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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), particularly 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 of p38 mitogen-activated protein kinase enzymes
• 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 (Smith, SJ. (2006) Br. J. Pharmacol. 149:393-404) and detectable in neutrophils, CD4+ T cells and endothelial cells Karin, K. (1999) J. Immunol.). Very little is known about the expression of p38 MAPK gamma but it is expressed more in brain, skeletal muscle and heart, as well as in lymphocytes and macrophages (www.ge . ne . card.grg).
• BIRB 796 Selective small molecule inhibitors of p38 MAPK-gamma and -delta are not currently available, but one existing compound, BIRB 796, is known to have pan-isoform inhibitory activity. The p38 gamma and p38 delta inhibition is observed at higher concentrations of the compound than those required to inhibit p38 alpha and p38 beta (Kuma, Y. (2005) J. Biol. Chem. 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 CO P D.
• 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 with certain subtype specificity, which show good anti-inflammatory potential, in particular suitable for use in therapy.
• R 1 is Ci -6 alkyl optionally substituted by a hydroxyl group
• R 2 is H or Ci-6 alkyl optionally substituted by a hydroxyl group
• R 3 is H, Ci-6 alkyl or C 0-3 alkylC 3-6 cycloalkyl
• Ar is a naphthyl or a phenyl ring either of which may be optionally substituted by one or more groups (for example 1 to 3, such as 1 , 2 or 3 groups) independently selected from Ci -6 alkyl, Ci -6 alkoxy, amino, Ci -4 mono or di-alkyl amino;
• L is a saturated or unsaturated branched or unbranched C-i-s alkylene chain, wherein one or more carbons (for example 1 to 3, such as 1 , 2 or 3 carbons) are optionally replaced by -O- and the chain is optionally substituted by one or more halogen atoms (for example 1 to 6);
• X is 5 or 6 membered heteroaryl group containing at least one nitrogen atom and optionally including 1 or 2 further heteroatoms selected from O, S and N;
• Q is selected from: a) a saturated or unsaturated, branched or unbranched C MO 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 selected from O, 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, an aryl group, a heteroaryl group, a heterocyclyl group or a C 3-8 cycloalkyl group, each aryl, heteroaryl, heterocyclyl or C 3- S cycloalkyl group bearing O to 3 substituents selected from halogen, hydroxyl, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono or di-alkyl amino, Ci -4 mono or di-acyl amino, S(O)qCi -6 alkyl, C
• Q is selected from: a) a saturated or unsaturated, branched or unbranched C MO alkyl chain, 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, each aryl, heteroaryl or heterocyclyl group bearing O to 3 substituents selected from halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono or di-alkyl amino, Ci -4 mono or di-acyl amino, with the proviso that the atom linked directly to the carbonyl in -NR 3 C(O)- is not an oxygen or a sulfur atom; and b) a Co-8 alkylC 5-6
• Q is selected from: a) a saturated or unsaturated, branched or unbranched C MO 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 optionally, substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group or a heterocyclyl group, each aryl, heteroaryl or heterocyclyl group bearing 0 to 3 substituents selected from halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, and Ci -4 mono or di- alkyl amino, with the proviso that the atom linked directly to the carbonyl in -NR 3 C(O)- is not an oxygen or a sulfur atom; and b) a Co-8 alkylC 5-6 heterocycle said heterocyclyl group comprising at least one heteroatom (for example
• Figure 1 shows a plot of the pre-dose time for the administration of the compound of Example
• Figure 2 shows a plot of the pre-dose time for the administration of the compound of Example
• Figure 3 shows the effects of dose for the compound of Example 1 on the numbers of activated macrophages in the BAL of mice exposed to cigarette smoke.
• Figure 4 shows the effects of dose for the compound of Example 1 on numbers of neutrophils in the BAL of mice exposed to cigarette smoke.
• Figure 5 shows the effect for the compound of Example 1 on lung function of ovalbumin- sensitised, para-influenza inoculated guinea pigs challenged with ovalbumin.
• Q is: a) a saturated or unsaturated, branched or unbranched C MO alkyl chain, 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 (for example 1 , 2 or 3) independently selected from oxo, halogen, an aryl group, a heteroaryl group, a heterocyclyl group or a C 3- S cycloalkyl, at least one of said aryl, heteroaryl or heterocyclyl groups (such as each group) bears a substituents Ci -4 mono or di-acyl amino and optionally 1 or 2 further substituents independently selected from the relevant list of substituents above for compounds of formula (I); or b) a Co-8 alkylC 5- 6 heterocycle said heterocyclyl group comprising at least one heteroatom (for example 1 , 2 or 3,
• 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 te/f-butyl. In one embodiment alkyl refers to straight chain alkyl.
• 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 alkylOC- ⁇ - 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 -Co alkylOCi_6 alkyl. In one embodiment the disclosure relates to 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) q , wherein q represents O, 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 SO 2 for -CH 2 - or N for a -CH- or a branched carbon group, as technically appropriate.
• Haloalkyl refers to alkyl groups having 1 to 6 halogen atoms, for example 1 to 5 halogens, such as per haloalkyl, in particular perfluoroalkyl, more specifically -CF 2 CF 3 or CF 3 .
• Ci- 4 mono or di-acyl amino is intended to refer to -NHC(O)Ci -3 alkyl and to (-NC(O)Ci -3 alkyl) C(O)Ci -3 alkyl) respectively.
• Ci -4 mono or di-alkyl amino is intended to refer to -NHCi -4 alkyl and -N(Ci -4 alkyl) (Ci -4 alkyl) respectively.
• Aryl as used herein refers to, for example C&-u mono or polycyclic groups 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 is 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 N 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.
• 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.
• Ci-io alkyl includes C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 or C 9 as well as Ci and Cio
• C 0-8 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 C MO alkyl chain 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
• the heteroatom may replace a primary, secondary or tertiary carbon, that is CH 3 , -CH 2 - or a -CH- or a branched carbon group, as technically appropriate.
• R 1 is methyl, ethyl, propyl, /so-propyl, butyl or fe/f-butyl, in particular fe/f-butyl.
• R 1 is -C(CH 3 ) 2 CH 2 OH.
• R 2 is methyl, ethyl, n-propyl, /so-propyl, n-butyl or te/f-butyl, in particular methyl.
• R 2 is -CH 2 OH.
• R 2 is in the 2, 3, or 4 position (i.e. ortho, meta or para position), in particular the para (4) position.
• Ar is naphthyl
• Ar is not substituted with optional substituents.
• Ar is substituted with 1 or 2 groups.
• Ar is phenyl optionally substituted by 1 or 2 substituents independently selected from Ci -3 alkyl or Ci -3 alkoxy, for example tolyl, xylyl, anisoyl, d i- methoxybenzene or methoxy-methylbenzene.
• the phenyl ring may, for example, be linked to the nitrogen of the urea through carbon 1 and and to the group L through carbon 4.
• the optional one or two substituents selected from Ci -3 alkyl or Ci -3 alkoxy may be located in any of the unoccupied positions in the aromatic ring, for example in position 2 or in position 3 or in positions 2 and 3 or in positions 2 and 6 or in positions 3 and 5.
• Embodiments encompassing other possible regioisomers also form an aspect of the present disclosure.
• L is a straight chain linker, for example:
• n 1 , 2, 3, 4, 5, 6, 7 or 8;
• n and m are independently O, 1 , 2, 3, 4, 5, 6 or 7, with the proviso that n+m is zero or an integer from 1 to 7, for example where n is 0 and m is 1 or 2 or alternatively, for example, where n is 1 or 2 and m is 0.
• L is -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O- Or -CH 2 CH 2 O-.
• L is a branched chain linker RO(CH 2 ) m wherein m is zero or an integer 1 , 2, 3, 4 or 5 and R a is a C 2-7 branched alkyl, with the proviso that the number of carbons in R a + m is an integer from 2 to 7, especially where m is zero, such as -CH(CH 3 )O-, -C(CHa) 2 O-, -CH 2 CH(CH 3 )O-, -CH(CH 3 )CH 2 O-, -C(CH 3 ) 2 CH 2 O- or -CH 2 C(CH 3 ) 2 O, in particular -CH(CH 3 )O-.
• L is a branched chain linker (CH 2 ) n OR b wherein n is zero or an integer 1 , 2, 3, 4 or 5 and R b is a C 2-7 branched alkyl, with the proviso that the number of carbons in R b + n is an integer from 2 to 7, for example n is zero, such as -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -OCH 2 CH(CH 3 )-, -OCH(CH 3 )CH 2 -, -OC(CH 3 ) 2 CH 2 - or -OCH 2 C(CH 3 ) 2 in particular -OCH(CH 3 )- or -OC(CH 3 ) 2 CH 2 -.
• L is a branched chain linker ROR b wherein R a and R b are independently selected from a C 2-7 branched alkylene with the proviso that the number of carbons in R a + R b is an integer from 4 to 7.
• L is a saturated unbranched d-C 8 alkylene chain or a saturated branched or unbranched C 2-3 alkylene chain.
• At least one carbon in L is replaced by -0-.
• L is -0-.
• Alkylene as employed herein refers to branched or unbranched carbon radicals, such as methylene (-CH 2 -) or chains thereof. In the context of the present specification where alkyl is a linker then the latter is used interchangeably with the term alkylene.
• the chain L includes 1 , 2 o r 3 halogen atom substituents, independently selected from fluoro, chloro, and bromo, for example an alkylene carbon may incorporate one or two chlorine atoms or one or two fluorine atoms and a terminal carbon atom, for example of a branch of an alkylene chain, may be bonded to one, two or three fluorine atoms or one, two or three chlorine atoms to provide a radical such as a trifluoromethyl or a trichloromethyl group.
• halogen atom substituents independently selected from fluoro, chloro, and bromo
• an alkylene carbon may incorporate one or two chlorine atoms or one or two fluorine atoms and a terminal carbon atom, for example of a branch of an alkylene chain, may be bonded to one, two or three fluorine atoms or one, two or three chlorine atoms to provide a radical such as a trifluoromethyl or a trichloro
• the chain L does not include a halogen atom or atoms.
• R 3 is H.
• R 3 is methyl, ethyl, n-propyl or /so-propyl.
• R 3 is cyclopropyl
• X is selected from, pyrrole, oxazole, thiazole, isothiazole, imidazole, pyrazole, isoxazole, oxadiazole, pyridazine, pyrimidine, pyrazine, or 1 ,2,3 and 1 ,2,4 triazole, such as pyrazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, or 1 ,2,3 and 1 ,2,4 triazole, in particular, pyrimidine, imidazole or pyridine, and especially pyridine or pyrimidine, more specifically pyridine.
• carbon atoms are replaced in the alkyl chain of Q by heteroatoms independently selected from O, N, S(0) p .
• heteroatom(s) replacing carbon(s) in the alkyl chain fragment of Q are selected from N and O.
• Q is a saturated or unsaturated, branched or unbranched Ci -3 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 2-3 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 is directly bonded to the carbonyl of the fragment -NR 3 C(O) and additionally may, for example, be a terminal amino group.
• Q represents Ci -6 alkylNH 2 or NH 2 .
• Q represents -NHCi -6 alkyl such as -NHCH 3 or -NHCH 2 CH 3 or -NHCH(CH 3 ) 2 .
• the fragment Q is a saturated or unsaturated, branched or unbranched C MO 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(O ) p , for example in such a manner as to provide a stable ⁇ /-acyl group, NR 3 C(O)Q, 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 or C 3-8 cycloalkyl each aryl, heteroaryl or heterocyclyl or C 3-8 cycloalkyl group bearing O to 3 substituents independently selected from a relevant substituent listed above for compounds of formula (I).
• the fragment Q is a saturated or unsaturated, branched or unbranched C MO 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(O ) p , for example in such a manner as to provide a stable ⁇ /-acyl group, NR 3 C(O)Q, wherein said chain is optionally substituted by one or more groups selected from oxo, halogen, an aryl group, a heteroaryl group or a heterocyclyl group, each aryl, heteroaryl or heterocyclyl group bearing O to 3 substituents independently selected from a relevant substituent listed above for compounds of formula (I), for example halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono or di- alkyl amino and Ci -4 mono or di-acyl amino.
• halogen Ci -6 alkyl
• the latter chain is optionally substituted by one or more groups selected from oxo, halogen, an aryl group, a heteroaryl group or a heterocyclyl group, each aryl, heteroaryl or heterocyclyl group bearing O to 3 substituents selected from halogen, Ci -6 alkyl, Ci- 6 alkoxy, Ci -6 haloalkyl, amino, and Ci -4 mono or di-alkyl amino.
• Q is Ci -4 alkyl-V-R 4 , such as Ci -3 alkyl-V-R 4 wherein:
• V is a heteroatom selected from NR V , O or S(O ) p ;
• R v represents H or Ci -3 alkyl;
• R 4 is H or -Ci -3 alkyl, and p is as defined above, with the proviso that the total alkyl chain length is not more than 10 carbon atoms, including replacement heteroatoms and that the resulting radical Q is a stable group, for example -CH 2 SCH 3, -CH 2 SO 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ), -C(CH 3 ) 2 NHCH 3 , -CH(CH 3 )N(CH 3 ) 2 , -(CH 2 ) 3 CHNHCH 3, -(CH 2 ) 3 N(CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , or -(CH 2 ) 2 OCH 3 .
• Q is Ci -3 alkyl-V-(Ci -3 alkyl-Z-R 5 ) k such as Ci -3 alkyl-V-(C 2-3 alkyl-Z- R 5 ) k wherein:
• V is a heteroatom selected from N, NH, O or S(O ) p , such as N or NH
• Z is independently selected from NH, O or S(0) p ;
• R 5 is H or -Ci -3 alkyl; k is an integer 1 or 2 (such as 1 ); and p is as defined above, with the proviso that the total alkyl chain length is not more than 10 carbon atoms, including replacement heteroatoms and that the resulting radical Q is a stable group.
• Ci- 3 alkyl-V-Ci -3 alkyl-OCH3 for example Ci -3 alkyl-V-C 2-3 alkyl-OCH 3 such as Ci -3 alkyl-V-(CH 2 )2 ⁇ CH 3 , in particular -CH 2 O(CH 2 ) 2 OCH 3 and CH 2 S(CH 2 ) 2 OCH 3 , or -CH 2 NH(CH 2 ) 2 OCH 3 , Ci -3 alkyl-V-(Ci.
• alkyl-OCH 3 ) k wherein k represents 2, for example Ci -3 alkyl-V-(C 2-3 alkyl-OCH 3 ) k such as -CH 2 N[(CH 2 ) 2 OCH 3 ] 2 .
• Q is Ci -3 alkyl-V-Ci -2 alkyl-Z-Ci -2 alkyl-Y-R 6 , or Ci -3 alkyl-V-C 2-3 alkyl- Z-C 2-3 alkyl-Y-R 6 , wherein V, Z and Y are independently a heteroatom selected from NH, O or S(O) P ,
• R 6 is H or methyl, and p is as defined above, with the proviso that the total alkyl chain length is not more than 10 carbon atoms, including replacement heteroatoms and that the resulting radical Q is a stable group.
• Q is -CH 2 V(CH 2 ) 2 O(CH 2 ) 2 OCH 3 , such as -CH 2 O(CH 2 ) 2 O(CH 2 ) 2 OCH 3, -CH 2 NH(CH 2 ) 2 O(CH 2 ) 2 OCH 3, or -CH 2 S(CH 2 ) 2 O(CH 2 ) 2 OCH 3 .
• Q represents -NR 7 R 8 and -NR 3 C(O)Q forms a urea, where R 7 and R 8 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(O) 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, 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, Ci -4 mono or di- alkyl amino and Ci -4 mono or 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 Q is a stable group.
• groups independently selected from oxo, halogen, an aryl group, a heteroaryl group, a heterocyclyl or C 3-8 cycloalkyl group, each aryl, heteroaryl or heterocyclyl group bearing 0 to
• Q represents -NR 7 R 8 and -NR 3 C(O)Q forms a urea
• R 7 and R 8 independently represent hydrogen or a Ci.g 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(O) P .
• 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, 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, Ci -4 mono or di-alkyl amino and Ci -4 mono or 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 Q is a stable group.
• groups independently selected from 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
• R 7 represents hydrogen
• ureas include those in which R 7 and R 8 are both hydrogen and Q is -NH 2 , or where Q is -NHCH 3 or -N(CH 3 ) 2 to provide, for example, a fragment -NR 3 C(O)NH 2 or -NR 3 C(O)NHCH 3 or -NR 3 C(O)N(CH 3 ) 2 .
• ureas containing a heteroatom in the alkyl chain include those in which Q is -NH(CH 2 ) 2 OCH 3 or -N[(CH 2 ) 2 OCH 3 )] 2 .
• Q represents -NHC 2-6 alkyl0Ci. 3 alkyl, such as-NHCH 2 CH 2 OCH 3 .
• ureas containing an oxo substitutent include those in which Q is -NHCH 2 C(O)NH-C 2 -3alkyl-X 1 -Ci -3 alkyl, wherein X 1 is a heteroatom selected from N, O or S(O) P a nd p is d efi ned as above.
• Q represents -NHCi -4 alkylC(0)NHC 2 alkyl0CH 3 such as-NHCH 2 C(O)NHCH 2 CH 2 OCH 3 .
• Q represents -NHCi_ 4 alkylC(O)R Q wherein R Q is selected from OH or -NR'R" where R' is hydrogen or Ci -3 alkyl and R" is hydrogen or Ci -3 alkyl, for example -NHCH 2 C(O)OH, -NHCH 2 C(O)NH 2 or -NHCH 2 C(O)NHCH 3 such as -NHCH 2 C(O)OH or -NHCH 2 C(O)NHCH 3 .
• Q represents -NHCi -4 alkylC(O)OCi -3 alkyl,such as -NHCH 2 C(O)OCH 2 CH 3 .
• sub-embodiment Q represents -N-R 9 Ci -3 alkyl-V-(Ci -3 alkyl-Z-R 10 ) k for example -N-R 9 C 2-3 alkyl-V-(C 2-3 alkyl-Z-R 10 ) 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 O, 1 or 2
• R 9 represents H or Ci -3 alkyl-V-(Ci -3 alkyl-Z-R 10 ) k such as C 2-3 alkyl-V-(C 2-3 alkyl-Z-R 10 ) k ;
• R 10 is H or Ci -3 alkyl such as Ci -3 alkyl; with the proviso that the total alkyl chain length is not more than 10 carbon atoms, including replacement heteroatoms and that the resulting radical Q is a stable group.
• Q is a saturated or unsaturated, branched or unbranched C MO 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 O 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, Ci -6 alkoxy, Ci -6 haloalkyl, amino and Ci -4 mono or di-alkyl amino and Ci -4 mono or di-acyl amino, such as a saturated or unsaturated, branched or unbranched C MO 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 O to 3 substituents, for example 1 , 2 or 3, such as 1 or 2 substituents independently selected from hal
• Q represents -NHC 0-6 alkylphenyl, such as -NHphenyl or NHbenzyl.
• Examples of the fragment -NR 3 C(O)Q wherein Q comprises substituted benzyl include: -NR 3 C(O)CH 2 NHCH 2 C 6 H 4 (OCH 3 ) such as -NHC(O)CH 2 NHCH 2 C 6 H 4 (OCH 3 ), for example where the methoxy substituent is in the ortho, meta or para position , such as the para position.
• Q is a saturated or unsaturated, branched or unbranched C MO 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 O 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, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkyl amino, Ci -4 mono or di-alkyl amino and Ci -4 mono or di-acyl amino, such as a saturated or unsaturated, branched or unbranched C MO 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 O to 3 substituents for example 1 , 2 or 3, such as 1 or 2 substituents selected from halogen, Ci
• 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.
• Q represents -NHC- ⁇ .6 alkylheteroaryl, for example -NH(CH 2 )3imidazolyl or -NHCH 2 isoxazole wherein the isoxazole is optionally substituted such as -NHCH 2 isoxazole(CH 3 ) .
• Q represents -NHCi -4 alkylC(O)NHCi-3alkylheteroaryl, for example a nitrogen containing heteroaryl group or a nitrogen and oxygen containing heteroaryl, more specifically -NHCH 2 C(O)NHCH 2 CH 2 pyridinyl, in particular where pyridinyl is linked through carbon, for example pyridin-4-yl or -NHCH 2 C(O)NHCH 2 CH 2 CH 2 ImIdBZoIyI, in particular where imidazolyl is linked through nitrogen.
• Q is a saturated or unsaturated, branched or unbranched C MO 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 O 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, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl amino, Ci -4 mono or di-alkyl amino and Ci -4 mono or di-acyl amino, such as a saturated or unsaturated, branched or unbranched C MO 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 O to 3 substituents, for example 1 , 2 or 3, such as 1 or 2 substituents selected from halogen, Ci
• said heterocyclyl 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, and
• a heterocyclic group may be linked to the alkyl chain of Q or to the carbonyl of -NR 3 C(O)- through carbon or nitrogen, in particular a nitrogen atom.
• Q is -C 0- 3alkylheterocycle (for example-Co-ialkylheterocycle) 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 the relevant substituents listed above for compounds of formula (I), for example halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono and di- alkyl amino and Ci -4 mono or di-acyl amino.
• heteroatom for example 1 , 2 or 3, in particular 1 or 2, heteroatoms
• Q is -Coalkylheterocycle, 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 ⁇ /-linked morpholine or an ⁇ /-linked piperidine or an ⁇ /-linked piperazine, said ⁇ /-linked piperizinyl group optionally bearing an additional C- or N- substituent (such as an ⁇ /-methyl group or /V-CH 2 CH 2 OCH 3 group .
• Q is a heterocyclyl linked through nitrogen such as piperidinyl, in particular 4-hydroxypiperidinyl or piperazinyl, such as 4-methyl pierazinyl.
• Q 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.
• Q is a -C-ialkylheterocycle, for example tetrahydropyranylmethyl or a C- or ⁇ /-linked piperazinylmethyl optionally bearing a substituent (for example a Ci -6 alkyl substitutent such as methyl or a Ci -6 alkoxy substituent such as -CH 2 CH 2 OCH 3 ).
• a substituent for example a Ci -6 alkyl substitutent such as methyl or a Ci -6 alkoxy substituent such as -CH 2 CH 2 OCH 3
• Additional examples include a C- or ⁇ /-linked pyrrolidinylmethyl, or a C- or N- linked oxoimidazolinylmethyl (such as 2-oxoimidazolidinylmethyl, said heterocycle optionally bearing a substitutent (such as ⁇ /-methyl or /V-SO 2 CH 3 ).
• Q represents -N H heterocyclyl (wherein the heterocyclyl bears O 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 -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono or di-alkyl amino, -S(O) q Ci -6 alkyl, Ci -4 mono or di-acyl amino, C 0-6 alkylC(O)Ci -6 alkyl or Co -6 alkylC(O)Ci -6 heteroalkyl), such as where the ring is linked through carbon, for example 2-piperidinyl o r 3-piperidinyl or 4-piperidinyl, in particular 1-acetylpiperidin-4-yl, 1- methylpiperidin-4-yl, 1 -(methylsulfonyl)piperidin-4-yl or 1 -(2-(2-methoxyethoxy)
• Q represents -NHCi -6 alkylheterocyclyl for example a nitrogen containing heterocyclyl group, in particular one linked through nitrogen, such as -NHCH 2 CH 2 rnorpholine, -NH(CH 2 ) 3 rnorpholine or -NH(CH 2 ) 4 rnorpholine.
• Q represents -NHCi -6 alkylC(O)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 -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono or di-alkyl amino, Ci -4 mono or di-acyl amino, C 0-6 alkylC(O)Ci -6 alkyl or C 0-6 alkylC(O)Ci -6 heteroalkyl) for example a nitrogen containing heterocyclyl group, in particular one linked through nitrogen, such as -NHCH 2 C(O)-I -pyrrolindinyl, -NHCH 2 C(O)-I -piperidinyl, -NHCH 2 C(O )-4-morpholinyl or -NHCH 2 C(O)piperazinyl such as -NHCHCH 2
• Q represents -NHCi -4 alkylC(O)NHCi -3 alkylheterocyclyl for example a nitrogen containing heterocyclyl group or a nitrogen and/or oxygen containing heterocyclyl, such as -NHCH 2 C(O)NHCH 2 CH 2 rmorpholinyl, in particular where morpholinyl is linked through nitrogen.
• Q represents -N(Ci -3 alkyl)Ci -6 alkylheterocyclyl, for example a nitrogen containing heterocyclyl group, in particular linked through nitrogen, such as -N(CH3)CH 2 CH 2 morpholine, -N(CH 3 )(CH 2 )3morpholine or -N(CH 3 )(CH 2 ) 4 morpholine.
• Q is -C-i-aalkyl-G-d-aalkylheterocycle wherein G is a heteroatom selected from NH, O or S(O) 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, Ci -4 mono and di-alkyl amino and Ci -4 mono or di-acyl amino such as one or two or three groups halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono and di-alkyl amino.
• G is a heteroatom selected from NH, O or S(O) P said heterocyclyl group comprising at least one heteroatom (for example
• Q is -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 Ci -6 alkyl substitutent such as methyl or a Ci -6 alkoxy substituent such as -CH 2 CH 2 OCH 3 ); 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 oxoimidazolinyl (such as 2-oxoimidazolidinyl) for example linked through N and optionally bearing an additional C- or N- substituten
• G is O.
• G is NH
• Q is a saturated or unsaturated C MO alkyl chain wherein at least one carbon (for example 1 , 2 or 3 carbons) is replaced by a heteroatom selected from O, N, S(O ) 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 3-8 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 -4 mono or di-alkyl amino, Ci -4 mono or di-acyl amino, S(O) q Ci -6 alkyl, C 0-6 alkylC(O)Ci_ 6 alkyl or C 0-6 alkylC(O)Ci -6 heteroalkyl.
• groups for example 1 , 2 or 3 groups
• Q represents -NHC 3-6 cycloalkyl, such as -NHcyclopropyl, -NHcyclopentyl or -NHcyclohexyl.
• the aryl, heteroaryl or heterocyclyl group bears at least one -S(O) q Ci -6 alkyl substitutent and optionally bears one or two further relevant substituents independently selected from the list of substituents defined above for compounds of formula (I).
• the C 5-6 heterocycle bears at least one -S(O) 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).
• the 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- 6heterocycle 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).
• aryl, heteroaryl or heterocyclyl group bears at least one Ci -4 mono and/or 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- 6heterocycle bears at least one Ci -4 mono and/or 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).
• aryl, heteroaryl or heterocyclyl group bears at least one Co-6 alkylC(O)Ci_6 heteroalkyl 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- 6heterocycle bears at least one C 0- 6 alkylC(O)Ci -6 heteroalkyl 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(O)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- 6heterocycle bears at least one C 0- 6 alkylC(O)Ci -6 alkyl substituent and optionally bears one or two further substituents independently selected from the relevant substituents defined above for compounds of formula (I).
• Q 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.
• alkyl chain fragment of Q does not bear any optional substituents.
• the alkyl chain is saturated.
• the alkyl chain is unbranched.
• alkyl chain fragment of Q 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.
• -CH(CH 3 )OCH 3 ; -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 -CH 2 NHCH 2 CH 2 OCH 3 or -CH 2 NHC(O)CH 2 OCH 3 ; -CH 2 SCH 3 , -CH 2 S(O) 2 CH 3 Or -CH 2 NHC(O)CH 2 S(O) 2 CH 3 ; or -CH 2 NHC(O)CH 2 .
• compounds of the disclosure include those in which the fragment -NR 3 C(O)Q in formula (I) is represented by: -NR 3 C(O)CH 2 OH, in particular -NHC(O)CH 2 OH;
• -NR 3 C(O)CH 2 OCi -6 alkyl in particular -NR 3 C(O)CH 2 OCH 3 , especially -NHC(O)CH 2 OCH 3 ; -NR 3 C(O)CH 2 O(CH 2 ) 2 OCH 3 , in particular -NHC(O)CH 2 O(CH 2 ) 2 OCH 3 ; -NR 3 C(O)CH(CH 3 )OCH 3 in particular -NHC(O)CH(CH 3 )OCH 3 ; -NR 3 C(O)CH(CH 3 )NHCi -3 alkyl in particular -NHC(O)CH(CH 3 )NHCH 3 ; -NR 3 C(O)CH(CH 3 )N(Ci -3 alkyl) 2 in particular -NHC(O)CH(CH 3 )N(CH 3 ) 2 ; -NR 3 C(O)C(CHs) 2 NHCH 3 in particular -NHC(O)C(CH 3
• -NR 3 C(O)(CH 2 ) 2 OCi -6 alkyl such as -NR 3 C(O)(CH 2 ) 2 OCH 3 , in particular -NHC(O)(CH 2 ) 2 OCH 3 ; -NR 3 C(O)(CH 2 ) 3 NHCi -3 alkyl in particular -NHC(O)(CH 2 ) 3 NHCH 3 ; -NR 3 C(O)(CH 2 ) 3 N(Ci -3 alkyl) 2 in particular -NHC(O)(CH 2 ) 3 N(CH 3 ) 2 ; -NR 3 C(O)CH 2 NHCi -3 alkyl in particular -NHC(O)CH 2 NHCH 3 ; -NR 3 C(O)CH 2 NH(CH 2 ) 2 OCH 3 in particular -NHC(O)CH 2 NH(CH 2 ) 2 OCH 3 ; -NR 3 C(O)CH 2 SCH 3 , in particular -
• -NR 3 C(O)NHCi -9 alkyl such as NR 3 C(O)NHCi -7 alkyl, in particular -NHC(O)NHCH 3 -NR 3 C(O)N(Ci -4 alkyl)Ci-5 alkyl in particular -NHC(O)N(CH 3 ) 2 ; or -NR 3 C(O)NHCH 2 CONH(CH 2 ) 2 OCH 3 in particular -NHC(O)NHCH 2 CONH(CH 2 ) 2 OCH 3 .
• compounds of the disclosure include compounds of formula (I) in which the fragment -NR 3 C(0)Co-8alkylheterocyclyl is represented by: -NHC(O)-(tetrahydropyranyl), such as -NHC(O)-(tetrahydro-2H-pyran-4-yl): -NHC(O)-(morpholinyl) such as -NHC(O )-(4-morpholinyl) or -NHC(O )-(3-morpholinyl); -NHC(O)-(pyrrolidinyl), such as -NHC(O )-(pyrrolidin-1-yl); -NHC(O)-(piperazinyl), such as -NHC(O )-(piperazin-1-yl); -NHC(O )-(methylpiperazinyl), such as -NHC(O )-(4-methylpiperazin-1-yl); -NHC(O )-(
• the saturated or unsaturated, branched or unbranched C MO alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from -O, -N, 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 Q above.
• R 1 , R 2 , Ar, L, R 3 and Q are as defined above.
• the substituent -NR 3 C(O)Q is in the 2 or 3 position.
• R 1 , R 2 , Ar, L, R 3 and Q are as defined above.
• R 1 , R 2 , Ar, L and R 3 are as defined above and p is 0, 1 or 2, in particular 0 or 2, and x is an integer from 1 to 6 (including 2, 3, 4 and 5) and y is zero or an integer from 1 to 5 (including 2, 3 and 4) with the proviso that x + y is an integer from 1 to 8 such as 1 to 6, for example x is 1 and y is 1.
• R 1 , R 2 , Ar, L and R 3 are as defined above x is an integer from 1 to 6 (including 2, 3, 4 and 5) and y is zero or an integer from 1 to 5 (including 2, 3 and 4), with the proviso that x + y is an integer from 1 to 6, for example x is 1 and y is 0.
• the fragment represented by -NR 3 C(O)(CH 2 ) ⁇ O(CH 2 )yCH3 is: -NR 3 C(O)CH 2 OCH 3 , especially -NHC(O)CH 2 OCH 3 .
• the disclosure relates to compounds of formula (IE):
• R 1 , R 2 , Ar, L, R 3 , R 7 and R 8 are as defined above.
• R 1 , R 2 , Ar, L and R 3 are as defined above and X 2 represents O, CH 2 , NH, NCH 3 or NCH 2 CH 2 OCH 3 .
• IG formula
• R 1 is Ci -6 alkyl optionally substituted by a hydroxyl group
• R 2 is H or Ci-6 alkyl optionally substituted by a hydroxyl group
• R 3 is H, Ci-6 alkyl or C 0-3 alkylC 3-6 cycloalkyl
• Ar is a naphthyl or a phenyl ring either of which may be optionally substituted by one or more groups independently selected from Ci -6 alkyl, Ci -6 alkoxy, amino, Ci -4 mono or di-alkyl amino;
• X is 5 or 6 membered heteroaryl group containing at least one nitrogen atom and optionally including 1 or 2 further heteroatoms selected from O, S and N;
• Q is selected from: a) a saturated or unsaturated, branched or unbranched C MO alkyl chain, 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 (for example 1 , 2 or 3) independently selected from oxo, halogen, an aryl group, a heteroaryl group, a heterocyclyl group or a C 3-8 cycloalkyl, each aryl, heteroaryl or heterocyclyl group bearing O to 3 substituents selected from halogen, hydroxyl, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono or di-alkyl amino, Ci -4 mono or di-acyl amino, S(O) q Ci -6 alkyl, C 0-6 alkylC(O)Ci
• R 1 , R 2 , Ar, R 3 and Q are as defined above.
• R 1 , R 2 , Ar, R 3 and Q are as defined above.
• R 1 , R 2 , Ar and R 3 are as defined above and
• Z represents a saturated or unsaturated, branched or unbranched C-i.g alkyl chain, 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 , or a Co-7 alkylC 5- 6 heterocycle said heterocyclyl group comprising 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 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, Ci -4 mono and di-alkyl amino.
• Z is -OCH 3 Or -OCH 2 CH 2 OCH 3 .
• Z is -SO 2 CH 3 .
• Z is -NR A R B wherein R A and R B are independently selected from hydrogen, Ci -6 alkyl, and C 3-6 alkoxy such that for example Z represents -NH 2 ,
• formula (IK) Z is -S(O) q CH 3 wherein n is O, 1 or 2, such as O or 2.
• formula (IK) Z represents a -C 5-6 heterocycle said heterocyclyl group comprising 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 is optionally substituted by one, 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, Ci -4 mono and di-alkyl amino, for example: morpholinyl (in particular linked through nitrogen) or tetrahydropyranyl, or piperazinyl (in particular linked through nitrogen) optionally substituted on the second nitrogen by -CH 3 Or -CH 2 CH 2 OCH 3 .
• the disclosure relates to compounds of formula (IL):
• R 1 , R 2 , Ar and R 3 are as defined above and
• R 7 and R 8 independently represent hydrogen, Ci -6 alkyl, or
• R 7 and R 8 together with the nitrogen to which they are attached represent a 5 or 6 membered heterocycle optionally comprising a further heteroatom selected from O, N and S, wherein said heterocycle is optionally substituted by one or two or three groups independently selected from the relevant sustituents listed above for compounds of formula (I), for example halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono and di-alkyl amino.
• the group -NR 7 R 8 represents -NH 2 , -NHCH 3 Or NHCH 2 CH 3 .
• R 1 , R 2 , Ar and R 3 are as defined above and
• Het represents a C 5-6 heterocycle said heterocyclyl group comprising 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 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, Ci -4 mono and di-alkyl amino.
• heteroatom for example 1 , 2 or 3, suitably 1 or 2, in particular 1 heteroatom
• Het is morpholinyl or tetrahydropyranyl.
• the compound is not: ⁇ /-(4-((4-(3-(3-te/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5- yl)ureido)naphthalen-1-yloxy)methyl) pyridin-2-yl)-2-methoxyacetamide.
• 2-(2-morpholinoethylsulfonyl)acetamide 2-(Bis(2-methoxyethyl)amino)- ⁇ /-(4-((4-(3-(3-te/f-butyl-1-p-tolyl-1 /-/-pyrazol-5-yl)ureido) naphthalen-1-yloxy)methyl)pyridin-2-yl)acetamide;
• 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 chiral centres, and the disclosure extends to include racemates, both enantiomers (for example each substantially free of the other enantiomer) and all stereoisomers resulting therefrom.
• one enantiomeric form is present in a substantially purified form that is substantially free of the corresponding entaniomeric form.
• the reaction is suitably carried out in the presence of a base (e.g. DIPEA).
• a base e.g. DIPEA
• the reaction is suitably carried out in an aprotic solvent or solvent mixture, e.g. DCM and DMF.
• LG 2 and LG 3 each independently represent leaving groups (e.g. LG 2 and LG 3 both represent imidazolyl followed by reaction with a compound of formula (V):
• the reaction is suitably carried out in an aprotic solvent (e.g. dichloromethane), using appropriate protecting groups for chemically sensitive groups and a base, for example DIPEA.
• aprotic solvent e.g. dichloromethane
• protecting groups for chemically sensitive groups and a base for example DIPEA.
• Compounds of formula (I) wherein R 2 is a hydroxyalkyl may be prepared by reacting a (hydrazinylphenyl)alkanoic acid with an alkanoyl acetonitrile such as R 1 C(O)CH 2 CN, for example.
• the coupling may be effected in presence of an alcohol solvent such as ethanol and a mineral acid, such as HCI followed by treatment with a lithium hydroxide in a solvent such as THF.
• the substituent R 2 comprising a hydroxyalkyl may be revealed by a reduction employing borane in a suitable solvent, for example THF to afford a compound of formula (IV) where R 2 is hydroxylated alkyl.
• the hydroxyl may then be protected, for example as a silyl ether and and (IV) carried through one of the routes described elsewhere in this section to generate a compound of formula (I) in which R 2 is a protected hydroxyalkyl group.
• the hydroxyl can be revealed by cleavage of the sillyl group, for example with tetrabutylammonium fluoride.
• a compound of formula (IVa) can be prepared by reacting a compound of formula (IV) with phosgene or a phosgene equivalent such as diphosgene or triphosgene in the presence of a base such DIPEA. It will be understood by persons skilled in the art that the compound of formula (IVa) is generally a reactive intermediate, and may be isolated and used directly in subsequent transformations or may be a transient intermediate, that is generated in situ and used without isolation.
• the reaction may be performed in the presence of a sterically hindered base such as DIPEA, in a suitable inert solvent such as dichloromethane.
• a sterically hindered base such as DIPEA
• a suitable inert solvent such as dichloromethane.
• a compound of (IVb) can be prepared by reacting a compound of formula (IV) with a compound of formula (Vl) in the presence of a base such as DIPEA. It will be understood by persons skilled in the art that the compound of formula (IVb) may be an intermediate, including a transient intermediate, that is not isolated.
• a compound of formula (V) may be prepared by reduction of a compound of formula (VII):
• the reaction is suitably carried out in polar protic solvent or mixture of solvents (e.g. methanol and acetic acid).
• polar protic solvent or mixture of solvents e.g. methanol and acetic acid.
• a compound of formula (V) where L is O may be prepared by deprotecting a compound of formula (Vila):
• a compound of formula (VII) wherein L represents -(CH 2 )n0(CH 2 )m or (CH 2 ) n OR b , as defined above, wherein n is zero and the linker L contains at least one -CH 2 - may be prepared by reaction of a compound of formula (Villa) or (VIIIb):
• R 3 is a protecting group or R 3 as defined above for compounds of formula (I) with a compound of formula (IX) or (X):
• the reaction may be performed under Mitsunobu conditions, such as in the presence of triphenylphosphine and diisopropylazodicarboxylate.
• the reaction is suitably carried out in a polar aprotic solvent (e.g. tetrahydrofuran, in particular anhydrous tetrahydrofuran).
• the compound formula (XII) is: (XIIa) (XIIb)
• the reaction may be performed in the presence of a strong base such as sodium hydride in a polar aprotic solvent such as DMF.
• a strong base such as sodium hydride in a polar aprotic solvent such as DMF.
• a compound of formula (XVI) Treatment of a compound of formula (XVI) with a base such as n-butyl lithium in an inert solvent such as THF followed by the addition of DMF provides compounds of formula (XVII).
• Compounds of formula (XVII) may be transformed into compounds of formula (XV) by an olefination step such as by reaction with a Wittig reagent generated in situ, such as the ylid generated from methyltriphenylphosphonium bromide in the presence of a base such potassium te/f-butoxide.
• a Wittig reagent generated in situ such as the ylid generated from methyltriphenylphosphonium bromide in the presence of a base such potassium te/f-butoxide.
• the reaction will be performed in an inert solvent, for example THF, and under an inert atmosphere such as nitrogen at a low temperature, such a -78°C.
• R 1 , R 2 , Ar, L, X, NR 3 are as defined above for compounds of formula (I) and LG 6 represents a leaving group, for example halogen such as chloro, with a compound of formula
• the reaction may, be performed in the presence of a sterically hindered base, for example DIPEA, in an inert solvent, for example dichloromethane.
• a sterically hindered base for example DIPEA
• an inert solvent for example dichloromethane
• LG ⁇ is defined above for compounds of formula (Ha), and LG 7 is a leaving group, for example a halogen such as chloro.
• the reaction may, for example be performed in the presence of a sterically hindered base, for example DIPEA, in an inert solvent, for example dichloromethane.
• a sterically hindered base for example DIPEA
• DIPEA a sterically hindered base
• an inert solvent for example dichloromethane
• Compounds of formula (lib) can be synthesisized by reaction of Compound (II) with an isocyanate of formula (HIb) in which Q is N-(CH 2 ) P -CO 2 Et, followed by hydrolysis of the resulting ethyl ester product using, for example, aqueous lithium hydroxide in THF.
• the reaction may, be performed in the presence of a sterically hindered base, for example DIPEA, in an inert solvent, for example dichloromethane.
• a sterically hindered base for example DIPEA
• an inert solvent for example dichloromethane
• R 1 , R 2 , Ar, X and R 3 are as defined above for compounds of formula (I) and LG 2 is a leaving group such as 2-isopropenyloxy.
• Compounds of formula (lie) can be synthesized by reaction of Compound (II) with a compound of formula (Vl), such as isopropenylchloroformate in the presence of a hindered base such as DIPEA.
• a compound of formula (Vl) such as isopropenylchloroformate
• DIPEA hindered base
• the reaction may, be performed in the presence of a sterically hindered base, for example DIPEA, in an inert solvent, for example dichloromethane.
• a sterically hindered base for example DIPEA
• an inert solvent for example dichloromethane
• X ' and Y ' independently represents CH or N.
• Ar is naphthyl and XNHR 3 represents 2-aminopyrimidinyl or 4-aminopyrimidinyl:
• 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 th 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 compounds developed to date have typically been intended for oral administration. This strategy involves optimizing compounds which achieve their duration of action by an appropriate pharmacokinetic profile. This ensures that there is a sufficient drug concentration established and maintained after and between doses to provide clinical benefit.
• the inevitable consequence of this approach is that all body tissues, especially liver and gut, are likely to be exposed to therapeutically active concentrations of the drug, whether or not they are adversely affected by the disease being treated.
• efficacy can be achieved either by (i) ensuring that the drug has a sustained duration of action and is retained in the relevant organ to minimize the risks of systemic toxicity or (ii) producing a formulation which generates a "reservoir" of the active drug which is available to sustain the drug's desired effects.
• Approach (i) is exemplified by the anticholinergic drug tiotropium (Spiriva), which is administered topically to the lung as a treatment for COPD, and which has an exceptionally high affinity for its target receptor resulting in a very slow off rate and a consequent sustained duration of action.
• Spiriva anticholinergic drug tiotropium
• a compound of formulation as a p38 MAP kinase 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.
• compositions may be prepared e.g. for parenteral, subcutaneous, intramuscular, intravenous, intra-articu lar 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.
• SEG soft elastic gelatin
• 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. 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.
• 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 C F C p ro p e l l a n t s i n c l u d e t ri c h l o ro m o n of l u o ro m e t h a n e ( p ro p e l l a n t 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).
• 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 microns.
• 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 ⁇ m 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.
• 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.
• 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 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 e.g. theophylline
• FCS foetal calf serum
• Labels given to intermediates in the examples are independent of labels given to intermediates in other parts of the description.
• SCX was purchased from Supelco and treated with 1 M hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with
• Example 8 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methyl-2-(methylamino)propanamide
• Example 12 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-4-methylpiperazine-1 -carboxamide
• Example 14 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-3-methoxypropanamide
• Example 18 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-3-(methylsulfonyl)-2-oxoimidazolidine-1 -carboxamide
• Example 20 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(methylsulfinyl)acetamide
• Example 25 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(2-methoxyethylamino)acetamide
• Example 30 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(2-(2-methoxyethoxy)ethylthio)acetamide
• reaction mixture was evaporated in vacuo and purified by flash column chromatography (SiO 2 , 12 g, 0-10% MeOH in DCM, gradient elution) to afford impure product which was triturated with a mixture of diethyl ether (3.0 ml_), DCM (3.0 ml.) and isohexane (5.0 ml.) and further purified by SCX capture and release to provide the title compound (Example 31 ) (14 mg, 21 %): m/z 708 (M+H) + (ES + ).
• Example 33 2-(Bis(2-methoxyethyl)amino)- ⁇ /-(4-((4-(3-(3-terf-butyl-1 -p-tolyl-1 H-pyrazol-5-)
• Example 34 1 -(4-((3-Methylureidopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-terf-butyl-1 - p-to
• Methyl isocyanate (8.5 ⁇ l_, 0.14 mmol) was added to a solution of Intermediate C (50 mg, 0.10 mmol) in pyridine (1.0 ml_). The reaction mixture was stirred for 2 hr at RT and a further portion of methyl isocyanate (8.5 ⁇ l_, 0.14 mmol) was added and stirring continued for 72 hr at RT. The solvent was removed in vacuo and the crude product was purified by column chromatography (SiO 2 , 4 g, 10-25% MeOH in DCM, gradient elution). The crude product fractions were combined and triturated with DCM (20 ml_).
• Example 36 ⁇ /-(4-((4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl) pyridin-3-yl)-2-(2-methoxyethoxy)acetamide
• Example 38 ⁇ /-(4-(2-(4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - ylo
• Example 39 4-(2-(4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)ethyl)-1 -methyl -3 -(pyridin-2-yl)urea
• Example 40 4-(2-(4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)ethyl)-3-(pyridin-2-yl)urea CCl 3 CONCO, Pyridine
• Methoxyacetyl chloride (17.5 ⁇ L, 0.192 mmol) was added dropwise to a solution of Intermediate G (41 mg, 0.077 mmol) and DIPEA (40.1 ⁇ L, 0.230 mmol) in DCM (3 mL) under nitrogen at 0 0 C. After 15 min the reaction mixture was warmed to RT and was stirred for 1.5 hr. A solution of NH 3 (1 % in MeOH, 1.5 mL) was added and stirring continued for a further 2 hr. The reaction mixture was evaporated in vacuo and the residue was subjected to SCX capture and release.
• the reaction mixture was quenched by the addition of saturated aq NH 4 CI solution (10 mL). Water (150 mL) and EtOAc (150 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were washed with brine, dried (MgSO 4 ) and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO 2 , 80 g, 0-60% EtOAc in isohexane, gradient elution) to afford the title compound (41 ) (282 mg, 8%) as a red oil: m/z 324 (M+H) + (ES + ).

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