 are independently selected from hydrogen; (1-6C)alkyl; hydroxy(1 4C)alkyl; (2-4C)alkenyl; (3-6C)cycloalkyl; (3-6C)cycloalkyl(1-2C)alkyl; (1 4C)alkoxy(1-4C)alkyl; 25 a phenyl(1-2C)alkyl group, the phenyl moiety of which is optionally substituted by (1-4C)alkoxy; tetrahydrofuranyl; WO 2006/024841 PCT/GB2005/003355 199 a heterocyclyl-(1-2C)alkyl group wherein the heterocyclyl moiety is carbon linked to the alkyl group and is either selected from the group consisting of a furan-2-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2 yl, thiazol-2-yl, indol-3-yl group, each of which is unsubstituted or substituted 5 with one to three substituents selected from the group consisting of halo, (1 4C)alkyl, or halo(1-4C)alkyl, or the heterocyclyl moiety is selected from 1,3 dimethyl-lH-pyrazol-5-yl, 3,5-dimethyl-l1H-pyrazol-4-yl, and 1-methyl-lH imidazol-4-yl; a group of sub-formula III: 10 R 9 RIoN-[CReRf]c-X 2 -[ CRgRh d (III) wherein: X 2 is selected from a direct bond; integer c is 1, or 2; 15 integer d is 0, or 1; each Re, R f , R9 and Rh group present is independently selected from hydrogen or (1-2C)alkyl; R 9 and R 1 0 are independently selected from hydrogen, (1 4C)alkyl, or R 9 and R 1 0 are linked so that, together with the 20 nitrogen atom to which they are attached, they form a pyrrolidinyl, or piperidinyl ring; or R 7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a 4 to 8-membered heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 3 25 azabicyclo[3.1.0]hexyl, hexahydropyrrolo[3,4-c]pyrrolyl, 7 azabicyclo[2.2.1]heptyl, and 2-azabicyclo[2.2.2]octyl, and wherein said heterocyclylic ring is optionally substituted on carbon by one to three substituents selected from: (a) halo, hydroxy, trifluoromethyl, (1-4C)alkyl, hydroxy(1-4C)alkyl, N-[(1- WO 2006/024841 PCT/GB2005/003355 200 4C)alkyl]amino, N,N-di-[(1-4C)alkyl] amino, a phenyl group which is optionally substituted with halo; pyrrolidinyl, morpholinyl, piperazinyl optionally substituted with (1-4C)alkyl, or pyridinyl, 5 (b) a group of the sub-formula VI: Q2-X 5 -Y 2 (VI) wherein: Y2 is a direct bond; 10 X 5 is selected from -C(O)-; and Q2 is selected from pyrrolidinyl, or morpholinyl; and, if said heterocyclic ring comprises a nitrogen atom then said nitrogen is optionally substituted by one or more substituent groups (for example 1, 2 or 3), which may be the same or different, selected from: 15 (a) (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-4C)alkenyl, (1-AC)alkanoyl, (1 4C)alkoxy-(1-4C)alkyl; a phenyl group which is optionally substituted with cyano; a heterocyclyl group selected from pyrrolidinyl, morpholinyl, piperazinyl, pyrazinyl, pyrimidinyl, and pyridinyl, and wherein said 20 ring is unsubstituted or substituted with cyano; (b) a group of the formula VII: R 23 R 24 N-[CRmRn]h (VII) wherein 25 integer h is 0, 1, or 2; each R m and R n group present is hydrogen; WO 2006/024841 PCT/GB2005/003355 201 R23and R 24 are each independently selected from hydrogen or (1-4C)alkyl; or (c) a group of the formula VIII: Q3-X6-Y3 5 (VIII) wherein Y 3 is a direct bond or -[CR 25 R 2 6 ]z- wherein z is 1 and R 25 and R 26 are both hydrogen; X 6 is -C(O)-, if Y 3 is -[CR 23 R 24 ]z-, and if Y 3 is a direct bond, X 6 is selected from -SO 2 - or -C(O)-; and 10 Q 3 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, or pyrrolidinyl, and wherein any non-aromatic heterocyclyl group within a Rb substituent group optionally bears 1 or 2 oxo substituents.
[6] 6. A compound according to any one of claims 1 to 3, wherein Rb is selected from is hydrogen, cyano, amino, methyl, hydroxymethyl, 1-hydroxyethyl, (methylamino)methyl, (ethylamino)methyl, 1-(ethylamino)ethyl, (propylamino)methyl, (isopropylamino)methyl, (cyclopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (cyclopentylamino)methyl, (1-methylpropylamino)methyl, (2-methylpropylamino)methyl, (allylamino)methyl, (di-ethylamino)methyl, [(ethyl)(methyl)amino]methyl, 20 [(isopropyl)(methyl)amino]methyl, [(propyl)(methyl)amino]methyl, [(butyl)(methyl)amino]methyl, [(cyclopropylmethyl)amino]methyl, [(cyclobutylmethyl)(methyl)amino]methyl, [(2-methoxyethyl)(methyl)amino]methyl, [(isopropyl)(2-methoxyethyl)amino]methyl, [(2-methoxyethyl)amino]methyl, [(ethyl)(2 methoxyethyl)amino]methyl, [(2-methoxy-l1-methylethyl)amnino]methyl, [(3 25 methoxypropyl)amino]methyl, [(3-isopropoxypropyl)amino]methyl, [(2 ethoxyethyl)amino]methyl, [(2-isopropoxyethyl)amino]methyl, [(3 ethoxypropyl)amino]methyl, [(2-propoxyethyl)amino]methyl, [(2-methoxy-2 methylpropyl)amino]methyl, [bis(2-methoxyethyl)amino]methyl, [(2 hydroxyethyl)(ethyl)amino]methyl, [(2-hydroxyethyl)(methyl)amino]methyl, { [2-(di- WO 2006/024841 PCT/GB2005/003355 202 methylamino)ethyl] amino } methyl, { [2-(di-ethylamino)ethyl] amino } methyl, {[2-(di methylamino)ethyl][methyl] amino}methyl, {[2-(di-ethylamino)ethyl] [methyl]amino}methyl, { [2-(di-methylamino)- 1-(methyl)ethyl] amino} methyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, 1 -piperidinylethyl, piperazinylmethyl, 7-azabicyclo[2.2.1]heptylmethyl, 2 5 azabicyclo[2.2.2]octylmethyl, {[2-(pyrrolidin- 1 -yl)ethyl]amino}methyl, {[2-(piperidin-1 yl)ethyl]amino}methyl, (3-fluoropyrrolidin-1-yl)methyl, (4-fluoropiperidin-1-yl)methyl, (3 hydroxypyrrolidin-1-yl)methyl, (3-hydroxypiperidin-1-yl)methyl, (4-hydroxypiperidin-1 yl)methyl, (4-trifluoromethylpiperidin-1-yl)methyl, [2,5-dimethylpyrrolidin-1-yl]methyl, (4 methylpiperidin-1-yl)methyl, (4-hydroxymethylpiperidin-1-yl)methyl, (3,3-dimethylpiperidin o10 1-yl)methyl, [6-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]methyl, (3 methylaminopyrrolidin-1-yl)methyl, [3-(dimethylamino)pyrrolidin-1-yl]methyl, [3 (diethylamino)pyrrolidin-1-yl]methyl, (3-phenylpyrrolidin-1-yl)methyl, (3-phenylpiperidin-1 yl)methyl, (4-phenylpiperidin-1-yl)methyl, [3-(4-fluorophenyl)piperidin-1-yl]methyl, (3 pyridin-2-ylpyrrolidin-1-yl)methyl, (4-morpholin-4-ylpiperidin-1-yl)methyl, [4-(2 15 oxopyrrolidin-1-yl)piperidin-1-yl]methyl, (4-pyrrolidin-1-ylpiperidin-1-yl)methyl, (4-pyridin 4-ylpiperidin-1-yl)methyl, [(4-methylpiperazin-1-yl)piperidin-1-yl]methyl, [4-(morpholin-4 ylcarbonyl)piperidin-1-yl]methyl, (4-methylpiperazin-1-yl)methyl, (4-ethylpiperazin-1 yl)methyl, [4-(2-hydroxyethyl)piperazin-1-yl]methyl, (4-isopropylpiperazin-1-yl)methyl, {4 [2-(dimethylamino)ethyl]piperazin-1-yl} methyl, (4-allylpiperazin-1-yl)methyl, (4 20 acetylpiperazin-1-yl)methyl, (5-butyrylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl, [4-(2 methoxyethyl)piperazin-1-yl]methyl, [4-(methylsulfonyl)piperazin-1-yl]methyl, [4 (ethylsulfonyl)piperazin-1-yl]methyl, [4-(2-cyanophenyl)piperazin-1-yl]methyl, [4-(pyridin 2-yl)piperazin-1-yl]methyl, [4-(3-cyanopyridin-2-yl)piperazin-1-yl]methyl, [4-(3 cyanopyrazin-2-yl)piperazin-1-yl]methyl, (4-pyrimidin-2-ylpiperazin-1-yl)methyl, (4-pyrazin 25 2-ylpiperazin-1-yl)methyl, [4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl, [4 (cyclopropylcarbonyl)piperazin-1-yl]methyl, {[(1,3-dimethyl- 1H-pyrazol-5 yl)methyl]amino}methyl, {[2-(3,5-dimethyl- 1H-pyrazol-4-yl)ethyl] amino}methyl, [methyl(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5-methylpyrazin-2 yl)methyl]amino} methyl, [6-(trifluoromethyl)pyridin-3-yl]methyl} amino)iiethyl, [(4-methyl 30 1,3-thiazol-2-yl)methyl]amino}methyl, [2-(1-methyl- lH-imidazol-4-yl)ethyl]amino}methyl, [(tetrahydrofuran-2-ylmethyl)amino]methyl, [(5-methyl-2-furyl)methyl]amino} methyl, (tetrahydro-2H-pyran-4-ylmethyl)amino]methyl, (tetrahydro-2H-pyran-4-ylamino)methyl, WO 2006/024841 PCT/GB2005/003355 203 {[2-(2-methyl-l1H-indol-3-yl)ethyl]amino}methyl, (2-methoxybenzyl)amino]methyl, [(3 methoxybenzyl)amino]methyl, { [2-(isopropylamino)ethoxy]methyl, [2 (ethylamino)ethoxy]methyl, and [2-(methylamino)ethoxy]methyl. 5
[7] 7. A compound according to any one of the preceding claims wherein Ric is selected from hydrogen, amino, (1-3C)alkyl, N-(1-3C)alkylamino, and N,N-di-[(1-3C)alkyl]amino;
[8] 8. A compound according to any one of the preceding claims, wherein said compound has the general formula IX: R 1 b N I N /NH2 R1 a IH N 10 10 IX wherein R l a is as defined in claim 1 or claim 3, and Rib is as defined in claim 1 or any one of claims 4 to 6.
[9] 9. A compound according to claim 8, wherein R l a is hydrogen or (1-3C) alkyl. 15
[10] 10. A compound according to any one of the preceding claims, wherein said compound has the general formula X shown below: WO 2006/024841 PCT/GB2005/003355 204 Rb Rlb CN N H NH2 /N X wherein R x b is as defined in claim 1 or any one of claims 4 to 6. 5
[11] 11. A compound according to any one of claims 2 to 7, wherein Rib is hydrogen and Ric is hydrogen.
[12] 12. A compound according to any one of claims 2 to 7, wherein Rlb is hydrogen and R a is selected from hydrogen or (1-3C)alkyl. 10
[13] 13. A compound which is any one of the following: N-(2-aminophenyl)-4-(3-cyanopyridin-2-yl)benzamide; N-(2-aminophenyl)-4- {3-cyano-6-[(2-hydroxyethyl)amino]-4-methylpyridin-2-yl}benzamide; N-(2-aminophenyl)-4-[3-cyano-5-(piperidin-1-ylmethyl)pyridin-2-yl]benzamide; 15 N-(2-aminophenyl)-4- {3-cyano-5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(diethylamino)methyl]pyridin-2-yl}benzamide; N-(2-aminophenyl)-4-[3-cyano-4-methyl-6-(4-methylpiperazin- 1 -yl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4-[3-cyano-5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(3-phenylpyrrolidin- 1 -yl)methyl]pyridin-2-yl}benzamide; 20 N-(2-aminophenyl)-4- {3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2 yl}benzamide; N-(2-aminophenyl)-4-[3-cyano-5-(piperazin-1-ylmethyl)pyridin-2-yl]benzamide; WO 2006/024841 PCT1GB20051003355 205 N-(2-amninophenyl)-4- {3-cyano-5-[(4-methylpiperazii- 1 -yl)methyl]pyridin-2-yl} benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(4-ethylpiperazin- 1 -yl)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(3-pyridin-2-ylpyrrolidin- 1 -yl)methyl]pyridin-2 yllbenzamide; 5 N-(2-amiinophenyl)-4-(3 -cyano-5 - [(2R,5R)-2,5-dimethylpyrrolidin- 1-y1]rmt-Cihy1}pyridin-2 yl)benzamide; N-(2-aminophenyl)-4- f{3-cyario-5-[(4-hydroxypiperidin- 1 -yl)methyl]pyridin-2-yllbenzarnide; N-(2-aminophenyl)-4-(3 -cyano-5- {[4-(trifluoromethyl)piperidin- 1-yl]methyllpyridin-2 yl)benzamide; 10 N-(2-aminophenyl)-4- {3 -cyano-5-[(4-morpholin-4-ylpiperidin- 1 -yl)methyl]pyridini-2 yl~benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(3 ,3 -dinaethylpiperidin- 1-yl)methyl]pyridin-2 yl} benzamide; N-(2-aminophenyl)-4-[5-(azetidin- 1 -ylmethyl)-3-cyanopyridin-2-yl]benzamide; 15 N-(2-aminophenyl)-4-(3 -cyano-5- {[4-(2-oxopyrrolidin- 1-yl)piperidin- 1-yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4- {3 -cyano-5-[(4-pyrrolidin- 1-ylpiperidin- 1 -yl)methyl]pyridin-2 yl~benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[(cyclobutylmethyl) (methyl) amino]methyllpyridin-2 20 yl)benzamide; N-(2-amninophenyl)-4-(3-cyano-5- f [(2 -methoxyethyl) (methyl)amino]methyllpyridin-2 yl)benzamnide; N-(2-aminophenyl)-4-(3 -cyano-5- f{[(3S)-3-(dimethylamino)pyrrolidin- 1 -ylljmethyllpyridin-2 yl)benzamide; 25 N-(2-aminophenyl)-4-(3 -cyano-5- {[(isopropy1)(2-rnethoxyethy1)amino]methyllpyridin-2 yl)benzamide; WO 2006/024841 PCT1GB20051003355 206 N-(2-aminophenyl)-4- { 3 -cyano-5-[(4-pyridin-4-ylpiperidin- 1 -yl)methyl]pyridin-2 yl} benzamide; N-(2-aminophenyl)-4-[5-(7-azabicyclo[2.2. 1]hept-7-yllmethyl)-3 -cyanopyridin-2 yl]benzamide; s N-(2-aminophenyl)-4-(3-cyano-5- {[(cyclopropylmethyl)arnino]methyl} pyridin-2 yl)benzamide; N-(2-aminophenyl)-4-[5-(2-azabicyclo[2.2.2]oct-2-ylmethyl)-3 -cyanopyridin-2-yl]benzamide; N-(2-aminophenyl)-4-[3-cyano-6-methyl-5-(1 -piperidin-1 -ylethyl)pyridin-2-yl]benzamnide; N-(2-aminophenyl)-4-(3-cyano-5 - {[4-(4-methylpiperazin- 1 -yl)piperidin- 1 -yllmethyllpyridin 10 2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f [isopropyl(methyl)aminolmethyllpyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[ethyl(2-methoxyethyl) amino] methyl~pyridin-2 yl)benzamide; N-(2-arninophenyl)-4-(3-cyano-5- {[methy1(propy)amino]methy1}pyridin-2-y1)benzamide; i5 4- f{5-[(4-allylpiperazin- 1 -yl)methyl]-3-cyanopyridin-2-yl} -N-(2-aminophenyl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f [4-(2-methoxyethiyl)piperazin- 1 -yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-[3-cyano-5-( { [2-(dimethylamino)ethyl] amino Imethyl)pyridin-2 yl]benzar-nide; 20 N-(2-aminophenyl)-4- [3 -cyano-5 -( {[2-(diethylamino)ethyl] amino} methyl)pyridin-2 yl]benzamide; N-(2-arninophenyl)-4-(3-cyano-5- {[(2-pyrrolidin- 1 -ylethyl)amino]methyl}pyridin-2 yl)benzamide; N-(2-amiinophenyl)-4-(3 -cyano-5- {[(2-piperidin- 1-ylethyl)amino]methyllpyridin-2 25 yl)benzamide; N-(2-amiuophenyl)-4-(3-cyano-5- {[4-(3-cyanopyridin-2-yl)piperazin- 1-yl]methyllpyridin-2 yl)benzamide; WO 2006/024841 PCT1GB20051003355 207 N-(2-aminophenyl)-4-[3-cyano-5-( {4-[2-(dimethylamino)ethyl]piperazin- 1 yllmethyl)pyridin-2-yl]benzamide; N-(2-ancinophenyl)-4- { 3 -cyano-5-[(4-pyridini-2-ylpiperazin-l1-yl)methyllpyridin-2 yllbenzamnide; 5 N-(2-aminophenyl)-4-(3-cyano-5- f{[[2-(dimethylamino)ethyl] (methyl)amino]methyllpyridin 2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[[2-(diethylamino)ethyl] (methyl) aminolmethyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4- 3 -cyano-5-[(propylamino)methyl]pyridin-2-yllbenzamide; 10 N-(2-aminophenyl)-4- f{5-[(butylamino)methyl]-3-cyanopyridin-2-yllbenzamide; N-(2-amTinophenyl)-4- {5-[(sec-butylamino)methyl] -3-cyanopyridin-2-yllbenzamnide; N-(2-aminophenyl)-4- {3-cyano-5 -I(cyclobutylamino)methyl]pyridin-2-yllbenzamide; N-(2--aminophenyl)-4- {3-cyano-5-[(isopropylamino)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(isobutylamnino)methyl]pyriclin-2-yl} be 1 zamnide; 1s 4- {5-[(allylamino)methyl]-3-cyanopyridin-2-ylI -N-(2-aminophenyl)benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(cyclopentylaminio)methy1]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- f{3-cyano-5-[(ethylamino)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- f{3-cyano-5 -[(4-pyrazin-2-ylpiperazin- 1 -yl)methyl]pyridin-2 yl}benzamide; 20 N-(2-amninophenyl)-4-[3-cyano-5-( {[2-(dimethylamino)- 1 methylethyl] amino) methyl)pyridin-2-yl]benzamide; N-(2-amTinophenyl)-4-(3 -cyano-5- {[3-(methylamnino)pyrrolidin- 1-yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f{[4-(2-cyanophenyl)piperazin- 1 -yl]methyllpyridin-2 25 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[ 4 -(3-cyanopyrazin-2-yl)piperazin- 1-yl]methyllpyridin-2 yl)benzamide; WO 2006/024841 PCT1GB20051003355 208 N-(2-aminophenyl)-4- {3-cyano-5-[ 1 -(ethylamino)ethyl]-6-methylpyridin-2-yl} benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(methylamino)methyl]pyridin-2-yllbenzamide; N-(2-amiliophenyl)-4-(3-cyano-5- {[(3R)-3-hydroxypyrrolidin- 1 -yflmethyl} pyridin-2 yl)benzamide; 5 N-(2-amninophenyl)-4-(3-cyano-5- { [(3R)-3 -fluoropyrrolidin- 1 -yl]methyl}pyridin-2 yl)benzamide; N-(2-aminoplienyl)-4-(3-cyano-5- f{[(2-hydroxyethyl)(methyl)aminolmethyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[4-(ethylsulfonyl)piperazin- 1 -yllmethyllpyridin-2 10 yl)benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(4-pyrimidin-2-ylpiperazin- 1-yl)methyl]pyridin-2 yllbenzamnide; 4 -( 5 -amino-3-cyano-.6-miethylpyridin-2-yl)-N-(2-aminophenyl)benzamide; N-(2-aminophenyl)-4-[3-cyano-5-( { [(1R)- 1 -methylpropyllaminolmethyl)py-ridin-2 15 yl]benzamide; N-(2-aminophenyl)-4-[3 -cyano-5-( {[(1 S)- I -methyipropyl] amino }methyl)pyridin-2 yl]benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[4-(methylsulfonyl)piperazin- 1-yl]methyllpyridin-2 yl)benzamide; 20 N-(2-aminophenyl)-4- [3-cyanio-5-( { [2-(2-methyl- 1H-indol-3-yl)ethyl] amino Imethyl)pyridin 2-yl]benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {II2-(isopropylamino)ethoxy]methy1}pyridin-2 yl)benzamide; N-(2-amninophenyl)-4-(3-cyano-5- { [2-(ethlylamino)ethoxy]methyl}pyridin-2-yl)benzamide; 25 N-(2-aminophenyl)-4-(3 -cyano-5- {[2-(methylamino)ethoxy]methyllpyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5-methylpyridin-2-y)benzamide; N-( 2 -aminophenyl)-4-[3-cyano-4-(dimethylainino)pyricin2yl]benzamide; WO 2006/024841 PCT1GB20051003355 209 N-(2-amninophenyl)-4-[3-cyano-6-(ethylamino)-4-methypyrdin-2y11bepnzajde; N-(2-aminophenyl)-4-(3-cyano-4,6-dimethylpyridin-2-yl)benzamide; N-(2-amninophenyl)-4-(3-cyano-6-methylpyridil-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyanio-5- f [4-(2-oxo-2-pyrrolidin- 1 -ylethyl)piperazin- 1 5 ylllmethyllpyridin-2-yl)benzamnide; N-(2-amninophenyl)-4-(3-cyano-5- {[4-(2-hydroxyethyl)piperazin- 1 -yllmethyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- I [(lR,55)-6-(hydroxymethyl)-3-azabicyclo[3. 1 .]hex-3 yl]rnethyllpyridin-2-yl)benzamnide; 10 N-(2-amiliophenyl)-4- f{3-cyano-5-[(4-hydroxymethylpiperidin- 1 -yl)methyl]pyridin-2 yl~benzamide; 4- {5-[(4-acetylpiperazin- 1-yl)methyl]-3-cyanopyridin-2-yl} -N-(2-aminophc ry1)benzamide; N-(2-amiliophenyl)-4- f{3-cyano-5-[(3-hydroxypiperidin- 1 -yl)methyl]pyridin-2-yl} benzamide; N-(2-aminopheniyl)-4- {5- [(5-butyrylhexahydropyrrolo[3 ,4-clpyrrol-2(IH)-yl)methyl]-3 15 cyanopyridin-2-yllbenzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[(2-hydroxyethy1)(ethy1)amino]methy1}pyridin-2 yl)benzamnide; N-(2-aminophenyl)-4-(3 -cyano-5- f{[(2-methoxyethyl)amino]methyllpyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f{[ethyl(methyl)arnino]methyllpyridin-2-yl)benzamide; 2o N-(2-aminophenyl)-4- {3-cyano-5-[(3-phenylpiperidin- 1 -yl)methyl]pyridin-2-yllbenzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(4-phenylpiperidin- 1-yl)methyl]pyridin-2-yl}benzarnide; N-(2-amninophenyl)-4-(3-cyano-5- {[3-(4-fluorophenyl)piperidin- 1-yl]methyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- f [4-(morpholin-4-ylcarbonyl)piperidin- 1 25 yl]methyllpyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3 -cyano-5- {[3-(diethylamino)pyrrolidin- 1-yl]methyllpyridin-2 yl)benzamide; WO 2006/024841 PCT1GB20051003355 210 N-(2--aminophenyl)-4-(5- { [butyl(methyl)amino]methyl} -3 -cyanopyridin-2-yl)benzamide; N-( 2 -aminophenyl)-4-(3-cyano-6-nitropyridin-2-yl)benzamide; N-( 2 -amninophenyl)-4-[3-cyano-6-(4-fluoropheny)pyridin-2-y1Ibenzamide; 4 -( 6 -amino- 3 , 5 -dicyanopyridin-2-yl)-N-(2-aminophenyl)benzamide; 5 N-(2-.aminophenyl)-4-(3-cyano-5- {[4-(cyclopropylcarbonyl)piperazin- 1 -ylltmethyllpyridin-2 yl)benzamide; N-(2-aminophenyl)-4- { 3 -cyano-5-[(methylamino)methyl]pyridin-2-yl}benzamide; N-(2-aminophenyl)-4-[3-cyano-5-( {[(1 ,3-dimethyl- 1H-pyrazol-5 yl)methyl]aminolmethyl)pyridin-2-yl]benzamide; 10 N-(2-aminophenyl)-4-[3 -cyano-5-( {[2-(3,5-dimethyl- 1H-pyrazol-4 yl)ethyl] amino} methyl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[(2-methoxy- I -methylethyl)amino]methyllpyridin-2 yl)benzamnide; N-(2-aminophenyl)-4-(3-cyano-5- f{[(3-methoxypropyl)amino]methyllpyridin-2 15 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [(2-methoxybenzyl)amino]methyllpyridini-2 yl)benzamide; N-(2-aminophenyl)-4-(3 -cyano-5- {[(3-methoxybenzyl)amino]methyl}pyridin-2 yl)benzamide; 20 N-(2-aminophenyl)-4-(3-cyano-5- {[(3-isopropoxypropyl)amnino]methyl}pyridin-2 yl)benzamide; N-(2-aminophenyl)-4- f{3-cyario-5- [( { [6-(trifluoromethyl)pyridin-3 yl]methyl} amiino)methyl]pyridin-2-yl}benzamnide; N-(2-aminophenyl)-4-[3-cyano-5-( {[(4-methyl- 1,3-thiazol-2 25 yl)methyl] amino Imethyl)pyridin-2-yl]benzamide; N-(2-aminophenyl)-4-[3-cyano-5-( {[2-(1 -methyl- 1H-imidazol-4 yl)ethyl] amino Imethyl)pyridin-2-yl]benzamide; WO 2006/024841 PCT/GB2005/003355 211 N-(2-aminophenyl)-4-(3-cyano-5- {[(tetrahydrofuran-2-ylmethyl)amino]methyl}pyridin-2 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[( 2 -isopropoxyethyl)amino]methyl}pyridin-2 5 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [(3-ethoxypropyl)amino]methyl} pyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[( 2 -propoxyethyl)amino]methyl}pyridin-2-yl)benzamide; N-(2-aminophenyl)-4-[3-cyano-5-({[(5-methyl-2-furyl)methyl]amino}methyl)pyridin-2 yl]benzamide; 10 N-(2-aminophenyl)-4-(3-cyano-5- { [(tetrahydro-2H-pyran-4-ylmethyl)amir 2]methyl} pyridin 2-yl)benzamide; N-(2-aminophenyl)-4- {3-cyano-5-[(tetrahydro-2H-pyran-4-ylamino)methyl]pyridin-2 yl}benzamide; N-(2-aminophenyl)-4-(3-cyano-5- { [(2-methoxy-2-methylpropyl)amino]methyl}pyridin-2 15 yl)benzamide; N-(2-aminophenyl)-4-(3-cyano-5- {[methyl(tetrahydrofuran-2 ylmethyl)amino]methyl}pyridin-2-yl)benzamide; N-(2-aminophenyl)-4-(5- { [bis(2-methoxyethyl)amino]methyl} -3-cyanopyridin-2 yl)benzamide; 20 or a pharmaceutically acceptable salt thereof
[14] 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 in association with a pharmaceutically-acceptable diluent or carrier. 25
[15] 15. A compound according to any one of claims 1 to 13 for use as a medicament. WO 2006/024841 PCT/GB2005/003355 212
[16] 16. The use of a compound according to anyone of claims 1 to 13 in the manufacture of a medicament for use in the production of a HDAC inhibitory effect in a warm-blooded animal such as man. 5
[17] 17. A method for producing a HDAC inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 13.
[18] 18. Use of a compound of the formula (I) in the manufacture of a medicament for use in io the treatment or prevention of cancer.
[19] 19. A method of treating or preventing cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 13. 15
[20] 20. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for use in the treatment of inflammatory diseases, autoinunmmune diseases and allergic/atopic diseases in a warm-blooded animal such as man. 20
[21] 21. A method of treating inflammatory diseases, autoimmune diseases and allergic/atopic diseases in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 13. 25
[22] 22. A process for preparing a compound according to claim 1, said process comprising the steps of: (a) the reaction of a compound of the formula (A) WO 2006/024841 PCT/GB2005/003355 213 X R4 H N (R 2 ) (R3)n (A) wherein X is a reactive group, with a compound of the formula (B) RIC. Rib' CN Ra' N ML Z 5 (B) wherein Ria' is a group R 1 a as defined in any one of claims 1 to 13 or a precursor thereof, Rb' is a group Rlb as defined in any one of claims 1 to 13 or a precursor 10 thereof, RIC' is a group RIc as defined in any one of claims 1 to 13 or a precursor thereof, M is a metal, L is a ligand, and 15 integer z is 0 to 3; and wherein if any one of said groups R la' , Rb' or R" ' is a precursor for a Ria, Rlb or Ric group respectively, then said process thereafter comprises a step of converting the compound formed by the reaction of a compound of the formula (A) with a compound of the formula (B) to a compound of formula (I) (by converting the precursor of any 20 one of groups R 1 a, RIb or R 1 c group to the appropriate R l ia Rlb or Ric group); or (b) The reaction of a compound of the formula (C) WO 2006/024841 PCT/GB2005/003355 214 LzM R4 H IN (R 2 )m 0 (R3)n (C) wherein M, L and integer z are as defined for process (a) above, with a compound of the formula (D) 5 Rc' Rlb' CN RIa' N x (D) wherein Ri a' , Rib' and Ric' are as defined for process (a) above and X is a reactive group; 10 and wherein if any one of said groups R a' , Rib' or R l c' is a precursor for a R la , Rl b or Ric group respectively, then said process comprises an additional step thereafter of converting the compound formed by the reaction of a compound of the formula (C) with a compound of the formula (D) to a compound of formula (I) (by converting the precursor of any one of groups R a , Rlb or R 1 c group to the appropriate R a , Rlb or R 1 l is group); or (c) the reaction, in the presence of 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4 methylmorpholinium chloride, of a compound of the formula (E) WO 2006/024841 PCT/GB2005/003355 215 0 HN O H 2 N (R3 )n (E) with a compound of the formula (F) Rio' R1 G'O Rib'CN N Rla' OH (R 2 )m 0 (F) wherein R l a' Rb' and RI c' are as defined for process (a) above, and wherein if any one of said groups Ri a ' , R1b' or Ric' is a precursor for a Ria, Rib or Ric group respectively, then said process comprises an additional step thereafter of converting the compound 10 formed by the reaction of a compound of the formula (E) with a compound of the formula (F) to a compound of formula (I) (by converting the precursor of any one of groups R l a , Rlb or Ri group to the appropriate R la , R l b or R group); and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); and/or 15 ii) removing any protecting groups.
[23] 23. A process for preparing a compound of formula (D') WO 2006/024841 PCT/GB2005/003355 216 R7 CN N O R 8 N X (D') wherein R 7 and R 8 are as defined in any one of claims 1 to 10, but with the proviso that R 7 and R are not hydrogen, said process comprising the steps of: 5 (i) reacting, in a suitable solvent, a substituted acrolein of formula (J), wherein R 50 is a suitable leaving group, R5 0 with formaldehyde and a compound of formula (H) R7 R8 H 10 (H) to form a compound of formula (L); R50 RT N R 8 0 (L) (ii) reacting, in a suitable solvent and in the presence of a suitable base, the compound 15is of formula (L) prepared in step (i) above with 2-cyanoacetamide to form a compound of formula (M) as a metal salt; and WO 2006/024841 PCT/GB2005/003355 217 R7N N R8 N 0 (iii) converting compound (M) to compounds of formula (D') 5 and thereafter, if necessary, removing any protecting groups.

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MX2007002612A|2007-04-27|

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AR050926A1|2006-12-06|

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JP4932720B2|2012-05-16|

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NO20071222L|2007-05-31|

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AU2005278966B2|2009-09-17|

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法律状态:
2010-01-21| FGA| Letters patent sealed or granted (standard patent)|

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2017-03-23| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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GB0419565A|GB0419565D0|2004-09-03|2004-09-03|Benzamide compounds|

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GB0419565.7||2004-09-03||

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GB0502545.7||2005-01-08||

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GB0502545A|GB0502545D0|2005-02-08|2005-02-08|Benzamide compounds|

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GB0506165.0||2005-03-29||

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GB0506165A|GB0506165D0|2005-03-29|2005-03-29|Benzamide compounds|

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PCT/GB2005/003355|WO2006024841A2|2004-09-03|2005-08-31|Benzamide compounds|

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