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Definitions

• the invention relates to compounds which are inhibitors of p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for example the alpha and gamma kinase sub-types thereof, and their use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, such as COPD.
• p38 mitogen-activated protein kinase enzymes referred to herein as p38 mitogen-activated protein kinase enzymes
• p38 MAP kinase inhibitors inhibitors which are inhibitors of p38 mitogen-activated protein kinase enzymes
• alpha and gamma kinase sub-types thereof for example the alpha and gamma kinase sub-types thereof
• p38 MAPK isoforms (alpha, beta, gamma and delta respectively) have been identified, each displaying a tissue-specific expression pattern.
• the p38 MAPK alpha and beta isoforms are ubiquitously expressed throughout the body and are found in many different cell types.
• the p38 MAPK alpha and beta isoforms are inhibited by certain known small molecule p38 MAPK inhibitors. Earlier generations of compounds were highly toxic due to the ubiquitous expression pattern of these isoforms and off-target effects of the compounds. More recent inhibitors are improved to be highly selective for p38 MAPK alpha and beta isoforms and have a wider safety margin.
• p38 MAPK gamma and delta isoforms are expressed in specific tissues/cells (unlike the p38 alpha and p38 beta isoforms).
• the p38 MAPK-delta isoform is expressed more in the pancreas, testes, lung, small intestine and kidney. It is also abundant in macrophages and detectable in neutrophils, CD4+ T cells and endothelial cells (Shmueli, O. et al., Comptes Rendus Biologies 326(10-11 ): 1067-1072, (2003)/Genecard; Smith, S. J. Br. J. Pharmacol., 2006, 149:393-404; Hale, K.
• BIRB 796 Selective small molecule inhibitors of p38 MAPK-gamma and p38 MAPK-delta are not currently available, although one existing compound, BIRB 796, is known to have pan- isoform inhibitory activity.
• the p38 MAPK gamma and delta isoform inhibition is observed at higher concentrations of the compound than those required to inhibit p38 MAPK alpha and p38 beta (Kuma, Y. J. Biol. Chem., 2005, 280:19472-19479).
• BIRB 796 also impaired the phosphorylation of p38 MAPKs or JNKs by the upstream kinase MKK6 or MKK4.
• p38 MAP kinase is believed to play a pivotal role in many of the signalling pathways that are involved in initiating and maintaining chronic, persistent inflammation in human disease, for example, in severe asthma and COPD.
• p38 MAP kinase is activated by a range of pro-inflammatory cytokines and that its activation results in the recruitment and release of further pro-inflammatory cytokines.
• COPD is a condition in which the underlying inflammation is reported to be substantially resistant to the anti-inflammatory effects of inhaled corticosteroids. Consequently, a superior strategy for treating COPD would be to develop an intervention which has both inherent antiinflammatory effects and the ability to increase the sensitivity of the lung tissues of COPD patients to inhaled corticosteroids.
• the recent publication of Mercado et al (2007; American Thoracic Society Abstract A56) demonstrates that silencing p38 gamma has the potential to restore sensitivity to corticosteroids. Thus there may be a "two pronged" benefit to the use of a p38 MAP kinase inhibitor for the treatment of COPD and severe asthma.
• An objective of the present invention is to provide compounds which inhibit p38 MAP kinase, for example with certain sub-type specificity, which show good anti-inflammatory potential, in particular suitable for use in therapy.
• Ar is a naphthylene or phenyl ring either of which may be optionally substituted by one or more groups (e.g. 1 , 2 or 3 groups) independently selected from Ci -6 alkyl, Ci -6 alkoxy, amino, C1-4 mono alkyl amino and C2-8 di-alkyl amino;
• groups e.g. 1 , 2 or 3 groups
• Q is N, or CH
• R 1 is H , phenyl, or a saturated or unsaturated branched or unbranched CMO alkylene in the form of an acyclic or alicyclic chain wherein one or more carbons in the chain (for example 1 to 3, such as 1 , 2 or 3 carbons) are optionally replaced by a heteroatom(s) independently selected from -0-, -N- and S(0) n and the chain is optionally substituted by:
• halogen atoms for example 1 to 6
• R 2A is H, halo, saturated or unsaturated branched or unbranched Ci -8 alkylene chain, wherein one or more carbons (for example 1 to 3, such as 1 , 2 or 3 carbons) are optionally replaced by a heteroatom(s) independently selected from -0-, -N- and/or S(0) m and the chain is optionally substituted by one or more halogen atoms (for example 1 to 6);
• R 2B is H, halo, d -6 alkoxy or Ci -6 alkyl optionally substituted by OH;
• L is saturated or unsaturated branched or unbranched Ci-6 alkylene chain (such as a C1-3 alkylene), wherein one or more carbons (for example 1 to 3, such as 1 , 2 or 3 carbons) are optionally replaced by a heteroatom selected from -O- and/or S, and the chain is optionally substituted by one or two oxo groups (for example 1 or 2);
• X is a pyridine or pyrimidine ring optionally substituted by Ci -3 alkyl, or Ci -3 haloalkyl; is H or C-i-4 alkyl;
• R 4 is selected from: a) a saturated or unsaturated, branched or unbranched CMO alkyl chain, wherein optionally at least one carbon (for example 1 , 2 or 3 carbons, suitably 1 or 2, in particular 1 carbon) is replaced by a heteroatom independently selected from 0, N, S(0) p , wherein said chain is optionally, substituted by one or more groups (for example 1 , 2 or 3 groups) independently selected from oxo, halogen, a C 6- io aryl group, a 5 or 6 membered heteroaryl group, a 5 or 6 membered heterocyclyl group or a C 3 -8 cycloalkyl group,
• the heterocyclyl group has 5 or 6 members and comprises at least one heteroatom (for example 1 , 2 or 3, suitably 1 or 2, in particular 1 heteroatom) selected from O, N, and S, and said heterocycle is optionally substituted by one, two or three groups independently selected from halogen, hydroxyl, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono and C 2 -e di-alkyl amino, C1-4 mono or C2-8 di-acyl amino, S(0) q Ci -6 alkyl, C 0- 6 alkylC(0)Ci -6 alkyl, C 0- 6 alkylC(O)NC 0 -6 alkyl C 0 . 6 alkyl or C 0 . 6 alkylC(O)C
• n 0, 1 or 2;
• p 0, 1 or 2;
• q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof with the proviso that when:
• L represents a saturated or unsaturated branched or unbranched Ci -8 alkylene chain wherein one or more carbons are optionally replaced by -O- and the chain is optionally substituted by one or more halogen atoms, and
• R 1 is C1-6 alkyl optionally substituted by a hydroxyl group
• J represents: wherein Q is CH
• R 2a is hydrogen
• R 2b does not represent H or Ci_6 alkyl optionally substituted by a hydroxyl group.
• Alkyl as used herein refers to straight chain or branched chain alkyl, such as, without limitation, methyl, ethyl, n-propyl, /so-propyl, butyl, n-butyl and ferf-butyl. In one embodiment alkyl refers to straight chain alkyl. Alkylene is to be interpreted in a similar manner to alkyl.
• An acyclic chain refers to a chain without ring atoms.
• An alicyclic chain refers to an aliphatic chain with ring atoms.
• Alkoxy as used herein refers to straight or branched chain alkoxy, for example methoxy, ethoxy, propoxy, butoxy. Alkoxy as employed herein also extends to embodiments in which the oxygen atom is located within the alkyl chain, for example -Ci_ 3 alkylOCi_ 3 alkyl, such as - CH 2 CH 2 OCH 3 or -CH 2 OCH 3 . Thus in one embodiment the alkoxy is linked through carbon to the remainder of the molecule. In one embodiment the alkoxy is linked through oxygen to the remainder of the molecule, for example -OCi_ 6 alkyl. In one embodiment the disclosure relates to a straight chain alkoxy.
• Heteroalkyl as employed herein is intended to refer to a branched or straight chain alkyl wherein one or more, such as 1 , 2 or 3 carbons are replaced by a heteroatom, selected from N, O or S(0) r , wherein r represents 0, 1 or 2.
• the heteroatom may replace a primary, secondary or tertiary carbon, that is, for example, SH, OH or NH 2 for CH 3 , or NH or O or S0 2 for -CH 2 - or N for a -CH- or a branched tertiary carbon, as technically appropriate.
• HaloalkyI refers to alkyl groups having 1 to 6 halogen atoms, for example 1 to 5 halogens, including perhaloalkyl, in particular perchloroalkyl or perfluoroalkyl, more specifically -CCI 3 , -CF 2 CF 3 or CF 3 .
• C 1 -4 mono acyl amino and C 2 -8 di-acyl amino are intended to refer to -NHC(0)Ci-4 alkyl and to alkyl) respectively.
• C 1 -4 mono alkyl amino and C 2- s di-alkyl amino are intended to refer to -NHC 1 .4 alkyl and to - N(Ci-4 alkyl) (C 1 .4 alkyl) respectively.
• Aryl as used herein refers to, for example C6-14 mono or polycyclic systems having from 1 to 3 rings wherein at least one ring is aromatic including phenyl, naphthyl, anthracenyl, 1 ,2,3,4- tetrahydronaphthyl and the like, such as phenyl and naphthyl.
• Heteroaryl is a 6 to 10 membered aromatic monocylic ring or bicyclic ring system wherein at least one ring is an aromatic nucleus comprising one or more, for example 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S.
• heteroaryls include: pyrrole, oxazole, thiazole, isothiazole, imidazole, pyrazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, benzothiophene, benzofuran, or 1 , 2, 3 and 1 , 2, 4 triazole.
• Heterocyclyl as employed herein refers to a 5 to 6 membered saturated or partially unsaturated non-aromatic ring comprising one or more, for example 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S optionally one or two carbons in the ring may bear an oxo substituent.
• the definition of C 5-6 heterocycle as employed herein refers to a 5 to 6 membered saturated or partially unsaturated non-aromatic carbocyclic ring comprising one or more, for example 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein each heteroatom replaces a carbon atom and optionally one or two carbons may bear an oxo substitutent.
• any valancies of a heteroatom not employed in forming or retaining the ring structure may be filled by hydrogen or a substituent, as appropriate.
• subsituents on heterocycles may be on carbon or on a heteroatom, such as nitrogen, as appropriate.
• heterocycles and C 5 -6 heterocycles include pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxoimidazolidine, dioxolane, thiazolidine, isoxazolidine, pyran, dihydropyran, piperidine, piperazine, morpholine, dioxane, thiomorpholine and oxathiane.
• Halogen includes fluoro, chloro, bromo or iodo, in particular fluoro, chloro or bromo, especially fluoro or chloro.
• S(0) q Ci-6 alkyl may, for example, include -S0 2 Me.
• C 3-8 cycloalkyl as employed herein is intended to refer to a saturated or partially unsaturated non-aromatic ring containing 3 to 8 carbon atoms, where the ring contains less than 8 carbons the ring may optionally bear one or more alkyl groups such that the number of carbon atoms in the ring plus the number of carbons in the alkyl substituents is not more than eight in total or 10 in the case of C 3- io cycloalkyl.
• C-i-10 alkyl includes C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 or C 9 as well as Ci and C 10 .
• Co-8 alkyl includes Ci, C 2 , C 3 , C 4 , C 5 , C 6 , or C 7 as well as C 0 and C 8 .
• a saturated or unsaturated, branched or unbranched CMO alkyl chain (or similar language used herein), wherein at least one carbon (for example 1 , 2 or 3 carbons, suitably 1 or 2, in particular 1 ) is replaced by a heteroatom selected from O, N, S(0) p , wherein said chain is optionally, substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group or a heterocyclyl group
• Saturated or unsaturated, branched or unbranched CMO alkyl alicyclic chain is intended to refer to C 3- io cycloalkyl.
• R 1 is -Ci -6 alkyl (optionally substituted by OH) C3-10 cycloalkyl, C 3 . 10 heterocycloalkyl, Ci -6 haloalkyl, Ci -6 alkylOC(0)CH 3 .
• R 1 is methyl, ethyl, propyl, /so-propyl, butyl or ieri-butyl, in particular ieri-butyl.
• R 1 is -C(CH 3 ) 2 CH 2 OH.
• R 1 is cyclopropyl, or 1-methylcyclopropyl, cyclopentyl, cyclohexyl, or 1 -methylcyclohexyl, or adamantly. In one embodiment R 1 is tetrahydropyranyl or 4-methyltetrahydro-2 - -pyran-4-yl.
• R 1 is -CF 3 , -CF 2 CF 3 or -CCI 3 .
• R 1 is phenyl
• R 2a is in the 2, 3, or 4 position (i.e. ortho, meta or para position), in particular the para (4) position.
• R 2a is methyl, ethyl, n-propyl, /so-propyl, r/-butyl or ieri-butyl, in particular methyl, for example in position 3 or 4.
• R 2a is -OH, for example in position 3 or 4.
• R 2a is halo, such as chloro, for example in position 3 or 4.
• R is -Ci_ 6 alkyl substituted by a hydroxyl group such as - CH 2 OH, for example in position 3 or 4.
• R is -Ci -6 alkoxy, such as -OCH 3 , for example in position 3 or 4.
• R 2a is -SC1-6 alkyl, such as -SCH 3 , for example in position 3 or 4.
• R 2a is -SO2C1.6 alkyl, such as -SO 2 CH3 for example in the 3 or 4 position.
• R 2a is -OCF 3 , for example located in position 3 or 4.
• R 2a is -N R ' R " wherein R ' is H , -Ci -3 alkyl or -S0 2 Ci-3alkyl, and R " is H or -C1-3 alkyl, for example located in position 3 or 4. In one embodiment R 2a is -NH 2 , for example in position 3 or 4.
• R 2a is -N HS02CH 3 , for example in position 3 or 4.
• R 2b is H .
• R 2b is halo such as chloro, for example in position 3.
• R 2a is chloro and R 2 is chloro, for example 3,4-dichloro.
• R 2a chloro is and R 2b is -OCH 3 , for example in positions 3,4 respectively.
• R 2a is -OCH 3 and R 2 is -OCH 3 , for example in position 3,4.
• R 2a chloro is and R 2b is -OH , for example in position 3,4 respectively.
• At least one of R 2a or R 2b is not hydrogen. In one embodiment both R 2a and R 2 are not hydrogen
• the substituents R 2a and R 2 on the ring are pharmaceutically acceptable and do not include those of a highly reactive nature (such as a halogen atom disposed ortho to the heteroatom) such that compounds of formula (I) would be unstable and thereby unsuitable for their intended utility.
• J is pyridine and R 2a is methyl, ethyl, n-propyl, / ' so-propyl, n-butyl or ierf-butyl, in particular methyl, for example in position 2 or 3.
• J is pyridine and R is -Ci_ 6 alkyl substituted by a hydroxyl group such as -CH2OH, for example in position 2 or 3.
• J is pyridine and R 2a is -Ci -6 alkoxy, such as -OCH 3 , for example in position 2 or 3.
• J is pyridine and R 2a is -SCi -6 alkyl, such as -SCH 3 , for example in position 2 or 3.
• J is pyridine and R 2a is -S0 2 Ci. 6 alkyl, such as -S0 2 CH 3 for example in the 3 position.
• J is pyridine and R 2a is -OCF 3 , for example located in position 3.
• R 2a is -NR ' R " wherein R ' is H, -Ci_ 3 alkyl or -S0 2 Ci -3 alkyl, and R " is H or -Ci_ 3 alkyl, for example located in position 2 or 3.
• R 2a is -NH 2 , for example in position 2 or 3.
• J is pyridine and R 2a is -NHS0 2 CH 3 , for example in position 2 or position 3.
• J is pyridine and R 2b is H.
• L represents -OCH 2 - or -OCH 2 CH 2 -.
• X is pyridine
• R 3 is H.
• R 4 is selected from: a) a saturated or unsaturated, branched or unbranched C1-10 alkyl chain, wherein at least one carbon (for example 1 , 2 or 3 carbons, suitably 1 or 2, in particular 1 carbon) is replaced by a heteroatom independently selected from 0, N, S(0) p , wherein said chain is optionally, substituted by one or more groups (for example 1 , 2 or 3 groups) independently selected from oxo, halogen, a C 6 -io aryl group, a 5 or 6 membered heteroaryl group, a 5 or 6 membered heterocyclyl group or a C 3- 8 cycloalkyl group,
• the heterocyclyl group has 5 or 6 members and comprises at least one heteroatom (for example 1 , 2 or 3, suitably 1 or 2, in particular 1 heteroatom) selected from O, N, and S, and said heterocycle is optionally substituted by one, two or three groups independently selected from halogen, hydroxyl, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono and C 2 .
• carbon atoms are replaced in the alkyl chain of R 4 by heteroatoms independently selected from O, N, S(0) p .
• the heteroatom(s) replacing carbon(s) in the alkyl chain fragment of R 4 are selected from N and O.
• the fragment R 4 is a saturated or unsaturated, branched or unbranched Ci -10 alkyl chain wherein at least one carbon (for example 1 , 2, 3 or 4 carbons, in particular 1 or 2 carbons) is replaced by a heteroatom selected from O, N, S(0) p , wherein said chain is optionally substituted by one or more groups selected from oxo, halogen, an aryl group, a heteroaryl group, a heterocyclyl group, or a C 3-8 cycloalkyl each aryl, heteroaryl, heterocyclyl or cycloalkyl group as per defined above for compounds of formula (I).
• R 4 is a saturated or unsaturated, branched or unbranched Ci -8 alkyl chain or a Ci -6 alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from -O, -N, S(0) p .
• the alkyl chain may be a C 2-8 alkyl or a C 3- 6 alkyl group, such as a C 4 alkyl or a C 5 alkyl group.
• a nitrogen atom in the alkyl chain of R 4 is directly bonded to the carbonyl of the fragment -NR 3 C(0) and additionally may, for example, be a terminal amino group.
• R 4 represents N(Ci -4 alkyl)Ci -4 alkyl, NHC 1 -9 alkyl or NH 2 .
• R 4 represents -NHCi -6 alkyl such as -NHCH 3 or -NHCH 2 CH 3 or -NHCH(CH 3 ) 2 .
• the CMO alkyl chain of R 4 is substituted by at least or only one oxo group, for example substitution on the chain consists of a single oxo group.
• the CMO alkyl chain of R 4 is substituted by at least or only 1 , 2, 3, 4, 5 or 6 halogen atoms.
• R 4 is Ci -4 alkyl-V-R 5 , such as Ci -3 alkyl-V-R 5 wherein: V is a heteroatom selected from NR V , O or S(0) p ;
• R v represents H or Ci_ 3 alkyl
• R 5 is H or -C-I.3 alkyl, and p is as defined above,
• the total alkyl chain length is not more than 10 carbon atoms, including replacement heteroatoms and that the resulting radical R 4 is a stable group, for example -CH2SCH3, -CH2SO2CH3, -CH2NHCH3, -CH 2 N(CH 3 ) 2 -C(CH 3 ) 2 NHCH 3 , -CH(CH 3 )N(CH 3 ) 2 , -(CH 2 ) 3 CH NHCH3, -(CH2)3N(CH 3 )2, -CH 2 OH, -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , or -(CH 2 ) 2 OCH 3 .
• R 4 is Ci_ 3 alkyl-V-(C 2 - 3 alkyl-Z-R 6 ) k wherein:
• V is a heteroatom selected from N , NH, O or S(0) p , such as N or NH
• Z is independently selected from NH, O or S(0) p ;
• R 6 is H or -C 1-3 alkyl
• k is an integer 1 or 2 (such as 1 );
• R 4 is C-
• R 4 is Ci -3 alkyl-V-C 2 - 3 alkyl-Z-C 2 - 3 alkyl-Y-R 7 , wherein
• V, Z and Y are independently a heteroatom selected from NH, O or S(0) p ,
• R 7 is H or methyl
• R 4 is -CH 2 V(CH2)20(CH 2 )20CH3, such as -CH 2 0(CH2)20(CH 2 ) 2 OCH3, -CH 2 NH(CH2)20(CH 2 )20CH3, or-CH 2 S(CH2)20(CH 2 )20CH3.
• R 4 represents -NR 8 R 9 and thus -NR 3 C(0)R 4 forms a urea, where R 8 and R 9 independently represent hydrogen or a Ci -9 saturated or unsaturated, branched or unbranched alkyl chain, wherein one or more carbons, such as 1 , 2 or 3 are optionally replaced by a heteroatom selected from O, N or S(0) p .
• Said chain is optionally substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group, a heterocyclyl or C 3- 8 cycloalkyl group (such as oxo, halogen, an aryl group, a heteroaryl group or a heterocyclyl group), each aryl, heteroaryl or heterocyclyl group bearing 0 to 3 substituents independently selected from the relevant substituents listed above for compounds of formula (I), for example halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, C 1 -4 mono or C 2 -8 di-alkyl amino and C 1 .4 mono or C 2 -8 di-acyl amino with the proviso that the total alkyl chain length is not more than 10 carbon atoms, including replacement heteroatoms and that the resulting radical R 4 is a stable group.
• R represents hydrogen.
• ureas include those in which R 8 and R 9 are both hydrogen and thus R 4 is -NH 2 , or where R 4 is -NHCH 3 or -N(CH 3 ) 2 thereby providing, for example, a fragment -NR 3 C(0)NH 2 or -NR 3 C(0)NHCH 3 or -NR 3 C(0)N(CH 3 ) 2 .
• ureas containing a heteroatom in the alkyl chain include those in which R 4 is -NH(CH 2 ) 2 OCH3 or -N[(CH 2 ) 2 OCH 3 )] 2 .
• R 4 represents -NHC 2-6 alkylOCi -3 alkyl, such as-NHCH 2 CH 2 OCH 3 .
• ureas containing an oxo substitutent include those in which R 4 is -NHCH 2 C(0)NH-C 2 . 3 alkyl-X 1 -Ci_ 3 alkyl, wherein X 1 is a heteroatom selected from N, O or S(0)p and p is defined as above. Examples of the latter include those wherein R 6 is -NHCH 2 C(0)NHCH 2 CH 2 OCH 3 .
• R 4 represents -NHC1-4 alkylC(0)NHC 2 alkylOCH 3 such as-NHCH 2 C(0)NHCH 2 CH 2 OCH 3 .
• R 4 represents -N HC1.4 alkylC(0)R 10 wherein R 10 is selected from OH or -NR 11 R 12 wh ere R 11 is hydrogen or Ci_ 3 alkyl and R 12 is hydrogen or Ci -3 alkyl, for example -NHCH 2 C(0)OH, -NHCH 2 C(0)NH 2 or -NHCH 2 C(0)NHCH 3 such as -NHCH 2 C(0)OH or -NHCH 2 C(0)NHCH 3 .
• R 4 represents -NHCi- 4 alkylC(0)OCi. 3 alkyl, such as
• R 4 represents -N(R 13 )C 2 . 3 alkyl-V-(C 2-3 alkyl-Z-R 14 ) k wherein:
• V represents N, NH, O, S(0) p ;
• Z represents NH, O, S(0) p ;
• k is an integer 1 or 2;
• p is an integer 0, 1 or 2
• R 13 represents H or C 2 . 3 alkyl-V-(C 2-3 alkyl-Z-R 14 ) k ;
• R 16 is H or C 1-3 alkyl such as Ci_ 3 alkyl
• the total alkyl chain length is not more than 10 carbon atoms, including replacement heteroatoms and that the resulting radical R 4 is a stable group.
• R 4 is a saturated or unsaturated, branched or unbranched CMO alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from O, N, and S(0) p , wherein said chain is substituted by an aryl group bearing 0 to 3 substituents, for example 1 , 2 or 3, such as 1 or 2 substituents independently selected from the relevant substituents listed above for compounds of formula (I), for example from halogen, Ci_6 alkyl, C1-6 alkoxy, Ci_6 haloalkyl, amino and C1-4 mono or C 2 _ 3 di-alkyl amino and C1-4 mono or C 2 _ 3 di-acyl amino, such as a saturated or unsaturated, branched or unbranched CMO alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from O, N, and S(0) p , wherein said chain is substituted by an aryl group bearing 0 to 3 substituents, for example 1 , 2 or 3, such as 1
• 4 represents -NHC 0 - 6 alkylphenyl, such as -NHphenyl or -NHbenzyl.
• fragment -N R 3 C(0)R 4 wherein R 4 comprises substituted benzyl
• R 4 comprises substituted benzyl
• examples of the fragment -N R 3 C(0)R 4 wherein R 4 comprises substituted benzyl include: -N R 3 C(0)CH 2 NHCH 2 C 6 H4(OCH3) such as -N HC(0)CH 2 NHCH 2 C 6 H4(OCH3), for example where the methoxy substituent is in the ortho, meta or para position, such as the para position.
• R 4 is a saturated or unsaturated, branched or unbranched Ci_io alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from O, N, and S(0) p , wherein said chain is substituted by a heteroaryl group bearing 0 to 3 substituents (for example 1 , 2 or 3, such as 1 or 2 substituents) independently selected from the relevant substituents listed above for compounds of formula (I), for example halogen, C 1-6 alkyl, Ci -6 alkoxy, Ci_ 6 alkyl amino, C- mono or C 2 .s di-alkyl amino and C1.
• C 2- s di-acyl amino such as a saturated or unsaturated, branched or unbranched CM O alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from O, N, and S(0) p , wherein said chain is substituted by a heteroaryl group bearing 0 to 3 substituents for example 1 , 2 or 3, such as 1 or 2 substituents selected from halogen, Ci -6 alkyl, Ci -S alkoxy, d -6 alkyl amino, C-
• the said heteroaryl group is selected from, thiophene, oxazole, thiazole, isothiazole, imidazole, pyrazole, isoxazole, isothiazole, oxadiazole, 1 ,2,3 or 1 ,2,4 triazole, pyridine, pyridazine, pyrimidine, pyrazine and, in particular pyridine and pyrimidine, especially pyridine.
• R 4 represents -NHCi. 6 alkylheteroaryl, for example -NH(CH 2 ) 3 imidazolyl or -NHCH 2 isoxazole wherein the isoxazole is optionally substituted such as -NHCH 2 isoxazole(CH 3 ).
• R 4 represents -NHC 1 . 4 alkylC(0)NHCi. 3 alkylheteroaryl, for example a nitrogen containing heteroaryl group or a nitrogen and oxygen containing heteroaryl, more specifically -NHCH 2 C(0)NHCH 2 CH 2 pyridinyl, in particular where pyridinyl is linked through carbon, for example pyridin-4-yl or -NHCH 2 C(0)NHCH 2 CH 2 CH 2 imidazolyl, in particular where imidazolyl is linked through nitrogen.
• R 4 is a saturated or unsaturated, branched or unbranched C-M O alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from O, N and S(0) p wherein said chain is substituted by a heterocyclyl group bearing 0 to 3 substituents (for example 1 , 2 or 3, such as 1 or 2 substituents) independently selected from the relevant substituents listed above for compounds of formula (I), for example halogen, C-i_ s alkyl, Ci_ 6 alkoxy, Ci -6 haloalkyl amino, C 1-4 mono or C 2 .
• substituents for example 1 , 2 or 3, such as 1 or 2 substituents
• Ci -4 mono or C 2-8 di-acyl amino such as a saturated or unsaturated, branched or unbranched C-M O alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from O, N and S(0) p wherein said chain is substituted by a heterocyclyl group bearing 0 to 3 substituents, for example 1 , 2 or 3, such as 1 or 2 substituents selected from halogen, Ci -6 alkyl, Ci -6 alkoxy, C-i-6 haloalkyl amino, Ci_ 4 mono or C 2- 8 di-alkyl amino.
• a heterocyclyl of R 4 is selected, from a 5 or 6 membered saturated or partially unsaturated ring system comprising one or more (for example 1 , 2 or 3 in particular 1 or 2) heteroatoms independently selected from O, N and S, for example pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, 1,4- dioxane, pyrrolidine and oxoimidazolidine such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, and 1 ,4-dioxane, in particular piperidine, piperazine, and morpholine.
• pyrrolidine tetrahydrofuran, tetrahydrothiophene
• piperidine piperazine, morpholine
• 1 ,4-dioxane in particular piperidine, piperazine,
• a heterocyclic group may be linked to the alkyl chain of R 6 or to the carbonyl of -NR 3 C(0)- through carbon or nitrogen, in particular a nitrogen atom.
• R 4 is -C0-3 alkylheterocycle (for example-Co-i alkylheterocycle) said heterocyclyl group comprising at least one heteroatom (for example 1, 2 or 3, in particular 1 or 2, heteroatoms) selected from 0, N and S, and is optionally substituted by one or two or three groups independently selected from the relevant substituents listed above for compounds of formula (I), for example halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, C1-4 mono and C2-8 di-alkyl amino and C1-4 mono or C2-8 di-acyl amino.
• R 4 is -Co alkylheterocycle, for example a tetrahydropyranyl or a pyrrolidinyl or a morpholinyl or a piperazinyl or an oxoimidazolinyl group, such as 2- oxoimidazolidinyl group.
• the heterocycle is linked through carbon, and is, for example, a C-linked tetrahydropyran or a C-linked piperidine or a C-linked morpholine or a C-linked piperazine.
• the heterocyclic group containing one or more N atoms is linked through N. This embodiment provides for ureas in which one of the urea nitrogens is embedded within a heterocyclic ring.
• Examples of this embodiment include, but are not limited to, an /V-linked morpholine or an /V-linked piperidine or an /V-linked piperazine, said /V-linked piperizinyl group optionally bearing an additional C- or N- substituent (such as an /V-methyl group or /V-CH 2 CH 2 OCH 3 group.
• R 4 is a heterocyclyl linked through nitrogen such as piperidinyl, in particular 4- hydroxypiperidinyl or piperazinyl, such as 4-methyl pierazinyl.
• R 4 represents a heterocyclyl group, for example a nitrogen containing heterocyclyl group, in particular linked through N, such as morpholinyl or piperazinyl optionally substituted by methyl, especially 4-methyl, or piperidinyl.
• R 4 represents tetrahydrofuranyl, morpholinyl, piperidinyl such as piperidinyl bearing one hyroxyl substituent, piperazinyl such as piperazinyl bearing one methyl substituent or pyrrolidinyl such a pyrrolidinyl bearing one di-methyl amino substituent.
• the ring may be linked through the heteroatom, such as nitrogen. Alternatively, the ring may be linked through carbon.
• the substituent may, for example be para relative to the atom through which the ring is linked to the remainder of the molecule.
• R 4 is a -Ci alkylheterocycle, for example tetrahydropyranylmethyl or a C- or /V-linked piperazinylmethyl optionally bearing a substituent (for example a Ci_ 6 alkyl substitutent such as methyl or a Ci_6 alkoxy substituent such as -CH2CH2OCH3).
• a substituent for example a Ci_ 6 alkyl substitutent such as methyl or a Ci_6 alkoxy substituent such as -CH2CH2OCH3
• Additional examples include a C- or N-linked pyrrolidinylmethyl, or a C- or N- linked oxoimidazolinylmethyl (such as 2-oxoimidazolidinylmethyl, said heterocycle optionally bearing a substitutent (such as /V-methyl or /V-S0 2 CH 3 ).
• R 4 represents -NH heterocyclyl (wherein the heterocyclyl bears 0 to 3 substituents selected from the relevant list of substituents listed above for compounds of formula (I), for example halogen, hydroxy, Ci -6 alkyl, C 1-6 alkoxy, Ci -6 haloalkyl, amino, Ci_ 4 mono or C 2- 8 di-alkyl amino, -S(0) q Ci -6 alkyl, Ci -4 mono or C 2 -s di-acyl amino, C 0-6 alkylC(0)Ci-6 alkyl or Co-6 alkylC(0)C-i_6 heteroalkyl), such as where the ring is linked through carbon, for example 2-piperidinyl or 3-piperidinyl or 4-piperidinyl, in particular 1 - acetylpiperidin-4-yl, 1 -methylpiperidin-4-yl, 1 -(methylsulfonyl)piperidin-4-yl or 1-(2-(2-methoxy eth
• R 4 represents -N HC1-6 alkylheterocyclyl for example a nitrogen containing heterocyclyl group, in particular one linked through nitrogen, such as -NHCH 2 CH 2 morpholine, -NH(CH 2 ) 3 morpholine or -NH(CH 2 ) 4 morpholine.
• R 4 represents -NHC 1-S alkylC(0)heterocyclyl (wherein the heterocyclyl bears 0 to 3 substituents selected from the relevant list of substituents listed above for compounds of formula (I), for example halogen, hydroxy, Ci. 6 alkyl, Ci.
• Ci -6 haloalkyl amino, C-i -4 mono or C 2-8 di-alkyl amino, Ci -4 mono or C 2-8 di-acyl amino, C 0- 6 alkylC(0)Ci-6 alkyl or C 0- 6 alkylC(0)Ci -6 heteroalkyl) for example a nitrogen containing heterocyclyl group, in particular one linked through nitrogen, such as -NHCH 2 C(0)-1 - pyrrolindinyl, -NHCH 2 C(0)-1-piperidinyl, -NHCH 2 C(0)-4-morpholinyl or
• -NHCH 2 C(0)piperazinyl such as -NHCH 2 C(0)-4-methyl-1 -piperazinyl.
• R 4 represents -NHC1-4 alkylC(0)NHCi -3 alkylheterocyclyl for example a nitrogen containing heterocyclyl group or a nitrogen and/or oxygen containing heterocyclyl, such as -NHCH 2 C(0)NHCH 2 CH 2 morpholinyl, in particular where morpholinyl is linked through nitrogen.
• R 4 represents -N(Ci_3 alkyl)Ci_6 alkylheterocyclyl, for example a nitrogen containing heterocyclyl group, in particular linked through nitrogen, such as -N(CH 3 )CH 2 CH 2 morpholine, -N(CH 3 )(CH 2 ) 3 morpholine or -N(CH 3 )(CH 2 ) 4 morpholine.
• R 4 is -Ci. 3 alkyl-G-Ci -3 alkylheterocycle wherein G is a heteroatom selected from NH, 0 or S(0) p said heterocyclyl group comprising at least one heteroatom (for example 1 , 2 or 3, in particular 1 or 2, heteroatoms) selected from O, N, and S, and is optionally substituted by one or two or three groups independently selected from relevant substituents listed above for compounds of formula (I), for example halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, C 1 - 4 mono and C 2-8 di-alkyl amino and Ci_ 4 mono or C 2 - 8 di-acyl amino such as one or two or three groups halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -S haloalkyl, amino, Ci_ mono and C 2-8 di-alkyl amino.
• G is a heteroatom selected from NH, 0 or S(0) p said hetero
• -CH 2 G(CH 2 ) 2 heterocycle for example -CH 2 G(CH 2 ) 2 tetrahydropyranyl; or -CH 2 G(CH 2 ) 2 morpholinyl in which the heterocyclyl is linked through nitrogen or carbon; or CH 2 G(CH 2 ) 2 piperazinyl in which the heterocyclyl is linked through nitrogen or carbon and optionally bearing a further C- or N- substituent (for example a C-i- 6 alkyl substitutent such as methyl or a Ci_ 6 alkoxy substituent such as -CH 2 CH 2 OCH3); or -CH 2 G(CH 2 ) 2 pyrrolidinyl, in which the heterocyclyl is linked through nitogen or carbon, for example linked through nitrogen; or -CH 2 G(CH 2 ) 2 0xoimidazolinyl (such as 2-oxo imidazolidinyl) for example linked through N and optionally bearing an additional C- or N- substitute
• G is O.
• G is NH
• R 4 is a saturated or unsaturated C-M O alkyl chain wherein at least one carbon (for example 1 , 2 or 3 carbons) is replaced by a heteroatom selected from O, N, S(0) p wherein said chain is substituted by a C 3-8 carbocyclyl group and said alkyl chain is optionally substituted by one or more (for example 1 or 2) groups selected from oxo and halogen.
• said C 3 -s carbocyclyl group bears one or more groups (for example 1 , 2 or 3 groups) independently selected from halogen, hydroxyl, Ci -6 alkyl, Ci -6 alkoxy, Ci_ 6 haloalkyl, amino, Ci_ mono or di-alkyl amino, Ci_ mono or di-acyl amino, S(0) q Ci- 6 alkyl, C 0 - 6 alkylC(0)Ci -6 alkyl or C 0 - S alkylC(0)C 1-6 heteroalkyl.
• groups for example 1 , 2 or 3 groups
• R 4 represents -NHC 3 - 6 cycloalkyl, such as -NHcyclopropyl, -NHcyclopentyl or -NHcyclohexyl.
• aryl, heteroaryl or heterocyclyl group bears at least one
• the C 5-6 heterocycle bears at least one -S(0) q Ci. 6 alkyl substitutent and optionally bears one or two further substituents independently selected from the relevant list of substituents defined above for compounds of formula (I).
• aryl, heteroaryl or heterocyclyl group bears at least one hydroxyl substituent and optionally bears one or two further substituents independently selected from the relevant list of substituents defined above for compounds of formula (I).
• the C 5 . 6 heterocycle bears at least one hydroxyl substituent and optionally bears one or two further substituents independently selected from the relevant list of substituents defined above for compounds of formula (I).
• the aryl, heteroaryl or heterocyclyl group bears at least one Ci -4 mono and/or C 2 -8 di-acyl amino substituent and optionally bears one or two further substituents independently selected from the relevant list defined above for compounds of formula (I).
• the C 5 _6 heterocycle bears at least one C 1 -4 mono and/or C 2 -8 di- acyl amino substituent and optionally bears one or two further substituents independently selected from the relevant list defined above for compounds of formula (I).
• the aryl, heteroaryl or heterocyclyl group bears at least one C 0- 6 alkylC(0)Ci_6 heteroalkyi substituent and optionally bears one or two further substituents independently selected from the relevant list defined above for compounds of formula (I).
• the C 5- 6 heterocycle bears at least one C 0- 6 alkylC(0)Ci -6 heteroalkyi substituent and optionally bears one or two further substituents independently selected from the relevant list defined above for compounds of formula (I).
• aryl, heteroaryl or heterocyclyl group bears at least one Co-6 alkylC(0)Ci_6 alkyl substituent and optionally bears one or two further substituents independently selected from the relevant list defined above for compounds of formula (I).
• the C 5- 6 heterocycle bears at least one C 0- 6 alkylC(0)Ci -5 alkyl substituent and optionally bears one or two further substituents independently selected from the relevant substituents defined above for compounds of formula (I).
• alkyl chain fragment of R 4 does not bear any optional substituents.
• the alkyl chain of R 4 is saturated.
• the alkyl chain of R 4 is unbranched.
• alkyl chain fragment of R 4 bears 1 , 2, or 3, for example 1 or 2, in particular 1 optional substituent.
• heteroatom may replace a primary, secondary or tertiary carbon, that is a CH 3 , -CH 2 - or a -CH-, group, as technically appropriate.
• p is 0 or 2.
• p is 1.
• compounds of the disclosure include those in which the fragment R 4 is: -CH 2 OH;
• compounds of the disclosure include those in which R 4 in formula (I) is represented by:
• -NHCi -9 alkyl such as -NHCi -7 alkyl, in particular -NHCH 3
• compounds of the disclosure include compounds of formula (I) in which C 0 - 8 alkylheterocyclyl of R 4 is represented by:
• -morpholinyl such as -4-morpholinyl or -NHC(0)(3-morpholinyl);
• -pyrrolidinyl such as -pyrrolidin-1-yl
• -piperazinyl such as -piperazin-1-yl
• -oxoimidazolidinyl such as -2-oxoimidazolidinyl, in particular -2-oxoimidazolidin-1-yl;
• -CH 2 -tetrahydropyranyl such as -CH 2 -tetrahydro-2H-pyran-4-yl
• -CH 2 -morpholinyl such as -CH 2 -4-morpholinyl
• -CH 2 -pyrrolidinyl such as -CH 2 -pyrrolidin-1-yl
• -CH 2 SCH 2 CH 2 -morpholinyl such as, for example, -CH 2 SCH 2 CH 2 -4-morpholinyl, or -CH 2 SCH 2 CH 2 -3-morpholinyl;
• -CH 2 S0 2 CH 2 CI-l 2 -morpholinyl such as for example -CH 2 S0 2 CH 2 CH 2 -4-morpholinyl, or - CH 2 S0 2 CH 2 CH 2 -3-morpholinyl.
• S(0) p is a linker selected from: -CH 2 OCH 2 -, -CH 2 NHCH 2 -, -CH 2 NH- and -CH 2 OCH 2 CH 2 -.
• These fragments may optionally terminate in an aryl group, a heteroaryl group a heterocyclyl group or C 3 . 8 cycloalkyl group, such as an aryl group, a heteroaryl group a heterocyclyl group as defined for fragment R 4 above.
• R 1 , R 2a , R 3 , R 4 , L and X are defined above for compounds of formula (I).
• the disclosure relates to compounds of formula (IE):
• R 1 , R 2a , R 2b , R 3 , R 4 and L are defined above for compounds of formula (I).
• the nitrogen linked substituent is located at position 2 of the pyridine.
• R 1 , R 2a , R 3 , R 4 and L are defined above for compounds of formula (I).
• the nitrogen linked substituent is located at position 2 of the pyridine.
• the compound of formula (I) is not 2-(5-(3-(4-(2-(2- methoxyacetamido)pyridin-4-yloxy)naphthalen-1 -yl)ureido)-1-(p-tolyl)-1 H-pyrazol-3-yl)-2- methylpropyl acetate.
• Compounds of formula (I) as employed herein, unless the context indicates otherwise, is intended to refer to compounds of formula (IA) to (IF) and specifically named compounds, as technically appropriate.
• the pharmaceutically acceptable salts as mentioned hereinabove are meant to include therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) is/are able to form.
• These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
• Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
• butanedioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
• salts of compound (I) include all pharmaceutically acceptable salts, such as, without limitation, acid addition salts of mineral acids such as HCI and HBr salts and addition salts of organic acids such as a methansulfonic acid salt.
• solvates of compounds of formula (I) include hydrates.
• the compounds of the disclosure include those where the atom specified is a naturally occurring or non-naturally occurring isotope.
• the isotope is a stable isotope.
• the compounds of the disclosure include, for example deuterium containing compounds and the like.
• the compounds described herein may include one or more stereogenic centres, and the disclosure extends to include racemates, and to both enantiomers (for example each substantially free of the other enantiomer) and all stereoisomers, such as diastereomers resulting therefrom.
• one enantiomeric form is present in a purified form that is substantially free of the corresponding enantiomeric form.
• the disclosure also extends to all polymorphic forms of the compounds herein defined.
• LGi is a leaving group for example halogen, such as chloro.
• LG 3 and LG 4 each independently represent leaving groups, to generate a compound of formula (Via), for example when LG 3 and LG 4 both represent imidazolyl; or a compound of formula (VIb), for example when the groups LG3 and LG 4 represent halogen, such chloro or trihalomethyl such as trichloromethyl)
• R 3 , Ar, L and X are as defined above for compounds of formula (I), with a compound of formula (Ilia) or (lllb).
• the reaction is suitably carried out in the presence of an organic base such as DIPEA or triethylamine in an aprotic solvent or solvent mixture, such as. DCM and DMF.
• an organic base such as DIPEA or triethylamine
• an aprotic solvent or solvent mixture such as. DCM and DMF.
• the compounds of formula (IX) may be reacted with a compound of formula (IVa) followed by reaction with an amine of formula R * NH 2 .
• the reaction may be effected in an alcoholic solvent such as ethanol and in the presence of a mineral acid, such as HCI followed by treatment with a base, such as lithium hydroxide, in a solvent such as THF, to liberate the product, as a free base.
• a mineral acid such as HCI
• a base such as lithium hydroxide
• THF a solvent such as THF
• a compound of formula (V) in which R 1 ,or R 2a or R 2b comprises a hydroxyalkyl may be converted into a compound of formula (I) by the methods described above, by protecting the hydroxyl functionality, for example as a silyl ether.
• the hydroxyl group can be revealed at the end of the synthetic sequence by cleavage of the protective group: for example a silyl protective group may be removed with, for example, tetrabutylammonium fluoride.
• any of the substituents R 1 , or R 2a or R 2b consists of a hydroxyalkyl such as, for example, -(CH 2 )nCH 2 OH may be prepared by the reduction of compounds of formula (V) in which one or more of the substiuents R 1 , or R 2a or R 2b comprises the corresponding acid such as, for example -(CH 2 ) X C0 2 H, wherein x is as appropriate for compounds of formula (I), employing a reagent such as borane in a suitable solvent, for example THF.
• hydroxyl may then be optionally protected, for example as a silyl ether, and this intermediate converted into a compound of formula (I) in which R 1 , or R 2a or R 2b is a protected hydroxyalkyl group, by one of the methods descibed above.
• Compounds of formula (VIII) may be prepared by the reduction of a compound of formula (IX) to the corresponding amine, for example using hydrogenation in the presence of a suitable catalyst such as palladium on carbon.
• Ar is as defined above for compounds of formula (I), for example under Mitsunobu coupling conditions, typically in the presence of a triarylphosphine such as triphenylphosphine and a dialkyi azodicarboxylate such as diisopropylazodicarboxylate.
• a triarylphosphine such as triphenylphosphine
• a dialkyi azodicarboxylate such as diisopropylazodicarboxylate.
• the reaction is suitably carried out in a polar aprotic solvent, such as THF.
• certain compounds of formula (IX) wherein the group L comprises of a fragment represented by -0(CH 2 )i- 5 - may be obtained by a nucleophilic aromatic substitution (S N Ar) reaction of a compound of formula (Xlla) with a compound of (XIV)
• reaction may be conducted in the presence of an organic base such DBU in a polar aprotic solvent such as acetonitrile.
• Certain compounds of formula (IX) wherein the group L is O, that is an oxa linker, may be obtained by the reaction of a compound of formula (Xllc),wherein X and R 3 are as defined for compounds of formula (I) and Y' is a halogen atom preferably chlorine
• reaction may be effected in a polar aprotic solvent, such as NMP, in the presence of a strong mineral acid, such cone, hydrochloric acid and at an elevated temparture for example at 170°C or 190°C.
• a polar aprotic solvent such as NMP
• a strong mineral acid such cone, hydrochloric acid
• Certain compounds of formula (VII) wherein the group L is O, that is an oxa linker, may be obtained via the reaction of a compound of formula (Xlld), o
• Certain compounds of formula (II) wherein X, R 1 , R 2a , R 2 and R 3 are as defined above for compounds of formula (I) and the group L is CH 2 , that is a methylene linker; or is C(O), that is a keto group; or is S, that is a thio ether linker; may be prepared from a compound of formula (VIII) wherein R 3 and X are as defined above and L is either is CH 2 , or is C(O) or is S; by reaction with a compound of formula (Via) or a compound of formula (Vlb) as described above.
• a compound of formula (VIII) wherein R 3 and X are as defined above and L is either CH 2 , or is C(O) may be obtained by the deprotection of the corresponding protected derivatives (Villa) or (Vlllb), respectively, wherein P 1 and P 2 represent suitable amine protective groups.
• P 1 and P 2 both represent Boc protective groups the desired compounds of formula (VIII) are revealed from compounds (Villa) or (Vlllb) by treatment with acid such as TFA, in an inert solvent such as DCM, conveniently at 0°C to RT.
• a compound of formula (Villa) may be obtained from a carbinol compound of formula (XVI) by a reductive process for the removal of the hydroxyl group.
• the compound of formula (XVI) can be converted into a sulfonate ester by treatment with a sulfonyl chloride, for example into the mesylate (XVIa) by treatment with methanesulfonyl chloride, in an aprotic solvent such as DCM at 0°C to RT in the presence of a base such as triethylamine:
• the compound of formula (XVIa) may then be transformed into the compound of formula (Villa) by reaction with a reducing agent, such as sodium borohydride, in a polar protic solvent such as methanol, typically at 0°C to RT.
• a reducing agent such as sodium borohydride
• a polar protic solvent such as methanol
• a compound of formula (Vlllb) may also be obtained from the carbinol compound of formula (XVI) by an oxidative process to convert the secondary alcohol into a keto group.
• the compound of formula (XVI) may be converted into the compound of formula (Vlllb) by treatment with an oxidising agent such as manganese dioxide in a suitable solvent such as DCM, at an appropriate temperature such as 0°C to RT.
• Compounds of formula (XVI) may be prepared by the the treatment of an aromatic bromide of formula (XVII), wherein Ar and P 1 are as defined above, with an alkyllithium, for example n-butyllithium, in an inert, aprotic solvent such at THF, at suitable temperature, for example at -78°C, if necessary with adjustment of the temperature to, for example, 0, followed by reaction with a carboxaldehyde of formula (XVIII), wherein X, R 3 , and P 2 are as defined above:
• Compounds of formula (VIII) wherein R 3 , Ar and X are as defined above and L is S, that is L is a thioether linker, may be prepared from a compound of formula (Vlllc) wherein the group Ar 1 is a electron rich aromatic nucleus, thereby making the radical -CH 2 -Ar 1 susceptible to cleavage by acidolysis.
• a suitable aromatic group for this purpose is, for example 2,4- dimethoxybenzene or the like.
• the desired compound of formula (VIII), as defined above, may be obtained from the compound of formula (Vlllc)
• Ar, X and Y' are defined above, for example by catalytic reduction using hydrogen and a suitable metal catalyst.
• the reduction step is conveniently carried out in a mixture of solvents such as EtOAc, MeOH and AcOH, over platinum on carbon, at an elevated temperature such as 50°C.
• Compounds of formula (XXI) may be prepared by the reaction of compounds of formula (XIV), as defined above, with a compound of formula (XXII) wherein X is as defined above, Z is a halogen atom, preferably fluorine and Y' is a halogen atom, preferably chlorine together with a suitable sulfur nucleophile: Z X ⁇ '
• reaction can be carried using sodium hydrogensulfide as the sulfur source in a polar aprotic solvent such as DMF and in the presence of a organic base, for example DIPEA, at ambient temperature.
• a polar aprotic solvent such as DMF
• DIPEA organic base
• Certain compounds of formula (I) wherein, R 3 is H and L is SO 2 , that is L is a sulfonyl linker, may be prepared from a compound of formula (He) by one or more of the processes described above
• the reaction is conveniently conducted in an inert aprotic solvent such as DCM and may be cooled, for example to 0°C.
• the desired compounds of formula (lie) are then revealed from the products so obtained by a deprotection step.
• P 1 represents a Boc group
• the compounds of formula (lie) are obtained following removal of the protective group with an acid such as TFA, in an inert solvent such as DCM, conveniently at 0°C to RT.
• the reduction may be carried out, for example, by hydrogenation over a suitable catalyst, such as palladium on carbon, in an appropriate solvent system such as a mixture of EtOAc, MeOH and AcOH, and if necessary with warming, for example at 30°C.
• a suitable catalyst such as palladium on carbon
• an appropriate solvent system such as a mixture of EtOAc, MeOH and AcOH
• XXIa (XXV) wherein Ar and X are as previously defined above and Y' is a halogen atom, preferably chlorine, by an amidation reaction employing a compound of formula (XXV).
• a suitable compound of formula (XXV) for this transformation is that in which R represents ierf-butyl such that the said compound (XXV) is H 2 NBoc.
• Suitable conditions for this conversion are, for example, the reaction of a compound of formula (XXIa) with a compound of formula (XXV) in the presence of a catalytic system, such as that generated from Pd2(dba)3 in the presence of the phosphine ligand such as XantPhos.
• XXVI (XXVII) by oxidation to a compound of formula (XXVII) followed by treatment with a chlorinating agent.
• a suitable chlorinating reagent for the conversion of a compound of formula (XXVI) into a compound of formula (XXVII) is, for example, m-CPBA.
• the reaction may be effected in a halogenated solvent such as DCM and typically below RT, for example at 0°C.
• the subsequent chlorination step may be carried out using a reagent such a phosphorus oxychloride at an elevated temperature, for example at 100°C.
• Protecting groups may be required to protect chemically sensitive groups during one or more of the reactions described above, to ensure that the process is efficient. Thus if desired or necessary, intermediate compounds may be protected by the use of conventional protecting groups. Protecting groups and means for their removal are described in "Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons Inc; 4 lh Rev Ed., 2006, ISBN-10: 0471697540.
• Novel intermediates are claimed as an aspect of the invention.
• the compounds are useful in treatment, for example COPD and/or asthma.
• the p38MAPK inhibitory compounds developed to date have typically been intended for oral administration. This method of dosing involves optimization to achieve an adequate duration of action by selecting compounds that have an appropriate pharmacokinetic profile. This strategy ensures that a therapeutically effective drug concentration is established and maintained after and between doses to provide the desired clinical benefit. The inevitable consequence of this regimen is that all body tissues, especially liver and gut, are likely to be exposed chronically to therapeutically active concentrations of the drug, whether or not they are adversely affected in the diseased state.
• An alternative strategy is to design treatment approaches in which the drug is dosed directly to the inflamed organ (topical therapy).
• lung diseases asthma, COPD
• skin diseases atopic dermatitis and psoriasis
• nasal diseases allergic rhinitis
• gastrointestinal diseases ulcerative colitis
• efficacy can be achieved either by ensuring that the drug has a sustained duration of action and is retained in the relevant organ to minimize the risk of systemic toxicity; or by producing a formulation which generates a "reservoir" of the active drug which is available to sustain the drug's desired effects.
• the first approach is exemplified by the anticholinergic drug tiotropium (Spiriva). This compound is administered topically to the lung as a treatment for COPD, and has an exceptionally high affinity for its target receptor resulting in a very slow off rate and a consequent sustained duration of action.
• a compound of formula (I) as a p38 MAP kinase inhibitor, in particular as an alpha and/or gamma p38MAPK inhibitor, for example administered topically to the lung.
• the compounds herein are particularly suitable for topical delivery, such as topical delivery to the lungs, in particular for the treatment of COPD.
• the compounds have a longer duration of actions than BIRB 796.
• the compounds are suitable for sensitizing patients to treatment with a corticosteroid.
• the compounds herein may also be useful for the treatment of rheumatoid arthritis.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to the disclosure optionally in combination with one or more pharmaceutically acceptable diluents or carriers.
• Diluents and carriers may include those suitable for parenteral, oral, topical, mucosal and rectal administration.
• such compositions may be prepared e.g. for parenteral, subcutaneous, intramuscular, intravenous, intra-articular or peri-articular administration, particularly in the form of liquid solutions or suspensions; for oral administration, particularly in the form of tablets or capsules; for topical e.g. pulmonary or intranasal administration, particularly in the form of powders, nasal drops or aerosols and transdermal administration; for mucosal administration e.g. to buccal, sublingual or vaginal mucosa, and for rectal administration e.g. in the form of a suppository.
• compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
• Formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
• Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray.
• typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
• compositions suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form.
• Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate.
• binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone
• fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine
• lubricants such as magnesium stearate, talc, polyethylene glycol
• Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
• suspending agents for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats
• emulsifying agents such as lecithin, or acacia
• vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil
• preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluen
• Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules.
• a dry shell formulation typically comprises of about 40% to 60% concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30% to 40% concentration of water.
• plasticizer such as glycerin, sorbitol or propylene glycol
• Other materials such as preservatives, dyes, opacifiers and flavours also may be present.
• the liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.
• suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000
• a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.
• the compound of formula (I) is administered topically to the lung.
• a pharmaceutical composition comprising a compound of the disclosure optionally in combination with one or more topically acceptable diluents or carriers.
• Topical administration to the lung may be achieved by use of an aerosol formulation.
• Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
• Suitable CFC propellants include trichloromonofluoromethane (propellant 1 1 ), dichlorotetrafluoromethane (propellant 1 14), and dichlorodifluoromethane (propellant 12).
• Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227).
• the propellant typically comprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalation composition.
• the formulation may comprise excipients including co- solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M).
• a metering valve e.g. as supplied by Bespak, Valois or 3M.
• Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension. This may be administered by means of a nebuliser. Topical administration to the lung may also be achieved by use of a dry- powder formulation.
• a dry powder formulation will contain the compound of the disclosure in finely divided form, typically with a mass mean diameter (MMAD) of 1-10 ⁇ .
• the formulation will typically contain a topically acceptable diluent such as lactose, usually of large particle size e.g. a mass mean diameter (MMAD) of 100 ⁇ or more.
• Example dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER.
• Compounds according to the disclosure are intended to have therapeutic activity.
• the present invention provides a compound of the disclosure for use as a medicament.
• Compounds according to the disclosure may also be useful in the treatment of respiratory disorders including COPD (including chronic bronchitis and emphysema), asthma, paediatric asthma, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, especially asthma, chronic bronchitis and COPD.
• COPD chronic bronchitis and emphysema
• asthma including chronic bronchitis and emphysema
• paediatric asthma cystic fibrosis
• cystic fibrosis sarcoidosis
• idiopathic pulmonary fibrosis allergic rhinitis
• rhinitis rhinitis
• sinusitis especially asthma, chronic bronchitis and COPD.
• Compounds of the disclosure may also re-sensitise the patient's condition to treatment with a corticosteroid, when the patient's condition has become refractory to the same.
• a compound of formula (I) is provide for use in preventing a patient becoming refractory to treatment with a corticosteroid.
• Compounds according to the disclosure are also expected to be useful in the treatment of certain conditions which may be treated by topical or local therapy including allergic conjunctivitis, conjunctivitis, allergic dermatitis, contact dermatitis, psoriasis, ulcerative colitis, inflamed joints secondary to rheumatoid arthritis or osteoarthritis.
• Compounds of the disclosure are also expected to be useful in the treatment of certain other conditions including rheumatoid arthritis, pancreatitis, cachexia, inhibition of the growth and metastasis of tumours including non-small cell lung carcinoma, breast carcinoma, gastric carcinoma, colorectal carcinomas and malignant melanoma.
• One or more compounds of the disclosure are believed to be useful as anti-viral agents, for example in the treatment of conditions including influenza.
• the compounds of the present disclosure may be suitable for the use in the treatment or prevention of said viral infection and in particular may be capable of reducing viral load and/or ameliorating symptoms after infection.
• the present invention provides a compound as described herein for use in the treatment of the above mentioned conditions.
• the present invention provides use of a compound as described herein for the manufacture of a medicament for the treatment of the above mentioned conditions.
• the present invention provides a method of treatment of the above mentioned conditions which comprises administering to a subject an effective amount of a compound of the disclosure or a pharmaceutical composition thereof.
• treatment is intended to embrace prophylaxis as well as therapeutic treatment.
• a compound of the disclosure may also be administered in combination with one or more other active ingredients e.g. active ingredients suitable for treating the above mentioned conditions.
• active ingredients suitable for treating the above mentioned conditions.
• active ingredients suitable for treating the above mentioned conditions.
• possible combinations for treatment of respiratory disorders include combinations with steroids (e.g. budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, fluticasone furoate), beta agonists (e.g. terbutaline, salbutamol, salmeterol, formoterol) and/or xanthines (e.g. theophylline).
• steroids e.g. budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, fluticasone furoate
• beta agonists e.g. terbutaline, salbutamol, salmeterol, formoterol
• xanthines
• FCS foetal calf serum
• Method 1 Agilent Scalar column C18, 5 ⁇ (4.6 x 50 mm) or Waters XBridge C18, 5 ⁇ (4.6 x 50 mm) flow rate 2.5 ml_ min "1 eluting with a H 2 0-MeCN gradient containing either 0.1 % v/v formic acid (Method 1 acidic) or NH 3 (Method 1 basic) over 7 min employing UV detection at 215 and 254 nm.
• Method 2 Agilent Extend C18 column, 1.8 ⁇ (4.6 x 30 mm) at 40°C; flow rate 2.5-4.5 mL min "1 eluting with a H 2 0-MeCN gradient containing 0.1 % v/v formic acid over 4 min employing UV detection at 254 nm.
• the reaction was acidified to pH 1 by the addition of cone hydrochloric acid and the resulting heterogeneous mixture was heated to 70°C for 5 hr, was then cooled to RT and concentrated in vacuo to a volume of -20 mL.
• the mixture was diluted with water (30 mL) and adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (30 mL) and then dried and evaporated in vacuo.
• the resulting mixture was diluted with DCM (5.0 mL) and was treated with an additional aliquot of chlorotriisopropylsilane (970 ⁇ , 870 mg, 4.5 mmol) and after a further 5 hr with imidazole (320 mg, 4.7 mmol). After 20 hr the reaction mixture was treated for a third time with chlorotriisopropylsilane (200 ⁇ , 180 mg, 0.90 mmol) and imidazole (100 mg, 1 .6 mmol) and after 3 days was evaporated in vacuo. The residue was taken up into EtOAc (20 mL) and was washed with water (20 mL) and brine (10 mL) and then dried and evaporated in vacuo.
• the resulting mixture was diluted with DCM (5.0 mL) and was treated with a second aliquot of chlorotnisopropylsilane (720 ⁇ , 650 mg, 3.40 mmol) and after a further 5 hr with additional imidazole (240 mg, 3.50 mmol). After 20 hr the reaction mixture was treated for a third time with chlorotriisopropylsilane (360 ⁇ , 330 mg, 1.70 mmol) and imidazole (120 mg, 1.8 mmol) and after 3 days was evaporated in vacuo.
• the resulting mixture was concentrated in vacuo to a volume of -15 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (1 .52 g, 9.57 mmol) was added.
• the mixture was acidified to pH 1 by the addition of cone hydrochloric acid and the resulting heterogeneous mixture was heated to 70°C for 2 hr, then cooled to RT and concentrated in vacuo to a volume of -20 mL.
• the mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and extracted with diethyl ether (2 x 20 mL).
• the resulting mixture was concentrated in vacuo to a volume of -10 mL and was then diluted with EtOH (10 mL), treated with p-tolylhydrazine hydrochloride (607 mg, 3.83 mmol) and was acidified to pH 1 by the addition of cone hydrochloric acid.
• the resulting heterogeneous mixture was heated to 70°C for 2 hr, was cooled to RT and concentrated in vacuo to a volume of -10 mL.
• the mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with EtOAc (2 x 20 mL).
• the resulting mixture was concentrated in vacuo to a volume of -10 mL and was then diluted with EtOH (20 mL), treated with p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) and was acidified to pH 1 by the addition of cone hydrochloric acid.
• the resulting heterogeneous mixture was heated to 70°C for 3 hr, was then cooled to RT and concentrated in vacuo to a volume of -20 mL.
• the mixture was diluted with water (30 mL), adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with EtOAc (2 x 20 mL).
• the resulting mixture was concentrated in vacuo to a volume of -20 mL, was diluted with EtOH (20 mL) and treated with p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) and was acidified to pH 1 by the addition of cone hydrochloric acid.
• the resulting heterogeneous mixture was heated to 70°C for 2 hr, then cooled to RT and concentrated in vacuo to a volume of - 20 mL.
• the residue was diluted with water (30 mL), adjusted to pH 12 by the addition of 2M aq NaOH and the mixture extracted with EtOAc (2 x 20 mL).
• the resulting mixture was maintained at RT for 2 hr, warmed to 30°C for 1 hr and then returmed to RT for a further 16 hr.
• the reaction was quenched by the addition of MeOH (30 mL) and after 30 min was evaporated in vacuo to provide a residue that was partitioned between DCM (400 mL) and 1 M aq HCI (100 mL).
• the organic layer was separated and was washed with sat. aq NaHC0 3 (100 mL), water (100 mL), and brine (100 mL) and then dried and evaporated in vacuo.
• the reaction mixture was re-cooled to 0°C and was treated with a solution of methylamine (2M in THF, 3.6 mL, 7.2 mmol) and then warmed to RT and treated with further aliquots of the methylamine solution after 2.5 hr (7.2 mL, 14.4 mmol) and 3.5 hr (3.6 mL, 7.2 mmol). After a further 16 hr the reaction was quenched by addition of methanolic NH 3 (1 % w/v, 10 mL) and the resulting mixture kept at RT for 15 min and then evaporated in vacuo. The residue was partitioned between DCM (200 mL) and water (50 mL).
• reaction mixture was loaded directly onto silica and purified by flash column chromatography (S1O2, 80g, EtOAc in isohexane, 30-70%, gradient elution) to afford 4-(4- aminonaphthalen-1-ylthio)-/V-(2,4-dimethoxybenzyl)pyridin-2-amine as a dark red oil (710 mg, 37%); R l 1.74 min (Method 2); m/z 418 (M+H) + (ES + ).
• reaction mixture was stirred at -78 °C for a further 1 hr and then warmed to RT for 18 hr.
• the mixture was cooled to 0°C and the reaction was quenched by the addition of MeOH (5.0 mL), then warmed to RT and partitioned between EtOAc and water. The aq layer was separated and was extracted twice with EtOAc and the combined organic extracts were washed with brine and then dried and evaporated in vacuo.
• Example 2 /V-(4-(4-(3-(3-ferf-Butyl-1 -(4-(methylsulfonamido)phenyl)-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-methoxyacetamide.
• Example 1 To a solution of Example 1 (42 mg, 0.072 mmol) in DCM (2.0 mL) and DIPEA (26 pL, 0.14 mmol) at 0°C was added methanesulfonyl chloride (8.0 pL, 0.1 mmol) in DCM (1.0 mL) and the reaction mixture was warmed to RT for 2 hr. Additional aliquots of DIPEA (26 ⁇ , 0.14 mmol) and methanesulfonyl chloride (4.0 [it, 0.05 mmol) were added and after a further 2 hr the reaction mixture was washed with saturated aq NaHC0 3 (2.0 mL).
• Example 3 N-(4-((4-(3-(3-(fert-Butyl)-1 -(4-methoxyphenyl)-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yl)oxy)pyridin-2-yl)-2-methoxyacetamide.
• Example 4 W-(4-(4-(3-(3-ferf-Butyl-1 -(4-methoxyphenyl)-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-yl)-2-hydroxyacetamide.
• Example 2 To a solution of Example 2 (50 mg, 0.084 mmol) in dry DCM (2.0 mL) at 0°C was added tribromoborane (1.0 M in DCM, 250 ⁇ , 0.25 mmol) and the reaction mixture maintained at 0°C for 5 min and then warmed to RT for 3 hr. The resulting mixture was partitioned between DCM (20 mL) and saturated aq. NaHC0 3 (10 mL) and the organic layer was separated, washed with brine (5.0 mL) and then dried and evaporated in vacuo.
• DCM 20 mL
• saturated aq. NaHC0 3 10 mL
• Example 5 V-(4-((4-(3-(3-(ferf-Butyl)-1 -(4-hydroxyphenyl)-1H-pyrazol-5-yl)ureido) naphthalen-1 -yl)oxy)pyridin-2-yl)-2-methoxyacetamide.
• Example 6 1 -(3-(feri-Butyl)-1 -(4-methoxyphenyl)-1 H-pyrazol-5-yl)-3-(4-(2-(3-cyclo propylureido)pyridin-4-yloxy)naphthalen-1 -yl)urea.
• Example 6 The solid was collected by filtration and was washed with isohexane (1 mL) and then re-suspended in EtOAc (1.0 mL). The mixture was sonicated briefly and then kept at RT for 16 hr. The solid was collected by filtration and was washed with isohexane to afford the title compound, Example 6, as a white solid (10 mg, 90% purity by LCMS), 1 1 %); R' 2.44 min (Method 2); m/z 606 (M+H) + (ES + ).
• Example 9 W-(4-((4-(3-(3-iert-Butyl-1 -(4-methoxyphenyl)-1 H-pyrazol-5-yl) naphthalen-1 -yl)oxy)pyridin-2-yl)morpholine-4-carboxamide.
• Example 10 N-(4-(4-(3-(3-ieri-Butyl-1 -(4-methoxyphenyl)-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-yl)-4-methylpiperazine-1 -carboxamide.
• Example 10 was isolated by filtration and dried in vacuo to afford Example 10 as a pink solid (8 mg, 10%); R' 4.75 min (Method 1 basic); m/z 649 (M+H) + (ES + ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 1.27 (9H, s), 2.37 (3H, br s), 2.55 (4H, br s, partially obscured by DMSO), 3.46 (4H, br s), 3.83 (3H, s), 6.38 (1 H, s), 6.62 (1 H, dd), 7.11 (2H, m), 7.30 (1 H, d), 7.35 (1 H, m), 7.48 (2H, m), 7.56 (1 H, ddd), 7.64 (1 H, ddd), 7.83 (1 H, dd), 7.95 (1 H, d), 8.10 (2H, m), 8.79 (1 H, br s), 9.15 (1 H, br s), 8.29 (1 H, br s).
• Example 11 /V-(4-(4-(3-(3-ferf-Butyl-1 -(3,4-dimethoxyphenyl)-1 H-pyrazol-5-yl) naphthalen-1 -yloxy)pyridin-2-yl)-2-methoxyacetamide.
• Example 12 /V-(4-((4-(3-(3-(ferf-Butyl)-1 -(3-chloro-4-hydroxyphenyl)-1W-pyrazol-5-yl) ureido)naphthalen-1 -yl)oxy)pyridin-2-yl)morpholine-4-carboxamide.
• Example 13 /V-(4-(4-(3-(3-ferf-Butyl-1 -(3-chloro-4-(hydroxymethyl)phenyl)-1W-pyrazol- 5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-methoxyacetamide.
• Example 14 W-(4-(4-(3-(3-iert-Butyl-1 -(4-(methylthio)phenyl)-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-yl)pyrrolidine-1 -carboxamide.
• Example 17 W-(4-(4-(3-(3-ierf-Butyl-1 -(6-hydroxypyridin-3-yl)-1H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-yl)-2-methoxyacetamide.
• Example 16 To a solution of Example 16 (44 mg, 0.073 mmol) in dioxane (1 .0 mL) was added HCI (4M in dioxane. 220 ⁇ , 0.88 mmol) and the reaction mixture heated to 60°C for 2 hr, during which time a grey solid precipitated and then redissolved. The reaction mixture was cooled to RT and was diluted with MeOH and purified by SCX capture and release.
• Example 19 /V-( -((4-(3-(1 ,3-Diphenyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy) pyridin-2-yl)-2-methoxyacetamide.
• Example 19 To a suspension of CDI (121 mg, 0.746 mmol) in DCM (1 mL) was added 1 ,3-diphenyl-1 H- pyrazol-5-amine, Intermediate A16, (175 mg, 0.744 mmol) and the reaction mixture maintained at RT for 2 hr and then treated with solid Intermediate B1 (150 mg, 0.46 mmol) and diluted with DCM (2.0 mL). After 16 hr at RT the reaction was quenched by the addition of MeOH (2.0 mL) and after a further 10 min the volatiles were evaporated in vacuo.
• Example 20 2-Methoxy-/V-(4-(4-(3-(3-(4-methyltetrahydro-2H-pyran-4-yl)-1 -p-tolyl-1 H- pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)acetamide.
• Example 21 W-(4-(4-(3-(3-feri-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl thio)pyridin-2-yl)-2-methoxyacetamide.
• Example 22 /V-(4-(4-(3-(3-(iert-Butyl)-1 -(p-tolyl)-1H-pyrazol-5-yl)ureido)-1 -naphthoyl) pyridin-2-yl)-2-(2-methoxyethoxy)acetamide.
• Example 23 1 -(3-(fer Butyl)-1 -( -tolyl)-1 H yrazol-5-yl)-3-(4-((2-(3-ethylureido)pyridin- 4-yl)methyl)naphthalen-1 -yl)urea.
• the reaction mixture was warmed to RT for 18 hr then cooled to 0°C and a further aliquot of the CDI-adduct (0.25 mL, 0.15 mL) was added.
• the resulting mixture was warmed to RT for 1 hr and was then partitioned between DCM and water.
• the aq. layer was extracted with DCM and the combined organic extracts were washed with brine, and then dried and evaporated in vacuo.
• the enzyme inhibitory activities of compounds disclosed herein were determined by fluorescence resonance energy transfer (FRET) using synthetic peptides labelled with both donor and acceptor fluorophores (Z-LYTE, Invitrogen Ltd., Paisley, UK).
• FRET fluorescence resonance energy transfer
• Z-LYTE synthetic peptides labelled with both donor and acceptor fluorophores
• Recombinant, phosphorylated p38 ⁇ MAK12 :lnvitrogen
• was diluted in HEPES buffer mixed with the test compound at the desired final concentrations and incubated for 2 hr at RT.
• the FRET peptide (2 ⁇ ) and ATP (100 ⁇ ) were added to the enzyme/compound mixture and incubated for 1 hr.
• MAPKa For the p38 MAPKa isoform (MAPK14: Invitrogen), enzyme activity was evaluated indirectly by determining the level of activation/phosphorylation of the down-stream molecule, MAPKAP-K2.
• the p38 MAPKa protein was mixed with the test compound for 2 hr at RT.
• the p38a inactive target MAPKAP-K2 (Invitrogen) and FRET peptide (2.0 ⁇ ), which is a phosphorylation target for MAPKAP-K2, and ATP (10.0 ⁇ ) were added to the enzymes / compound mixture and the resulting mixture incubated for 1 hr. Development reagent was then added and the mixture incubated for 1 hr before detection by fluorescence completed the assay protocol.
• the inhibition of TNFa production was calculated as a percentage of that achieved by 10 ⁇ g/mL of BIRB796 at each concentration of test compound by comparison against vehicle control.
• the relative 50% effective concentration (REC 5 o) was determined from the resultant concentration-response curve.
• the inhibition of IL-8 production was calculated at each concentration of test compound by comparison with vehicle control.
• the 50% inhibitory concentration (IC 5 o) was determined from the resultant concentration-response curve.
• THP-1 cells a human monocytic cell line
• LPS from E. Coli; 011 1 :B4, Sigma
• sandwich ELISA Duo-set, R&D systems
• the inhibition of TNFa production was calculated at each concentration by comparison with vehicle control.
• the 50% inhibitory concentration (IC 5 o) was determined from the resultant concentration- response curve.
• Poly l:C ( ⁇ g/mL) (Invivogen Ltd., San Diego, CA) was transfected into BEAS2B cells (human bronchial epithelial cells, ATCC) with Oligofectamine (Invitrogen, Carlsbad, CA). Cells were pre-incubated with final concentrations of test compounds for 2 hr and the level of ICAM1 expression on the cell surface was determined by cell-based ELISA. At a time point 18 hr after poly l:C transfection, cells were fixed with 4% formaldehyde in PBS and then endogenous peroxidase was quenched by the addition of 0.1 % sodium azide and 1% hydrogen peroxide.
• the cells were then washed with PBS-Tween and total cell numbers in each well were determined by reading absorbance at 595 nm after Crystal Violet staining and elution by 1 % SDS solution. The measured OD 450-655 readings were corrected for cell number by dividing with the OD595 reading in each well. The inhibition of ICAM-1 expression was calculated at each concentration of test compound by comparison with vehicle control. The 50% inhibitory concentration (IC 50 ) was determined from the resultant concentration-response curve.
• mice Non-fasted Balb/c mice were dosed by the intra tracheal route with either vehicle, or the test substance at the indicated times (within the range 2-12 hr) before stimulation of the inflammatory response by application of an LPS challenge.
• mice were placed into an exposure chamber and exposed to LPS. After a further 8 hr the animals were anesthetized, their tracheas cannulated and BALF extracted by infusing and then withdrawing from their lungs 1.0 mL of PBS via the tracheal catheter. Total and differential white cell counts in the BALF samples were measured using a Neubaur haemocytometer.
• Cytospin smears of the BALF samples were prepared by centrifugation at 200 rpm for 5 min at RT and stained using a DiffQuik stain system (Dade Behring). Cells were counted using oil immersion microscopy.
• mice The ability of selected compound examples disclosed herein, to inhibit LPS-induced neutrophil accumulation in the lungs of mice, using the screening protocol described above, are presented below (Tables 5-7). Treatment of mice with compound Example 67 was found to produce a marked and long-lasting inhibition of neutrophil accumulation into the BALF when administered 2 and 12 hr prior to LPS challenge (Table 5).
• Table 5 The effects of treatment with compound Example 67 on LPS-induced airway neutrophilia in mice.
• mice with each of the following compound Examples: 13, 16, 34, or 45 produced inhibitory effects versus neutrophil accumulation into the BALF when the test substances were dosed 8 hr prior to LPS challenge (Tables 6 and 7).
• the inhibitory effects of treatment with either compound Example 13 (Table 6) or compound Example 16 (Table 7) were particularly marked.
• Table 6 The effects of treatment with compound Examples 45 and 13 on LPS-induced airway neutrophilia in mice.
• Table 7 The effects of treatment with compound Examples 34 and 16 on LPS-induced airway neutrophilia in mice.

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