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WO2011070368A1 - Utilisation antivirale de composés d'urée - Google Patents

Utilisation antivirale de composés d'urée Download PDF

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Publication number
WO2011070368A1
WO2011070368A1 PCT/GB2010/052066 GB2010052066W WO2011070368A1 WO 2011070368 A1 WO2011070368 A1 WO 2011070368A1 GB 2010052066 W GB2010052066 W GB 2010052066W WO 2011070368 A1 WO2011070368 A1 WO 2011070368A1
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WIPO (PCT)
Prior art keywords
ureido
butyl
pyrazol
tolyl
naphthalen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/GB2010/052066
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English (en)
Inventor
John King-Underwood
Kazuhiro Ito
Peter Strong
Garth Rapeport
Catherine Elisabeth Charron
Peter John Murray
Jonathan Gareth Williams
Stuart Thomas Onions
Robert Fenton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Respivert Ltd
Original Assignee
Respivert Ltd
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Filing date
Publication date
Application filed by Respivert Ltd filed Critical Respivert Ltd
Publication of WO2011070368A1 publication Critical patent/WO2011070368A1/fr
Priority to US13/805,552 priority Critical patent/US9079893B2/en
Priority to EP11729150.0A priority patent/EP2582433B1/fr
Priority to CN2011800298034A priority patent/CN103096978A/zh
Priority to PCT/GB2011/051139 priority patent/WO2011158042A2/fr
Priority to PCT/GB2011/051136 priority patent/WO2011158039A1/fr
Priority to JP2013514787A priority patent/JP6159251B2/ja
Priority to JP2013514786A priority patent/JP2013530179A/ja
Priority to EP11728920.7A priority patent/EP2582432B1/fr
Priority to US13/805,485 priority patent/US20130123260A1/en
Priority to AU2011266797A priority patent/AU2011266797B2/en
Anticipated expiration legal-status Critical
Priority to US14/924,541 priority patent/US20160045482A1/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present disclosure relates to use of compounds of formula (I) in the treatment and/or prophylaxis of viral infection, for example the treatment and/or prophylaxis of infection with influenza virus, as a monotherapy or in combination with other anti-viral agents concomitantly or sequentially.
  • the disclosure also extends to combination formulations that comprise said active components.
  • Seasonal influenza is a sub-acute illness which causes significant mortality in well defined subsets of the population, in particular the very young, the elderly and those suffering from chronic diseases, such as congestive heart failure. In addition infection with the virus produces significant morbidity in the wider population (Nichol, K. L. et al., N. Engl. J. Med., 1995, 333:889-893.). Recent human history also demonstrates that occasionally a more virulent strain of the influenza virus arises which is responsible for substantial mortality and morbidity amongst the "healthy young".
  • Vaccination is the principle intervention deployed to control the impact of seasonal influenza in both at-risk groups and the wider population.
  • Many at-risk patients are suitable for preventative treatment by vaccination, such as those suffering from diabetes, congestive heart failure, renal failure, or chronic obstructive pulmonary disease.
  • it is not suitable for other immuno- suppressed groups, such as cancer patients undergoing chemotherapy.
  • control of the threat posed by pandemic influenza requires that this regimen be supplemented by the use of treatments which target the propagation of the virus directly, thereby limiting clinical disease in infected individuals. This is the approach adopted by public health authorities around the world in response to the recent global outbreak of Swine influenza.
  • the principle medicines available for clinical use target the viral neuraminidase enzyme and include the products zanamivir (Relenza) and oseltamivir (Tamiflu).
  • the efficacy of these medicines is limited by several factors which include the need for administration in a prophylactic regimen or very soon after the onset of infection (Gubareva, L.V. et al., Lancet 2000, 355:827-835.).
  • the benefit (symptom relief and duration) arising from the treatment of an established (12-24 hr) infection in the wider population has been revealed to be modest, although high doses of neuraminidase inhibitors are used as part of the treatment protocol on intensive care units.
  • influenza strains have emerged that express mutant enzymes which render the virus resistant to these therapies (see for example, Aoki, F.Y.; Boivin, G.; and Roberts, N. Antivir. Ther., 2007,12(4 Part B):603-616.). These factors make it highly desirable for new, safe and/or more effective medicines to be identified which inhibit the propagation of the influenza virus and provide benefit in alleviating or preventing the clinical consequences of the disease.
  • Virus entry into host cells is associated with the activation of a number of intracellular signalling pathways which are believed to play a prominent role in the initiation of virus-mediated inflammatory processes (reviewed by Ludwig, S. Signal Transduction, 2007, 7(1 ):81 -88.) and of viral propagation and subsequent release.
  • PI3 kinase / Akt pathway One such mechanism, which mediates influenza virus propagation in vitro, is the PI3 kinase / Akt pathway.
  • the activation of this pathway by the NS1 protein of the virus has been described (Shin, Y-K. et at., J. Gen. Virol., 2007, 88:13-18.) and its inhibition has been reported to reduce resultant titres of progeny virus (Ehrhardt, C. et a/., Cell Microbiol., 2006, 8(8):1336-1348.).
  • the MEK inhibitor, U0126 has been reported to inhibit viral propagation without detection of resistant variants of the virus (Ludwig, S. et ai, FEBS Lett, 2004, 561 (1 -3):37-43.).
  • 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 C 2-8 di-alkyl amino;
  • L is a 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 -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 Co-8 alkyl-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 which 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- 8 di-alkyl amino, Ci -4 mono or C 2-8 di-acyl amino, S(0) q Ci -6 alkyl, C 0- 6 alkylC(0)Ci -6 alkyl, Co-6 alkylC(O)NC 0 -6 alkyl C 0-6 alkyl or C 0-6 alkylC(O)C 0 - 6 heteroalkyl; and
  • p 0, 1 or 2;
  • q 0, 1 or 2;
  • the compound of formula (I) is not ⁇ /-(4-(4- (3-(3-ie f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prophylaxis of viral infection, for example influenza virus infection.
  • influenza virus for example A, B and C strains thereof.
  • Figure 1 shows the effects of prophylactic treatment with combinations of compound
  • Example 1 and zanamavir on influenza -induced haemaglutinnin expression assessed using Method 1.
  • Figure 2 shows survival curves resulting from treatments with compound Example 1 and oseltamivir alone and in combination on mortality following influenza A/NWS/33(H1 N1 ) virus infection in mice
  • Figure 3 shows the effects on CPE, as assessed in an MTT assay, resulting from treatment with zanamavir ( Figure 3a) or Compound Example 1 ( Figure 3b) at either 2 or 24 hr after inoculation with influenza virus.
  • Figure 3a shows the RSV Memphis 37 induced IL-8 release in primary 3D cultured nasal epithelial cells arising from treatment with Compound Example 1.
  • Figure 3b shows the RSV Memphis 37 virus load in primary 3D cultured nasal epithelial cells arising from treatment with Compound Example 1 .
  • 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 ie 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 alkylOCi -3 alkyl, such as -CH2CH2OCH 3 or -CH2OCH 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 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 carbon group, as technically appropriate.
  • Haloalkyl as employed herein 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
  • C1-4 mono or C 2-8 di-acyl amino is intended to refer to -NHC(0)Ci -3 alkyl and to (-NC(0)Ci -3 alkyl) C(0)d -3 alkyl) respectively.
  • C1-4 mono or C 2- 8 di-alkyl amino is intended to refer to -NHC1-4 alkyl and -N(Ci -4 alkyl) (Ci -4 alkyl) respectively.
  • Aryl as used herein refers to, for example C 6- i 4 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.
  • C1-10 alkyl includes C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 or C 9 as well as Ci and C10
  • 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 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 ie f-butyl, in particular ie f-butyl.
  • R 1 is -C(CH 3 )2CH 2 OH.
  • R 2 is methyl, ethyl, n-propyl, /so-propyl, n-butyl or ie f-butyl, in particular methyl. In one embodiment 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, di-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.
  • L is a straight chain linker, for example:
  • n 1 , 2, 3, 4, 5, 6, 7 or 8;
  • n and m are independently 0, 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 0- or -CH 2 CH 2 0-.
  • L may represent -OCH 2 -.
  • L is a branched chain linker RO(CH 2 ) m wherein m is zero or an integer 1 ,
  • R a is a C 2-7 branched alkyl, with the proviso that the number of carbons in R a added to m is an integer from 2 to 7, especially where m is zero, such as -CH(CH 3 )0-, -C(CH 3 ) 2 0-, -CH 2 CH(CH 3 )0-, -CH(CH 3 )CH 2 0-, -C(CH 3 ) 2 CH 2 0- or -CH 2 C(CH 3 ) 2 0, in particular - CH(CH 3 )0-.
  • L is a branched chain linker (CH 2 ) n OR b wherein n is zero or an integer 1 , 2,
  • R b is a C 2-7 branched alkyl, with the proviso that the number of carbons in R b added to 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 and 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 total number of carbons in R a and R b is an integer from 4 to 7.
  • L is a saturated unbranched Ci-C 8 alkylene chain or a saturated branched or unbranched C 2-8 alkylene chain. In one embodiment 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 or 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.
  • 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.
  • 1 , 2, 3 or 4 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 -8 alkyl chain or a C-i-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 is directly bonded to the carbonyl of the fragment -NR 3 C(0) 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 CMO 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 , for example in such a manner as to provide a stable /V-acyl group, NR 3 C(0)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 0 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 CMO 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 , for example in such a manner as to provide a stable /V-acyl group, NR 3 C(0)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 0 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 C 2-8 di-alkyl amino and Ci -4 mono or C 2-8 di-acyl amino.
  • halogen Ci -6 al
  • 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 0 to 3 substituents selected from halogen, Ci -6 alkyl, C-i-6 alkoxy, Ci -6 haloalkyl, amino, and Ci -4 mono or C 2-8 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(0) p ;
  • R v represents H or Ci -3 alkyl
  • R 4 is H or -Ci-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 Q is a stable group, for example -CH 2 SCH 3, -CH 2 S0 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 -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(0) 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 );
  • Q is Ci_ 3 alkyl-V-Ci -3 alkyl-OCH 3 for example Ci -3 alkyl-V-C 2-3 alkyl-OCH 3 such as Ci -3 alkyl-V-(CH 2 ) 2 OCH 3 , in particular -CH 2 0(CH 2 ) 2 OCH 3 and CH 2 S(CH 2 ) 2 OCH 3 , or -CH 2 NH(CH 2 ) 2 OCH 3 , d -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(0) p , R 6 is H or methyl, and p is as defined above,
  • Q is -CH 2 V(CH 2 ) 2 0(CH 2 ) 2 OCH 3 , such as -CH 2 0(CH 2 ) 2 0(CH 2 ) 2 OCH 3 , -CH 2 NH(CH 2 ) 2 0(CH 2 ) 2 OCH 3 , or-CH 2 S(CH 2 ) 2 0(CH 2 ) 2 OCH 3 .
  • Q represents -NR 7 R 8 and -NR 3 C(0)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(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, 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 C 2- 8 di-alkyl amino and Ci -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 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 heterocycly
  • Q represents -NR 7 R 8 and -NR 3 C(0)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(0) 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 C 2-8 di-alkyl amino and Ci -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 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
  • 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(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 Q is - NH(CH 2 ) 2 OCH 3 or -N[(CH 2 ) 2 OCH 3 )] 2 .
  • Q represents -NHC 2-6 alkylOCi -3 alkyl, such as-NHCH 2 CH 2 OCH 3 .
  • ureas containing an oxo substitutent include those in which Q 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 Q is -NHCH2C(0)NHCH2CH 2 OCH3. Thus in one embodiment Q represents -NHCi -4 alkylC(0)NHC 2 alkylOCH 3 such as-NHCH2C(0)NHCH 2 CH 2 OCH3.
  • Q represents -NHCi -4 alkylC(0)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(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 .
  • the radical Q represents -NHCi -4 alkylC(0)OCi -3 alkyl, such as -NHCH 2 C(0)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 0, 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
  • 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 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, Ci -6 alkoxy, Ci -6 haloalkyl, amino and Ci -4 mono or C 2-8 di-alkyl amino and Ci -4 mono or C 2-8 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 or 2
  • Q represents -NHC 0- 6 alkylphenyl, such as -NHphenyl or NHbenzyl.
  • -NR 3 C(0)CH 2 NHCH 2 C 6 H 4 OCH 3
  • -NHC(0)CH 2 NHCH 2 C 6 H 4 OH 3
  • 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 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 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, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkyl amino, Ci -4 mono or C 2-8 di-alkyl amino and Ci -4 mono or C 2-8 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 a heteroaryl group bearing 0 to 3 substituents for example 1 , 2 or 3, such as 1 or 2 substituents
  • 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 -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 ) .
  • Q represents -NHCi -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.
  • Q 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 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, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl amino, Ci -4 mono or C 2-8 di-alkyl amino and Ci -4 mono or C 2-8 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 a heterocyclyl group bearing 0 to 3 substituents, for example 1 , 2 or 3, such as 1 or 2 substituents
  • 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.
  • a heterocyclic group may be linked to the alkyl chain of Q or to the carbonyl of -NR 3 C(0)- through carbon or nitrogen, in particular a nitrogen atom.
  • Q is -C 0-3 alkylheterocycle (for example-C 0 -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 C 2- 8 di-alkyl amino and Ci -4 mono or C 2- 8 di-acyl amino.
  • heteroatom for example 1 , 2 or 3, in particular 1 or 2, heteroatoms
  • Q is -C 0 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 N- 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 /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 -CH2CH2OCH 3 ).
  • a substituent for example a Ci -6 alkyl substitutent such as methyl or a Ci -6 alkoxy substituent such as -CH2CH2OCH 3
  • Additional examples include a C- or /V-linked pyrrolidinylmethyl, or a C- or N- linked oxoimidazolinylmethyl (such as 2-oxoimidazolidinylmethyl, said heterocycle optionally bearing a substitutent (such as /V-methyl
  • Q represents -NHheterocyclyl (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 C 2- 8 di-alkyl amino, -S(0) q Ci -6 alkyl, 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), 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
  • Q represents -NHCi -6 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 -6 alkoxy, Ci -6 haloalkyl, amino, Ci -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 Co-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 -piperazin
  • Q represents -NHCi -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.
  • Q 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.
  • Q is -Ci -3 alkyl-G-Ci -3 alkylheterocycle wherein G is a heteroatom selected from NH, O 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, Ci -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 -6 haloalkyl, amino, Ci -4 mono and C 2-8 di-alkyl amino.
  • G is a heteroatom selected from NH, O or S(0) p said heterocyclyl group comprising at
  • 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
  • G is O or NH.
  • G is O.
  • G is NH.
  • Q is a saturated or unsaturated CMO 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- 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 C 2-8 di-alkyl amino, Ci -4 mono or C 2-8 di-acyl amino, S(0) q Ci -6 alkyl, C 0- 6 alkylC(0)Ci -6 alkyl or C 0-6 alkylC(0)d -6 heteroalkyl.
  • Q represents -NHC 3- 6 cycloalkyl, such as -NHcyclopropyl, -NHcyclopentyl or -NHcyclohexyl.
  • the aryl, heteroaryl or heterocyclyl group bears at least one -S(0) 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(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).
  • 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 - 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).
  • 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 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 aryl, heteroaryl or heterocyclyl group bears at least one C 0- 6 alkylC(0)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 5-6 heterocycle bears at least one C 0- 6 alkylC(0)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 C 0- 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 -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. In one embodiment the alkyl chain is saturated. In one embodiment 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.
  • compounds of the disclosure include those in which the fragment -NR 3 C(0)Q in formula (I) is represented by:
  • -NR 3 C(0)CH 2 OCi -6 alkyl in particular -NR 3 C(0)CH 2 OCH 3 , especially -NHC(0)CH 2 OCH 3 ;
  • -NR 3 C(0)(CH 2 )20Ci-6alkyl such as -NR 3 C(0)(CH 2 ) 2 OCH 3 , in particular-NHC(0)(CH 2 ) 2 OCH 3 ; -NR 3 C(0)(CH 2 ) 3 NHCi -3 alkyl, and in particular -NHC(0)(CH 2 ) 3 NHCH 3 ;
  • -NR 3 C(0)NHCi-9 alkyl such as NR 3 C(0)NHCi -7 alkyl, and in particular -NHC(0)NHCH 3
  • compounds of the disclosure include compounds of formula (I) in which the fragment -NR 3 C(O)C 0-8 alkylheterocyclyl is represented by:
  • -NHC(0)-(morpholinyl) such as -NHC(0)-(4-morpholinyl) or -NHC(0)-(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 Q above.
  • R 1 , R 2 , Ar, L, R 3 and Q are as defined above.
  • the substituent -NR 3 C(0)Q is in the 2 or 3 position.
  • 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 the sum of x and 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 the sum of xand y is an integer from 1 to 6, for example x is 1 and y is 0.
  • the fragment represented by -NR 3 C(0)(CH 2 ) x O(CH 2 ) y CH 3 is: -NR 3 C(0)CH 2 OCH 3 , especially -NHC(0)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 is Ci -6 alkyl optionally substituted by a hydroxyl group
  • R 2 is H or C1-6 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 C 2- 8 di-alkyl amino;
  • X is 5 or 6 membered heteroaryl group containing at least one nitrogen atom
  • Q is selected from:
  • a Co-8 alkylC 5- 6 heterocycle or 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 halogen, hydroxyl, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, amino, Ci -4 mono and C 2- 8 di-alkyl amino, Ci -4 mono or C 2- 8 di-acyl amino, S(0) q Ci -6 alkyl, C 0-6 alkylC(0)Ci -6 alkyl or C 0-6 alkylC(0)d -6 heteroalkyl; and
  • p 0, 1 or 2;
  • 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 Ci -9 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 C 2-8 di-alkyl amino.
  • heteroatom for example 1 , 2 or 3, suitably 1 or 2, in particular 1 heteroatom
  • Z is -OCH 3 or -OCH 2 CH 2 OCH 3 .
  • Z is -S0 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 , -IMHCH3, -N(CH 3 ) 2 or -NHCH 2 CH 2 OCH 3 .
  • Z is -S(0) q CH 3 wherein n is 0, 1 or 2, such as 0 or 2.
  • 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 C 2-8 di-alkyl amino, for example:
  • piperazinyl in particular linked through nitrogen
  • piperazinyl 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 C 2-8 di-alkyl amino.
  • the group -NR 7 R 8 represents -NH 2 , -NHCH 3 or NHCH 2 CH 3 .
  • -NR 7 R 8 represents morpholinyl or piperazinyl.
  • 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 C 2- 8 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: /V-(4-(4-(3-(3-fe/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl) ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-methoxyacetamide.
  • 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.
  • the disclosure herein extends to solvates of compounds of formula (I). Examples of solvates include hydrates.
  • the compounds, of the disclosure include those in which one or more of the atoms 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 disclosure also extends to all polymorphic forms of the compounds herein defined.
  • LG-i is a leaving group for example halogen, such as chloro.
  • reaction is suitably carried out in the presence of a base (e.g. DIPEA).
  • a base e.g. DIPEA
  • 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.
  • the reaction may be performed in the presence of a sterically hindered base such as
  • DIPEA inert solvent
  • a suitable inert solvent such as dichloromethane
  • 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(0)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 (VI) 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):
  • P 1 , P 2 and P 3 are protecting groups and R 3 is a protecting group, for example acetyl such as -C(0)CH 2 OCH 3 or R 3 as defined above for compounds of formula (I).
  • a compound of formula (VII) wherein L represents -(CH 2 )nO(CH2) 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 (Vlllb):
  • 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).
  • P 3 and R 3 are as defined above in the presence of an dry inert solvent such as THF and a suitable palladium catalyst, for example under a nitrogen atmosphere, followed by deprotection of both the original and newly introduced protected amines, for example employing dichloromethane and TFA.
  • an dry inert solvent such as THF
  • a suitable palladium catalyst for example under a nitrogen atmosphere, followed by deprotection of both the original and newly introduced protected amines, for example employing dichloromethane and TFA.
  • LG 5 LG 4 ( XIV )
  • LG 4 represents a leaving group such as chloro and LG 5 represents a leaving group such a fluoro.
  • 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 ie f-butoxide.
  • a Wittig reagent generated in situ such as the ylid generated from methyltriphenylphosphonium bromide in the presence of a base such potassium ie 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 (XVIII):
  • H represents hydrogen
  • V represents a heteroatom selected from N, NH, O, or S
  • 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 6 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
  • R 1 , R 2 , Ar, L, X and R 3 9 are as defined above for compounds of formula (I) and d is an integer 1 to 5 (such as 1 to 4), and an amine R 8 NH 2 using a coupling reagent such as EDC.
  • Compounds of formula (lib) can be synthesisized by reaction of Compound (II) with an isocyanate of formula (lllb) in which Q is N-(CH 2 ) p -C0 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 (He) can be synthesized by reaction of Compound (II) with a compound of formula (VI), such as isopropenylchloroformate in the presence of a hindered base such as DIPEA.
  • a compound of formula (VI) 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
  • examples of the disclosure wherein L, R 1 , R 2 , R 3 and Q are as defined above for compounds of formula (I), Ar is naphthyl and X is pyridinyl, may be prepared according to the transformations set out below (Schemes 8a-f). Particular routes disclosed below (Scheme 8b and 8c) provide for examples of compounds of formula (I) wherein NHR or NRR ' represent Q and wherein Q together with NHC(O) forms a urea.
  • 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.
  • the viral infection is influenza, including subtypes influenza A virus, influenza B virus, avian strain H5N1 , A/H1 N1 and/or influenza pandemic.
  • the disclosure also extends to a method of treatment or prophylaxis of viral infection, for example infection caused by the influenza virus, including the influenza A virus, which gives rise to flu pandemics such as that which arose in the Spring of 2009 as a result of a new influenza A (H1 N 1 ) strain; the influenza B and the influenza C viruses comprising administering a therapeutically effective amount of a compound of formula (I).
  • a method of treatment or prophylaxis of viral infection for example infection caused by the influenza virus, including the influenza A virus, which gives rise to flu pandemics such as that which arose in the Spring of 2009 as a result of a new influenza A (H1 N 1 ) strain; the influenza B and the influenza C viruses comprising administering a therapeutically effective amount of a compound of formula (I).
  • the disclosure also extends to a method of treatment or prophylaxis of viral infection, for example that caused by the influenza A virus, including subtypes H1 N 1/09, which gave rise to the flu pandemic which arose in the Spring of 2009, avian strain H5N1 , H1 N1 , H1/N2, H3/N2. H2/N3, the influenza B and the influenza C viruses, comprising administering a therapeutically effective amount of a compound of formula (I).
  • the disclosure also provides use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of viral infection for example influenza, including subtypes influenza A virus, influenza B virus, avian strain H5N1 , A/H1 N1 , H3N2 and/or influenza pandemic.
  • influenza including subtypes influenza A virus, influenza B virus, avian strain H5N1 , A/H1 N1 , H3N2 and/or influenza pandemic.
  • the compound of formula (I) is provided as a monotherapy. In one embodiment the compound of formula (I) is provided as a combination therapy.
  • the compound may be provided as a pharmaceutical formulation or composition.
  • compositions may be used either as prophylaxis or to treat an influenza infection. Nasal administration may be particularly helpful for prophylaxis.
  • Formulations for nasal administration may be solid or aqueous or oily preparations where the therapeutic agent is either a compound of formula (I) alone or a combination of a compound of formula (I) and an anti-viral agent, for example a neuraminidase inhibitor such as, but not limited to, zanamivir for use in the form of nasal drops or metered spray.
  • a pharmaceutical composition comprising a compound of formula (I), or combinations as discussed herein, optionally in combination with one or more topically acceptable diluents or carriers.
  • a pharmaceutical composition comprising a combination of a compound of formula (I) and an anti-viral agent, for example a neuraminidase inhibitor such as, but not limited to, zanamivir for use in the form of nasal drops or metered spray.
  • an anti-viral agent for example a neuraminidase inhibitor such as, but not limited to, zanamivir for use in the form of nasal drops or metered spray.
  • 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).
  • a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • 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).
  • co-solvents e.g. ethanol
  • 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 one or more compound(s) 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.
  • a compound of the present is provided as a micronized dry powder formulation, for example comprising lactose of a suitable grade, filled into a device such as DISKUS.
  • oral administration of the compound of formula (I) may be more suitable. Therefore, in an alternative embodiment there is provided a pharmaceutical composition for oral administration comprising a compound of formula (I), or combinations as discussed herein, optionally in combination with one or more orally acceptable diluents or carriers.
  • Oral compositions may be in any conventional form, for example tablets, capsules, suspensions, syrups and elixirs.
  • a compound as defined herein for example a compound of formula (I) formulated in combination with an antiviral medicament, for example a neuroamidase inhibitor.
  • the formulation is a co-formulation, for example a nasal formulation or a topical such as an inhaled formulation.
  • Anti-viral agents in the context of the present specification include neuraminidase inhibitors such as oseltamivir, zanamivir, peramivir, amantadine, rimantadine, ribavirin; interferon, acyclovir and/or zidovudine.
  • neuraminidase inhibitors such as oseltamivir, zanamivir, peramivir, amantadine, rimantadine, ribavirin; interferon, acyclovir and/or zidovudine.
  • Particular combinations include a compound of formula (I) and oseltamivir, a compound of formula (I) and zanamivir, a compound of formula (I) and peramivir, a compound of formula (I) and amandadine, a compound of formula (I) and rimantadine, a compound of formula (I) and ribavirin, a compound of formula (I) and acyclovir, a compound of formula (I) and zidovudine, a compound of formula (I), amantadine and ribavirin, a compound of formula (I), oseltamivir and amantadine, a compound of formula (I), oseltamivir and ribavirin, a compound of formula (I), acyclovir and zidovudine or a compound of formula (I), oseltamivir, ribavirin and amantadine.
  • the neuraminidase inhibitor may, for example be oseltamivir, zanamivir, peramivir.
  • the formulation may comprise an M2 inhibitor, for example amantadine or rimantadine.
  • the use of a combination product may allow one or more of the active agents to be provided at a lower dose than would otherwise be required for a therapeutic effect, employing a single active ingredient as a monotherapy.
  • the neuraminidase inhibitor for example zanamivir, oseltamivir, laninamivir, peramivir; ribavarin interferon is provided at a lower dose than is conventionally used in clinical practice, for example, for the anti-viral agent such as zanamavir, the dose range may be 0.03 to 10 mg per treatment or preferentially 0.3 to 3 mg per treatment.
  • the anti-viral agent is provided a dose of: 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 024, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83,
  • Compounds of formula (I) may be administered at doses in the range 0.01 to 500 mg per dose, for example 0.05 to 250 mg, such as 0.1 to 100 mg.
  • the compound of formula (I) or the combination comprising the same is administered once or twice daily.
  • the combinations according to the present disclosure at least have an additive therapeutic effect, but may in have a synergistic therapeutic effect.
  • the antiviral active agents for example those described supra, are coadministered.
  • the subsequent active agent may, for example be administered 15, 30, 45 min or 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 1 1 or 12 hr after administration of the first active agent.
  • composition described herein for use in treatment or prophylaxis, for example the treatment or prophylaxis of viral infections such as, influenza, in particular the sub-types described herein.
  • the disclosure also extends a method of treatment or prophylaxis, of a patient in need thereof, comprising administering a therapeutically effective amount of a composition described herein.
  • composition described herein for the manufacture of a medicament for the treatment or prophylaxis of viral infection, for example influenza, in particular a sub-type defined herein.
  • use in the treatment or prophylaxis of humans and sub- populations thereof for example those populations of patients with: chronic disease or illness such as diabetes, congestive heart failure, renal failure, chronic obstructive pulmonary disease, asthma, and/or
  • immunosuppression such as patients undergoing chemotherapy, pregnant women, HIV and AIDS patients, and/or
  • complications arising from influenza infection for example pulmonary or systemic complications.
  • use in the treatment or prophylaxis of infants from 1 day to 1 year old
  • child for example child under the age of 5.
  • animals for example farm animals, including horses and pigs, birds including domestic birds such as fowl, geese, ducks, swans and the like, domestic animals including cats and dogs.
  • the treatment of animals may be advantageous in that it limits the transmission of the virus to humans and therefore reduces the risk of a flu epidemic.
  • FCS foetal calf serum
  • RSV respiratory syncytial virus
  • Labels given to intermediates in the examples are independent of labels given to intermediates in other parts of the description.
  • 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 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.
  • Example 8 W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methyl-2-(methylamino)propanamide:
  • Example 12 yV-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-4-methylpiperazine-1 -carboxamide: Intermediate A
  • Example 14 yV-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-3-methoxypropanamide:
  • Example 15 2-(3-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)ureido)-yV-(2-methoxyethyl)acetamide:
  • Example 17 yV-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-3-(methylsulfonyl)propanamide:
  • Example 20 W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 ⁇ yloxy)methyl)pyridin-2-yl)-2-(methylsulfinyl)acetamide:
  • Example 25 W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(2-methoxyethylamino)acetamide:
  • Example 30 W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(2-(2-methoxyethoxy)ethylthio)acetamide:
  • Example 32 W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(2-morpholinoethylsulfonyl)acetamide: OXONE®
  • Example 33 2-(Bis(2-methoxyethyl)amino)-yV-(4-((4-(3-(3-ferf-butyl-1 -p-tolyl-1 H-pyrazol- 5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-yl)acetamide:
  • reaction mixture was stirred at RT for 12 hr whereupon further di-ie f-butyldicarbonate (2.33 g, 10.7 mmol) was added and the reaction mixture was stirred at RT for 12 hr.
  • the reaction was partitioned between EtOAc (100 mL) and saturated aq NaHC0 3 solution (50 mL). The organic layer was collected, dried and concentrated in vacuo to afford an orange oil.
  • Example 34 1 -(4-((3-Methylureidopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ferf-butyl- 1 -p-tolyl-1 H-pyrazol-5-yl)urea: MeNCO
  • Methyl isocyanate (8.5 ⁇ _, 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 ⁇ _, 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 (Si0 2 ,4 g, 10-25% MeOH in DCM, gradient elution). The crude product fractions were combined and triturated with DCM (20 mL).
  • Example 36 W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 ⁇ yloxy)methyl) pyridin-3-yl)-2-(2-methoxyethoxy)acetamide:
  • Example 38 W-(4-(2-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)ethyl)pyridin-2-yl)-2-(2-methoxyethoxy)acetamide:
  • Example 39 4-(2-(4-(3-(3-ferf-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-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - y I oxy)ethy I )-3 -(py rid i n -2 -y I) u rea :
  • Methoxyacetyl chloride (17.5 ⁇ , 0.192 mmol) was added dropwise to a solution of Intermediate G (41 mg, 0.077 mmol) and DIPEA (40.1 ⁇ , 0.230 mmol) in DCM (3 mL) under nitrogen at 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.
  • Methoxyacetyl chloride (28 ⁇ , 0.30 mmol) was added dropwise under nitrogen to a solution of Intermediate H (66 mg, 0.12 mmol) in DCM (3.0 mL) and DIPEA (63 ⁇ _, 0.36 mmol) at 0°C.
  • the reaction mixture was stirred at 0°C for 15 min and then at RT for 2.5 hr.
  • a solution of NH 3 (1 % in MeOH, 1 .5 mL) was added and the mixture was stirred for 30 min and was then evaporated in vacuo.
  • a second portion of 3-fe/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-amine (141 mg, 0.615 mmol) in DCM (1 mL) was processed in a similar manner to the first, by reaction with CDI (100 mg, 0.615 mmol) in DCM (1 mL) and the resulting adduct was then added to the reaction mixture. After a further 2.5 hr the mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine and then dried (MgS0 4 ) and evaporated in vacuo.
  • Methoxyacetyl chloride (17 ⁇ , 0.18 mmol) was added dropwise to a stirred solution of Intermediate J (40 mg, 0.073 mmol) and DIPEA (38 ⁇ _, 0.22 mmol) in DCM (3 mL) at 0°C under nitrogen. After 20 min the reaction mixture was warmed to RT. After a further 4 hr a solution of NH 3 (1 % in MeOH, 3 mL) was added and stirring continued for 1 hr.

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Abstract

La présente invention concerne des composés de formule (I) : où R1, R2, R3, Ar, L, X et Q sont tels que définis dans la présente, qui sont utiles pour le traitement ou la prophylaxie d'infections virales, en particulier des infections par l'influenzavirus.
PCT/GB2010/052066 2009-12-11 2010-12-10 Utilisation antivirale de composés d'urée Ceased WO2011070368A1 (fr)

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AU2011266797A AU2011266797B2 (en) 2010-06-17 2011-06-17 Methods
PCT/GB2011/051136 WO2011158039A1 (fr) 2010-06-17 2011-06-17 Dérivés d'uréido-pyrazole destinés à être utilisés dans le traitement d'infections par un rhinovirus
EP11729150.0A EP2582433B1 (fr) 2010-06-17 2011-06-17 Dérivés d'uréido-pyrazole destinés à être utilisés dans le traitement d'infections par un rhinovirus
CN2011800298034A CN103096978A (zh) 2010-06-17 2011-06-17 方法
PCT/GB2011/051139 WO2011158042A2 (fr) 2010-06-17 2011-06-17 Méthodes
US13/805,552 US9079893B2 (en) 2010-06-17 2011-06-17 Ureido-pyrazole derivatives for use in the treatment of respiratory syncitial virus (RSV) infection
JP2013514787A JP6159251B2 (ja) 2010-06-17 2011-06-17 方法
JP2013514786A JP2013530179A (ja) 2010-06-17 2011-06-17 呼吸器合胞体ウイルス（ｒｓｖ）感染の処置に使用するためのウレイド−ピラゾール誘導体
EP11728920.7A EP2582432B1 (fr) 2010-06-17 2011-06-17 Dérivés d'uréido-pyrazole destinés à être utilisés dans le traitement d'infections par un rhinovirus
US13/805,485 US20130123260A1 (en) 2010-06-17 2011-06-17 Methods
US14/924,541 US20160045482A1 (en) 2010-06-17 2015-10-27 Ureido-pyrazole derivatives

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011158039A1 (fr) * 2010-06-17 2011-12-22 Respivert Limited Dérivés d'uréido-pyrazole destinés à être utilisés dans le traitement d'infections par un rhinovirus
WO2011158042A3 (fr) * 2010-06-17 2013-03-28 Respivert Limited Méthodes
EP2578582A1 (fr) * 2011-10-03 2013-04-10 Respivert Limited 1-Pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napthtalèn-1-yl) urées comme inhibiteurs de la p38 MAP kinase
WO2013050757A1 (fr) * 2011-10-03 2013-04-11 Respivert Limited L-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)naphtalén-1-yl)urées en tant qu'inhibiteurs de p38 map kinase
WO2013083604A1 (fr) 2011-12-09 2013-06-13 Chiesi Farmaceutici S.P.A. Inhibiteurs de kinases
WO2013083606A1 (fr) 2011-12-09 2013-06-13 Chiesi Farmaceutici S.P.A. Inhibiteurs de kinases
US8927563B2 (en) 2013-04-02 2015-01-06 Respivert Limited Kinase inhibitor
US8933228B2 (en) 2010-06-17 2015-01-13 Respivert, Ltd. Respiratory formulations and compounds for use therein
US9120789B2 (en) 2010-02-01 2015-09-01 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
US9155737B2 (en) 2007-12-19 2015-10-13 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-B]pyrazin-8-substituted compounds and their use
US9242960B2 (en) 2009-04-03 2016-01-26 Respivert, Ltd. P38MAP kinase inhibitors
US9249125B2 (en) 2012-08-29 2016-02-02 Respivert Limited Pyrazole derivatives as p38 MAP inhibitors
US9447076B2 (en) 2014-02-14 2016-09-20 Respivert Ltd. Inhibitor of p38 map kinase
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US9701670B2 (en) 2012-08-17 2017-07-11 Respivert Limited Pyrazolyl-ureas as kinase inhibitors
US9708317B2 (en) 2013-11-25 2017-07-18 Cancer Research Technology Limited Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-B]pyrazin-3-one derivatives
US9725447B2 (en) 2013-11-25 2017-08-08 Cancer Research Technology Limited 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer
US9732063B2 (en) 2012-11-16 2017-08-15 Respivert Limited Kinase inhibitors
US9771353B2 (en) 2013-04-02 2017-09-26 Topivert Pharma Limited Kinase inhibitors based upon N-alkyl pyrazoles
US9783556B2 (en) 2012-08-29 2017-10-10 Respivert Limited Kinase inhibitors
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US10072034B2 (en) 2016-04-06 2018-09-11 Respivert Limited Kinase inhibitors

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000043384A1 (fr) 1999-01-19 2000-07-27 Boehringer Ingelheim Pharmaceuticals, Inc. Composes heterocycliques aromatiques utilises comme agents anti-inflammatoires
WO2003072569A1 (fr) * 2002-02-25 2003-09-04 Boehringer Ingelheim Pharmaceuticals, Inc. Composes de cycloalkyle uree benzofusionnes a disubstitution en position 1,4 utiles dans le traitement de maladies mediees par la cytokine
WO2006136562A1 (fr) 2005-06-20 2006-12-28 Tibotec Pharmaceuticals Ltd Benzimidazoles substitués par un hétérocyclylaminoalkyle
WO2007087448A1 (fr) 2006-01-30 2007-08-02 Irm Llc Dérivés d'imadazole spiro utilisés comme modulateurs du récepteur ppar
WO2007089512A1 (fr) 2006-01-27 2007-08-09 Array Biopharma Inc. Activateurs de glucokinases
WO2007096764A2 (fr) 2006-02-27 2007-08-30 Glenmark Pharmaceuticals S.A. Dérivés d'hétéroaryles bicycliques en tant que modulateurs des récepteurs cannabinoïdes
WO2010067130A1 (fr) * 2008-12-11 2010-06-17 Respivert Limited Inhibiteurs de kinase map p38

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000043384A1 (fr) 1999-01-19 2000-07-27 Boehringer Ingelheim Pharmaceuticals, Inc. Composes heterocycliques aromatiques utilises comme agents anti-inflammatoires
WO2003072569A1 (fr) * 2002-02-25 2003-09-04 Boehringer Ingelheim Pharmaceuticals, Inc. Composes de cycloalkyle uree benzofusionnes a disubstitution en position 1,4 utiles dans le traitement de maladies mediees par la cytokine
WO2006136562A1 (fr) 2005-06-20 2006-12-28 Tibotec Pharmaceuticals Ltd Benzimidazoles substitués par un hétérocyclylaminoalkyle
WO2007089512A1 (fr) 2006-01-27 2007-08-09 Array Biopharma Inc. Activateurs de glucokinases
WO2007087448A1 (fr) 2006-01-30 2007-08-02 Irm Llc Dérivés d'imadazole spiro utilisés comme modulateurs du récepteur ppar
WO2007096764A2 (fr) 2006-02-27 2007-08-30 Glenmark Pharmaceuticals S.A. Dérivés d'hétéroaryles bicycliques en tant que modulateurs des récepteurs cannabinoïdes
WO2010067130A1 (fr) * 2008-12-11 2010-06-17 Respivert Limited Inhibiteurs de kinase map p38

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
AOKI, F.Y.; BOIVIN, G.; ROBERTS, N., ANTIVIR. THER., vol. 12, no. 4, 2007, pages 603 - 616
EHRHARDT, C. ET AL., CELL MICROBIOT., vol. 8, no. 8, 2006, pages 1336 - 1348
GUBAREVA, L.V. ET AL., LANCET, vol. 355, 2000, pages 827 - 835
LUDWIG, S. ET AL., FEBS LETT., vol. 561, no. 1-3, 2004, pages 37 - 43
LUDWIG, S., SIGNAL TRANSDUCTION, vol. 7, no. 1, 2007, pages 81 - 88
NEWTON, S. E. ET AL., VIROLOGY, vol. 128, no. 2, 1983, pages 495 - 501
NGUYEN J.T. ET AL., ANTIMICROB. AGENTS CHEMOTHER., vol. 53, no. 10, 2009, pages 4115 - 4126
NICHOL, K. L. ET AL., N. ENGL. J. MED., vol. 333, 1995, pages 889 - 893
READING, P.C. ET AL., J. VIROL., vol. 71, no. 11, 1997, pages 8204 - 8212
REGAN, J. ET AL., J. MED. CHEM., vol. 46, 2003, pages 4676 - 4686
SHIN, Y-K. ET AL., J. GEN. VIROL., vol. 88, 2007, pages 13 - 18
THEODORA W. GREENE; PETER G.M. WUTS: "Protective Groups in Organic Synthesis", 2006, JOHN WILEY & SONS INC

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