WO2011070368A1 - Antiviral use of urea compounds - Google Patents

Antiviral use of urea compounds 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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WO
WIPO (PCT)
Prior art keywords
ureido
butyl
pyrazol
tolyl
naphthalen
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PCT/GB2010/052066
Other languages
French (fr)
Inventor
John King-Underwood
Kazuhiro Ito
Peter Strong
Garth Rapeport
Catherine Elisabeth Charron
Peter John Murray
Jonathan Gareth Williams
Stuart Thomas Onions
Robert Fenton
Original Assignee
Respivert Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Respivert Limited filed Critical Respivert Limited
Publication of WO2011070368A1 publication Critical patent/WO2011070368A1/en
Priority to JP2013514786A priority Critical patent/JP2013530179A/en
Priority to EP11729150.0A priority patent/EP2582433B1/en
Priority to JP2013514787A priority patent/JP6159251B2/en
Priority to AU2011266797A priority patent/AU2011266797B2/en
Priority to PCT/GB2011/051139 priority patent/WO2011158042A2/en
Priority to US13/805,485 priority patent/US20130123260A1/en
Priority to PCT/GB2011/051136 priority patent/WO2011158039A1/en
Priority to CN2011800298034A priority patent/CN103096978A/en
Priority to US13/805,552 priority patent/US9079893B2/en
Priority to EP11728920.7A priority patent/EP2582432B1/en
Priority to US14/924,541 priority patent/US20160045482A1/en

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    • 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

Compounds of formula (I) wherein R1, R2, R3, Ar, L, X and Q are as defined herein are useful for the treatment or prophylaxis of viral infections, especially influenza virus infections.

Description

ANTIVIRAL USE OF UREA COMPOUNDS
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.
Background to the invention
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. However, it is not suitable for other immuno- suppressed groups, such as cancer patients undergoing chemotherapy. However, 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. Currently, 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.
In common with other viruses, 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. 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.). Furthermore, 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.).
In addition to studying the propagation of influenza virus in cells, it is possible to characterise the effects of treatment on viral load using in vivo models, such as the mouse and ferret models. By exploiting a combination of in vitro and in vivo systems it is possible to compare the effects of novel compounds, intended to inhibit influenza virus propagation, with the properties of established clinical agents such as zanamivir (Relenza) and oseltamivir (Tamiflu) both as monotherapy regimens and in combination with these and/or other agents.
It is noteworthy that combination therapy can be a highly effective approach in the palliation of infectious diseases. This is well illustrated by the evolution of drug treatment for HIV infection, which began as monotherapy but has developed steadily to the point where triple therapy, using drugs directed against two distinct viral proteins, is regarded as the gold standard. Indeed, a recent publication has reported that the anti-influenza combination incorporating oseltamivir, amantadine, and ribavirin, display synergistic activity against multiple influenza virus strains in vitro (Nguyen J.T. et al., Antimicrob. Agents Chemother., 2009, 53(10):41 15- 4126.). It is likely therefore, to be advantageous for new medicines to be compatible with use in combination with existing neuraminidase inhibitors, particularly in the setting of the intensive care unit.
Brief description of the invention
We have discovered that certain compounds of formula (I) (below) are effective inhibitors of influenza viral load in vitro and in vivo. As an example, we have evaluated the ability of Λ/-[4- ({4-[3-(3-ie f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido]naphthalen-1 -yloxy}methyl)pyridin-2-yl]-2- methoxyacetamide (Compound Example 1 ) to inhibit influenza-induced protein expression (haemaglutinnin or nuclear protein) and CPE in MDCK cells and in vivo in a mouse model. This revealed that the compound provides remarkably potent activity in vitro against the influenza H1 N1 (PR8). (Newton, S. E. et al. Virology, 1983, 128(2):495-501 ; Reading, P.C. et al., J. Virol. 1997, 71 (1 1 ):8204-8212) and other strains. Thus the present invention provides a compound of formula (I):
Figure imgf000004_0001
wherein R1 is Ci-6 alkyl optionally substituted by a hydroxyl group;
R2 is H or Ci-6 alkyl optionally substituted by a hydroxyl group;
R3 is H, Ci-6 alkyl or C0-3 alkylC3-6 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 C2-8 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) 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 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 C3-8 cycloalkyl group,
each aryl, heteroaryl, heterocyclyl or C3-8 cycloalkyl group bearing 0 to 3 substituents selected from halogen, hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, amino, Ci-4 mono or C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, S(0)qCi-6 alkyl, C0-6 alkylC(0)d-6 alkyl or C0-6 alkylC(0)Ci-6 heteroalkyl, with the proviso that the atom linked directly to the carbonyl in -NR3C(0)- is not an oxygen or a sulfur atom; and
b) 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 C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, S(0)qCi-6 alkyl, C0-6 alkylC(0)Ci-6 alkyl, Co-6 alkylC(O)NC0-6 alkyl C0-6 alkyl or C0-6 alkylC(O)C0-6 heteroalkyl; and
p is 0, 1 or 2;
q is 0, 1 or 2; or
or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers, tautomers and isotopic derivatives thereof, with the proviso that the compound of formula (I) is not Λ/-(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.
Thus there is provided use of compounds of formula (I) for:
the treatment including to decrease the severity and/or duration of symptoms; or prophylaxis to prevent or limit the severity of infection by influenza virus (for example A, B and C strains thereof).
A Brief Description of the Figures
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. shows the RSV Memphis 37 induced IL-8 release in primary 3D cultured nasal epithelial cells arising from treatment with Compound Example 1. shows the RSV Memphis 37 virus load in primary 3D cultured nasal epithelial cells arising from treatment with Compound Example 1 .
Detailed description of the invention
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 -CH2CH2OCH3 or -CH2OCH3. 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 NH2 for CH3, or NH or O or S02 for -CH2- 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
Figure imgf000006_0001
C1-4 mono or C2-8 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 C2-8 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 C6-i4 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. Examples of 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 C5-6 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. Clearly any valancies of a heteroatom not employed in forming or retaining the ring structure may be filled by hydrogen or a substituent, as appropriate. Thus subsituents on heterocycles may be on carbon or on a heteroatom, such as N as appropriate. Examples of heterocycles and C5-6 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.
Oxo as used herein refers to C=0 and will usually be represented as C(O). C3-8 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 C2, C3, C4, C5, C6, C7, C8 or C9 as well as Ci and C10
Co-8 alkyl includes Ci, C2, C3, C4, C5, C6, or C7 as well as C0 and C8.
In relation to 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, it will be clear to persons skilled in the art that the heteroatom may replace a primary, secondary or tertiary carbon, that is CH3, -CH2- or a -CH- or a branched carbon group, as technically appropriate.
In one embodiment of the disclosure there is provided compounds of formula (I), wherein R1 is methyl, ethyl, propyl, /'so-propyl, butyl or ie f-butyl, in particular ie f-butyl. In one embodiment R1 is -C(CH3)2CH2OH.
In one embodiment R2 is methyl, ethyl, n-propyl, /so-propyl, n-butyl or ie f-butyl, in particular methyl. In one embodiment R2 is -CH2OH.
In one embodiment R2 is in the 2, 3, or 4 position (i.e. ortho, meta or para position), in particular the para (4) position. In one embodiment Ar is naphthyl.
In one embodiment Ar is not substituted with optional substituents.
In one embodiment Ar is substituted with 1 or 2 groups.
In one embodiment 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. In such a case 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. In one embodiment L is a straight chain linker, for example:
-(CH2)n- wherein n is 1 , 2, 3, 4, 5, 6, 7 or 8; or
-(CH2)nO(CH2)m- wherein 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.
In one embodiment L is -OCH2-, -OCH2CH2-, -CH20- or -CH2CH20-. For example, L may represent -OCH2-.
In one embodiment L is a branched chain linker RO(CH2)m wherein m is zero or an integer 1 ,
2, 3, 4 or 5 and Ra is a C2-7 branched alkyl, with the proviso that the number of carbons in Ra added to m is an integer from 2 to 7, especially where m is zero, such as -CH(CH3)0-, -C(CH3)20-, -CH2CH(CH3)0-, -CH(CH3)CH20-, -C(CH3)2CH20- or -CH2C(CH3)20, in particular - CH(CH3)0-.
In one embodiment L is a branched chain linker (CH2)nORb wherein n is zero or an integer 1 , 2,
3, 4 or 5 and Rb is a C2-7 branched alkyl, with the proviso that the number of carbons in Rb added to n is an integer from 2 to 7, for example n is zero, such as -OCH(CH3)-, -OC(CH3)2-, -OCH2CH(CH3)-, -OCH(CH3)CH2-, -OC(CH3)2CH2- or -OCH2C(CH3)2 and in particular -OCH(CH3)- or -OC(CH3)2CH2-.
In one embodiment L is a branched chain linker RORb wherein Ra and Rb are independently selected from a C2-7 branched alkylene with the proviso that the total number of carbons in Ra and Rb is an integer from 4 to 7.
In one embodiment L is a saturated unbranched Ci-C8 alkylene chain or a saturated branched or unbranched C2-8 alkylene chain. In one embodiment at least one carbon in L is replaced by -0-.
In one embodiment L is -0-.
Alkylene as employed herein refers to branched or unbranched carbon radicals, such as methylene (-CH2-) 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.
In one embodiment 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. In one embodiment the chain L does not include a halogen atom or atoms. In one embodiment R3 is H. In one embodiment R3 is methyl, ethyl, n-propyl or /'so-propyl. In one embodiment R3 is cyclopropyl.
In one embodiment 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. In one embodiment 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.
In one embodiment the heteroatom(s) replacing carbon(s) in the alkyl chain fragment of Q are selected from N and O.
In one embodiment 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. Alternatively, in this embodiment the alkyl chain may be a C2-8 alkyl or a C3-6 alkyl group, such as a C4 alkyl or a C5 alkyl group.
In one embodiment a nitrogen atom in the alkyl chain is directly bonded to the carbonyl of the fragment -NR3C(0) and additionally may, for example, be a terminal amino group.
In one embodiment Q represents Ci-6 alkylNH2 or NH2.
In one embodiment Q represents -NHCi-6 alkyl such as -NHCH3 or -NHCH2CH3 or -NHCH(CH3)2.
In one embodiment 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, NR3C(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 C3-8 cycloalkyl each aryl, heteroaryl or heterocyclyl or C3-8 cycloalkyl group bearing 0 to 3 substituents independently selected from a relevant substituent listed above for compounds of formula (I). In one embodiment 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, NR3C(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 C2-8 di-alkyl amino and Ci-4 mono or C2-8 di-acyl amino.
In one embodiment 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 C2-8 di-alkyl amino.
In one embodiment Q is Ci-4alkyl-V-R4, such as Ci-3alkyl-V-R4 wherein:
V is a heteroatom selected from NRV, O or S(0)p;
Rv represents H or Ci-3 alkyl;
R4 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 -CH2SCH3, -CH2S02CH3, -CH2NHCH3, -CH2N(CH3)2 -C(CH3)2NHCH3, -CH(CH3)N(CH3)2, -(CH2)3CHNHCH3, -(CH2)3N(CH3)2, -CH2OH, -CH2OCH3, -CH(CH3)OCH3, or -(CH2)2OCH3. In one embodiment Q is Ci-3 alkyl-V-(Ci-3 alkyl-Z-R5)k such as Ci-3 alkyl-V-(C2-3 alkyl-Z-R5)k wherein:
V is a heteroatom selected from N, NH, O or S(0)p, such as N or NH
(V is N in the case where k = 2, or will be selected from NH, O or S(0)p, in the case where k =1 , in particular NH);
Z is independently selected from NH, O or S(0)p;
R5 is H or -Ci-3alkyl;
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. Suitably Q is Ci_ 3alkyl-V-Ci-3alkyl-OCH3 for example Ci-3alkyl-V-C2-3alkyl-OCH3 such as Ci-3alkyl-V-(CH2)2OCH3, in particular -CH20(CH2)2OCH3 and CH2S(CH2)2OCH3, or -CH2NH(CH2)2OCH3, d-3alkyl-V-(Ci. 3alkyl-OCH3)k wherein k represents 2, for example Ci-3alkyl-V-(C2-3alkyl-OCH3)k such as- CH2N[(CH2)2OCH3]2.
In one embodiment Q is Ci-3 alkyl-V-Ci-2 alkyl-Z-Ci-2 alkyl-Y-R6, or Ci-3 alkyl-V-C2-3 alkyl-Z-C2-3 alkyl-Y-R6, wherein V, Z and Y are independently a heteroatom selected from NH, O or S(0)p, R6 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. Suitably Q is -CH2V(CH2)20(CH2)2OCH3, such as -CH20(CH2)20(CH2)2OCH3, -CH2NH(CH2)20(CH2)2OCH3, or-CH2S(CH2)20(CH2)2OCH3.
In one embodiment Q represents -NR7R8 and -NR3C(0)Q forms a urea, where R7 and R8 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 C3-8 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 C2-8 di-alkyl amino and Ci-4 mono or C2-8 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.
In one embodiment Q represents -NR7R8 and -NR3C(0)Q forms a urea, where R7 and R8 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 C2-8 di-alkyl amino and Ci-4 mono or C2-8 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.
In this urea embodiment in one sub-embodiment R7 represents hydrogen.
Examples of ureas include those in which R7 and R8 are both hydrogen and Q is -NH2, or where Q is -NHCH3 or -N(CH3)2 to provide, for example, a fragment -NR3C(0)NH2 or -NR3C(0)NHCH3 or -NR3C(0)N(CH3)2.
Examples of ureas containing a heteroatom in the alkyl chain include those in which Q is - NH(CH2)2OCH3 or -N[(CH2)2OCH3)]2. In one embodiment Q represents -NHC2-6alkylOCi-3alkyl, such as-NHCH2CH2OCH3.
Examples of ureas containing an oxo substitutent include those in which Q is -NHCH2C(0)NH-C2-3alkyl-X1-Ci-3 alkyl, wherein X1 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)NHCH2CH2OCH3. Thus in one embodiment Q represents -NHCi-4 alkylC(0)NHC2alkylOCH3 such as-NHCH2C(0)NHCH2CH2OCH3.
In one embodiment Q represents -NHCi-4alkylC(0)RQ wherein RQ 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 -NHCH2C(0)OH, -NHCH2C(0)NH2 or -NHCH2C(0)NHCH3 such as -NHCH2C(0)OH or -NHCH2C(0)NHCH3.
In one embodiment the radical Q represents -NHCi-4alkylC(0)OCi-3alkyl, such as -NHCH2C(0)OCH2CH3.
In a further urea sub-embodiment Q represents -N-R9Ci-3 alkyl-V-(Ci-3 alkyl-Z-R10)k for example -N-R9C2-3 alkyl-V-(C2-3 alkyl-Z-R10)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
R9 represents H or Ci-3 alkyl-V-(Ci-3 alkyl-Z-R10)k such as C2-3 alkyl-V-(C2-3 alkyl-Z-R10)k; and
R10 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.
In one embodiment 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 C2-8 di-alkyl amino and Ci-4 mono or C2-8 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 substituents independently selected from halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, amino and Ci-4 mono or C2-8 di-alkyl amino. In one embodiment the said aryl group is phenyl, for example substituted phenyl or unsubstituted phenyl.
In one embodiment Q represents -NHC0-6 alkylphenyl, such as -NHphenyl or NHbenzyl.
Examples of the fragment -NR3C(0)Q wherein Q comprises substituted benzyl include:
-NR3C(0)CH2NHCH2C6H4(OCH3) such as -NHC(0)CH2NHCH2C6H4(OCH3), for example where the methoxy substituent is in the ortho, meta or para position, such as the para position.
In one embodiment 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 C2-8 di-alkyl amino and Ci-4 mono or C2-8 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 selected from halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkyl amino, Ci-4 mono or C2-8 di-alkyl amino. In one embodiment 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.
In one embodiment Q represents -NHCi-6 alkylheteroaryl, for example -NH(CH2)3imidazolyl or -NHCH2isoxazole wherein the isoxazole is optionally substituted such as -NHCH2isoxazole(CH3) .
In one embodiment Q represents -NHCi-4 alkylC(0)NHCi-3alkylheteroaryl, for example a nitrogen containing heteroaryl group or a nitrogen and oxygen containing heteroaryl, more specifically -NHCH2C(0)NHCH2CH2pyridinyl, in particular where pyridinyl is linked through carbon, for example pyridin-4-yl or -NHCH2C(0)NHCH2CH2CH2imidazolyl, in particular where imidazolyl is linked through nitrogen.
In one embodiment 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 C2-8 di-alkyl amino and Ci-4 mono or C2-8 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 selected from halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl amino, Ci-4 mono or C2-8 di-alkyl amino.
In one embodiment 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 -NR3C(0)- through carbon or nitrogen, in particular a nitrogen atom.
In one embodiment Q is -C0-3alkylheterocycle (for example-C0-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 C2- 8 di-alkyl amino and Ci-4 mono or C2-8 di-acyl amino.
In one embodiment Q is -C0alkylheterocycle, for example a tetrahydropyranyl or a pyrrolidinyl or a morpholinyl or a piperazinyl or an oxoimidazolinyl group, such as 2-oxoimidazolidinyl group. In one embodiment in which Q is -C0alkylheterocycle, 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.
In one embodiment in which Q is -C0alkylheterocycle, 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-CH2CH2OCH3 group . In one embodiment Q is a heterocyclyl linked through nitrogen such as piperidinyl, in particular 4-hydroxypiperidinyl or piperazinyl, such as 4-methyl pierazinyl.
In one embodiment 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.
In one embodiment 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 -CH2CH2OCH3). 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
Figure imgf000014_0001
In one embodiment 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 C2-8 di-alkyl amino, -S(0)qCi-6 alkyl, Ci-4 mono or C2-8 di-acyl amino, C0-6 alkylC(0)Ci-6 alkyl or C0-6 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-methoxyethoxy)acetyl) piperidin-4-yl In one embodiment Q represents -NHCi-6 alkylheterocyclyl for example a nitrogen containing heterocyclyl group, in particular one linked through nitrogen, such as -NHCH2CH2morpholine, -NH(CH2)3morpholine or -NH(CH2)4morpholine.
In one embodiment 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 C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, C0-6 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 -NHCH2C(0)-1 -pyrrolindinyl, -NHCH2C(0)-1 -piperidinyl, -NHCH2C(0)-4-morpholinyl or -NHCH2C(0)piperazinyl such as - NHCH2C(0)-4-methyl-1 -piperazinyl.
In one embodiment Q represents -NHCi-4 alkylC(0)NHCi-3alkylheterocyclyl for example a nitrogen containing heterocyclyl group or a nitrogen and/or oxygen containing heterocyclyl, such as -NHCH2C(0)NHCH2CH2morpholinyl, in particular where morpholinyl is linked through nitrogen.
In one embodiment 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)CH2CH2morpholine, -N(CH3)(CH2)3morpholine or -N(CH3)(CH2)4morpholine.
In one embodiment Q is -Ci-3alkyl-G-Ci-3alkylheterocycle 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 C2-8 di-alkyl amino and Ci-4 mono or C2-8 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 C2-8 di-alkyl amino. Suitably Q is -CH2G(CH2)2heterocycle for example -CH2G(CH2)2tetrahydropyranyl; or -CH2G(CH2)2morpholinyl in which the heterocyclyl is linked through nitrogen or carbon; or CH2G(CH2)2piperazinyl 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 -CH2CH2OCH3); or - CH2G(CH2)2pyrrolidinyl, in which the heterocyclyl is linked through nitogen or carbon, for example linked through nitrogen; or
-CH2G(CH2)2oxoimidazolinyl (such as 2-oxoimidazolidinyl) for example linked through N and optionally bearing an additional C- or N- substitutent (such as /V-methyl or /V-S02CH3), and in which G is O or NH. In one embodiment G is O. In one embodiment G is NH.
In one embodiment 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 C3-8 carbocyclyl group and said alkyl chain is optionally substituted by one or more (for example 1 or 2) groups selected from oxo and halogen. In one embodiment said C3-8 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 C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, S(0)qCi-6 alkyl, C0-6 alkylC(0)Ci-6 alkyl or C0-6 alkylC(0)d-6 heteroalkyl. In one embodiment Q represents -NHC3-6 cycloalkyl, such as -NHcyclopropyl, -NHcyclopentyl or -NHcyclohexyl.
In one embodiment the aryl, heteroaryl or heterocyclyl group bears at least one -S(0)qCi-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).
In one embodiment the C5-6 heterocycle bears at least one -S(0)qCi-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).
In one embodiment 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). In one embodiment the C5-6heterocycle 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).
In one embodiment the aryl, heteroaryl or heterocyclyl group bears at least one Ci-4 mono and/or C2-8 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).
In one embodiment the C5-6heterocycle bears at least one Ci-4 mono and/or C2-8 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). In one embodiment the aryl, heteroaryl or heterocyclyl group bears at least one C0-6 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). In one embodiment the C5-6heterocycle bears at least one C0-6 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).
In one embodiment the aryl, heteroaryl or heterocyclyl group bears at least one C0-6 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).
In one embodiment the C5-6heterocycle bears at least one C0-6 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).
In one embodiment 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.
In one embodiment the 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.
In one embodiment the alkyl chain fragment of Q bears 1 , 2, or 3, for example 1 or 2, in particular 1 optional substituent.
It will be clear to persons skilled in the art that the heteroatom may replace a primary, secondary or tertiary carbon, that is a CH3, -CH2- or a -CH-, group, as technically appropriate. In one embodiment p is 0 or 2.
In one embodiment p is 1.
In one embodiment compounds of the disclosure include those in which the fragment Q is:
-CH2OH;
-CH2OCi-6 alkyl, in particular -CH2OCH3;
-CH2CH2OCH3; -CH20(CH2)2OCH3;
-CH(CH3)OCH3;
-CH2NHCH3 or -CH2N(CH3)2
-CH2NHCH2CH2OCH3 or -CH2NHC(0)CH2OCH3;
-CH2SCH3, -CH2S(0)2CH3 or -CH2NHC(0)CH2S(0)2CH3; or
-CH2NHC(0)CH2.
In one embodiment compounds of the disclosure include those in which the fragment -NR3C(0)Q in formula (I) is represented by:
-NR3C(0)CH2OH, and in particular -NHC(0)CH2OH;
-NR3C(0)CH2OCi-6 alkyl, in particular -NR3C(0)CH2OCH3, especially -NHC(0)CH2OCH3;
-NR3C(0)CH20(CH2)2OCH3, and in particular -NHC(0)CH20(CH2)2OCH3;
-NR3C(0)CH(CH3)OCH3, and in particular -NHC(0)CH(CH3)OCH3;
-NR3C(0)CH(CH3)NHCi-3alkyl, and in particular -NHC(0)CH(CH3)NHCH3;
-NR3C(0)CH(CH3)N(Ci-3alkyl)2, and in particular -NHC(0)CH(CH3)N(CH3)2;
-NR3C(0)C(CH3)2NHCH3, and in particular -NHC(0)C(CH3)2NHCH3;
-NR3C(0)(CH2)20Ci-6alkyl, such as -NR3C(0)(CH2)2OCH3, in particular-NHC(0)(CH2)2OCH3; -NR3C(0)(CH2)3NHCi-3alkyl, and in particular -NHC(0)(CH2)3NHCH3;
-NR3C(0)(CH2)3N(Ci-3alkyl)2, and in particular -NHC(0)(CH2)3N(CH3)2;
-NR3C(0)CH2NHCi-3alkyl, and in particular -NHC(0)CH2NHCH3;
-NR3C(0)CH2NH(CH2)2OCH3 , and in particular -NHC(0)CH2NH(CH2)2OCH3;
-NR3C(0)CH2SCH3, in particular -NHC(0)CH2SCH3;
-NR3C(0)CH2S(CH2)2OCH3, in particular -NHC(0)CH2S(CH2)2OCH3;
-NR3C(0)CH2S(CH2)20(CH2)2OCH3, and in particular -NHC(0)CH2S(CH2)20(CH2)2OCH3 -NR3C(0)CH2SOCH3, and in particular -NHC(0)CH2SOCH3
-NR3C(0)CH2S(0)2CH3, and in particular -NHC(0)CH2S(0)2CH3;
-NR3C(0)CH2N[(CH2)2OCH3]2, and in particular -NHC(0)CH2N[(CH2)2OCH3]2;
-NR3C(0)NH2, and in particular -NHC(0)NH2;
-NR3C(0)NHCi-9 alkyl, such as NR3C(0)NHCi-7 alkyl, and in particular -NHC(0)NHCH3
-NR3C(0)N(Ci-4 alkyl)Ci-5 alkyl, and in particular -NHC(0)N(CH3)2; or
-NR3C(0)NHCH2CONH(CH2)2OCH3, in particular -NHC(0)NHCH2CONH(CH2)2OCH3.
In one embodiment compounds of the disclosure include compounds of formula (I) in which the fragment -NR3C(O)C0-8alkylheterocyclyl is represented by:
-NHC(0)-(tetrahydropyranyl), such as -NHC(0)-(tetrahydro-2H-pyran-4-yl):
-NHC(0)-(morpholinyl) such as -NHC(0)-(4-morpholinyl) or -NHC(0)-(3-morpholinyl);
-NHC(0)-(pyrrolidinyl), such as -NHC(0)-(pyrrolidin-1 -yl);
-NHC(0)-(piperazinyl), such as -NHC(0)-(piperazin-1 -yl);
-NHC(0)-(methylpiperazinyl), such as -NHC(0)-(4-methylpiperazin-1 -yl);
-NHC(0)-[(methoxyethyl)piperazinyl], such as -NHC(0)-[4-(2-methoxyethyl)piperazin-1 -yl]; -NHC(0)-(oxoimidazolidinyl) such as -NHC(0)-(2-oxoimidazolidinyl), in particular -NHC(0)-(2- oxoimidazolidin-1 -yl);
-NHC(0)CH2-(tetrahydropyranyl), such as -NHC(0)CH2-(tetrahydro-2H-pyran-4-yl); -NHC(0)CH2-(morpholinyl), such as -NHC(0)CH2-(4-morpholinyl);
-NHC(0)CH2-(pyrrolidinyl), such as -NHC(0)CH2-(pyrrolidin-1 -yl);
-NHC(0)CH2-(piperazinyl), such as -NHC(0)CH2-(piperazin-1 -yl);
-NHC(0)CH2-(methylpiperazinyl), such as -NHC(0)CH2-(4-methylpiperazin-1 -yl);
-NHC(0)CH2-[(methoxyalkyl)piperazinyl], such as -NHC(0)CH2-[4-(2-methoxyethyl)piperazin -1 -yl];
-NHC(0)CH2SCH2CH2-(morpholinyl), such as -NHC(0)CH2SCH2CH2-(4-morpholinyl), or -NHC(0)CH2SCH2CH2-(3-morpholinyl); and
-NHC(0)CH2S02CH2CH2-(morpholinyl), such as -NHC(0)CH2S02CH2CH2-(4-morpholinyl), or -NHC(0)CH2S02CH2CH2-(3-morpholinyl).
In one embodiment of the fragment Q, the saturated or unsaturated, branched or unbranched C-i-10 alkyl chain, wherein at least one carbon is replaced by a heteroatom selected from -O, -N, S(0)p is a linker selected from: -CH2OCH2-, -CH2NHCH2-, -CH2NH- and -CH2OCH2CH2-. These fragments may optionally terminate in an aryl group, a heteroaryl group a heterocyclyl group or C3-8 cycloalkyl group, such as an aryl group, a heteroaryl group a heterocyclyl group as defined for fragment Q above.
In one embodiment the disclosure relates to compounds of formula (IA):
Figure imgf000019_0001
wherein R1, R2, Ar, L, R3 and Q are as defined above.
In one embodiment of the compounds of formula (IA) the substituent -NR3C(0)Q is in the 2 or 3 position.
In a further embodiment the disclosure relates to compounds of formula (IB):
Figure imgf000019_0002
wherein R1, R2, Ar, L, R3 and Q are as defined above. yet another embodiment the disclosure relates to compounds of formula (IC):
Figure imgf000020_0001
wherein R1, R2, Ar, L and R3 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.
In one embodiment the disclosure relates to compounds of formula (ID):
Figure imgf000020_0002
wherein R1, R2, Ar, L and R3 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. In one embodiment of the compounds of formula (ID) the fragment represented by -NR3C(0)(CH2)xO(CH2)yCH3 is: -NR3C(0)CH2OCH3, especially -NHC(0)CH2OCH3.
In one embodiment the disclosure relates to compounds of formula (IE):
Figure imgf000020_0003
wherein R1, R2, Ar, L, R3, R7 and R8 are as defined above.
In one embodiment the disclosure relates to compounds of formula (IF):
Figure imgf000021_0001
wherein R1, R2, Ar, L and R3 are as defined above and X2 represents O, CH2, NH, NCH3 or
Figure imgf000021_0002
In one aspect there is provided a compound of formula (IG):
Figure imgf000021_0003
wherein R1 is Ci-6 alkyl optionally substituted by a hydroxyl group;
R2 is H or C1-6 alkyl optionally substituted by a hydroxyl group;
R3 is H, Ci-6 alkyl or C0-3 alkylC3-6 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 C2-8 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 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 (for example 1 , 2 or 3) independently selected from oxo, halogen, an aryl group, a heteroaryl group, a heterocyclyl group or a C3-8 cycloalkyl,
each aryl, heteroaryl or heterocyclyl group bearing 0 to 3 substituents selected from halogen, hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, amino, Ci-4 mono or C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, S(0)qCi-6 alkyl, C0-6 alkylC(0)Ci-6 alkyl or C0-6 alkylC(0)d-6 heteroalkyl,
with the proviso that the atom linked directly to the carbonyl in -NR3C(0)- is not an oxygen or a sulfur atom; and
b) a Co-8 alkylC5-6 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 C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, S(0)qCi-6 alkyl, C0-6 alkylC(0)Ci-6 alkyl or C0-6 alkylC(0)d-6 heteroalkyl; and
p is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
In one embodiment the disclosure relates to compounds of formula (IH):
Figure imgf000022_0001
wherein R1, R2, Ar, R3 and Q are as defined above.
In a further embodiment the disclosure relates to compounds of formula (IJ):
Figure imgf000022_0002
wherein R1, R2, Ar, R3 and Q are as defined above. In yet another embodiment the disclosure relates to compounds of formula (IK):
Figure imgf000022_0003
wherein R1, R2, Ar and R3 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 alkylC5-6 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 C2-8 di-alkyl amino.
In one embodiment of formula (IK) Z is -OCH3 or -OCH2CH2OCH3.
In one embodiment of formula (IK) Z is -S02CH3.
In one embodiment of formula (IK) Z is -NRARB wherein RA and RB are independently selected from hydrogen, Ci-6 alkyl, and C3-6 alkoxy such that for example Z represents -NH2, -IMHCH3, -N(CH3)2 or -NHCH2CH2OCH3.
In one embodiment of formula (IK) Z is -S(0)qCH3 wherein n is 0, 1 or 2, such as 0 or 2.
In one embodiment of formula (IK) Z represents a -C5-6 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 C2-8 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 -CH3 or -CH2CH2OCH3. one embodiment the disclosure relates to compounds of formula (IL):
Figure imgf000023_0001
wherein R1, R2, Ar and R3 are as defined above and
R7 and R8 independently represent hydrogen, Ci-6 alkyl, or
R7 and R8 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 C2-8 di-alkyl amino. In one embodiment of compounds of formula (IL) the group -NR7 R8 represents -NH2, -NHCH3 or NHCH2CH3. In one embodiment of compounds of formula (IL) -NR7 R8 represents morpholinyl or piperazinyl.
In an alternative embodiment the disclosure relates to compounds of formula (IM):
Figure imgf000024_0001
wherein R1, R2, Ar and R3 are as defined above and
Het represents a C5-6 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 C2-8 di-alkyl amino.
In one embodiment of compounds of formula (IM) Het is morpholinyl or tetrahydropyranyl.
In one embodiment 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.
In one embodiment the compound is:
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-methoxyacetamide or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
In one embodiment the compound is:
Methyl 4-((4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-ylurea;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2- yl)tetrahydro-2/-/-pyran-4-carboxamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)-2-methoxypropanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)-2-methoxypropanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-morpholinoacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(pyrrolidin-1 -yl)acetamide; /V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(4-methylpiperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(4-(2-methoxyethyl)piperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-methoxyethylamino)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(dimethylamino)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylamino)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-((4-methoxybenzyl)(methyl)amino)acetamide;
1 -(4-((3-Methylureidopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ie f-butyl-1 -p-tolyl-1 H-pyrazol- 5-yl)urea;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-3- yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-3- yl)-2-(2-methoxyethoxy)acetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-(2-methoxyethoxy)acetamide;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-1 -methyl-3- (pyridin-2-yl)urea;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-3-(pyridin-2- yl)urea;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-(2-methoxyethoxy)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyrimidin-2-yl)-2-methoxyacetamide;
Λ/-(1 -(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-1 H- imidazol-4-yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfonyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-hydroxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-methyl-2-(methylamino)propanamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)-2-(methylamino)propanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)morpholine-3-carboxamide; (S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)morpholine-3-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-methylpiperazine-1 -carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)morpholine-4-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-methoxypropanamide;
2-(3-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)ureido)-/V-(2-methoxyethyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-(dimethylamino)butanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)propanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)-2-oxoimidazolidine-1 -carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfinyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-methoxyethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-(2-methoxyethoxy)ethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylsulfonyl)acetamide;
2-(Bis(2-methoxyethyl)amino)-/V-(4-((4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)methyl)pyridin-2-yl)acetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-methoxyacetamide;
N-(4-(2-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)ethoxy)pyridin-2-yl) 2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)-2-methyl propyl) pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propyl)pyridin-2 yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propan-2-yl) pyridin-2-yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 -pyrazol-5-yl)ureido)naphthalen-1 -yloxy)-2-methyl propan-2-yl)pyridin-2-yl)-2-methoxyacetamide; /V-(4-((4-(3-(3-ie/f-Butyl-1 -(4-(hydroxymethyl)phenyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide;
N-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- (methylsulfonyl)acetamide
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
In one embodiment the compound according to the disclosure is:
Methyl 4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-ylurea;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)tetrahydro-2/-/-pyran-4-carboxamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) methyl) pyridin-2-yl)-2-methoxypropanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)-2-methoxypropanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfonyl)acetamide
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-hydroxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-methyl-2-(methylamino)propanamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)-2-(methylamino)propanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)morpholine-3-carboxamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)morpholine-3-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-methylpiperazine-1 -carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)morpholine-4-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-methoxypropanamide;
2-(3-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-yl)ureido)-/V-(2-methoxyethyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-(dimethylamino)butanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)propanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)-2-oxoimidazolidine-1 -carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2- yl)-2-(methylthio)acetamide; /V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfinyl)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-morpholinoacetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(pyrrolidin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(4-methylpiperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(4-(2-methoxyethyl)piperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-methoxyethylamino)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(dimethylamino)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylamino)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-((4-methoxybenzyl)(methyl)amino)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-methoxyethylthio)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-(2-methoxyethoxy)ethylthio)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylthio)acetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylsulfonyl)acetamide;
2-(Bis(2-methoxyethyl)amino)-/V-(4-((4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)methyl)pyridin-2-yl)acetamide;
1 -(4-((3-Methylureidopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ie f-butyl-1 -p-tolyl-1 H-pyrazol- 5-yl)urea;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-3- yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-3- yl)-2-(2-methoxyethoxy)acetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-(2-methoxyethoxy)acetamide;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-1 -methyl-3- (pyridin-2-yl)urea;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-3-(pyridin-2- yl)urea;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-(2-methoxyethoxy)acetamide;
N-(4-(2-(4-(3-(3-ie/f-butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)ethoxy)pyridin-2-yl) 2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)-2-methyl propyl)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propyl)pyridin-2 yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propan-2-yl) pyridin-2-yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 -pyrazol-5-yl)ureido)naphthalen-1 -yloxy)-2-methyl propan-2-yl)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -(4-(hydroxymethyl)phenyl)-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyrimidin -2-yl)-2-methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- (methylsulfonyl)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2- methoxyethoxy)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl) tetrahydro-2/-/-pyran-4-carboxamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- (methylthio)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-3- methoxypropanamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- hydroxyacetamide;
/V-(4-(4-(3-(3-/sopropyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-Ethyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide;
Λ/-(4-(4-(3-(3-(1 -Hydroxy-2-methylpropan-2-yl)-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-butyl-1 -(2!3!5,6-tetradeutero-4-(trideuteromethyl)phenyl)-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- morpholinoacetamide; /V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)- (dimethylamino)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2- methoxyethylamino)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- ureidoacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2- methoxyacetamido)acetamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)tetrahydro-2/-/-pyran-4-carboxamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)isonicotinamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2- (methylsulfonyl)acetamido)acetamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)-3-morpholinopropanamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)morpholine-4-carboxamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)-2,6-difluoro-3-(2-(2-methoxyethoxy)ethoxy)benzamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)phenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-2-methylphenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-3-methylphenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-2-methoxyphenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-2,3-dimethylphenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-3-methoxyphenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-Ethyl-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyridin-: ylurea;
4-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2 -ylurea;
/V-Propan-2-yl-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2 -ylurea;
1 -(3-(ie/f-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)-3-(4-((2-(3-phenylureido)pyridin-4-yl)oxy) naphthalen-1 -yl)urea;
1 -(4-((2-(3-Benzylureido)pyridin-4-yl)oxy)naphthalen-1 -yl)-3-(3-(ie/f-butyl)-1 -(p-tolyl)-l H- pyrazol-5-yl)urea;
1 -(4-((2-(3-Cyclopropylureido)pyridin-4-yl)oxy)naphthalen-1 -yl)-3-(3-(ie/f-butyl)-1 -(p-tolyl)-l H- pyrazol-5-yl)urea; 1 -(3-(ie/f-Butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)-3-(4-((2-(3-(2-methoxyethyl)ureido)pyridin-4-yl) oxy)naphthalen-1 -yl)urea;
1 - (3-(ie/f-Butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)-3-(4-((2-(3-cyclopentyl)ureido)pyridin-4-yl)oxy) naphthalen-1 -yl)urea;
1 -(3-(ie/f-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)-3-(4-((2-(3-methyl)ureido)pyridin-4-yl)oxy) naphthalen-1 -yl)urea;
Ethyl 2-(3-(4-((4-(3-(3-(ferf-butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy) pyridin-2-yl)ureido)acetate;
4-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl) ureido)piperidine;
/V-Acetyl 4-(3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyridin-2-yl)ureido)piperidine;
2- (2-Methoxyethoxy)-1 -(4-(3-(4-(4-(3-(3-ferf-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)
naphthalen-1 -yloxy)pyridin-2-yl)ureido)piperidin-1 -yl)ethanone;
/V-Methylsulfonyl-4-(3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)ureido)piperidine;
N-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl) morpholine-4-carboxamide;
/V-(4-((4-(3-(3-(ie/f-butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy)pyridin-2-yl)-4- methylpiperazine-1 -carboxamide;
3- (4-((4-(3-(3-(ie/f-butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy)pyridin-2-yl)-1 ,1 - dimethylurea;
/V-(4-((4-(3-(3-(ie/f-Butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy)pyridin-2- yl)piperidine-1 -carboxamide;
/V-Methyl-/V-(2-(morpholin-4-yl)ethyl)-/V'-4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-ylurea;
/V-(4-(morpholin-4-yl)butyl)-/V'-4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)
naphthalen-1 -yloxy)pyridin-2-ylurea;
/V-(2-(morpholin-4-yl)ethyl)-/V'-4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)
naphthalen-1 -yloxy)pyridin-2-ylurea;
/V-(3-methylisoxazol-5-yl)methyl-/V-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-ylurea;
Λ/-(1 -methyl)piperidin-4-yl-/V- 4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)
naphthalen-1 -yloxy)pyridin-2-ylurea;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-4- hydroxypiperidine-1 -carboxamide;
/V-(3-(imidazol-1 -yl)propyl)-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)
naphthalen-1 -yloxy)pyridin-2-ylurea;
/V-(2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetyl)pyrrolidine;
(R)-/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-3- (dimethylamino)pyrrolidine-l -carboxamide; /V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)pyrrolidine-1 -carboxamide;
2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)-/V-methylacetamide;
2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)-/V-(2-morpholinoethyl)acetamide;
2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetyl morpholine;
2- (3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)-/V-(2-(pyridin-4-yl)ethyl)acetamide;
/V-(3-(1 H-lmidazol-1 -yl)propyl)-2-(3-(4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-yl)ureido)acetamide;
1 -(2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetyl)-4-methylpiperazine;
/V-(3-(1 H-lmidazol-1 -yl)propyl)-2-(3-(4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-yl)ureido)acetamide;
/V-(6-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyrimidin-4-yl)-2- methoxyacetamide;
/V-(6-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)phenoxy)pyrimidin-4-yl)-2-methoxy acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-2-yl)-2- methoxyacetamide;
3- (4-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-2-yl) urea;
1 -Methyl-3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyrimidin-2-yl)urea;
1 ,1 -Dimethyl-3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyrimidin-2-yl)urea;
1 -Cyclopropyl-3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyrimidin-2-yl)urea;
(4-(4-(3-(3-ie f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-2-yl) morpholine-4-carboxamide;
3-(6-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-4-yl) urea; 2-(3-(4-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetic acid.
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
Examples of 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. In one embodiment the isotope is a stable isotope. Thus 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. In one embodiment 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.
The disclosure also extends to all polymorphic forms of the compounds herein defined.
Compounds of formula (I) can be prepared by a process comprising reacting compounds of formula (II):
Figure imgf000033_0001
wherein Q is not -NHR* (wherein R* is the remainder of the Q fragment) with a compound of formula (Ilia):
Q LG1
(Ilia)
where LG-i is a leaving group for example halogen, such as chloro.
When NR3C(0)Q is NR3C(0)NHR* compounds of formula (I) can be prepared by reacting compounds of formula (II) with a compound of formula (1Mb):
Q=C=0
(1Mb) The reaction is suitably carried out in the presence of a base (e.g. DIPEA). The reaction is suitably carried out in an aprotic solvent or solvent mixture, e.g. DCM and DMF.
Compounds of formula (II) can be prepared by reacting a compound of formula (IV):
Figure imgf000034_0001
(IV)
where R1 and R2 are as defined above for compounds of formula (I), with a compound of formula (VI):
Figure imgf000034_0002
(VI)
wherein LG2 and LG3 each independently represent leaving groups (e.g. LG2 and LG3 both represent imidazolyl followed by reaction with a compound of formula (V):
H2N LT NHR3
(V)
wherein Ar, L, X and R3 are defined above for compounds of formula (I)
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.
Specifically compounds of formula (II) can be prepared by reacting a compound of formula (IVa):
Figure imgf000034_0003
(IVa)
where R1 and R2 are as defined above for compounds of formula (I), with a compound of formula (V).
The reaction may be performed in the presence of a sterically hindered base such as
DIPEA, in a suitable inert solvent such as dichloromethane.
DIPEA, in a suitable inert solvent such as dichloromethane. Compounds of formula (I) wherein R2 is a hydroxyalkyl may be prepared by reacting a (hydrazinylphenyl)alkanoic acid with an alkanoyl acetonitrile such as R1C(0)CH2CN, 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 R2 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 R2 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 R2 is a protected hydroxyalkyl group. The hydroxyl can be revealed by cleavage of the sillyl group, for example with tetrabutylammonium fluoride.
Compounds of formula (I) wherein R1 is a hydroxylated alkyl species may be prepared by reacting protected benzyloxyalkanoyl acetonitrile an aryl hydrazine employing analogous conditions to those described directly above.
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.
More specifically compounds of formula (II) may be prepared by reacting a compound of formula (IVb):
Figure imgf000035_0001
where LG2 is as defined above with a compound of formula (VI).
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 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):
0,N LT NHR3
(VII) wherein Ar, L, X and R3 are as defined above for compounds of formula (I), for example by hydrogenation in the presence of a catalyst such as platinum supported on carbon.
The reaction is suitably carried out in polar protic solvent or mixture of solvents (e.g. methanol and acetic acid).
Alternatively, a compound of formula (V) where L is O may be prepared by deprotecting a compound of formula (Vila):
Ar X
P1P2N^ ^O^ ^NR3'P3
(Vila)
wherein P1, P2 and P3 are protecting groups and R3 is a protecting group, for example acetyl such as -C(0)CH2OCH3 or R3 as defined above for compounds of formula (I).
A compound of formula (VII) wherein L represents -(CH2)nO(CH2)m or (CH2)nORb, as defined above, wherein n is zero and the linker L contains at least one -CH2- may be prepared by reaction of a compound of formula (Villa) or (Vlllb):
ΗΟ-(θΗ2)-Χ— NHR3' H0-(-Rb x— NHR3'
'm '
(Villa) (Vlllb) or analogues thereof and wherein m, X and R are as defined above for compounds of formula
(I) and R3 is a protecting group or R3 as defined above for compounds of formula (I) with a compound of formula (IX) or (X):
Figure imgf000036_0001
(IX) (X)
wherein compounds (IX) and (X) may bear optional substitutents as defined above for compounds of formula (I).
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).
In an alternative process, certain compounds of formula (V), wherein Ar, L and X are as defined above for compounds of formula (I) may be prepared by reacting a compound of formula (XI):
H2N LT LG4
(XI)
or a protected derivative thereof, such as a carbamate, wherein Ar, L and X are as defined above and LG4 represents a leaving group such as chloro (in particular where L represents 0) with an amidation reagent, for example with the carbamate (XII):
Figure imgf000037_0001
wherein P3 and R3 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.
In one embodiment the compound formula (XII) is:
Figure imgf000037_0002
(Xlla) (XMb)
Compounds of formula (XI), where L is linked to X through O, for example, wherein L represents -(CH2)nO(CH2)m or RO(CH2)m, as defined above, wherein m is zero, may be prepared by reacting a compound of formula (XIII):
^Ar^ /OH
H2N L*
(XIII)
or a protected derivative thereof, for example where the free amine is protected as a carbamate, wherein Ar is as defined above and L* and OH taken together represent L (in particular L* represents alkylene or a bond), with a compound of formula (XIV):
LG5 LG4 (XIV)
wherein X is as defined above and LG4 represents a leaving group such as chloro and LG5 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.
Compounds of formula (XIII) may be prepared from compounds of formula (XV):
H2N-A^
(XV)
wherein the free amine is suitably protected, for example as a carbamate, and Ar is as defined above, and wherein L represents -(CH2)nO(CH2)m, as defined above, wherein n is 2 and m is zero by hydroboration with a reagent such as 9-BBN followed by oxidation using hydrogen peroxide in the present of a base such as sodium hydroxide . Compounds of formula (XV) may be prepared in a two step transformation from compounds of formula (XVI) via compounds of formula (XVII), wherein Ar is as defined above and the free amine is suitably protected, for example as a carbamate:
,Ar ,Ar
Η,Ν' Br Η,Ν'
(XVI) (XVII)
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. Generally 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.
Compounds of formula (I) wherein Q is linked to -NR3C(0) by -CH2V, wherein V is a heteroatom selected from N, O, or S, can be prepared by the process comprising of a nucleophilic displacement reaction on a compound of formula (Ha):
Figure imgf000038_0001
wherein R1, R2, Ar, L, X, NR3 are as defined above for compounds of formula (I) and LG6 represents a leaving group, for example halogen such as chloro, with a compound of formula (XVIII):
H V— q
(XVIII)
wherein H represents hydrogen, V represents a heteroatom selected from N, NH, O, or S and q represents the residual portion of Q (i.e. -CH2V'-q = Q).
The reaction may, be performed in the presence of a sterically hindered base, for example DIPEA, in an inert solvent, for example dichloromethane.
Compounds of formula (Ha) may be prepared by reacting a compound of formula (II) with a compound of formula (XVI):
Figure imgf000038_0002
(XIX) wherein LG6 is defined above for compounds of formula (Ha), and LG7 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.
Compounds of formula (I) wherein Q is NH-(CH2)d-C(0)NHR8, can be prepared by the process comprising of an amide coupling between (lib):
Figure imgf000039_0001
wherein R1, R2, Ar, L, X and R3 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 R8NH2 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-(CH2)p-C02Et, 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.
Compounds of formula (I) wherein Q is NR7R8 can be prepared by the process comprising of reaction between an amine RR'NH and a compound of formula (He):
Figure imgf000039_0002
wherein R1, R2, Ar, X and R3 are as defined above for compounds of formula (I) and LG2 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.
The reaction may, be performed in the presence of a sterically hindered base, for example DIPEA, in an inert solvent, for example dichloromethane.
The preparation of classes of intermediates of broad synthetic utility and generic routes providing access to various embodiments of the invention are summarised below (Schemes 1 to 16). A synthestic approach for the preparation of aminopyridine building blocks represented by Intermediate a is outlined below (Scheme 1 ) wherein R1, R2, R3 and L are as defined above for compounds of formula (I).
Scheme 1
Figure imgf000040_0001
n erme a e c n erme a e a
The preparation of activated aminopyrazoles represented by Intermediate b and Intermediate c from commercially available compounds, wherein R1, and R2 are as defined above for compounds of formula (I), is illustrated below (Scheme 2).
Scheme 2
Figure imgf000040_0002
Intermediate b
A preparative route to compounds represented by Intermediate d and Intermediate e, where L therein represents 0(CH2)n is shown below (Scheme 3):
Scheme 3
Figure imgf000041_0001
Methodologies which may be exploited to prepare compounds of the genus represented by Intermediate d for which L therein represents O and the specific diamine Intermediate e1 are summarised below (Scheme 4).
Scheme 4
Figure imgf000041_0002
The preparation of compounds represented by Intermediate f wherein R1, R2 and L are as defined above for compounds of formula (I), Ar is naphthyl and X is pyridinyl is outlined below (Scheme 5).
Scheme 5 Intermediate a
Figure imgf000042_0001
A generic process for the preparation of compounds represented by Intermediate g wherein L and R3 are as defined above for compounds of formula (I), Ar is naphthyl, X is pyridinyl and Q is NRR' is summarised below (Scheme 6).
Scheme 6
Figure imgf000042_0002
The preparation of compounds represented by Intermediate h and Intermediate j wherein L, R1, R2, and R3 are as defined above for compounds of formula (I), Ar is naphthyl and X is pyridinyl is summarised below (Scheme 7). Scheme 7
Figure imgf000043_0001
From the Intermediates described herein above, examples of the disclosure wherein L, R1, R2, R3 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.
Scheme 8a
Figure imgf000043_0002
Intermediate d
Scheme 8b
Intermediate a
Figure imgf000043_0003
Scheme 8c Intermedia diate f
RR'NCOCI RR NH
Figure imgf000044_0001
Similar methods may be used to prepare compounds of formula (I) wherein Ar is phenyl and X is as defined above for compounds of formula (I).
A general method of preparing compounds of formula (I) is provided below (Scheme 9) wherein Ar is naphthyl and X is pyridinyl and the fragment NR3C(0)Q is a glycinamide derivative
Scheme 9
Intermediate h
Figure imgf000044_0002
Similar methods may be used to prepare compounds of formula (I) wherein Ar is phenyl and X is as defined above for compounds of formula (I).
A synthetic approach for preparing compounds of formula (I) wherein Ar is naphthyl and X is pyridinyl and the fragment NR3C(0)Q is an /V-acyl glycinamide derivative is provided below (Scheme 10), where LG is a leaving group and RC(0)NHCH2 is Q.
Figure imgf000044_0003
Similar methods may be used to prepare compounds of formula (I) wherein Ar is phenyl and X is as defined above for compounds of formula (I).
Synthetic routes are disclosed below suitable for the generation of additional intermediates, required for the preparation of examples of compounds of formula (I) wherein the fragment XNHR3 represents 2-aminopyrimidinyl or 4-aminopyrimidinyl.
Processes for the synthesis of the fragment H2N-Ar-L-X-NHR3 wherein Ar is naphthyl and L is O and the fragment X-NHR3 is 2-aminopyrimidinyl are outlined below (Scheme 11 ).
Sche
Figure imgf000045_0001
A procedure for the preparation of the fragment 02N-Ar-L-X-NHR3 wherein Ar is naphthyl and L is O and the fragment X-NHR3 is 4-aminopyrimidinyl is dislclosed below (Scheme 12).
Scheme 12
Figure imgf000045_0002
A procedure for the preparation of the fragment 02N-Ar-L-X-NHR3 wherein Ar is phenyl and L is O and the fragment X-NHR3 is 4-aminopyrimidinyl is dislclosed below (Scheme 13). Scheme 13
Figure imgf000046_0001
Those starting materials of the genera H2N-Ar-L-X-NHR3 and 02N-Ar-L-X-NHR3 in which the fragment X-NHR3 is an aminopyrimidinyl group and where L is a linker other than O can be prepared by analogous methods to those shown above. A generic process for the preparation of compounds represented by Intermediate k wherein L and R3 are as defined above for compounds of formula (I), Ar is naphthyl and the fragment XNR3 is either 2-aminopyrimidinyl [Y'=CH; X'=N] or 4-aminopyrimidinyl [Y'=N; X'=CH] and NR3C(0)Q taken together represent an amide, is summarised below (Scheme 14). Sche
Figure imgf000046_0002
Intermediate k
Analogous structures represented by Intermediate m wherein L and R3 are as defined above for compounds of formula (I), Ar is naphthyl and the fragment XNR3 is either 2-aminopyrimidinyl [Y'=CH; X'=N] or 4-aminopyrimidinyl [Y'=N; X'=CH] and NR3C(0)Q taken together represent a urea, are accessible by the processes illustrated below (Scheme 15).
Scheme 15
Figure imgf000046_0003
Intermediate m Compounds represented by Intermediate n wherein R1, R2, are as defined above for compounds of formula (I), Ar is naphthyl and L is O and the fragment XNR3 is 2- aminopyrimidinyl and R3 is H, may be prepared by the processes illustrated below (Scheme 16).
Sc
Figure imgf000047_0001
Compounds represented by Intermediate p wherein R1 and R2 are as defined above for compounds of formula (I), Ar is naphthyl and L is OCH2 and the fragment XNR3 is 2- aminopyrimidinyl and R3 is H, may be prepared as disclosed below (Scheme 17).
Scheme 17
Figure imgf000047_0002
From the Intermediates described herein above, examples of the disclosure wherein L, R1, R2, R3 and Q are as defined above for compounds of formula (I), Ar is naphthyl and wherein the fragment XNHR3 represents 2-aminopyrimidinyl or 4-aminopyrimidinyl, may be prepared according to the transformations set out below (Schemes 18a-d). Particular routes disclosed below (Scheme 18c and 18d) provide for examples of compounds of formula (I) wherein NHR or NRR' represent Q and wherein Q together with NHC(O) forms a urea.
Scheme 18a
Figure imgf000048_0001
r2 A/-Acylaminopyrimidines I
Figure imgf000048_0002
Scheme 18b
Figure imgf000048_0003
Scheme 18c
Figure imgf000048_0004
Scheme 18d
Figure imgf000049_0001
Similar methods may be used to prepare compounds of formula (I) wherein L, R1, R2 and R3 are as defined above for compounds of formula (I), the fragment XNHR3 represents 2- aminopyrimidinyl or 4-aminopyrimidinyl and wherein NHR or NRR' represent Q and wherein Q together with NHC(O) forms a urea and wherein Ar represents phenyl.
Compounds of formulae (Ilia), (Nib), (IV), (IVa), (IVb), (VI), (Villa), (Vlllb), (IX), (X), (XII), (Xlla), (Xllb), (XIII), (XIV), (XV), (XVI), (XVI) and (XIX) and certain other compounds illustrated in the schemes are either commercially available, or are known, or are novel and can be readily prepared by conventional methods. See for example Regan, J. et al., J. Med. Chem., 2003, 46, 4676-4686, WO 00/043384, WO 2007/087448 and WO 2007/089512.
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; 4th Rev Ed., 2006, ISBN-10: 0471697540.
In one embodiment 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).
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.
Compound of formula (I) as employed herein is intended to refer to compounds disclosed herein including compounds of formula (IA) to (IF) and specifically named compounds unless the context indicates otherwise.
In one embodiment 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.
To treat an influenza infection, topical administration to the lung is a therapeutically effective option. Hence in one embodiment there is provided 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.
In an alternative embodiment there is provided 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.
Topical administration to the lung may be achieved by use of an aerosol formulation.
Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFC propellants include trichloromonofluoromethane (propellant 1 1 ), dichlorotetrafluoromethane (propellant 1 14), and dichlorodifluoromethane (propellant 12). Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC- 227). The propellant typically comprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalation composition. The formulation may comprise excipients including co-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M).
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 μηη. 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 μηη or more. Example dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER. In one embodiment 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.
In some cases, however, 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.
In one embodiment there is provided a compound as defined herein, for example a compound of formula (I) formulated in combination with an antiviral medicament, for example a neuroamidase inhibitor. In one embodiment 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. 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. Thus the neuraminidase inhibitor may, for example be oseltamivir, zanamivir, peramivir. Alternatively, or in addition the formulation may comprise an M2 inhibitor, for example amantadine or rimantadine. Advantageously, 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.
In one embodiment 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.
In one embodiment 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, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96,
1.97, 1.98, 2.00.2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.30, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.40, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.50, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.60, 2.61, 2.62, 2.63, 2.64, 22.65, 2.66, 2.67, 2.68, 2.69, 2.70, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.80, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.90, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97,
2.98, 2.99 or 3.00 mg.
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.
In one embodiment 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. In one embodiment the antiviral active agents, for example those described supra, are coadministered. Co-administration as employed herein where the active agents are provided as separate formulations and administered either approximately simultaneously (at about the same time) or sequentially. Sequential administration is intended to refer to where one active is still present in the patient, when the second or third active is administered. 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.
The disclosure also extends to a 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.
In a further aspect there is provided use of a 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. In one aspect there is a provided 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. In one embodiment there is provided use in the treatment or prophylaxis of infants (from 1 day to 1 year old) and child (for example child under the age of 5).
In one embodiment there is a provided use in the treatment or prophylaxis of 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.
Experimental Section
Abbreviations
AcOH glacial acetic acid
aq aqueous
Ac acetyl ATP adenosine-5'-triphosphate
BALF bronchoalveolae lavage fluid
9-BBN 9-borabicyclo[3.3.1 ]nonane
Boc ie f-butoxycarbonyl
br broad
BSA bovine serum albumin
CatCart® catalytic cartridge
CCID50 cell culture infectious dose 50%
CDI 1 ,1 -carbonyl-diimidazole
COPD chronic obstructive pulmonary disease
d doublet
DCM dichloromethane
DIAD diisopropylazadicarboxylate
DIBAL-H diisobutylaluminium hydride
DIPEA Λ/,/V-diisopropylethylamine
DMEM Dulbecco's modified Eagle's medium
d-U937 differentiated U937 cells
DMF Λ/,/V-dimethylformamide
DMSO dimethyl sulfoxide
EDAC.HCI 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide
(ES+) electrospray ionization, positive mode
Et ethyl
EtOAc ethyl acetate
FCS foetal calf serum
HOBt 1 -hydroxybenzotriazole
hr hour(s)
HRP horseradish peroxidase
HRV human rhinovirus
i.n. intra-nasal
i.p. intra-peritoneal
JNK c-Jun N-terminal kinase
KHMDS potassium hexamethyldisilazane
(M+H)+ protonated molecule
MAPK mitogen protein activated protein kinase
MDCK Madin-Darby canine kidney cells
Me methyl
MeOH methanol
MHz megahertz
min minute(s)
MOI multiple of infection
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide m/z: mass-to-charge ratio
NMP 1 -methylpyrrolidin-2-one (/V-methyl-2-pyrrolidone) NMR nuclear magnetic resonance (spectroscopy)
OD optical density
OXONE® potasium peroxymonosulfate
PBS phosphate buffered saline
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
PPh3 triphenylphosphine
PyBOP® (benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate q quartet
RSV: respiratory syncytial virus
R-EC50: relative EC5o
RT room temperature
RP HPLC reverse phase high performance liquid chromatography
s singlet
SCX solid supported cation exchange (resin)
SDS sodium dodecyl sulfate
t triplet
TCID50 50% tissue culture infection dose
TFA trifluoroacetic acid
THF tetrahydrofuran
TMB 3,3',5,5'-tetramethylbenzidine
TNFa tumor necrosis factor alpha
TPCK L-1 -tosylamido-2-phenylethyl chloromethyl ketone
WB washing buffer
XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
COMPOUND EXAMPLES
Labels given to intermediates in the examples are independent of labels given to intermediates in other parts of the description.
General Procedures
All starting materials and solvents were either obtained from commercial sources or prepared according to the literature citation. Organic solutions were routinely dried over magnesium sulfate. Hydrogenations were preformed on a Thales H-cube flow reactor under the conditions stated. 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 MeOH. The desired material was then eluted by washing with 1 % NH3 in MeOH. Column chromatography was performed on pre-packed silica (230-400 mesh, 40-63 μΜ) cartridges using the amount indicated.
Preparative Reverse Phase High Performance Liquid Chromatography: Agilent Scalar column C18, 5 μηη (21.2 x 50 mm), flow rate 28 mL.min"1 eluting with a H20-MeCN gradient containing 0.1 % v/v formic acid over 10 mins using UV detection at 215 and 254 nm. Gradient information: 0.0-0.5 min: 95% H20-5% MeCN; 0.5 -7.0 min; Ramped from 95% H20-5% MeCN to 5% H20- 95% MeCN; 7.0-7.9 min: Held at 5% H20-95% MeCN; 7.9-8.0 min: Returned to 95% H20-5% MeCN; 8.0-10.0 min: Held at 95% H20-5% MeCN. Analytical Methods
Reverse Phase High Performance Liquid Chromatography was performed by one of the two methods described below: Method 1 : Agilent Scalar column C18, 5 μηι (4.6 x 50 mm) or Waters XBridge C18, 5 μηι (4.6 x 50 mm) flow rate 2.5 mL min"1 eluting with a H20-MeCN gradient containing either 0.1 % v/v formic acid (Method 1 acidic) or NH3 (Method 1 basic) over 7 min employing UV detection at 215 and 254 nm. Gradient information: 0.0-0.1 min, 95% H20-5% MeCN; 0.1 -5.0 min, ramped from 95% H20-5% MeCN to 5% H20-95% MeCN; 5.0-5.5 min, held at 5% H20-95% MeCN; 5.5-5.6 min, held at 5% H20-95% MeCN, flow rate increased to 3.5 mL min"1; 5.6-6.6 min, held at 5% H20-95% MeCN, flow rate 3.5 mL min"1; 6.6-6.75 min, returned to 95% H20-5% MeCN, flow rate 3.5 mL min"1; 6.75-6.9 min, held at 95% H20-5% MeCN, flow rate 3.5 mL min"1; 6.9- 7.0 min, held at 95% H20-5% MeCN, flow rate reduced to 2.5 mL min"1. Method 2: Agilent Extend C18 column, 1 .8 μηι (4.6 x 30 mm) at 40°C; flow rate 2.5-4.5 mL.min" 1 eluting with a H20-MeCN gradient containing 0.1 % v/v formic acid over 4 min employing UV detection at 254 nm. Gradient information: 0-3.00 min, ramped from 95% H20-5% MeCN to 5% H20-95% MeCN; 3.00-3.01 min, held at 5% H20-95% MeCN, flow rate increased to 4.5 mL min"1; 3.01 -3.50 min, held at 5% H20-95% MeCN; 3.50-3.60 min, returned to 95% H20-5% MeCN, flow rate reduced to 3.50 mL min"1; 3.60-3.90 min, held at 95% H20-5% MeCN; 3.90- 4.00 min, held at 95% H20-5% MeCN, flow rate reduced to 2.5 mL min"1.
1H NMR Spectroscopy was performed on a Bruker Avance III 400 MHz spectrometer, using residual undeuterated solvent as the internal reference standard.
Intermediate A: 1 -(4-((2-Aminopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ferf-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000057_0001
To a solution of 4-nitronaphthalen-1 -ol (2) (5.17 g, 27.3 mmol), PPh3 (10.75 g, 41 .0 mmol) and 2-aminopyridine-4-methanol (1 ) (5.09g, 41 .0 mmol) in THF (50 mL) was added dropwise DIAD (8.07 mL, 41 .0 mmol) at -15°C. The mixture was stirred overnight at RT and the volatiles were removed in vacuo. The crude product was triturated from EtOAc (150 mL) and was collected by filtration and washed with EtOAc (100 mL). A second trituration from MeOH (100 mL) gave 2- amino-4-((4-nitronaphthalen-1 -yloxy)methyl)pyridine (3) (4.54 g, 56%) as a yellow solid: m/z 296 (M+H)+ (ES+). A solution of (3) (4.50 g, 15.24 mmol) in a mixture of MeOH (200 mL) and AcOH (200 mL) was passed through a Thales H-cube (2.0 mL.min"1, 40°C, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo. The crude product was subjected to SCX capture and release eluting with 1 % NH3 in MeOH solution and the solvent was removed in vacuo to give 2-amino-4-((4-aminonaphthalen-1 -yloxy)methyl)pyridine (4) (3.82g, 94%) as a purple solid: m/z 266 (M+H)+ (ES+).
To a solution of CDI (4.18 g, 25.8 mmol) in DCM (15 mL) was added dropwise under nitrogen a solution of 3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-amine (5) (WO 200/0043384) (5.91 g, 25.8 mmol) in DCM (15 mL) over 40 min. The resulting solution was stirred at RT for 1 hr then added dropwise under nitrogen to a solution of 2-amino-4-((4-aminonaphthalen-1 - yloxy)methyl)pyridine (4) (3.80 g, 12.9 mmol). The mixture was stirred overnight and the volatiles were removed in vacuo. The crude material was purified by column chromatography (120 g); eluting with 0 to 6% MeOH in DCM to give the title compound, Intermediate A as an off white solid (4.27 g, 63%): m/z 521 (M+H)+ (ES+).
Example 1 : W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide:
Figure imgf000058_0001
Intermediate A
Me Example 1
To a mixture of Intermediate A (526 mg, 0.96 mmol) and DIPEA (184 μΙ_, 1 .06 mmol) in DCM/DMF (10:1 , 1 1 mL) was added methoxyacetyl chloride (92 μί, 1 .01 mmol). After stirring for 1 hr at RT, further DIPEA (184 μί, 1 .06 mmol) and methoxyacetyl chloride (92 μΙ_, 1.01 mmol) were added sequentially and stirring was continued for 1 hr. After the addition of a solution of 1 % NH3 in MeOH (40 mL), the mixture was stirred for 15 min and evaporated in vacuo. The crude product was purified by column chromatography (40 g); eluting with 0 to 6% MeOH in DCM to furnish the title compound, Example 1 , as a white solid (286 mg, 49%): m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.39 (3 H, s), 3.32 (3 H, s), 4.08 (2H, s), 5.39 (2H, s), 6.36 (1 H, s), 7.03 (1 H, d), 7.28 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, m), 7.93 (1 H, m), 8.30-8.35 (3H, m), 8.58 (1 H, s), 8.79 (1 H, s), 10.02 (1 H, s).
Example 2: Methyl 4-((4-(3-(3-ieri-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-ylurea:
MeNCO
Intermediate A *-
Figure imgf000058_0002
To a solution of Intermediate A (70 mg, 0.13 mmol) in anhydrous pyridine (1.5 mL) was added methyl isocyanate (14 μί, 0.24 mmol) and the mixture allowed to stir at RT for 72 hr. Pyridine was removed in vacuo and the residue triturated with DCM (3.0 mL). Filtration afforded the title compound, Example 2, as an off-white powder, (36 mg, 45 %): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.74 (3H, d), 5.30 (2H, s), 6.36 (1 H, s), 6.99 (1 H, d), 7.05 (d, 1 H), 7.35, (2H, d), 7.44 (2H, d), 7.54-7.64 (4H, m), 7.93 (1 H, d), 8.19 (1 H, d), 8.23 (1 H, brs), 8.35 (1 H, d), 8.58 (1 H, s), 8.79 (1 H, s), 9.36 (1 H, s).
Example 3: W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide: Intermediate A
Figure imgf000059_0001
Neat DMF (2 drops) was added to a stirred solution of tetrahydropyran-2/-/-4-carboxylic acid and oxalyl chloride (21 μΙ_, 0.25 mmol) in DCM (1.0 mL) and the resulting solution was stirred at RT for 1 hr. The solution was evaporated in vacuo to give a colourless oil, which was redissolved in DCM (1 .0 mL) and added dropwise to a stirred mixture of Intermediate A (50 mg, 0.10 mmol) and DIPEA (84 μί, 0.50 mmol) in DCM (1 .0 mL). Stirring was continued for 18 hr. The reaction mixture was stirred in 1 % NH3 in MeOH (20 mL) for 30 mins, evaporated in vacuo, pre-adsorbed on silica, and purified by column chromatography (12 g, 0-5% MeOH in DCM, gradient elution) to give the title compound, Example 3, as a light tan solid (18 mg, 28%): m/z 633 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .26 (9H, s), 1 .57-1 .72 (4H, m), 2.38 (3H, s), 2.75 (1 H, m), 3.28-3.33 (2H, m), 3.88 (2H, m), 5.35 (2H, s), 6.34 (1 H, s), 6.99 (1 H, d), 7.24 (1 H, dd), 7.35 (2H, m), 7.43 (2H, m), 7.55-7.64 (3H, m), 7.92 (1 H, m), 8.27-8.33 (3H, m), 8.58 (1 H, s), 8.78 (1 H, s), 10.50 (1 H, s).
Example 4: (S)-/V-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy) methyl)pyridin-2-yl)-2-methoxypropanamide:
Figure imgf000059_0002
1 -Chloro-/V,/V-dimethylethenamine (50 μί, 0.48 mmol) was added to a stirring solution of (S)-2- methoxypropionic acid (50 mg, 0.48 mmol) in DCM (1 .0 mL) and the resulting yellow solution was stirred at RT for 1 hr. The solution was added dropwise to a stirring mixture of Intermediate A (50 mg, 0.10 mmol) and DIPEA (167 μΙ_, 0.96 mmol) in DCM (1 .0 mL). Stirring was continued overnight. The reaction mixture was stirred in 1 % NH3 in MeOH (20 mL), evaporated in vacuo, pre-adsorbed on silica and purified by column chromatography (12 g, 10- 50% EtOAc in isohexane, gradient elution) to give the title compound, Example 4, as a colourless solid (18 mg, 30%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1 .31 (3H, s), 2.38 (3H, s), 3.30 (3H, s), 4.02 (1 H, q), 5.39 (2H, s), 6.37 (1 H, s), 7.00 (1 H, d), 7.29 (1 H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1 H, m), 8.30-8.37 (3H, m), 8.58 (1 H, s), 8.79 (1 H, s), 10.06 (1 H, s).
Example 5: (/?)-/V-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methoxypropanamide:
Intermediate A
Figure imgf000060_0001
1 -Chloro-/V,/V-dimethylethenamine (38 μΙ_, 0.36 mmol) was added to a stirred solution of {R)-2- methoxypropionic acid (37 mg, 0.36 mmol) in DCM (1 .0 mL) and the resulting solution was stirred at RT for 1 hr. The solution was added dropwise to a stirred mixture of Intermediate A (75 mg, 0.14 mmol) and DIPEA (75 μΙ_, 0.43 mmol) in DCM (2.0 mL) at 0°C. Stirring was continued for a further 48 hr. The mixture was poured in to 1 % NH3 in MeOH (20 mL) and stirred for 1 hr, and evaporated in vacuo to give a yellow residue. Column chromatography (12 g, 20-50% EtOAc in isohexane) gave the title compound, Example 5, as a light pink solid (39 mg, 43%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1.30 (3H, s), 2.39 (3H, s), 3.31 (3H, s), 4.02 (1 H, q), 5.39 (2H, s), 6.35 (1 H, s), 7.02 (1 H, d), 7.29 (1 H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1 H, m), 8.30-8.37 (3H, m), 8.58 (1 H, s), 8.79 (1 H, s), 10.09 (1 H, s). Example 6: W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(methylsulfonyl)acetamide:
Intermediate A
Figure imgf000060_0002
To a stirred suspension of methanesulfonylacetic acid (40 mg, 0.29 mmol) and oxalyl chloride (29 μί, 0.34 mmol) in DCM (1 .0 mL) was added DMF (1 drop) and the reaction mixture was stirred at RT for 1 hr. The solution was added dropwise to a stirred mixture of Intermediate A (50 mg, 0.10 mmol) and DIPEA (167 μΙ_, 1 .0 mmol) in DCM / DMF (10:1 v/v, 1 .1 mL) and stirring was continued for 18 hr. The reaction mixture was stirred with 1 % NH3 in MeOH (2.0 mL) and evaporated in vacuo. The residue was subjected to capture and release on SCX to afford the title compound, Example 6, as a pale yellow solid (1 1 mg, 18%): m/z 641 (M+H)+ (ES+). 1H NMR (400M Hz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 3.17 (3H, s), 4.44 (2H, s), 5.40 (2H, s), 6.35 (1 H, s), 7.02 (1 H, d), 7.33 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, overlapping m), 7.93 (1 H, m), 8.30-8.33 (2H, overlapping m), 8.39 (1 H, dd), 8.59 (1 H, br s), 8.79 (1 H, br s), 10.98 (1 H, br s).
Example 7: W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1■ yloxy)methyl)pyridin-2-yl)-2-hydroxyacetamide:
Intermediate A
Figure imgf000061_0001
To a solution of Intermediate A (75 mg, 0.14 mmol) and DIPEA (125 μΙ_, 0.72 mmol) in DCM / DMF (10:1 v/v, 1 .10 mL) was added a solution of acetoxyacetyl chloride (39 μΙ_, 0.36 mmol) in DCM (0.25 mL). The reaction mixture was stirred at RT for 2 hr and then 1 % NH3 in MeOH (3.0 mL) was added and stirring continued for 18 hr. The reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, 30-100% EtOAc in isohexane, gradient elution) to afford the title compound, Example 7, as a pale orange solid (24 mg, 28%): m/z 579 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 4.06 (2H, d), 5.39 (2H, s), 5.77 (1 H, t), 6.35 (1 H, s), 7.02 (1 H, d), 7.29 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, overlapping m), 7.93 (1 H, m), 8.32 (1 H, m) 8.34 (1 H, d), 8.36 (1 H, br s), 8.60 (1 H, br s), 8.81 (1 H, br s), 9.75 (1 H, br s).
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:
Figure imgf000062_0001
To a stirred suspension of 2-(ie f-butoxycarbonyl(methyl)amino)-2-methylpropanoic acid (125 mg, 0.58 mmol) in DCM (2.0 mL) was added 1 -chloro-/V,/V,2-trimethylprop-1 -en-1 -amine (95 μΙ_, 0.72 mmol) and the mixture was stirred at RT for 2 hr. The reaction mixture was then added to a solution of Intermediate A (75 mg, 0.14 mmol) and DIPEA (101 μΙ_, 0.58 mmol) in DCM (1 .0 mL) and stirred for 18 hr. A solution of ammonia in MeOH (7M, 1 mL) was added and the mixture was evaporated in vacuo. The residue was purified twice by column chromatography (Si02, 12 g, 0-100% EtOAc in isohexane, gradient elution) to afford ie/f-butyl 1 -(4-((4-(3-(3-ie/f- butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2-ylamino)-2-methyl-1 - oxopropan-2-yl(methyl)carbamate (6) as an off-white solid (30 mg, 28%): m/z 620 ((M-Boc)+H)+ (ES+).
A solution of the carbamate (6) (25 mg, 0.04 mmol) in DCM / TFA (1 :1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to SCX capture and release to afford the title compound, Example 8, as a pale brown solid (20mg, 89%): m/z 620 (M+H)+ (ES+). 1 H NMR (400 MHz, DMSO-d6) δ: 1 .25 (6H, s), 1 .27 (9H, s), 2.20 (3H, s), 2.39 (3H, s), 5.38 (2H, s), 6.35 (1 H, s), 7.00 (1 H, d), 7.27 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.62 (3H, overlapping m), 7.93 (1 H, m), 8.29-8.34 (3H, overlapping m), 8.59 (1 H, br s), 8.79 (1 H, br s).
Example 9: (S)-/V-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(methylamino)propanamide: Intermediate A
Figure imgf000063_0001
TFA, DCM
Me Example 9
To a stirred suspension of /V-Boc-methyl-L-alanine (1 17 mg, 0.58 mmol), PyBOP® (300 mg, 0.58 mmol) and DIPEA (101 μΙ_, 0.58 mmol) in DMF (2.0 mL) was added Intermediate A (75 mg, 0.14 mmol) in one portion. The reaction mixture was heated to 55°C and stirred for 18 hr and was cooled to RT and partitioned between water (10 mL) and EtOAc (10 mL). The organic layer was separated and evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, 0-100% EtOAc in isohexane, gradient elution). The resulting impure product was purified by SCX capture and release to afford (S)-ieri-butyl 1 -(4-((4-(3-(3- ie f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-ylamino)-1 - oxopropan-2-yl(methyl)carbamate (7) as a brown solid (25 mg, 23%): m/z 706 (M+H)+ (ES+).
A solution of the carbamate (7) (25 mg, 0.04 mmol) in DCM / TFA (1 :1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to SCX capture and release and then purified by flash column chromatography (Si02, 4 g, 0-100% EtOAc in MeOH, gradient elution) to afford the title compound (Example 9) as an off-white solid (13 mg, 57%): m/z 606 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.20 (3H, d), 1 .27 (9H, s), 2.26 (3H, s), 2.39 (3H, s), 3.20 (1 H, q), 5.38 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.28 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, overlapping m), 7.93 (1 H, m), 8.31 (1 H, m), 8.34 (1 H, dd), 8.36 (1 H, br s), 8.60 (1 H, s), 8.80 (1 H, s).
Example 10: (/?)-/V-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)morpholine-3-carboxamide:
Figure imgf000064_0001
To a stirred suspension of (R)-morpholine-3,4-dicarboxylic acid-4-ie f-butyl ester (133 mg, 0.58 mmol), PyBOP® (300 mg, 0.58 mmol) and DIPEA (101 μΙ_, 0.58 mmol) in DMF (2.0 mL) was added Intermediate A (75 mg, 0.14 mmol) in one portion. The reaction mixture was heated to 55°C and stirred for 18 hr. The reaction mixture was cooled to RT and partitioned between water (10 mL) and EtOAc (10 mL). The organic extract was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, 0-100% EtOAc in isohexane, gradient elution) to afford an impure product which was purified further by SCX capture and release to give (R)-ie/f-butyl 3-(4-((4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-ylcarbamoyl)morpholine-4-carboxylate (8) as a brown solid (28 mg, 25%): m/z 734 (M+H)+ (ES+).
A solution of the carbamate (8) (28 mg, 0.04 mmol) in DCM / TFA (1 :1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to capture and release on SCX and then triturated from diethyl ether (10 mL) to afford the title compound, Example 10, as an off-white solid (13 mg, 53%): m/z 634 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, overlapping m), 3.56-3.64 (4H, overlapping m), 3.82 (1 H, m), 5.38 (2H, s), 6.35 (1 H, s), 7.00 (1 H, d), 7.29 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.62 (3H, overlapping m), 7.92 (1 H, m), 8.28-8.35 (3H, overlapping m), 8.58 (1 H, br s), 8.79 (1 H, br s), 10.09 (1 H, br s) [partial assignment].
Example 11 : (S)-W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)morpholine-3-carboxamide: I
Figure imgf000065_0001
e Example 11
To a stirred suspension of (S)-morpholine-3,4-dicarboxylic acid-4-ie f-butyl ester (133 mg, 0.58 mmol), PyBOP® (300 mg, 0.58 mmol) and DIPEA (101 μΙ_, 0.58 mmol) in DMF (2.0 mL) was added Intermediate A (75 mg, 0.14 mmol) in one portion. The reaction mixture was heated to 55°C in a pre-heated oil bath and stirred for 18 hr. The reaction mixture was cooled to RT and partitioned between water (10 mL) and EtOAc (10 mL). The organic layer was separated, evaporated in vacuo and the residue was purified by column chromatography (12 g, 0-100% EtOAc in isohexane, gradient elution). Product fractions were concentrated in vacuo and the residue was triturated from DCM (5.0 mL) and isohexane (5.0 mL) to afford (S)-ieri-butyl 3-(4- ((4-(3-(3-ie f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- ylcarbamoyl) morpholine-4-carboxylate (9) as a white solid (50 mg, 43%): m/z 734 (M+H)+
(ES+).
A solution of the carbamate (9) (30 mg, 0.04 mmol) in DCM / TFA (1 :1 v/v, 2.0 mL) was stirred at RT for 1 hr and was then evaporated in vacuo, the resulting residue was subjected to capture and release on SCX and then triturated from DCM (5.0 mL) and isohexane (5.0 mL) to afford the title compound, Example 11 , as a brown solid (15 mg, 63%): m/z 634 (M+H)+ (ES+).
1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, overlapping m),
3.56-3.64 (4H, overlapping m), 3.82 (1 H, m), 5.38 (2H, s), 6.34 (1 H, s), 7.00 (1 H, d), 7.29 (1 H, dd), 7.35 (2H, m), 7.42 (2H, m), 7.55-7.62 (3H, overlapping m), 7.91 (1 H, m), 8.30 (1 H, dd),
8.32 (1 H, br s), 8.35 (1 H, dd), 8.56 (1 H, br s), 8.77 (1 H, br s) 10.16 (1 H, br s).
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
Figure imgf000066_0001
To a solution of Intermediate A (50 mg, 0.10 mmol) in pyridine (1.0 mL) was added a suspension of 4-methylpiperazine-1 -carbonyl chloride hydrochloride (38 mg, 0.19 mmol) in pyridine (1 .50 mL). DIPEA (50 μί, 0.29 mmol) was added and the mixture was stirred at RT for 3 days. The reaction mixture was evaporated in vacuo and the residue was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated and evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 4 g, 0-10% DCM in MeOH, gradient elution) to afford the title compound, Example 12, as a brown solid (17 mg, 27%): m/z 647 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ : 1 .27 (9H, s), 2.18 (3H, s), 2.29 (4H, t), 2.39 (3H, s), 3.46 (4H, t), 5.32 (2H, s), 6.35 (1 H, s), 6.99 (1 H, d), 7.13 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, overlapping m), 7.92 (1 H, m), 7.99 (1 H, s), 8.25 (1 H, d), 8.29 (1 H, m), 8.60 (1 H, br s), 8.80 (1 H, br s), 9.22 (1 H, br s). Example 13: yV-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)morpholine-4-carboxamide:
Intermediate A
Figure imgf000066_0002
To a solution of Intermediate A (70 mg, 0.13 mmol) in pyridine (1 .50 mL) was added morpholine-4-carbonyl chloride (28 μί, 0.24 mmol) and the solution was stirred at RT for 18 hr. A further portion of morpholine-4-carbonyl chloride (28 μί, 0.24 mmol) was added to the reaction mixture and stirring continued for 24 hr. The mixture was stirred with 1 % NH3 in MeOH (3.0 mL) and then evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, 0-5% MeOH in DCM, gradient elution) and recrystallized from isopropanol (5.0 mL) to afford the title compound, Example 13, as a white solid (17 mg, 20%): m/z 634 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 3.45 (4H, t), 3.59 (4H, t), 5.33 (2H, s), 6.35 (1 H, s), 6.99 (1 H, d), 7.14 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, overlapping m), 7.92 (1 H, m), 8.01 (1 H, br s), 8.26 (1 H, d), 8.29 (1 H, m), 8.58 (1 H, br s), 8.79 (1 H, br s), 9.27 (1 H, br s). 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:
Intermediate A
Figure imgf000067_0001
Oxalyl chloride (1 1 .0 μΙ_, 0.1 15 mmol) and then DMF (1 drop) were added to a suspension of 3- methoxypropionic acid (9.0 μΙ_, 0.096 mmol) in DCM (1 mL) and the mixture was stirred at 0°C for 10 min and then allowed to warm to RT. After 2 hr the solvent was removed in vacuo and the residue was taken up in to DCM (1 mL) and added to a solution of Intermediate A (50 mg, 0.096 mmol) and DIPEA (33.5 μΙ_, 0.192 mmol) in DCM (1 mL). After 16 hr the mixture was quenched by the addition of saturated aqueous NaHC03 solution. The organic layer was separated and a solution of NH3 in MeOH (7M) was added and the mixture was stirred for 10 min and then evaporated in vacuo. The residue was purified by flash chromatography (Si02, 4g, 0 to 100% EtOAc in isohexane, gradient elution) to afford the title compound, Example 14, as a pale yellow solid (15 mg, 26%). m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.65 (2H, t), 3.23 (3H, s), 3.61 (2H, t), 5.37 (2H, s), 6.35 (1 H, s), 7.00 (1 H, d), 7.25 (1 H, d), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.63 (3H, overlapping m), 7.83-7.85 (1 H, d), 7.93 (1 H, d), 8.29-8.34 (3H, overlapping m), 8.62 (1 H, br s), 8.82 (1 H, br s), 10.54 (1 H, br s).
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:
Figure imgf000067_0002
To a solution of Intermediate A (200 mg, 0.384 mmol) in pyridine (3 mL) was added ethyl isocyanatoacetate (129 μΙ_, 1 .152 mmol) and the reaction was stirred at RT for 16 hr. The mixture was evaporated in vacuo and was then co-evaporated with toluene and the residue was triturated with methanol to afford ethyl 2-(3-(4-((4-(3-(3-ie f-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-yl)ureido)acetate (10) as a solid (191 mg, 76%): m/z 650 (M+H)+, (ES+).
To a suspension of the ester (10) (200 mg, 0.308 mmol) in a mixture of THF / H20 (4:1 v/v, 5 mL) was added lithium hydroxide (10.0 mg, 0.418 mmol) and the mixture was stirred at RT for 1 hr. The reaction mixture was acidified to pH3, by the addition of 1 M hydrochloric acid and evaporated in vacuo to half of its original volume. The resulting preciptate was collected by filtration and was washed with water and dried in vacuo to provide 2-(3-(4-((4-(3-(3-)-butyl-1 -p- tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-yl)ureido)acetic acid (11 ) (185mg, 97%): m/z 622 (M+H)+, (ES+). To a suspension of the acid (11 ) (60 mg, 0.097 mmol) in DCM (1 .5 mL) was added 2- methoxyethylamine (25.0 μΙ_, 0.290 mmol), HOBt (19.56 mg, 0.145 mmol), DIPEA (50.5 μΙ_, 0.290 mmol), and EDC. HCI (27.8 mg, 0.145 mmol) and the mixture was stirred at RT for 1 hr. The reaction mixture became very viscous and was diluted with DMF (1 mL) and stirred for 16 hr. The reaction mixture was diluted with DCM and was washed with water. The organic phase was dried (MgS04) and the solvent was evaporated in vacuo. The residue was triturated with MeOH to afford the title compound, Example 15, as an off white solid (22 mg, 34%): m/z 679 (M+H)+, (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 3.24 (3H, s), 3.25 (2H, m), 3.34 (2H, m), 3.82 (2H, d), 5.31 (2H, s), 6.35 (1 H, s), 7.00 (1 H, d), 7.07 (1 H, d), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.65 (4H, overlapping m), 7.93 (1 H, m), 8.03 (1 H, t), 8.21 (1 H, d), 8.34 (1 H, m), 8.51 (1 H, very br s), 8.58 (1 H, br s), 8.79 (1 H, br s), 9.46 (1 H, br s)
Example 16: W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-4-(dimethylamino)butanamide:
Intermediate A
Figure imgf000068_0001
To a stirred suspension of 4-(dimethylamino)butyric acid. HCI (97 mg, 0.576 mmol) in DCM (2 mL) at 0°C was added thionyl chloride (42.0 μί, 0.576 mmol) and DMF (one drop) and the mixture was allowed to warm to RT. After 16 hr the reaction mixture was evaporated in vacuo and the residue was dissolved in DCM / THF (1 :1 v/v, 2 mL) and added to a solution of Intermediate A (60 mg, 0.1 15 mmol) in THF (1 mL) containing DIPEA (101 μΙ_, 0.576 mmol). The mixture was stirred at 55°C and after 4 hr the mixture was cooled to RT, diluted with water (10 mL) and was extracted with EtOAc (10 mL). The organic layer was separated and was treated with a solution of ammonia (7M in MeOH, 2 mL) for 5 min and the mixture evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12g, (10% NH3 in MeOH) - EtOAc gradient elution) to afford the title compound, Example 16, as a pale brown solid (25 mg, 34%): m/z 634 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 1.74 (2H, m), 2.21 (6H, s), 2.35 (2H, m), 2.39 (3 H, s), 2.40 (2H, m), 5.36 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.24 (1 H, d), 7.36 (2H, m), 7.44 (2H, m), 7.54-7.63 (3H, overlapping m), 7.93 (1 H, m), 8.30-8.37 (3H, overlapping m), 8.59 (1 H, s), 8.79 (1 H, s), 10.54 (1 H, br s). 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:
Intermediate A
Oxone®
Figure imgf000069_0001
To a suspension of 3-methanethiopropionic acid (1 17 mg, 0.97 mmol) in DCM (1 .0 mL) was added oxalyl chloride (85.0 μί, 0.97 mmol), followed by DMF (2 drops) and the mixture was stirred at RT for 1 hr. The solvent was removed by evaporation in vacuo and the residue was redissolved in DCM (2.5 mL) and was then added dropwise to a solution of Intermediate A (145 mg, 0.28 mmol) and DIPEA (218 μΙ_, 1.25 mmol) in DCM (2.0 mL). After 2 hr a solution of ammonia in MeOH (7M, 3.0 mL) was added and stirring was continued for 1 hr. The volatiles were evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, 0-5% MeOH in DCM, gradient elution) to afford A/-(4-((4-(3-(3-iert-butyl-1 -p-tolyl-1 H- pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-yl)-3-(methylthio)propanamide (12) (1 10 mg, 61 %): m/z 623 (M+H)+ (ES+). To a stirred solution of the sulfide (12) (47 mg, 0.075 mmol) in DMF (0.5 mL) was added a solution of Oxone (93 mg, 0.151 mmol) in water (1 .0 mL). After 10 min a precipitate had formed and MeOH (2 mL) was added and stirring continued for 1 hr. The mixture was diluted with a further aliquot of MeOH (2.0 mL) and glacial AcOH (0.5 mL) was added. The suspension was subjected to SCX capture and release and then purified by flash column chromatography (Si02, 12 g, 2-8% MeOH in DCM, gradient elution) to afford the title compound, Example 17, (20 mg, 38%): m/z 655 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.90 (2H, t), 3.01 (3H, s), 3.43 (2H, t), 5.38 (2H, s), 6.35 (1 H, s), 7.00 (1 H, d), 7.27 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.65 (3H, overlapping m), 7.93 (1 H, m), 8.29-8.33 (2H, overlapping m), 8.34 (1 H, d), 8.58 (1 H, br s), 8.79 (1 H, br s), 10.72 (1 H, br s).
Figure imgf000070_0001
To a solution of Intermediate A (100 mg, 0.192 mmol) in pyridine (1 .5 mL) was added 3- chlorocarbonyl-1 -methanesulfonyl-2-imidazolidinone (131 mg, 0.576 mmol) in pyridine (1.5 mL) and the reaction mixture was stirred at RT. After 3 days the reaction mixture was evaporated in vacuo and the residue was stirred with NH3 (1 % v/v in MeOH). The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 4 g, 100% DCM then 2% MeOH in DCM, isocratic elutions) to afford an impure product which was recrystallized from methanol to give the title compound, Example 18, as a white crystalline solid (12 mg, 9%): m/z 71 1 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 3.39 (3H, s), 3.87 (4H, s), 5.40 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.31 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, m), 7.93 (1 H, m), 8.21 (1 H, br s), 8.31 (1 H, m), 8.35 (1 H, d), 8.58 (1 H, br s), 8.79 (1 H, br s), 10.40 (1 H, br s).
Intermediate B: W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-chloroacetamide.
Intermediate A
Figure imgf000070_0002
To a solution of DIPEA (1.37 mL, 7.68 mmol) and Intermediate A (2.00 g, 3.84 mmol) in DCM (40 mL) and DMF (8.0 mL) was added chloroacetyl chloride (0.61 mL, 7.68 mmol). The reaction mixture was stirred at RT for 1 hr and a further portion of chloroacetyl chloride (100μΙ, 1 .25mmol) was added. After 1 hr at RT, the reaction mixture was partitioned between DCM (40 mL) and saturated aq NaHC03 solution (40 mL). The organic phase was concentrated in vacuo and purified by column chromatography (80 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with diethyl ether (20 mL) and isohexane (20 mL). The solid was collected by filtration to afford the title compound, Intermediate B, as a pale purple solid (1.07g, 42%): m/z 597, 599 (M+H)+ (ES+).
Example 19; yV-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl) pyridin-2-yl)-2-(methylthio)acetamide;
Intermediate B
Figure imgf000071_0001
Intermediate B (100 mg, 0.17 mmol) was added portionwise to a stirred solution of sodium thiomethoxide (35 mg, 0.50 mmol) in MeOH (5.0 mL) and the resulting mixture was stirred at RT for 1 hr. The mixture was evaporated in vacuo and partitioned between brine (20 mL) and DCM (30 mL). The organic layer was concentrated in vacuo, the residue pre-adsorbed on silica and purified by column chromatography (SI02, 12 g, 10-100% EtOAc in isohexane, gradient elution). Product fractions were evaporated in vacuo to give the title compound Example 19 as a light yellow solid (28 mg, 26%): m/z 610 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.16 (3H, s), 2.39 (3H, s), 3.53 (2H, s), 5.37 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.26 (1 H, dd), 7.35 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, m), 7.92 (1 H, m), 8.30-8.35 (3H, m), 8.58 (1 H, s), 8.78 (1 H, s), 10.60 (1 H, s).
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:
OXONE®
Example 19
Figure imgf000071_0002
To a solution of compound Example 19 (20 mg, 0.03 mmol) in a mixture of DMF / H20 (1 :1 v/v, 1 .OmL) was added OXONE® (10 mg, 0.03 mmol) and the reaction was stirred at RT for 3 days. A second portion of OXONE® (10 mg, 0.03 mmol) was added, the mixture was stirred for a further 24 hr and was then partitioned between brine (20 mL) and DCM (20 mL). The organic extract was washed with brine (20 mL), dried (MgS04) and evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 4 g, 30-100% EtOAc in isohexane, gradient elution) and subjected to SCX capture and release to afford the title compound, Example 20, as a tan coloured solid (1 1 mg, 52%): m/z 625 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1.27 (9H, s), 2.39 (3H, s), 2.69 (3H, s), 3.88 (2H, d), 4.04 (2H, d) 5.39 (2H, s), 6.35 (1 H, s), 7.02 (1 H, d), 7.31 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.64 (3H, overlapping m), 7.93 (1 H, m), 8.30-8.33 (2H, overlapping m), 8.37 (1 H, d), 8.59 (1 H, br s), 8.79 (1 H, br s), 10.85 (1 H, br s).
Example 21 : W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-morpholinoacetamide:
Figure imgf000072_0001
To a stirred solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (21 .9 μΙ_, 0.13 mmol) was added morpholine (1 1 .0 μΙ_, 0.13 mmol) and the reaction mixture stirred at RT for 3 hr and then at 40°C for 12 hr. A further portion of morpholine (1 1 .0 μί, 0.13 mmol) was added and the reaction mixture stirred at 40°C for 5 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue was triturated with MeOH (5.0 mL). The solid was collected by filtration to afford the title compound Example 21 as a light yellow solid (1 1 mg, 20%): m/z 648 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 2.39 (3 H, s), 2.54 (4 H, m), 3.20 (2 H, s), 3.63 (4 H, m), 5.39 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.28 (1 H, d), 7.35 (2H, d), 7.43 (2H, d), 7.63 - 7.56 (3H, m), 7.92 (1 H, d), 8.37 - 8.29 (3H, m), 8.58 (1 H, s), 8.79 (1 H, s), 10.01 (1 H, s).
Example 22; W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(pyrrolidin-1 -yl)acetamide:
Intermediate B
Figure imgf000072_0002
To a solution of Intermediate B (50 mg, 0.08 mmol) in DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (22 μί, 0.13 mmol) was added pyrrolidine (7.0 μί, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr and then at 40°C for 12 hr. A further portion of pyrrolidine (7.0 μί, 0.08 mmol) was added and the reaction mixture stirred at 40°C for 5 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford the title compound, Example 22, as a light orange solid (17 mg, 32%): m/z 632 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 1 .76 (4 H, m), 2.39 (3 H, s), 2.62 (4 H, m), 5.39 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.28 (1 H, d), 7.34 (2H, d), 7.44 (2H, d), 7.65- 7.55 (3H, m), 7.92 (1 H, d), 8.36-8.29 (3H, m), 8.58 (1 H, s), 8.79 (1 H, s), 9.93 (1 H, s).
Example 23; W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(4-methylpiperazin-1 -yl)acetamide:
Intermediate B
Figure imgf000073_0001
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (22 μί, 0.13 mmol) was added /V-methyl piperazine (9.3 μί, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr and then at 40°C for 12 hr. A further portion of N- methyl piperazine (9.0 μί, 0.08 mmol) was added and the reaction mixture stirred at 40°C for 5 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and isohexane (2:1 :2, 5.0 mL) to give the title compound, Example 23, as a light orange solid (26 mg, 47%): m/z 661 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5: 1 .27 (9 H, s), 2.39 (3 H, s), 2.69-2.60 (3 H, br m), 2.88-2.73 (3 H, br m), 3.17-2.95 (4 H, br m), 5.39 (2H, s), 6.34 (1 H, s), 7.00 (1 H, d), 7.29 (1 H, d), 7.35 (2H, d), 7.45 (2H, d), 7.66-7.56 (3H, m), 7.98 (1 H, d), 8.37-8.28 (3H, m), 8.73 (1 H, s), 8.91 (1 H, s), 10.12 (1 H, s).
Example 24; W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(4-(2-methoxyethyl)piperazin-1 -yl)acetamide:
Intermediate B
Figure imgf000073_0002
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (22 μί, 0.13 mmol) was added /V-methoxyethyl piperazine (12.5 μί, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr and then at 40°C for 12 hr. A further portion of /V-methoxyethyl piperazine (12.5 μΙ_, 0.08 mmol) was added and the reaction mixture stirred at 40°C for 5 hr. The crude reaction mixture was purified by column chromatography (Si02, 12 g, 0-10% MeOH in DCM, gradient elution) to afford the title compound, Example 24, as a light orange solid (45 mg, 73%): m/z 705 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO) δ: 1.27 (9 H, s), 2.39 (3 H, s), 2.46-2.48 (3 H, m, obscured by DMSO), 2.57-2.50 (4 H, m), 3.17 (2 H, s), 3.23 (3 H, s), 3.42 (2 H, t), 5.39 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.29 (1 H, d), 7.35 (2H, d), 7.43 (2H, d), 7.65 - 7.55 (3H, m), 7.93 (1 H, d), 8.36 - 8.30 (3H, m), 8.58 (1 H, s), 8.79 (1 H, s), 9.92 (1 H, s).
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:
Intermediate B
Figure imgf000074_0001
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 ml_), DMF (0.1 mL) and DIPEA (17 μΙ_, 0.10 mmol) was added 2-methoxyethylamine (7.0 μΙ_, 0.08 mmol). The reaction mixture was heated to 40°C and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (Si02,.12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1 :2, 5.0 mL) to afford the title compound, Example 25, as an off- white solid (6 mg, 1 1 %): m/z 637 (M+H)+ (ES+). 1 H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 2.39 (3 H, s), 2.71 (2 H, t), 3.24 (3 H, s), 3.33 (2 H, m (obscured by DHO)), 3.40 (2 H, t), 5.38 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.27 (1 H, d), 7.36 (2H, d), 7.43 (2H, d), 7.64 - 7.57 (3H, m), 7.92 (1 H, m), 8.36 - 8.30 (3H, m), 8.59 (1 H, s), 8.79 (1 H, s).
Example 26; W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(dimethylamino)acetamide:
Intermediate B
Figure imgf000074_0002
To a solution of Intermediate B (50 mg, 0.08 mmol) in DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (17 μί, 0.1 mmol) was added dimethylamine (2.0M solution in THF) (41 μί, 0.08 mmol). The reaction mixture was heated to 40°C and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g silica, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and isohexane (2:1 :2, 5.0 mL) to afford the title compound, Example 26, as an orange solid (18 mg, 35%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 2.31 (6 H, s), 2.39 (3 H, s), 3.14 (2 H, s), 5.39 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.29 (1 H, d), 7.35 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.94 (1 H, m), 8.38-8.28 (3H, m), 8.59 (1 H, s), 8.79 (1 H, s), 9.93 (1 H, s).
Example 27; W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1■ yloxy)methyl)pyridin-2-yl)-2-(methylamino)acetamide:
Intermediate B
Figure imgf000075_0001
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.2 mL) and DIPEA (17 μί, 0.10 mmol) was added methylamine (2.0M solution in THF) (41 μί, 0.08 mmol). The reaction mixture was heated to 40°C and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were contaminated with an impurity and the crude material was re-purified by column chromatography (Si02,12 g, 0-10% MeOH in DCM, gradient elution) to give the title compound, Example 27, as a light brown solid (6 mg, 12%): m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1 .27 (9 H, s), 2.32 (3 H, s), 2.39 (3 H, s), 3.28 (2 H, s), 5.39 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.27 (1 H, d), 7.35 (2H, d), 7.44 (2H, d), 7.63-7.55 (3H, m), 7.93 (1 H, m), 8.37 - 8.30 (3H, m), 8.59 (1 H, s), 8.80 (1 H, s).
Example 28; W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1■ yloxy)methyl)pyridin-2-yl)-2-((4-methoxybenzyl)(methyl)amino)acetamide:
Intermediate B
Figure imgf000075_0002
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.2 mL) and DIPEA (17.5 μί, 0.10 mmol) was added /V-(4-methoxybenzyl)-/V-methylamine (15.5 μί, 0.09 mmol) and the reaction mixture was stirred at 55°C for 12 hr. The crude reaction mixture was purified by column chromatography (Si02,12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and isohexane (2:1 :2, 5.0 mL) to afford the title compound, Example 28, as a white solid (7 mg, 1 1 %): m/z 713 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 2.25 (3 H, s), 2.39 (3 H, s), 3.22 (2 H, s), 3.59 (2 H, s), 3.72 (3 H, s), 5.38 (2H, s), 6.35 (1 H, s), 6.90 (2H, m), 7.01 (1 H, m), 7.27 (3H, m), 7.35 (2H, m), 7.43 (2H, m), 7.64-7.55 (3H, m), 7.94 (1 H, m), 8.37-8.28 (3H, m), 8.58 (1 H, s), 8.79 (1 H, s), 9.97 (1 H, s).
Example 29: 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-methoxyethylthio)acetamide:
Intermediate B
Figure imgf000076_0001
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (17 μί, 0.10 mmol) was added 2-methoxyethane-1 -thiol (8.0 μί, 0.10 mmol). The reaction mixture was heated to 40 °C and stirred for 18 hr, after which further portions of 2- methoxyethane-1 -thiol (8.0 μί, 0.10 mmol) and DIPEA (17 μί, 0.10 mmol) were added and stirring continued at 40 °C for 2 days. The reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, 0-10% MeOH in DCM, gradient elution) to afford an impure product which was triturated with diethyl ether (3.0 mL) and further purified by SCX capture and release to give the title compound, Example 29, (25 mg, 44%): m/z 653 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.80 (2H, t), 3.22 (3H, s), 3.41 (2H, s), 3.51 (2H, t), 5.38 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.27 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, overlapping m), 7.93 (1 H, m), 8.29-8.33 (2H, overlapping m), 8.35 (1 H, m), 8.58 (1 H, br s), 8.79 (1 H, br s), 10.61 (1 H,br s).
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:
Intermediate B
Figure imgf000076_0002
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 ml_), DMF (0.1 mL) and DIPEA (17 μΙ_, 0.10 mmol) was added 2-(2-methoxyethoxy)ethanethiol (14 μΙ_, 0.10 mmol). The reaction mixture was heated to 40 °C and stirred for 18 hr, after which further portions of 2-(2-methoxyethoxy)ethanethiol (14 μΙ_, 0.10 mmol) and DIPEA (17 μΙ_, 0.10 mmol) were added and stirring continued at 40 °C for 2 days. The reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, 0-10% MeOH in DCM, gradient elution) to afford an impure product which was triturated with diethyl ether (3.0 mL) and further purified by SCX capture and release to give the title compound, Example 30, (19 mg, 32%): m/z 697 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.79 (2H, t), 3.21 (3H, s), 3.39-3.42 (4H, overlapping m), 3.49 (1 H, d), 3.50 (1 H, dd), 3.59 (2H, t), 5.38 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.27 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56- 7.64 (3H, overlapping m), 7.93 (1 H, m), 8.29-8.32 (2H, overlapping m), 8.35 (1 H, dd), 8.58 (1 H, br s), 8.79 (1 H, br s), 10.61 (1 H, br s). Example 31 : yV-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-(2-morpholinoethylthio)acetamide:
Intermediate B
Figure imgf000077_0001
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (17 μΙ_, 0.10 mmol) was added 2-morpholin-4-yl-ethane-1 -thiol (12 μΙ_, 0.10 mmol). The reaction mixture was heated to 40°C for 18 hr after which further portions of 2- morpholin-4-yl-ethane-1 -thiol (12 μί, 0.10 mmol) and DIPEA (17 μί, 0.10 mmol) were added and stirring continued at 40 °C for 2 days. The reaction mixture was evaporated in vacuo and purified by flash column chromatography (Si02, 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+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.43 (4H, very br s), 2.59 (2H, very br s), 2.78 (2H, br t), 3.42 (2H, s), 3.55 (4H, br s), 5.38 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.27 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, overlapping m), 7.95 (1 H, m), 8.29-8.32 (2H, overlapping m), 8.35 (1 H, dd), 8.63 (1 H, s), 8.83 (1 H, s), 10.63 (1 H,s).
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 31
Figure imgf000078_0001
A solution of OXONE® (39 mg, 0.13 mmol) in water (0.4 mL) was added to a solution of compound, Example 31 , (30 mg, 0.04 mmol) in DMF (2.0 mL) and the mixture was stirred at RT for 18 hr. The reaction mixture was diluted with glacial AcOH (1 .0 mL) and brine (4.0 mL) and extracted with DCM (4.0 mL). The organic phase was evaporated in vacuo and the residue was subjected to SCX capture and release and was then purified by flash column chromatography (Si02, 12 g, 0-10% (1 % NH3 in MeOH) in DCM, gradient elution). The impure product so obtained was triturated with DCM (0.5 mL) and isohexane (3.0 mL) to afford the title compound, Example 32, as a white solid (7 mg, 21 %): m/z 740 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.43 (4H, br m), 2.77 (2H, t), 3.51 (2H, t), 3.56 (4H, br t), 4.53 (2H, s), 5.40 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.32 (1 H, m), 7.35 (2H, m), 7.44 (2H, m), 7.54-7.63 (3H, overlapping m), 7.93 (1 H, m), 8.30-8.32 (2H, overlapping m), 8.38 (1 H, d), 8.64 (1 H, br s), 8.84 (1 H, br s), 10.98 (1 H, br s). 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:
Intermediate B
Figure imgf000078_0002
To a solution of Intermediate B (50 mg, 0.08 mmol) in a mixture of DCM (1 .0 mL), DMF (0.1 mL) and DIPEA (17 μί, 0.10 mmol) was added bis(2-methoxyethyl)amine (15 μί, 0.10 mmol). The reaction mixture was stirred at 40°C, for 18 hr and then further portions of bis(2- methoxyethyl)amine (15 μί, 0.10 mmol) and DIPEA (17 μί, 0.10 mmol) were added and stirring continued at 40°C for 4 days. The reaction mixture was evaporated in vacuo and the residue was purified three times by flash column chromatography (Si02, 2 x 12 g, 0-20% MeOH in DCM and Si02, 4 g, 0-10% [1 % NH3 in MeOH] in DCM, gradient elution) to afford the title compound, Example 33, (13 mg, 22%): m/z 694 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.39 (3H, s), 2.79-2.81 (4H, t), 3.21 (6H, s), 3.34 (2H, s), 3.42 (4H, t), 5.38 (2H, s), 6.35 (1 H, s), 7.01 (1 H, d), 7.27 (1 H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.63 (3H, overlapping m), 7.93 (1 H, m), 8.30-8.35 (2H, overlapping m), 8.38 (1 H, br s), 8.58 (1 H, br s), 8.79 (1 H, br s), 10.14 (1 H, br s).
Intermediate C: 1 -(4-((3-Aminopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ferf-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000079_0001
To a solution of (3-amino-pyridin-4-yl)-methanol (13) (4.00 g, 32.2 mmol) in anhydrous THF (160 mL) at 0°C was added sodium hydride (1 .55 g, 38.7 mmol, 60 wt%). After stirring for 20 min, 1 -fluoro-4-nitronaphthalene (14) (6.16 g, 32.2 mmol) was added, the ice bath was removed and the reaction mixture left to warm to RT and stirred for 12 hr. The reaction mixture was partitioned between EtOAc (200 mL) and saturated aq NaHC03 solution (150 mL). The remaining yellow solid was collected by filtration and washed sequentially with water (50 mL), MeOH (50 mL) and diethyl ether (100 mL) and was identified as the desired product by LC-MS and 1H NMR. The filtrate was returned to a separating funnel; the organic phase was collected and washed with brine (100 mL), dried and concentrated in vacuo to afford an orange residue. Trituration of the orange residue with MeOH (200 mL) afforded an orange solid which was washed with diethyl ether (200 mL). LC-MS and 1H NMR analysis of the orange solid was identical to that observed for the insoluble solid obtained earlier. The two products were combined to afford 4-((4-nitronaphthalen-1 -yloxy)methyl)pyridin-3-amine (15) (7.80 g, 77%): m/z 296 (M+H)+ (ES+). To a suspension of (15) (3.00 g, 10.2 mmol) and DMAP (0.25 g, 2.03 mmol) in THF (30 mL) was added a solution of di-ie f-butyldicarbonate (2.33 g, 10.7 mmol) in THF (15 mL). After 2-3 min a solution was obtained. The 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 NaHC03 solution (50 mL). The organic layer was collected, dried and concentrated in vacuo to afford an orange oil. The oil was purified by column chromatography (0-50% EtOAc in isohexane, gradient elution) to afford di-ie/f-butyl 4-((4-nitronaphthalen-1 -yloxy) methyl) pyridin-3-yliminodicarbonate (16) as an orange oil which subsequently crystallised on standing (2.33 g, 43%): m/z 496 (M+H)+ (ES+).
A solution of (16) (2.30 g, 4.64 mmol) in MeOH (100 mL) and AcOH (20 mL) was passed through a Thales H-cube (1 .0 mL.min"1, 25°C, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo to afford di-ie/f-butyl 4-((4-aminonaphthalen -1 -yloxy)methyl)pyridin-3-yliminodicarbonate (17) as a brown oil (2.12 g, 82%): m/z 466 (M+H)+ (ES+).
A solution of (5) (1 .55 g, 6.77 mmol) in DCM (4.0 mL) was added dropwise over 25 min to a suspension of CDI (1.10 g, 6.77 mmol) in DCM (4.0 mL) at RT. The reaction mixture was stirred for 80 min at RT and a solution of di-fe/f-butyl 4-((4-aminonaphthalen-1 -yloxy)methyl)pyridin-3- yliminodicarbonate (17) (2.10 g, 4.51 mmol) in DCM (10 mL) was added to the reaction mixture in one portion and stirred for 12 hr. The reaction mixture was partitioned between saturated aq NaHC03 solution (20 mL) and DCM (20 mL). The organic layer was collected, dried and concentrated in vacuo to afford a purple residue. The crude material was purified by column chromatography (80 g, 0-100% EtOAc in isohexane, gradient elution,) to afford di-ie/f-butyl 4- ((4-(3-(3-fe/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl) ureido) naphthalen-1 -yloxy)methyl)pyridin-3-yliminodicarbonate (18) as a purple solid (1 .77 g, 53%): m/z 721 (M+H)+ (ES+). To a solution of the iminodicarbonate (18) (1 .70 g, 2.36 mmol) in DCM (10 mL) was added TFA (2.0 mL). After 1 hr at RT further TFA (2.0 mL) was added and the reaction mixture stirred for 12 hr at RT. The solvents were removed in vacuo and the product purified by SCX capture and release, followed by trituration with DCM (20 mL) to afford the title compound, Intermediate C, as a pale buff solid (0.96 g, 77%): m/z 521 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.39 (3 H, s), 5.16 (2 H, s), 5.38 (2 H, s), 6.35 (1 H, s), 7.05 (1 H, d), 7.32 (1 H, d), 7.35 (2H, d), 7.43 (2H, m), 7.64-7.51 (2H, m), 7.63 (1 H, d), 7.82 (1 H, d), 7.91 (1 H, m), 8.03 (1 H, s), 8.29 (1 H, m), 8.57 (1 H, s), 8.78 (1 H, s).
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
Intermediate C
Figure imgf000081_0001
Methyl isocyanate (8.5 μΙ_, 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 μΙ_, 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 (Si02,4 g, 10-25% MeOH in DCM, gradient elution). The crude product fractions were combined and triturated with DCM (20 mL). The solid was filtered off to afford the title compound (Example 34) (8 mg, 14%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 2.39 (3 H, s), 2.68 (3 H, d), 5.27 (2H, s), 6.35 (1 H, s), 6.53 (1 H, m), 6.98 (1 H, d), 7.35 (2H, d), 7.45 (2H, d), 7.65 - 7.52 (4H, m), 7.92 (1 H, d), 8.16 (1 H, s), 8.28 (2H, m), 8.61 (1 H, s), 8.82 (1 H, s), 8.88 (1 H, s).
Example 35: W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) methyl) pyridin-3-yl)-2-methoxyacetamide:
Intermediate C
Figure imgf000081_0002
To a solution of Intermediate C (50 mg, 0.10 mmol) and DIPEA (33.5 μί, 0.19 mmol) in anhydrous DCM (1 .0 mL) and anhydrous DMF (0.1 mL) was added methoxyacetyl chloride (10 L, 0.1 1 mmol) and the reaction mixture stirred for 12 hr at RT Additional methoxyacetyl chloride (10 μί, 0.1 1 mmol) was added and the reaction mixture was stirred at RT for 5 hr. A further portion of methoxyacetyl chloride (8 μί, 0.09 mmol) was added and after 2 hr a solution of ammonia (1 % in MeOH, 10 mL) was added and the reaction mixture was stirred for 20 min at RT. The solvents were removed in vacuo to afford a purple oily solid. This was dissolved in MeOH (2.0 mL) and 3 drops of AcOH were added. The solution was subjected to SCX capture and release, eluting the product with 1 % NH3 in MeOH. The solvent was removed in vacuo and the residue was triturated with diethyl ether (10 mL) to afford the title compound, Example 35, as a light purple solid (24 mg, 41 %) m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9 H, s), 2.39 (3 H, s), 3.31 (3 H, s (obscured by DHO peak)), 4.06 (2H, s), 5.34 (2H, s), 6.35 (1 H, s), 6.96 (1 H, d), 7.35 (2H, d), 7.43 (2H, d), 7.64-7.54 (4H, m), 7.93 (1 H, d), 8.29 (1 H, dd), 8.45 (1 H, d), 8.58 (1 H, s), 8.70 (1 H, s), 8.79 (1 H, s), 9.76 (1 H, s). 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:
Intermediate C
Figure imgf000082_0001
To a solution of Intermediate C (50 mg, 0.10 mmol) and DIPEA (33.5 μΙ_, 0.19 mmol) in a mixture of anhydrous DCM (1 .0 mL) and anhydrous DMF (0.2 mL) was added 2-(2- methoxyethoxy)acetyl chloride (15 μί 0.1 1 mmol) and the reaction mixture was stirred for 12 hr at RT. A second aliquot of 2-(2-methoxyethoxy) acetyl chloride (15 μί, 0.1 1 mmol) was added and the reaction mixture stirred at RT for 6 hr. Methanol (2.0 mL) and AcOH (5 drops) were added and the reaction mixture was subjected to SCX capture and release, eluting with 1 % NH3 in MeOH. The solvent was removed in vacuo and the crude material purified by column chromatography (Si02, 4 g, 0-10% MeOH in EtOAc, gradient elution) to afford the title compound, Example 36, as a white solid (27 mg, 43%): m/z 637 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1 .27 (9 H, s), 2.39 (3 H, s), 3.18 (3 H, s), 3.36 (2 H, m), 3.61 (2 H, m), 4.14 (2H, s), 5.33 (2H, s), 6.35 (1 H, s), 6.97 (1 H, d), 7.35 (2H, d), 7.43 (2H, d), 7.67 - 7.55 (4H, m), 7.92 (1 H, d), 8.27 (1 H, d), 8.46 (1 H, d), 8.58 (1 H, s), 8.74 (1 H, s), 8.80 (1 H, s), 9.65 (1 H, s).
Intermediate D: 1 -(4-(2-(2-Aminopyridin-4-yl)ethoxy)naphthalen-1 -yl)-3-(3-ferf-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000082_0002
To a stirred solution of ethyl 2-(2-(ie f-butoxycarbonylamino)pyridin-4-yl)acetate (19) (WO 2007/089512) (10.0 g, 35.7 mmol) under nitrogen in THF (100 mL), at -78°C, was added DIBAL (1 M solution in THF, 71 .3 mL, 71 .3 mmol) over 1 hr. The reaction mixture was stirred at -78 to - 60°C for 40 min and was then warmed to -15°C over 1 hr. The solution was re-cooled to -78°C and was treated with further DIBAL (1 M solution in THF, 35 mL, 35.7 mmol). The mixture was allowed to warm to -40°C and stirred for 1 hr. Water (10 mL) was added cautiously to quench the reaction followed by MgS04 (20 g) and the solids removed by filtration. The filtrate was evaporated to dryness in vacuo and the residue subjected to column chromatography (Si02, 330 g, 65 % EtOAc in hexanes) to give fe/f-butyl 4-(2-hydroxyethyl)pyridin-2-ylcarbamate (20) (6.00 g, 64%) as a yellow solid: m/z 239 (M+H)+ (ES+).
To a solution of ie f-butyl 4-(2-hydroxyethyl)pyridin-2-ylcarbamate (20) (6.00 g, 25.2 mmol) in THF (70 mL) was added sodium hydride (2.52 g, 63.0 mmol, 60 wt%) at 0 °C. The bright yellow suspension was stirred for 20 min at 0°C and the 1 -fluoro-4-nitronaphthalene (14) (4.81 g, 25.2 mmol) added in a single portion. After stirring at RT for 2 hr, water (100 mL) was added followed by EtOAc (100 mL). The solid formed between the layers was collected by filtration and the organic phase was washed with saturated aq NaHC03 solution (100 mL), brine (100 mL) and dried. The volatiles were removed to give an orange solid. The solids were combined and triturated from MeOH (50 mL) to give ie/f-butyl 4-(2-(4-nitronaphthalen-1 - yloxy)ethyl)pyridin-2-ylcarbamate (21 ) as a yellow solid (1 1 .0 g, 98%): m/z 410 (M+H)+ (ES+).
A mixture of ie/f-butyl 4-(2-(4-nitronaphthalen-1 -yloxy)ethyl)pyridin-2-ylcarbamate (21 ) (5.20 g, 12.7 mmol) and iron mesh (4.30 g, 76 mmol) was suspended in AcOH and EtOH (1 :2, 120 mL) and was heated to 60°C and stirred rapidly until the reaction was judged to be complete by LC- MS. The mixture was cooled to RT, poured carefully onto saturated aq NaHC03 solution (1000 mL) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with saturated aq NaHC03 solution (1000 mL), water (1000 mL), brine (1000 mL) and dried. The solution was filtered and evaporated in vacuo to give fe/f-butyl 4-(2-(4-aminonaphthalen-1 - yloxy)ethyl)pyridin-2-ylcarbamate (22) as a yellow oil (5.00 g, 95%): m/z 380 (M+H)+ (ES+).
To a stirred suspension of CDI (3.00 g, 18.18 mmol) in DCM (15 mL) was added a solution of the pyrazole amine (5) (4.17 g, 18.18 mmol) in DCM (40 mL) over 1.5 hrs. After 2 hr at RT a solution of the naphthyl amine (22) (3.00 g, 7.91 mmol) in DCM (15 mL) was added. After stirring overnight, the solution was diluted with MeOH (10 mL) and absorbed onto silica gel (30 g) and subjected to column chromatography (Si02, 330 g, 30% to 100% EtOAc in isohexane and then 0% to 6% MeOH in EtOAc) to give ferf-butyl-4-(2-(4-(3-(3-ferf-butyl-1 -p-tolyl-1 H- pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2-ylcarbamate (23) as a beige solid (4.20 g, 80%): m/z 635 (M+H)+ (ES+).
To a suspension of the carbamate (23) (1.35 g, 2.20 mmol) in DCM (10 mL) was added TFA (10 mL). After stirring at RT for 2 hr, the volatiles were evaporated and the residue was taken up in EtOAc (50 mL) and extracted with saturated aq NaHC03 solution (50 mL). The organic layer was separated and was washed with brine (50 mL), and then dried and evaporated to give the title compound, Intermediate D, as a pale pink solid (1 .20 g, 100%): m/z 535 (M+H)+ (ES+).
Example 37; 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-methoxyacetamide:
Intermediate D
Figure imgf000084_0001
To a suspension of Intermediate D (35 mg, 0.065 mmol) in DCM (0.5 mL) was added DIPEA (23 μί, 0.131 mmol) and methoxyacetyl chloride (7 μί, 0.072 mmol) and the mixture stirred at RT, until judged to be complete by LC-MS. The reaction mixture was diluted with saturated aq NaHC03 solution (1.5 mL) and the layers were separated through a phase separator cartridge. The organics were collected, evaporated under reduced pressure and the residue subjected to SCX capture and release. The resulting residue was purified further by preparative RP HPLC to give the title compound, Example 37, as a white solid (5 mg, 13%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .26 (9 H, s), 2.37 (3 H, s), 3.20 (2 H, t), 3.37 (3 H, s), 4.06 (2 H, s), 4.38 (2 H, t), 6.33 (1 H, s), 6.95 (1 H, d), 7.19 (1 H, dd), 7.33 (2 H, m), 7.42-7.47 (3 H, m), 7.54 (1 H, m), 7.59 (1 H, d), 7.87 (1 H, d), 8.12 (1 H, d), 8.18 (1 H, br s), 8.23 (1 H, d), 8.67 (1 H, s), 8.84 (1 H, s), 9.89 (1 H, s).
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:
Intermediate D
Figure imgf000084_0002
To a suspension of Intermediate D (35 mg, 0.065 mmol) in DCM (0.5 mL) was added DIPEA (23 μί, 0.131 mmol) and 2-(2-methoxy)ethoxyacetyl chloride (1 1 mg, 0.072 mmol) and the mixture stirred at RT until judged to be complete by LC-MS. The reaction mixture was diluted with saturated aq NaHC03 solution (1 .5 mL) and the layers were separated through a phase separator cartridge. The organics were collected, evaporated under reduced pressure and the residue subjected to SCX capture and release. The resulting residue was purified further by preparative RP HPLC to give the title compound, Example 38, as an off white solid (13 mg, 31 %): m/z 651 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .26 (9 H, s), 2.38 (3 H, s), 3.21 (2 H, t), 3.28 (3 H, s), 3.49-3.51 (2 H, m), 3.66-3.68 (2 H, m), 4.13 (2 H, s), 4.38 (2 H, t), 6.34 (1 H, s), 6.95 (1 H, d), 7.19 (1 H, dd), 7.34 (2 H, m), 7.41 -7.48 (3 H, m), 7.51 -7.56 (1 H, m), 7.59 (1 H, d), 7.87 (1 H, d), 8.1 1 -8.14 (1 H, dd), 8.20 (1 H, br s), 8.23-8.25 (1 H, dd), 8.55 (1 H, s), 8.75 (1 H, s), 9.83 (1 H, s). 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:
MeNCO
Intermediate D
Figure imgf000085_0001
To a solution of Intermediate D (50 mg, 0.094 mmol) in pyridine (1 .0 mL) was added methyl isocyanate (5.3 mg, 0.094 mmol) and the mixture was stirred at RT for 72 hr. The solvent was evaporated under reduced pressure and the resulting residue was triturated from MeOH (5.0 mL) to give the title compound, Example 39, as an off white solid (7 mg, 13%): m/z 592 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .26 (9 H, s), 2.38 (3 H, s), 3.13 (2 H, t), 3.31 (3 H, s, obscured by H20),4.32 (2 H, t), 6.34 (1 H, s), 6.93 (1 H, d), 7.34 (2 H, m), 7.40-7.48 (6 H, m), 7.53-7.57 (1 H, m), 7.61 (1 H, d), 7.81 -7.83 (2 H, d), 7.86-7.89 (1 H, d), 8.02-8.04 (1 H, dd), 8.55 (1 H, s), 8.75 (1 H, s). 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 :
Intermediate D
Figure imgf000085_0002
To a solution of Intermediate D (50 mg, 0.094 mmol) in pyridine (1 .0 mL) was added trichloroacetylisocyanate (12 μί, 0.103 mmol) and the mixture was stirred at RT until judged to be complete by LC-MS. The solvent was evaporated in vacuo and the resulting residue was subjected to SCX capture and release and then triturated from DCM (10 mL) to give the title compound, Example 40, as an off white solid (25 mg, 44%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1 .26 (9 H, s), 2.38 (3 H, s), 3.12 (2 H, t), 4.35 (2 H, t), 6.34 (1 H, s), 6.94-6.99 (2 H, m), 7.19 (1 H, dd), 7.33-7.35 (2 H, m), 7.41 -7.50 (5 H, m), 7.52-7.56 (1 H, m), 7.60 (1 H, d), 7.87 (1 H, d), 8.09-8.13 (2 H, m), 8.54 (1 H, s), 8.75 (1 H, s), 9.08 (1 H, s).
Intermediate E: 1 -(4-(2-(3-Aminopyridin-4-yl)ethoxy)naphthalen-1 -yl)-3-(3-ferf-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000086_0001
A solution of 2-(3-nitropyridin-4-yl)ethanol (24) (WO 2006/136562) (2.00 g, 1 1.89 mmol) in MeOH (150 mL) was passed through a Thales H-cube (2.0 mL.min"1, 30 °C, 30 bar, Pd/C Cat- Cart, 55 mm, controlled mode). Analysis by LC-MS showed a significant amount of starting material was still present and the solution was passed through the H-cube twice more (2.0 mL.min"1, full hydrogen mode, RT, and 2.0 mL.min"1, full hydrogen mode, 40°C). Evaporation of the volatiles gave 2-(3-aminopyridin-4-yl)ethanol (25) as a purple oil (1 .30 g, 81 %): m/z 139 (M+H)+ (ES+). To a solution of 4-nitronaphthalen-1 -ol (2) (0.95 g, 5.00 mmol), PPh3 (1 .97 g, 7.50 mmol) and 2- (3-aminopyridin-4-yl)ethanol (25) (1 .04 g, 7.50 mmol) in THF (20 mL) was added dropwise DIAD (590 μί, 3.75 mmol) at -15 °C. The mixture was stirred for 1 hr at RT and the volatiles removed in vacuo. The residues was absorbed on silica (20 g) and purified by column chromatography (Si02, 80 g, 50-100% EtOAc in isohexane, gradient elution and then 5% MeOH in EtOAc, isocratic elution) to give 4-(2-(4-nitronaphthalen-1 -yloxy) ethyl)pyridin-3-amine (26) (1.36 g, 88 %): m/z 310 (M+H)+ (ES+).
A solution of 4-(2-(4-nitronaphthalen-1 -yloxy)ethyl)pyridin-3-amine (26) (700 mg, 2.263 mmol) in a mixture of MeOH (50 mL), EtOAc (25 mL),and DCM (25 mL) was passed through a Thales H-cube (10 % Pt/C, 30mm, 1 .0 mL.min"1, 40°C, full hydrogen mode). The solvent was removed in vacuo to give 4-(2-(4-aminonaphthalen-1 -yloxy)ethyl)pyridin-3-amine (27) as a brown solid (612 mg, 92%). m/z 280 (M+H)+ (ES+).
To a solution of 3-fe/f-butyl-1 -p-tolyl-1 H-pyrazol-5-amine (5) (1 .00 g, 4.36 mmol) in DCM (90 mL) was added a saturated aq solution of NaHC03 (60 mL). The mixture was stirred vigorously, cooled to 0 °C and diphosgene (2.1 mL, 17.4 mmol) was added in a single portion. After stirring for 1 hr at RT, the layers were separated and the organics dried and evaporated to give a brown oil. The oil was triturated with isohexane (5.0 mL) and the solid filtered. The filtrate was concentrated in vacuo to give 3-fe/f-butyl-5-isocyanato-1 -p-tolyl-1 H-pyrazole (28) as a light brown oil (1 .00 g, 3.92 mmol, 90 %). m/z 288 (in MeOH) (M+H+MeOH)+ (ES+). A solution of 3-fe/f-butyl-5-isocyanato-1 -p-tolyl-1 H-pyrazole (28) (530 mg, 2.076 mmol) in THF (2.0 mL) was added to a solution of 4-(2-(4-aminonaphthalen-1 -yloxy)ethyl)pyridin-3-amine (27) (580 mg, 2.076 mmol) and DIPEA (1085 μΙ_, 6.23 mmol) in THF (10 mL) and MeCN (1.0 mL) and the reaction mixture stirred at RT overnight. The mixture was poured into brine (25 mL) and extracted with EtOAc (2 x 25 mL), dried, filtered and the solvent removed in vacuo. The product was pre-adsorbed onto hyflo (10 g), and purified by reverse phase column chromatography (40 g, Ci8 [from Silicycle], acetonitrile/water, 0 to 100%) and the product fractions concentrated in vacuo to give the title compound. Intermediate E, as an off white solid (410 mg, 36 %). m/z 535 (M+H)+ (ES+).
Example 41 : W-(4-(2-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)ethyl)pyridin-3-yl)- -methoxyacetamide:
Intermediate E
Figure imgf000087_0001
To a solution of Intermediate E (50 mg, 0.094 mmol) and DMAP (5.71 mg, 0.047 mmol) in DCM (3.0 mL) was added methoxyacetyl chloride (25.7 μί, 0.281 mmol) at 0°C and the reaction mixture stirred at RT for 1 .5 hr. The solvent was removed in vacuo and the residue subjected to SCX capture and release. The impure product was purified by flash column chromatography (Si02, 4.0 g, 0-10% MeOH in DCM, gradient elution) to give the title compound, Example 41 , as a pale pink solid (45 mg, 77%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1 .27 (9H, s), 2.39 (3H, s), 3.18 (2H, t), 3.40 (3H, s), 4.08 (2H, s), 4.39 (2H, t), 6.35 (1 H, s), 6.96 (1 H, d), 7.35 (2H, m), 7.43 (2H, m), 7.50 (2H, m), 7.58 (1 H, m), 7.61 (1 H, d), 7.88 (1 H, d), 8.09 (1 H, dd), 8.37 (1 H, d), 8.52 (1 H, s), 8.56 (1 H. br s), 8.76 (1 H, br s), 9.66 (1 H, br s.).
Example 42; W-(4-(2-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide:
Intermediate E
Figure imgf000087_0002
To a solution of Intermediate E (50 mg, 0.094 mmol) and DMAP (5.71 mg, 0.047 mmol) in DCM (3.0 mL) was added 2-(2-methoxyethoxy)acetyl chloride (30 μΙ_, 0.281 mmol) at 0°C and the reaction mixture stirred at RT for 1 .5 hr. The solvent was removed in vacuo and the residue subjected to SCX capture and release. The residue was purified by column chromatography (Si02 ,4.0 g, 0-8% MeOH in DCM, gradient elution) and the product fractions concentrated in vacuo to give the title compound, Example 42, as a light purple solid (35 mg, 56%): m/z 651 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1 H, s), 6.98 (1 H, d), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1 H, d), 7.87 (1 H, d), 8.07 (1 H, dd), 8.36 (1 H, d), 8.56 (1 H. br s), 8.60 (1 H, s), 8.76 (1 H, br s), 9.55 (1 H, br s.). Intermediate F: 1 -(4-(2-(2-Aminopyridin-4-yloxy)ethyl)naphthalen-1 -yl)-3-(3-ieri-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000088_0001
To a solution of ie f-butyl 4-bromonaphthalen-1 -ylcarbamate (29)(3.00 g, 9.31 mmol) in THF (100 mL) at -78°C under nitrogen was added n-BuLi (1 .6M in hexane, 20.4 mL, 32.6 mmol) and the reaction mixture was stirred at -78°C for 1 hr. Neat DMF (4.50 mL, 58.1 mmol) was added and the reaction mixture was stirred at -78°C for 1 hr, then warmed to RT and stirred for a further 1 hr. Water (5 mL) was added and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with brine, dried (MgS04) and evaporated in vacuo. The residue was triturated with isohexane to afford ie f-butyl 4- formylnaphthalen-1 -ylcarbamate (30) as a beige solid (2.20 g, 87%): m/z 272 (M+H)+ (ES)+.
To a suspension of methyltnphenylphosphonium bromide (3.82 g, 10.69 mmol) in THF (20 mL) at 0°C under nitrogen was added potassium ie f-butoxide (1 .20 g, 10.69 mmol) and the reaction mixture was stirred at 0°C for 15 min, then warmed to RT and stirred for a further 45 min. The suspension was cooled to 0°C and a solution of (30) (1 .16 g, 4.28 mmol) in THF (10 mL) was added dropwise. The reaction mixture was warmed to RT and stirred for 2 hr. Saturated aqueous NH4CI solution (30 mL) was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 0-10% ethyl acetate in isohexane, gradient elution) to afford fe/f-butyl 4-vinylnaphthalen-1 -ylcarbamate (31 ) as a white solid (0.831 g, 72%): m/z 268 (M-H)" (ES").
To a solution of (31 ) (0.83 g, 3.08 mmol) in THF (10 mL) was added 9-BBN (0.5M in THF, 9.9 mL, 4.95 mmol) dropwise under nitrogen at 0°C. The mixture was warmed to RT and stirred for 16 hr. Water (1 mL), aqueous NaOH solution (3M, 10.0 mL, 30 mmol) and hydrogen peroxide (35% in water, 8.0 mL) were added. The reaction mixture was warmed to 50°C and stirred for 2 hr and was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 10-60% ethyl acetate in isohexane, gradient elution) to afford ie f-butyl 4-(2-hydroxyethyl)naphthalen-1 -ylcarbamate (32) (763 mg, 86%); m/z 288 (M+H)+, (ES+)
To a degassed solution of (32) (0.64 g, 2.23 mmol) in DMF (10 mL) was added sodium hydride (0.267 g, 60% dispersion in mineral oil, 6.68 mmol) under nitrogen at 0°C. The solution was warmed to RT and was stirred for 30 min and then cooled to 0°C. To this mixture was added a solution of 2-chloro-4-fluoro-pyridine (0.381 g, 2.90 mmol) in DMF (5.0 mL) and the reaction mixture was warmed to RT and stirred for 16 hr. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine (3x), dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 0-40% ethyl acetate in isohexane, gradient elution) to afford ie f-butyl 4-(2-(2- chloropyridin-4-yloxy)ethyl)naphthalen-1 -ylcarbamate (33) (670 mg, 75%); m/z 399 (M+H)+, (ES+)
To a degassed suspension of (33) (600 mg, 1 .50 mmol), ie/f-butyl carbamate (176 mg, 1.50 mmol), Cs2C03 (733 mg, 2.26 mmol) and Xathphos (43 mg, 0.075 mmol) in THF (10 mL) was added Pd2dba3 (34 mg, 0.038 mmol) and the reaction mixture was heated at reflux under nitrogen for 16 hr. Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 0-50% hexane in ethyl acetate, gradient elution) to afford a mixture of the desired Boc protected product and starting material, which was dissolved in a mixture of DCM (2 mL) and TFA (2 mL) and stirred at RT for 1 hr. The solvent was evaporated in vacuo and the residue was dissolved in DCM and washed with saturated aqueous NaHC03 solution and brine, then dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 5% MeOH in DCM, isocratic elution) to afford 4-(2-(4-aminonaphthalen-1 -yl)ethoxy)pyridin-2-amine (34) (45 mg, 1 1 %); m/z 280 (M+H)+, (ES+).
To a suspension of CDI (122 mg, 0.752 mmol) in DCM (2 mL) was added a solution of (5) (172 mg, 0.752 mmol) in DCM (2.0 mL) and the reaction mixture was stirred at RT for 16 hr. An aliquot (1 .0 mL) of this reaction mixture was added to a stirred suspension of (34) (42 mg, 0.150 mmol) in DCM (2.0 mL). THF (0.5 mL) was added and the reaction mixture was stirred for 1 hr. A second aliquot (1 .0 mL) of the CDI reaction mixture was added and the mixture was stirred for a further 20 hr at RT. Methanol was added and stirring continued for 30 min. The solvent was evaporated and the residue was purified by flash column chromatography (Si02, 0- 5% MeOH in DCM, gradient elution). The resulting impure product was dissolved in ethyl acetate, washed with water and brine, dried (MgS04) and evaporated in vacuo to afford the title compound, Intermediate F, (42 mg, 52%); m/z 535 (M+H)+, (ES+). Example 43: N-(4-(2-(4-(3-(3-ferf-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yl)ethoxy)pyridin-2-yl)-2-methoxyacetamide:
Intermediate F
Figure imgf000090_0001
To a solution of Intermediate F (40 mg, 0.075 mmol) and DIPEA (0.059 mL, 0.337 mmol) in DCM (1 .5 mL) was added methoxyacetyl chloride (32 mg, 0.299 mmol) and the reaction mixture was stirred for 16 hr at RT. A solution of ammonia (1 % in methanol) was added and the stirring continued for 30 min. The solvent was evaporated in vacuo and the residue was purified by SCX capture and release. The crude product was purified by flash column chromatography (Si02, 0-5% MeOH in DCM, gradient elution) to afford the title compound, Example 43, (10 mg, 20%) : m/z 607 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9H, s), 2.39 (3H, s), 3.35 (3H, s), 3.51 (2H, t), 4.03 (2H, s), 4.35 (2H, t), 6.39 (1 H, s), 6.72 (1 H, dd), 7.35 (2H, d), 7.42- 7.47 (3H, overlapping m), 7.55-7.63 (2H, overlapping m), 7.67 (1 H, d), 7.82 (1 H, d), 8.03 (1 H, m), 8.10 (1 H, d), 8.19 (1 H, d), 8.72 (1 H, br s), 9.01 (1 H, br s), 9.87 (1 H, br s). Intermediate G: 1 -(4-(1 -(2-aminopyridin-4-yl)ethoxy)naphthalen-1 -yl)-3-(3-ieri-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000091_0001
To a stirred solution of methyl-2-aminopyridine-4-carboxylate (35) (1 .00 g, 6.57 mmol) in THF (100 mL), at -78°C under nitrogen, was added methyllithium (1 .6 M in diethyl ether, 16.4 mL, 26.3 mmol), over 10 min. After a further 30 min at -78°C, the viscous reaction mixture was warmed to 0°C. After a further 3 hr, the reaction was quenched at 0°C by the cautious addition of iso-propanol (8.0 mL). The mixture was warmed to RT, brine (200 mL) and EtOAc (150 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x100 mL), and the combined organic extracts were dried and the solvents removed in vacuo. The crude residue was purified by column chromatography (Si02, 80 g, 0-8% MeOH in EtOAc, gradient elution) to give 1 -(2-aminopyridin-4-yl)ethanone (36) (176 mg, 20%) as a yellow powder: m/z 137 (M+H)+ (ES+).
To a mixture of (36) (168 mg, 1.234 mmol) in MeOH (10 mL), under nitrogen at 0°C, was added sodium borohydride (46.7 mg, 1 .234 mmol). The reaction mixture was stirred at RT for 2 hr, and the volatiles were removed under reduced pressure. The residue was taken up into EtOAc (25 mL), and extracted with saturated aq NaHC03 solution (30 mL). The aqueous layer was back extracted with EtOAc (2 x 20 mL), and the combined organic extracts were washed with brine (30 mL), dried and the solvents removed in vacuo to give 1 -(2-aminopyridin-4-yl)ethanol (37) (77 mg, 45%) as a yellow oil: m/z 139 (M+H)+ (ES+).
To a stirred solution of (37) (73 mg, 0.528 mmol) in DMF (1 .5 mL), under nitrogen at 0°C, was added sodium hydride (32 mg, 0.793 mmol, 60 wt%). The resulting mixture was stirred at 0°C for 40 min, and a solution of 1 -fluoro-4-nitronaphthalene (14) (101 mg, 0.528 mmol) in DMF (1 .5 mL) was added dropwise. The resulting dark-red mixture was stirred at 0°C for 5 min and at RT for 40 min and was quenched by the addition of 1 .0 mL of NH4CI solution. Water (20 mL) and EtOAc (20 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine, dried and the solvents removed in vacuo. The crude material was purified by column chromatography (Si02, 12 g, 0-80% EtOAc in isohexane, gradient elution) to give 4-(1 -(4- nitronaphthalen-1 -yloxy)ethyl)pyridin-2-amine (38) (94.6 mg, 57%) as an orange gum: m/z 310 (M+H)+ (ES+).
A solution of (38) (91 mg, 0.294 mmol) in MeOH (15 mL) and AcOH (3.0 mL) was passed through a Thales H-cube (1.0 mL.min"1, 30°C, 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode). The volatiles were removed under reduced pressure, leaving a purple solid, which was then subjected to SCX capture and release to give 4-(1 -(4-aminonaphthalen-1 -yloxy)ethyl)pyridin-2- amine (39) (81 mg, 99%) as a purple oil: m/z 280 (M+H)+ (ES+). To a solution of (5) (57 mg, 0.250 mmol) in DCM (6.0 mL) was added saturated aq NaHC03 solution (4.0 mL) The mixture was stirred vigorously and was cooled to 0°C and trichloromethylchloroformate (0.091 mL, 0.750 mmol) was added in one portion. The resulting mixture was stirred at 0°C for 1 .5 hr. The biphasic mixture was separated and the organic extract was dried and the solvents removed under reduced pressure to afford an oil, which was dried under high vacuum, at 35°C for 35 min. The resulting oil was taken up into THF (5.0 mL), and then added to 4-(1 -(4-aminonaphthalen-1 -yloxy)ethyl)pyridin-2-amine (39) (81 mg, 0.290 mmol). DIPEA (179 μί, 1.029 mmol) was added, and the reaction mixture was stirred at RT for 16 hr. Water (15 mL) and EtOAc (10 mL) were added to the reaction mixture and the layers were separated. The aq layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (20 mL), dried and the solvents removed under reduced pressure. The resulting residue was dissolved in MeOH (5.0 mL) and AcOH (2.0 mL) and subjected to SCX capture and release. The crude mixture was purified by column chromatography (Si02, 12 g, 0-10% MeOH in DCM, gradient elution) to give the title compound, Intermediate G, (63 mg, 38%) as a beige powder: m/z 535 (M+H)+ (ES+).
Example 44: Λ/-(4-(1 -(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)ethyl)pyridin-2-yl)-2-methoxyacetamide:
Intermediate G
Figure imgf000092_0001
Methoxyacetyl chloride (17.5 μί, 0.192 mmol) was added dropwise to a solution of Intermediate G (41 mg, 0.077 mmol) and DIPEA (40.1 μί, 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 NH3 (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. Fractions containing the desired material were combined, evaporated in vacuo and purified by flash column chromatography (Si02, 12 g, 3-6% MeOH in DCM, gradient elution; then Si02, 12 g, 0-40% EtOAc in ether, gradient elution) to give the title compound, Example 44, as a beige solid (24 mg, 51 %): m/z 607 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO d6) δ: 1 .26 (9H, s), 1 .67 (3H, d), 2.38 (3H, s), 4.03 (2H, s), 5.75 (1 H, q), 6.32 (1 H, s), 6.81 (1 H, d), 7.22 (1 H, dd), 7.35 (2H, m), 7.42 (2H, m), 7.48 (1 H, s), 7.59 (2H, m), 7.88 (1 H, m), 8.24 (1 H, br s), 8.27 (1 H, d), 8.36 (1 H, m), 8.59 (1 H, br s), 8.76 (1 H, br s), 9.99 (1 H, br s).
Intermediate H: 1 -(4-(1 -(2-Aminopyridin-4-yl)-2-methylpropan-2-yloxy)naphthalen-1 -yl) -3-(3-ferf-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000093_0001
To a stirred solution of methyl-2-aminopyridine-4-carboxylate (35) (2.00 g, 13 mmol) in THF (200 mL), at -78°C under nitrogen, was added methyllithium (1 .6 M in diethyl ether, 33 mL, 53 mmol) over 10 min. After 30 min the viscous reaction mixture was warmed to 0°C for 3.5 hr and was quenched at 0°C by the cautious addition of isopropanol (15 mL). The mixture was warmed to RT, and brine (400 mL) and EtOAc (300 mL) were added. The aqueous layer was separated and extracted with EtOAc (3 x 200 mL) and the combined organic extracts were dried (MgS04) and evaporated in vacuo. The crude residue was purified by flash column chromatography (Si02, 120 g, 0-10% MeOH in EtOAc, gradient elution) to afford the 2-(2- aminopyridin-4-yl)propan-2-ol (40) (1 .27 g, 63%) as a yellow amorphous solid: 1H NMR (400 MHz, CD3OD) δ: 1 .47 (6H, s), 6.68-6.71 (2H, overlapping m), 7.80-7.81 (1 H, dd).
To a stirred solution of (40) (1 .55 g, 10.0 mmol) in DMF (30 mL), under nitrogen at 0°C, was added sodium hydride (60% wt, 0.61 g, 15.0 mmol) and the resulting mixture was stirred at 0°C for 5 min., A solution of 1 -fluoro-4-nitronaphthalene (14) (1.95 g, 10 mmol) in DMF (30 mL) was added dropwise and the resulting dark-red mixture was stirred at 0°C for a further 5 min and then at RT for 2 hr. The reaction mixture was quenched by the addition of saturated aq NH4CI solution (10 mL). Water (150 mL) and EtOAc (150 mL) were added, and the layers were separated. The aq layer was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were washed with brine, dried (MgS04) and evaporated in vacuo. The crude residue was purified by flash column chromatography (Si02, 80 g, 0-60% EtOAc in isohexane, gradient elution) to afford 4-(2-(4-nitronaphthalen-1 -yloxy)propan-2-yl)pyridin-2-amine (41 ) (282 mg, 8%) as a red oil: m/z 324 (M+H)+ (ES+).
A solution of (41 ) (282 mg, 0.87 mmol) in MeOH (45 mL) was passed through a Thales H-cube (1 .0 mL.min"1, 30°C, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo to afford 4-(2-(4-aminonaphthalen-1 -yloxy)propan-2-yl)pyridin-2-amine (42) (253 mg, 89%) as a brown foam: m/z 294 (M+H)+ (ES+).
To a solution of (5) (447 mg, 1.75 mmol) in DCM (40 mL) was added saturated aq NaHC03 solution (27 mL). The mixture was stirred vigorously and was cooled to 0°C and then trichloromethylchloroformate (0.63 mL, 5.25 mmol) was added in one portion. The resulting mixture was stirred at 0°C for 1 .5 hr. The biphasic mixture was separated and the organic layer was dried (MgS04) and evaporated in vacuo. The oily residue which was taken up in THF (15 mL) and was added to a solution of (42) (253 mg, 0.86 mmol) in THF (2.0 mL). Neat DIPEA (451 μί, 2.59 mmol) was added and the reaction mixture was stirred at RT for 2 hr. Water (30 mL) and EtOAc (20 mL) were added and the layers were separated. The aq layer was extracted with EtOAc (3 x 15 mL) and the combined organic layers were washed with brine (40 mL), dried (MgS04), and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 40 g, 0-10% MeOH in DCM, gradient elution) to afford the title compound, Intermediate H, (249 mg, 51 %) as a purple amorphous solid: m/z 549 (M+H)+ (ES+).
Example 45: W-(4-(2-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)-2-methylpropyl)pyridin-2-yl)-2-methoxyacetamide:
Intermediate H
Figure imgf000094_0001
Methoxyacetyl chloride (28 μί, 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 μΙ_, 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 NH3 (1 % in MeOH, 1 .5 mL) was added and the mixture was stirred for 30 min and was then evaporated in vacuo. The residue was subjected to SCX capture and release then purified three times by column chromatography (Si02, 12 g, 0-7% MeOH in DCM, gradient elution; Ci8, 12 g, 0-100% MeCN in water, gradient elution and Si02, 12 g, 0-65% EtOAc in Et20, gradient elution) to afford the title compound, Example 45, as a white solid (18 mg, 24%): m/z 621 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9H, s), 1 .39 (6H, s), 2.39 (3H, s), 3.22 (3H, s), 3.80 (1 H, d), 4.16 (1 H, d), 5.27 (1 H, s), 6.41 (1 H, s), 7.26 (1 H, dd), 7.37 (2H, m), 7.46 (2H, m), 7.56 (1 H, d), 7.60 (2H, overlapping m), 7.76 (1 H, br s), 7.95 (1 H, m), 8.01 (1 H, d), 8.09 (1 H, m), 8.22 (1 H, d), 8.94 (1 H, br s), 9.28 (1 H, br s).
Intermediate J: 1 -(4-(1 -(2-Aminopyridin-4-yl)propan-2-yloxy)naphthalen-1 -yl)-3-(3-ieri- butyl-1 -p-tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000095_0001
A solution of LDA (2.0 M in THF, 809 mL, 1 .62 mol) was added dropwise over 3 hr to a stirred solution of 2-chloropicoline (43) (59.1 mL, 674 mmol) in THF (500 mL) at -78°C. The reaction mixture was stirred for a further 15 min and then diethylcarbonate (106 mL, 876 mmol) was added in a single portion. After 10 min the reaction mixture was allowed to warm to 0°C, was stirred at this temperature for 20 min and then a saturated aq solution of NH4CI (800 mL) was added. The mixture was extracted with ether and the organic phase was washed with water, dried (MgS04), and evaporated in vacuo to give a dark oil, (~200g) which was purified in three batches by flash column chromatography (Si02, 330 g, 5-20% EtOAc in isohexane, gradient elution) to give ethyl 2-(2-chloropyridin-4-yl)acetate (44) (72 g, 51 %): m/z 200 (M+H)+ (ES+)
A mixture of (44) (15.0 g, 75.0 mmol), ie/f-butylcarbamate (26.4 g, 225 mmol), Pd2(dba)3 (1 .719 g, 1 .88 mmol), caesium carbonate (36.7 g, 1 13 mmol) and Xantphos® (2.17 g, 3.76 mmol) in THF (100 mL) was purged with nitrogen and was then stirred at 65°C for 8 hr. The mixture was cooled to RT and was diluted with water and extracted with ether. The ether extracts were combined and washed with water and brine and then dried (MgS04), and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 330g, 5-20% EtOAc in isohexane, gradient elution) then subjected to SCX capture and release to provide ethyl 2-(2- (fe/f-butoxycarbonylamino)pyridin-4-yl)acetate (45) (12.0g, 51 %): m/z 281 (M+H)+ (ES+).
A solution of methyllithium (1 .6 M in diethyl ether, 17.4 mL, 27.9 mmol) was added dropwise over 12 min to a stirred solution of (45) (1 .56 g, 5.58 mmol) in THF (140 mL) under nitrogen at - 78°C. After 3 hr isopropanol (5.0 mL) was added and the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic extracts were washed with brine then dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 80g, 0-80% EtOAc in isohexane, gradient elution) to afford fe/f-butyl 4-(2-oxopropyl)pyridin-2-ylcarbamate (46) (300 mg, 21 %) as a white solid: m/z 251.0 (M+H)+ (ES+).
To a stirred solution of (46) (300 mg, 1 .20 mmol) in methanol (12 mL) at 0°C, under nitrogen, was added sodium borohydride (45.3 mg, 1 .20 mmol). After 10 min the reaction mixture was warmed to RT and stirring continued for 75 min. The mixture was evaporated in vacuo and the residue was taken up into EtOAc and washed with aq NaHC03 solution. The aqueous layer was extracted twice with EtOAc and the combined organic extracts were washed with brine, then dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, 10-80% EtOAc in isohexane, gradient elution) to afford ie f-butyl 4-(2-hydroxypropyl)pyridin-2-ylcarbamate (47) (262 mg, 85%) as a white powder; m/z 253.0 (M+H)+ (ES+).
Sodium hydride (1 19 mg, 2.97 mmol) was added to a stirred solution of (47) (250 mg, 0.991 mmol) in DMF (6.0 mL) at 0°C, under nitrogen and after 45 min a solution of 1 -fluoro-4- nitronaphthalene (14) (189 mg, 0.991 mmol) in DMF (6.0 mL) was added dropwise, over 2 min. The resulting dark-brown reaction mixture was stirred at 0°C for 5 min, and was then warmed to RT. After 70 min, a saturated aq solution of NH4CI (3.0 mL) was added and the mixture was partitioned between water and EtOAc. The aq layer was extracted twice with EtOAc and the combined organic extracts were washed with brine, dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 40 g; 0-70% EtOAc in isohexane, gradient elution) to afford ie f-butyl 4-(2-(4-nitronaphthalen-1 -yloxy)propyl)pyridin-2- ylcarbamate (48) (293 mg, 65%) as an orange foam: m/z 424.0 (M+H)+ (ES+).
A solution of (48) (271 mg, 0.614 mmol) in MeOH (30 mL) was passed through a Thales H- cube (1 .0 mL.min"1, 30°C, 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo to afford ie/f-butyl 4-(2-(4-aminonaphthalen-1 -yloxy)propyl)pyridin-2- ylcarbamate (49) (241 mg, 100%) as a purple foam: m/z 394.0 (M+H)+ (ES+).
A solution of (5) (212 mg, 0.923 mmol) in DCM (1 mL) was added to a stirred solution of CDI (150 mg, 0.923 mmol) in DCM (1 mL), under nitrogen at RT over 5 min. After 1 .5 hr a solution of (49) (242 mg, 0.615 mmol) in DCM (2 mL) was added and stirring was continued at RT for 16 hr. 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 (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford ie f-butyl 4-(2-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen
-1 -yloxy)propyl)pyridin-2-ylcarbamate (50) (163 mg, 40%) as a purple foam: m/z 649 (M+H)+ (ES+).
To a stirred solution of the ie/f-butyl carbamate (50) (158 mg, 0.244 mmol) in DCM (4.0 mL) at 0°C under nitrogen was added TFA (2.0 mL). After 5 min the reaction mixture was warmed to RT and stirred for a further 2 hr. The mixture was evaporated in vacuo and the residue was subjected to SCX capture and release to afford the title compound, Intermediate J, (138 mg, >100%): m/z 549 (M+H)+ (ES+).
Example 46: W-(4-(2-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)propyl)pyridin-2-yl)-2-methoxyacetamide:
Intermediate J
Methoxyacetyl chloride (17 μί, 0.18 mmol) was added dropwise to a stirred solution of Intermediate J (40 mg, 0.073 mmol) and DIPEA (38 μΙ_, 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 NH3 (1 % in MeOH, 3 mL) was added and stirring continued for 1 hr. The reaction mixture was evaporated in vacuo and the residue was subjected to SCX capture and release and was then purified by flash column chromatography (Si02, 12 g, 0-5% MeOH in DCM, gradient elution) to give the title compound, Example 46, (5.6 mg, 12%): m/z 621 (M+H)+ (ES+). 1H NMR (400 MHz, CDCI3) δ: 1 .31 (9H, s), 1 .45 (3H, d), 2.22 (3H, s), 3.06 (1 H, dd), 3.20 (1 H, dd), 3.47 (3H, s), 3.95 (2H, s), 4.86 (1 H, m), 6.42 (1 H, s), 6.50 (1 H, br s), 6.56 (1 H, br s), 6.71 (1 H, d), 6.89 (2H, br d), 6.97 (2H, br d), 7.00 (1 H, dd) 7.31 (1 H, d), 7.49 (2H, m), 7.81 (1 H, br m), 8.17 (1 H, d), 8.19 (1 H, br s), 8.26 (1 H, m), 8.83 (1 H, br s). Intermediate K: 1 -(4-(2-(2-Aminopyridin-4-yl)propoxy)naphthalen-1 -yl)-3-(3-ieri-butyl-1 -p- tolyl-1 H-pyrazol-5-yl)urea
Figure imgf000098_0001
To a stirred solution of ethyl 2-(2-chloropyridin-4-yl)acetate (44) (2.5 g, 12.52 mmol) in THF (25 mL), under nitrogen at -78 °C was added a solution of KHMDS (0.5M in toluene, 26.3 mL, 13.2 mmol). The mixture was warmed to RT for 10 min, then re-cooled to -78 °C and methyl iodide (0.820 mL, 13.15 mmol) added in a single portion and the mixture allowed to warm to RT. Saturated aq. NH4CI solution was added and the mixture was diluted with ether. The organic layer was washed with water and brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 100g, 5-10% EtOAc in isohexane, gradient elution) to afford ethyl 2-(2-chloropyridin-4-yl)propanoate (51 ) (1 .57 g, 56%): m/z 214 (M+H)+ (ES+).
A mixture of (51 ) (1 .55 g, 7.25 mmol), ie f-butylcarbamate (2.55 g, 21.76 mmol), Pd2dba3 (0.166 g, 0.181 mmol), caesium carbonate (3.55 g, 10.88 mmol) and Xantphos (0.210 g, 0.363 mmol) in THF (10 mL) was purged with nitrogen and heated at 65°C for 48 hr. The mixture was then cooled to RT, diluted with water and extracted with ether. The ether layer was washed with water and brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 100g, 5-10% EtOAc in isohexane, gradient elution) to afford ethyl 2-(2-(ie f-butoxycarbonylamino)pyridin-4-yl)propanoate (52) (1 .35 g, 61 %): m/z 295 (M+H)+ (ES+)
A solution of DIBAL (1 M in DCM, 13.8 mL, 13.8 mmol) was added dropwise over 10 min to a stirred solution of the ester (52) (1 .35 g, 4.59 mmol) in THF (25 mL) under nitrogen at -78 °C. The reaction mixture was warmed to RT and then re-cooled to -78 °C and a second aliquot of DIBAL (1 M in DCM, 4.5 mL, 4.5 mmol) was added. The reaction mixture was allowed to warm to RT, then cooled to 0°C and water (5 mL) and then MgS04 were added. The mixture was diluted with DCM and filtered to remove the solids. The filter cake was washed with EtOAc, MeOH and DCM and the combined filtrate and washings were evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 40g, 25-50% EtOAc in isohexane, gradient elution) to afford fe/f-butyl 4-(1 -hydroxypropan-2-yl)pyridin-2-ylcarbamate (53) (0.62 g, 50%): m/z 253 (M+H)+ (ES+).
To a solution of the alcohol (53) (0.62 g, 2.46 mmol) in DMF (4.0 mL) was added sodium hydride (60% dispersion in mineral oil, 0.246 g, 6.14 mmol) in a single portion and the mixture sonicated under a flow of nitrogen and then stirred at RT for 30 min. The resulting yellow suspension was cooled to 0°C and a solution of 1-fluoro-4-nitronaphthalene (14) (470 mg, 2.46 mmol) in DMF (2.0 mL) was added over 10 min. The reaction mixture was warmed to RT and glacial acetic (1 .0 mL) was added. The mixture was poured onto saturated aq NaHC03 solution and extracted with EtOAc. The organic layer was washed with saturated aq Na2C03, solution, three times with water and twice with brine then dried (MgS04) and evaporated in vacuo to give a yellow solid. The solid was suspended in MeOH (20 mL) and sonicated and the insoluble residue was collected by filtration and was washed with MeOH (10 mL) and then ether to afford ie f-butyl 4-(1 -(4-nitronaphthalen-1 -yloxy)propan-2-yl)pyridin-2-ylcarbamate (54) as an off white solid (0.73 g, 67%): m/z 424 (M+H)+ (ES+). A solution of the nitroarene (54) (0.61 g, 1 .441 mmol) in a mixture of MeOH (20.0 mL), AcOH (5.0 mL) and EtOAc (10.0 mL) was passed through a Thales H-Cube (1 .0 mL.min"1, 45°C, 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode). The solvent was evaporated in vacuo and the residue was partitioned between saturated aq NaHC03 solution and EtOAc. The organic layer was washed with water and brine and then dried and evaporated in vacuo to furnish ie f-butyl 4-(1 -(4-aminonaphthalen-1 -yloxy)propan-2-yl)pyridin-2-ylcarbamate (55) (610 mg, 97%): m/z 394 (M+H)+ (ES+).
A solution of (5) 612 mg, 2.67 mmol) in DCM (2.0 mL) was added dropwise over 1 .5 hr to a suspension of CDI (433 mg, 2.67 mmol) in DCM (2.0 mL) under nitrogen and the mixtre was stirred at RT for 1 hr. A solution of the amine (55) (700 mg, 1 .78 mmol) in DCM (4.0 mL) was added in a single portion and the reaction mixture was stirred for 16 hr, during which time a precipitate formed. The mixture was taken up in DCM (10 mL) and was purified by flash column chromatography (Si02, 80g, 0-20% EtOAc in isohexane, gradient elution) to afford ie/f-butyl 4- (1 -(4-(3-(3-fe/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propan-2-yl)pyridin-2- ylcarbamate (56) (590 mg, 50%): m/z 649 (M+H)+ (ES+)
To a suspension of the ie/f-butyl carbamate (56) (0.57 g, 0.88 mmol) in DCM (10.0 mL) was added TFA (5.0 mL) and the resulting dark green solution stirred at RT for 1 hr. The mixture was evaporated in vacuo and the residue was dissolved in MeOH (10.0 mL) and subjected to SCX capture and release to afford the title compound, Intermediate K, as a red oil (488 mg, 98%): m/z 549 (M+H)+ (ES+).
Example 47: Λ/-(4-(1 -(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)propan-2-yl)pyridin-2-yl)-2-methoxyacetamide:
Intermediate K
Figure imgf000100_0001
To a stirred solution of Intermediate K (58 mg, 0.106 mmol) in DCM (2.0 mL) was added methoxyacetyl chloride (9.7 μί, 0.106 mmol) followed by DIPEA (18.4 μί, 0.106 mmol) and the mixture stirred at RT for 1 hr. A solution of NH3 (1 % in MeOH, 3.0 mL) was added and the mixture was stirred for 30 min and was then evaporated in vacuo. The residue was subjected to SCX capture and release and the product was triturated with MeCN (5.0 mL) and was washed with MeCN (5.0 mL) and then ether (5.0 mL) to afford the title compound (Example 47) as a white solid (32 mg, 48%): m/z 621 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 1 .42 (3H, d), 2.39 (3H, s), 3.38 (3H, s), 3.40 (1 H, m), 4.07 (2H, s), 4.21 -4.30 (2H, overlapping m), 6.35 (1 H, s), 6.95 (1 H, d), 7.22 (1 H, dd), 7.35 (2H, d), 7.40-7.47 (3H, overlapping m), 7.54 (1 H, m), 7.60 (1 H, d), 7.86 (1 H, d), 8.07 (1 H, d), 8.20 (1 H, br s), 8.25 (1 H, d), 8.55 (1 H, br s), 8.75 (1 H, d), 9.94 (1 H, br s).
Intermediate L: 1 -(4-(2-(2-aminopyridin-4-yl)-2-methylpropoxy)naphthalen-1 -yl)-3-(3-ferf- butyl-1 -p-tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000100_0002
To a stirred solution of ethyl 2-(2-chloropyridin-4-yl)acetate (44) (3.47 g, 17.4 mmol) in THF (40 mL), under nitrogen at -78°C was added a solution of KHMDS (36.5 mL, 0.5M in toluene, 18.25 mmol) in a single portion The mixture was warmed to RT for 10 min and then re-cooled to -78 °C, and treated with methyl iodide (1 .14 mL, 18.3 mmol). The mixture was warmed to RT during which time a precipitated was thrown down. The mixture was cooled to -78 °C and a further aliquot of the KHMDS solution (36.5 mL, 0.5M in toluene, 18.25 mmol) was added. The mixture was warmed to RT for 10 min and the suspension then re-cooled to -78°C, and a second aliquot of methyl iodide (1 .1 mL, 18.3 mmol) was added. The mixture was warmed to RT and sodium hydride (0.730 g, 18.25 mmol) was added and the mixture stirred at this temperature for 1 hr and then a third aliquot of methyl iodide (1 .1 mL, 18 3mmol) was added. After 1 hr, a saturated aq solution of NH4CI was added and the mixture was extracted with ether. The combined organic layers were washed with water and brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 100g, 5-10% EtOAc in isohexane, gradient elution) to afford ethyl 2-(2-chloropyridin-4-yl)-2-methylpropanoate (57) (2.81 g, 67%): m/z 228 (M+H)+ (ES+).
A mixture of (57) (2.80 g, 12.3 mmol), ie/f-butylcarbamate (4.32 g, 36.9 mmol), Pd2(dba)3 (281 mg, 0.307 mmol), Xantphos (355 mg, 0.615 mmol) and caesium carbonate (6.01 g, 18.5 mmol) in THF (10.0 mL) was purged with nitrogen and then stirred at 65°C for 72 hr. The mixture was cooled to RT and was diluted with water and extracted with ether. The organic layer was washed with water and brine and was then dried, and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 120g, 5-8% EtOAc in isohexane, gradient elution) to give ethyl 2-(2-(ie f-butoxycarbonylamino)pyridin-4-yl)acetate (58) (1 .47 g, 37%): m/z 309 (M+H)+ (ES+).
To a stirred solution of the ester (58) (1 .43 g, 4.64 mmol) in THF (25 mL) at -78°C under nitrogen was added a solution of DIBAL (18.5 mL, 1 M in DCM, 18.5 mmol) dropwise over 10 min. The reaction mixture was warmed to RT then cooled to 0 °C and water (5.0 mL) was added, followed by MgS04. The mixture was diluted with DCM and filtered and the filter cake was washed consecutively with EtOAc, MeOH and DCM. The filtrate and washings were combined, and evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 40 g, 25-50% EtOAc in isohexane, gradient elution) to yield ie f-butyl 4- (1 -hydroxy-2-methylpropan-2-yl)pyridin-2-ylcarbamate (59) (1 .13 g, 86%): m/z 267 (M+H)+ (ES+).
To a stirred solution of the alcohol (59) (1 .1 1 g, 4.17 mmol) in DMF (10.0 mL) at 0°C under nitrogen was added sodium hydride (350 mg, 8.75 mmol) in a single portion. The mixture was warmed to RT for 30 min and was then sonicated, flushed with nitrogen and re-cooled to 0°C. A solution of 1 -fluoro-4-nitronaphthalene (14) (797 mg, 4.17 mmol) in DMF (4.0 mL) was added over 5 min and the reaction mixture allowed to warm to RT and after 30 min glacial acetic acid (1 .0 mL) was added. The reaction mixture was poured onto saturated aq NaHC03 solution and extracted twice with EtOAc. The combined organic extracts were washed three times with water and with brine and then dried (MgS04), and evaporated in vacuo. The residue was triturated from EtOAc and washed with ether (20 mL) to afford fe/f-butyl 4-(2-methyl-1 -(4- nitronaphthalen-1 -yloxy)propan-2-yl)pyridin-2-ylcarbamate (60) as a yellow solid (1 .23 g, 64 %): m/z 438 (M+H)+ (ES+). A solution of the nitroarene (60) (1 .15 g, 2.63 mmol) in a mixture of MeOH (40 mL), AcOH (10 mL) and DCM (20 mL) was passed through a Thales H-cube (1 .0 mL.min"1, 45°C, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The solvent was evaporated in vacuo and the residue subjected to SCX capture and release to furnish ie f-butyl 4-(1 -(4-aminonaphthalen-1 -yloxy)-2- methylpropan-2-yl)pyridin-2-ylcarbamate (61 ) (1 .15 g, 84%): m/z 408 (M+H)+ (ES+).
A solution of (5) (760 mg, 3.31 mmol) in DCM (2.0 mL) was added dropwise over 1 .5 hr to a suspension of CDI (537 mg, 3.31 mmol) in DCM (2.0 mL) under nitrogen and the solution was stirred at RT for 1 hr. A solution of the naphthylamine (61 ) (1 .00 g, 2.21 mmol) in DCM (4.0 mL) was added in a single portion and the solution was stirred for 16 hr, during which time a precipitate formed. The reaction mixture was taken up in DCM (10 mL) and purified by flash column chromatography (Si02, 80 g, 20-80% EtOAc in isohexane, gradient elution) to afford ie/f-butyl 4-(1 -(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yl oxy)-2-methylpropan-2-yl)pyridin-2-ylcarbamate (62) (780 mg, 52%): m/z 663 (M+H)+ (ES+) To a suspension of (62) (780 mg, 1.18 mmol) in DCM (10 mL) was added TFA (8.0 mL) and the resulting dark green solution stirred at RT for 2 hr. The mixture was evaporated in vacuo and the residue was taken up in MeOH (10 mL) and subjected to SCX capture and release to afford the title compound, Intermediate L, (690 mg, 100%): m/z 563 (M+H)+ (ES+). Example 48: Λ/-(4-(1 -(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 -pyrazol-5-yl)ureido)naphthalen-1 -yloxy)- 2-methylpropan-2-yl)pyridin-2-yl)-2-methoxyacetamide:
Intermediate L
Figure imgf000102_0001
To a solution of Intermediate L (52 mg, 0.092 mmol) in DCM (2.0 mL) was added methoxyacetyl chloride (8.5 μΙ_, 0.092 mmol) followed by DIPEA (16. μΙ_, 0.092 mmol) and the mixture was stirred at RT for 1 hr. A solution of NH3 (1 % in MeOH, 3.0 mL) was added and the mixture was stirred for 30 min and was then evaporated in vacuo. The residue was purified by flash column chromatography (Si02,12g, 0-100% EtOAc in isohexane, gradient elution) to afford the title compound, Example 48, (32 mg, 53%): m/z 635 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-de) δ 1 .27 (9H, s), 1.50 (6H, s), 2.39 (3H, s), 3.37 (3H, s), 4.06 (2H, s), 4.19 (2H, s), 6.35 (1 H, s), 6.95 (1 H, d), 7.30 (1 H, dd), 7.34 (2H, m), 7.43 (2H, m), 7.45 (1 H, m), 7.53 (1 H, m), 7.61 (1 H, d), 7.87 (1 H, d), 8.02 (1 H, dd), 8.25 (1 H, d), 8.34 (1 H, br s) 8.54 (1 H, br s), 8.75 (1 H, br s), 9.90 (1 H, br s).
Intermediate M: W-(4-((4-aminonaphthalen-1 -yloxy)methyl)pyridin-2-yl)-2-methoxy acetamide.
Figure imgf000103_0001
R = N02; (63)
(3) Fe, AcOH
R = NH2; Intermediate M
Methoxyacetyl chloride (24.2 mL, 264 mmol) was added dropwise over 10 min to a stirred suspension of the amine (3) (60.0 g, 203 mmol) in a mixture of DCM (300 mL), THF (450 mL) and DIPEA (53.1 mL, 305 mmol) under nitrogen at -5°C. After 10 min the reaction mixture was allowed to warm to RT during which time a dark solution formed. After 30 min a solution of NH3 in MeOH (7M, 30 mL) was added and stirring continued for 1 hr during which time a precipitate formed. The suspension was evaporated in vacuo and the residue was triturated with water (500 mL). The precipitate was collected by filtration, and washed with water (300 mL) and diethyl ether (500 mL) and was then dried in vacuo at 60°C to furnish 2-methoxy-/V-(4-((4- nitronaphthalen-1 -yloxy)methyl)pyridin-2-yl)acetamide (63) as a yellow solid (68 g, 88%): m/z 368 (M+H)+ (ES+).
A suspension of the nitroarene (63) (30.0 g, 82.0 mmol) and iron powder (22.8 g, 408 mmol) in AcOH (300 mL) was heated at 50°C for 1 .5 hr, and was then cooled to RT. Solid sodium carbonate was added portionwise to the reaction mixture until effervescence was no longer observed. The mixture was extracted with ethyl acetate (2 x 700 mL) and the combined organic extracts were washed with saturated aqueous sodium carbonate and with brine and then dried (MgS04). Evaporation in vacuo furnished the title compound, Intermediate M, as a brown solid (25.0 g, 77%): m/z 338 (M+H)+ (ES+).
Intermediate N: 3-ferf-Butyl-1 -(4-((ferf-butyldimethylsilyloxy)methyl)phenyl)-1 H- pyrazol-5-amine.
Figure imgf000103_0002
Intermediate N To a suspension of 4-hydrazinobenzoic acid (64) (1 .00 g, 5.30 mmol) in EtOH (20 mL) containing cone hydrochloric acid (0.5 mL) was added pivaloylacetonitrile (0.730 g, 5.83 mmol) and the mixture heated to reflux for 5 hr. The reaction mixture was stirred at RT for 64 hr and the solvent evaporated in vacuo. The residue was suspended in THF and an aqueous solution of LiOH (1 M, 30 mL, 30 mmol) was added and the mixture was stirred at RT for 2 hr. The THF was removed by evaporation in vacuo and the resulting aqueous solution was diluted with AcOH and subjected to SCX capture and release. Fractions containing the desired compound were combined and evaporated in vacuo. The residue was dissolved in DCM and was dried (MgS04) and evaporated in vacuo. Co-evaporation with acetonitrile in vacuo furnished 4-(5- amino-3-tert-butyl-1 /-/-pyrazol-1 -yl)benzoic acid (65) as an orange solid (1 .50 g, >100 % recovery): m/z 260 (M+H)+ (ES+); 258 (M-H)" (ES").
To a stirred solution of the benzoic acid (65) (1 .50 g, 5.7 mmol) in THF at 0°C was added a solution of borane (2M in THF, 17.4 mL, 34.8 mmol). The reaction mixture was warmed to RT and was stirred for 16 hr. An additional aliquot of the BH3 solution (2M in THF, 8.0 mL, mmole) was added and stirring continued for a further 3 hr. The reaction mixture was cooled to 0°C and 1 M hydrochloric acid was added to quench the reaction. The solution was neutralized and extracted into EtOAc. The extracts were washed with aq Na2C03 solution and brine and then dried and evaporated in vacuo to afford (4-(5-amino-3-ie f-butyl-1 /-/-pyrazol-1 - yl)phenyl)methanol (66) (0.64 g, 45 %).
To a stirred solution of the benzyl alcohol (66) (640 mg, 2.61 mmol) and imidazole (266 mg, 3.91 mmol) in DMF (5.0 mL) at RT was added TBDMS-CI (590 mg, 3.91 mmol). After 3 hr the reaction mixture was diluted with water and extracted with Et20. The organic layer was washed with brine, dried (MgS04) and then evaporated in vacuo to afford the title compound, Intermediate N, (875 mg, 89%): m/z 360 (M+H)+ (ES+).
Example 49: W-(4-((4-(3-(3-ferf-Butyl-1 -(4-(hydroxymethyl)phenyl)-1 H-pyrazol-5-yl) ureido)naphthalen-1 -yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide:
Intermediate M
Figure imgf000104_0001
The pyrazole amine Intermediate N (100 mg, 0.278 mmol) was added portionwise to a stirred suspension of CDI (45.1 mg, 0.278 mmol) in DCM (0.5 mL) over 1 hr and the mixture was stirred at RT for 16 hr. A solution of, Intermediate M, (47 mg, 0.139 mmol) in DCM (0.5 mL) was added dropwise over 2 hr and after a further 2hr the mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12g, 30-70% EtOAc in isohexane, gradient elution) to yield /V-(4-((4-(3-(3-ie/f-butyl-1 -(4-((ie/f-butyl dimethylsilyloxy)methyl)phenyl)-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-yl)- 2-methoxyacetamide (67) (42 mg, 20 %): m/z 723 (M+H)+ (ES+).
To a solution of the silyl ether (67) (42 mg, 58 μηηοΙ) in THF under nitrogen at -5°C was added a solution of TBAF (1 M in THF, 58 μΙ_, 58 μηηοΙ). The mixture was warmed to RT and a second aliquot of TBAF (1 M in THF, 58 μΙ_, 58 μηηοΙ) was added. After 1 hr the mixture was diluted with EtOAc and washed with saturated aq ammonium chloride. The aq layer was extracted with EtOAc and the combined organic layers were washed with water and brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, 2- 6% MeOH in DCM, gradient elution) to provide the title compound, Example 49, (23 mg, 63%): m/z 609 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9 H, s), 3.37 (3H, s) 4.08 (2H, s), 4.59 (2H, d), 5.32 (1 H, t), 5.39 (2H, s), 6.36 (1 H, s), 7.02 (1 H, d), 7.29 (1 H, dd), 7.48 (2H, m), 7.52 (2H, m), 7.54-7.63 (3H, overlapping m), 7.93 (1 H, m), 8.30-8.37 (3H, overlapping m), 8.63 (1 H, s), 8.81 (1 H, s), 10.02 (1 H, br s).
Intermediate P: 1 -(4-((2-Aminopyrimidin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ferf-butyl-1 - p-tolyl-1 H-pyrazol-5-yl)urea.
Figure imgf000105_0001
Hydrochloric acid (2M, 207 mL, 414 mmol) was added to 4-(dimethoxymethyl)pyrimidin-2- amine (68) (WO 2007/096764) (14.0 g, 83 mmol) and the mixture heated at 48°C for 16 hr. The mixture was cooled to RT and was neutralized with solid Na2C03 which produced a precipitate at pH 7. The suspension was diluted with EtOAc (300 mL) and the solid removed by filtration. The organic layer was separated and the aqueous layer was extracted with 1 % MeOH in THF (4 x 300 mL). The organics were combined, dried and then evaporated in vacuo. The residue (ca. 4.0 g) was suspended in a mixture of MeOH (100 mL), THF (100 mL) and water (100 mL) and treated with NaBH4 (1 .57 g, 41 .4 mmol). After stirring for 1 hr a solution of NaOH (1 M, 20 mL) was added and the mixture was allowed to stand at RT for 48 hr. The solvents were evaporated to give a yellow solid which was partitioned between water (50 mL) and EtOAc (100 mL). The solid which formed at the interface was removed by filtration and the aq layer was extracted with THF (3 x 300 mL) then dried and evaporated to give a yellow solid. The material was suspended in THF (100 mL) and MeOH (50 mL) and absorbed onto silica gel (20 g) and subjected to column chromatography (80 g, 15% MeOH in DCM isocratic elution) to give (2- aminopyrimidin-4-yl)methanol (69) as an off-white solid (720 mg, 7%): m/z 126 (M+H)+ (ES+).
To a stirred mixture of (69) (700 mg, 3.92 mmol), 4-nitronaphthol (2) (741 mg, 3.92 mmol) and PPh3 (1 .23 g, 4.70 mmol) in THF (20 mL) under nitrogen at -50°C was added DIAD (996 μΙ_, 4.70 mmol) dropwise over 5 min. The mixture was allowed to warm to RT and stirred for 1 hr during which time a yellow precipitate formed. The suspension was stirred overnight and the volatiles were evaporated in vacuo. The residue was triturated from MeOH (50 mL) and the pale yellow solid collected by filtration and washed with diethyl ether (50 mL) to give 4-((4- nitronaphthalen-1 -yloxy)methyl)pyrimidin-2-amine (70) (1 .10 g, 93 %): m/z 297 (M+H)+ (ES+). A solution of the nitroarene (70) (1 .10 g, 3.71 mmol) in a a mixture of DCM (50 mL) and AcOH (40 mL) was passed through a Thales H-cube (1 .0 mL min"1, 55 mm, 10% Pt/C, 40°C, full hydrogen mode). LC-MS analysis of the resulting solution showed a mixture comprising of mainly starting material and ca. 20% product. The DCM was removed by evaporation in vacuo and the solution re-subjected to reduction using the same conditions at RT. The volatiles were evaporated in vacuo to give 4-((4-aminonaphthalen-1 -yloxy)methyl)pyrimidin-2-amine (71 ) (ca. 70% by LC-MS) as a purple solid (0.90 g, 64 % yield): m/z 267 (M+H)+ (ES+).
A solution of (5) (980 mg, 4.26 mmol) in DCM (4.0 mL) was added dropwise over 1 hr, to a suspension of CDI (690 mg, 4.26 mmol) in DCM (3.0 mL) and the mixture was stirred at RT for 2 hr. This solution was then added dropwise to a solution of the naphthylamine (71 ) (900 mg, 2.37 mmol) in DCM (10 mL), such that after each 1 .0 mL aliquot was added, the reaction was stirred for 1 hr. The reaction was quenched with MeOH (20 mL), and silica was added (20 g) and the volatiles were evaporated in vacuo. The residue was subjected to purification by column chromatography (100 g, 50 to 100% EtOAc in isohexane, gradient elution). The resulting product was triturated from DCM (20 mL) and the solid collected, and washed with diethyl ether (50 mL) to give the title compound, Intermediate P, as a purple solid (480 mg, 38 %): m/z 523 (M+H)+ (ES+).
Example 50; W-(4-((4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl) pyrimidin-2-yl)-2-methoxyacetamide:
Intermediate P
Figure imgf000106_0001
A suspension of Intermediate P (52 mg, 0.10 mmol) in DCM (1 .0 mL) and DMF (100 μΙ_) was treated with methoxyacetyl chloride (27 μΙ_, 0.30 mmol) followed by DIPEA (52 μΙ_, 0.30 mmol) and the mixture stirred overnight at RT. The volatiles were evaporated in vacuo and the residue suspended in a mixture of MeOH (2.0 mL) and AcOH (2.0 mL). The suspension was subjected to SCX capture and release under standard conditions. As only a low recovery of material was obtained the SCX cartridge was extracted with MeOH (50 mL) and the solvent evaporated, to give an off white solid. This was triturated from MeOH (1.0 mL) and diethyl ether (5.0 mL) to give the title compound, Example 50, as a white solid (12 mg, 19 %): m/z 594 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1 .27 (9H, s), 2.40 (3H, s), 3.34 (3H, s), 4.24 (2H, s), 5.34 (2H, s), 6.35 (1 H, s), 7.02 (1 H, d), 7.35 (2H, d), 7.44 (3H, m), 7.60 (3H, m), 7.95 (1 H, m), 8.36 (1 H, m), 8.59 (1 H, br s), 8.68 (1 H, d), 8.80 (1 H, br s), 10.44 (1 H, br s).
Intermediate Q: 1 -(4-(2-Aminopyridin-4-yloxy)naphthalen-1 -yl)-3-(3-ferf-butyl-1 -p-tolyl-1 H- pyraz
Figure imgf000107_0001
To a stirred solution of 2-chloro-4-fluoropyridine (1 .26 g, 9.58 mmol) and 4-amino-1 -naphthol hydrochloride (750 mg, 3.83 mmol) in NMP (40 mL), at -20°C, was added potassium tert- butoxide (1 .290 g, 1 1 .50 mmol). The reaction mixture was allowed to warm to RT and after 2.5 hr the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL then 2 x 80 mL). The combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and release and the solvent was removed in vacuo to give 4-(2-chloropyridin-4-yloxy)naphthalen-1 -amine (72) (1.02 g, 92%) as a brown solid: m/z 271 (M+H)+ (ES+). To a stirred solution of (72) (1 .02 g, 3.76 mmol) in THF (30 mL) at 0°C was added DMAP (0.034 g, 0.282 mmol) and di-ie/f-butyl dicarbonate (0.904 g, 4.14 mmol) and the reaction mixture stirred at 0°C for 30 min, and then at RT for 1 .5 hr. The mixture was cooled to 0°C, and a further aliquot of di-ie f-butyl dicarbonate (0.904 g, 4.14 mmol) was added and stirring continued at 0°C for 15 min and then at RT for 16 hr. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (75 mL), dried and evaporated in vacuo. The crude material was purified by flash column chromatography (Si02; 80 g, 0-40% EtOAc in isohexane, gradient elution) to give 4-(2-chloropyridin-4-yloxy)naphthalen-1 -/V,/V-di-ie/f-butylcarbamate (73) (892 mg, 48%) as a purple solid: m/z 471 (M+H)+ (ES+).
A mixture of the chloropyridine (73) (892 mg, 1.89 mmol), fe/f-butyl carbamate (666 mg, 5.68 mmol), caesium carbonate (926 mg, 2.84 mmol), Pd2(dba)3 (43 mg, 0.047 mmol) and XantPhos (55 mg, 0.095 mmol) was suspended in THF (10 mL). The reaction mixture was purged with nitrogen, and was then heated at reflux for 15 hr. The mixture was cooled to RT, was diluted with water (35 mL) and extracted with EtOAc (35 mL, 25 mL). The combined organic extracts were washed with brine (50 mL), dried and evaporated in vacuo. The crude material was purified by flash column chromatography (Si02; 80 g, 0-30% EtOAc in isohexane, gradient elution) to give ie f-butyl 4-(4-(,/V,/V-di-ie f-butylcarbamyl)naphthalen-1 -yloxy)pyridin-2- ylcarbamate (74) (289 mg, 28%) as a white solid: m/z 552 (M+H)+ (ES+).
To a stirred solution of the bis ie/f-butyl carbamate (74) (289 mg, 0.524 mmol) in DCM (8.0 mL), at 0°C, was added TFA (4.0 mL). The resulting mixture was stirred and allowed to warm to RT. After 5 hr, the volatiles were removed in vacuo and the residue was taken up in MeOH (5 mL) and subjected to SCX capture and release. The solvent was removed in vacuo to afford 4- (4-aminonaphthalen-1 -yloxy)pyridin-2-amine (75) (1 16 mg, 85%) as a brown-orange oil: m/z 252 (M+H)+ (ES+).
To a solution of (5) (206 mg, 0.900 mmol) in DCM (20 mL) was added a saturated aq. solution of NaHC03 (14 mL). The mixture was stirred vigorously, cooled to 0°C and trichloromethylchloroformate (0.326 mL, 2.70 mmol) was added in one portion. The reaction mixture was stirred vigorously at 0°C for a further 80 min. The layers were separated and the organic layer was dried, evaporated in vacuo and the resulting orange oil was dried further for 30 min under high vacuum. The resulting crude isocyanate was then taken up into THF (6.0 mL) and kept under nitrogen at 0°C. To a stirred solution of (75) (1 16 mg, 0.462 mmol) and DIPEA (241 μί, 1 .385 mmol) in THF (3.0 mL), at 0°C, was added an aliquot of the isocyanate solution prepared above (2.0 mL, 0.30 mmol) and the resulting mixture vigorously stirred and alllowed to warm to RT. Two additional aliquots of the isocyanate solution were added to the reaction mixture, the first after 1 .5 hr, (1 .0 mL, 0.15 mmol) and the second after 3.5 hr (0.50 mL, 0.075 mmol). After a further 20 hr water (30 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (50 mL) then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02; 12 g, 25-100% [5% MeOH in EtOAc] in isohexane, gradient elution) to furnish the title compound, Intermediate Q, (127 mg, 49%) as a brown oil: m/z 507 (M+H)+ (ES+).
Example 51 : N-(4-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)-2-(methylsulfonyl)acetamide: Intermediate Q
Figure imgf000109_0001
To a suspension of methanesulfonylacetic acid (40 mg, 0.29 mmol) in DCM (2.0 mL) under nitrogen was added 1 -chloro-/V,/V,2-trimethylpropenylamine (48 μί, 0.37 mmol), and the mixture was stirred at RT for 2 hr. The resulting mixture was added to a solution of Intermediate Q (37 mg, 0.07 mmol) and DIPEA (51 μΙ_, 0.29 mmol) in DCM (2.0 mL) and stirring continued at RT for 3 hr. The reaction mixture was treated with 1 % NH3 in MeOH (3.0 mL) for 45 min and was then evaporated in vacuo. The residue was subjected to SCX capture and release and was then purified by flash column chromatography (Si02, 12 g, 0-70% [5% MeOH in EtOAc] in isohexane, gradient elution) to afford the title compound, Example 51 , as a white powder (13 mg, 28%): m/z 627 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.39 (3H, s), 3.10 (3H, s), 4.36 (2H, s), 6.40 (1 H, s), 6.71 (1 H, dd), 7.33-7.38 (3H, overlapping m), 7.47 (2H, m), 7.56 (1 H, m), 7.65 (1 H, m), 7.69 (1 H, m), 7.85 (1 H, d), 7.96 (1 H, d), 8.1 1 (1 H, d), 8.22 (1 H, d), 8.91 (1 H, br s), 9.23 (1 H, br s), 10.96 (1 H, br s). Example 52: 4-(4-(3-(3-ieri-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyridin-2-ylurea:
Intermediate Q
Figure imgf000109_0002
xamp e
To a solution of Intermediate Q (50 mg, 0.099 mmol) in dry pyridine (1 .5 mL) at 0°C under nitrogen was added trichloroacetyl isocyanate (15 μί, 0.12 mmol) and after 30 min at 0°C the reaction mixture was warmed to RT. After 24 hr a further aliquot of trichloroacetyl isocyanate (29 μί, 0.25 mmol) was added and after 42 hr the reaction was quenched by addition of 1 % NH3 in MeOH (2.0 mL). After an additional 30 min the resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, [5% MeOH in EtOAc] in isohexane, 0-75%, gradient elution) to afford the title compound, Example 52 as a white solid (7 mg, 13%): Rl 2.21 min (Method 2); m/z 550 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-de) δ: 1.28 (9H, s), 2.40 (3H, s), 6.41 (1 H, s), 6.52 (1 H, dd), 6.95 (1 H, d), 7.31 (1 H, d), 7.37 (2H, d), 7.45-7.47 (2H, m), 7.54-7.61 (1 H, m), 7.62-7.67 (1 H, m), 7.83 (1 H, dd), 7.95 (1 H, d), 8.06 (1 H, d), 8.09 (1 H, d), 8.81 (1 H, s), 9.03 (1 H, s), 9.15 (1 H, s). Example 53: 1 -(3-(ferf-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)-3-(4-((2-(3-methyl)ureido) pyridin-4-yl)oxy)naphthalen-1 -yl)urea:
MeNCO
Intermediate Q
Figure imgf000110_0001
To a solution of Intermediate Q (50 mg, 0.099 mmol) in pyridine (1 .0 mL) was added methyl isocyanate (50 μΙ_, 0.806 mmol) and the mixture maintained at RT for 24 hr. Additional aliquots of methyl isocyanate (150 μΙ_, 0.26 mmol) and pyridine (0.5 mL) were added and the reaction mixture maintained at RT for 96 hr and then partitioned between DCM (30 mL) and saturated aq. NaHC03 (10 mL). The aqueous layer was separated and extracted with DCM (10 mL) and the combined organic extracts were dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, MeOH in DCM, 0-10%, gradient elution) to afford the title compound, Example 53 as a white solid (12 mg, 21 %): R' 5.24 min (Method 1 basic); m/z 564 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9H, s), 2.39 (3H, s), 2.65 (3H, d), 6.40 (1 H, s), 6.54 (1 H, dd), 6.87 (1 H, d), 7.31 (1 H, d), 7.37 (2H, d), 7.46 (2H, m), 7.58 (1 H, m), 7.64 (1 H, m), 7.81 (1 H, d), 7.88 (1 H, br s), 7.95 (1 H, d), 8.05 (1 H, d), 8.08 (1 H, d), 8.76 (1 H, s), 9.09 (1 H, s), 9.1 1 (1 H, s).
Example 54: 3-(4-((4-(3-(3-(ferf-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)ureido)naphthalen-1■ yl)oxy)pyridin-2-yl)-1 ,1 -dimethyl urea:
Intermediate Q
Figure imgf000110_0002
To a solution of Intermediate Q (50 mg, 0.099 mmol) and DIPEA (34 μί, 0.20 mmol) in dry pyridine (1 .5 mL) was added dimethylcarbamoyl chloride (18 μί, 0.20 mmol) and the reaction mixture maintained at RT for 64 hr. The reaction was quenched by the addition of 1 % NH3 in MeOH (2.0 mL) and after 30 min the resulting mixture was evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 12 g, MeOH in DCM, 0-5%, gradient elution; then Si02, 4 g, [5% MeOH in EtOAc] in isohexane, 50-90%, gradient elution) to afford the title compound, Example 54 as an off-white solid (5 mg, 8%): R' 5.15 min (Method 1 basic); m/z 578 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9H, s), 2.40 (3H, s), 2.86 (6H, s), 6.41 (1 H, s), 6.67 (1 H, br s), 7.32 (2H, d), 7.37 (2H, d), 7.47 (2H, d), 7.58 (1 H, t), 7.65 (1 H, t), 7.84 (1 H, d), 7.97 (1 H, d), 8.09-8.13 (2H, m), 8.82 (1 H, s), 9.00 (1 H, br s), 9.15 (1 H, s). Example 55: W-(4-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)morpholine-4-carboxamide:
Intermediate Q
Figure imgf000111_0001
To a solution of Intermediate Q (50 mg, 0.099 mmol) and DIPEA (52 μΙ_, 0.30 mmol) in dry pyridine (1.5 mL) under nitrogen at 0°C was added morpholine-4-carbonyl chloride (14 μΙ_, 0.12 mmol) dropwise The reaction mixture was maintained at 0°C for 15 min, was warmed to 40°C for 4 hr and was then left at RT for 20 hr. The reaction mixture was reheated to 40°C for 3 hr and was then quenched by the addition of 1 % NH3 in MeOH (2.0 mL). After 45 min the resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 12 g, [5% MeOH in EtOAc] in isohexane, 0-80%, gradient elution) to afford the title compound, Example 55 as a beige powder (16 mg, 25%): R' 2.18 min (Method 2); m/z 620 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9H, s), 2.40 (3H, s), 3.36 (4H, t), 3.53 (4H, t), 6.41 (1 H, s), 6.61 (1 H, dd), 7.31 (1 H, d), 7.34-7.41 (3H, m), 7.46 (2H, d), 7.55-7.59 (1 H, m), 7.63-7.68 (1 H, m), 7.84 (1 H, dd), 7.96 (1 H, d), 8.08 (1 H, d), 8.1 1 (1 H, d), 8.80 (1 H, s), 9.13 (1 H, s), 9.25 (1 H, s). Example 56: W-(4-((4-(3-(3-(ferf-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)ureido)naphthalen-1 - yl)oxy)pyridin-2-yl)-4-methylpiperazine-1 -carboxamide:
Intermediate Q
Figure imgf000111_0002
To a solution of Intermediate Q (70 mg, 0.138 mmol) and DIPEA (120 μΙ_, 0.691 mmol) in dry pyridine (1 .5 mL) was added 4-methylpiperazine-1 -carbonyl chloride hydrochloride (138 mg, 0.691 mmol) and the mixture maintained at RT for 64 hr. The reaction was quenched by the addition of 1 % NH3 in MeOH (2.0 mL) and after 30 min the resulting mixture was evaporated in vacuo and the residue was taken up into EtOAc. The organic solution was washed with water and brine and was dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, [7% NH3 in MeOH] in DCM, 0-5%, gradient elution) to afford the title compound, Example 56 as a pale brown solid (28 mg, 31 %): R' 5.15 min (Method 1 basic); m/z 633 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9H, s), 2.15 (3H, s), 2.23 (4H, t), 2.40 (3H, s), 3.37 (4H, t), 6.41 (1 H, s), 6.58 (1 H, dd), 6.95 (1 H, d), 7.31 (1 H, d), 7.38 (2H, d), 7.46 (2H, d), 7.57 (1 H, t), 7.65 (1 H, t), 7.84 (1 H, d), 7.95 (1 H, d), 8.07-8.1 1 (2H, m), 8.79 (1 H, s), 9.12 (1 H, s), 9.19 (1 H, s).
Example 57: W-(3-(lmidazol-1 -yl)propyl)-W'-4-(4-(3-(3-ferf-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-ylurea:
To a solution of Intermediate Q (1 .1 g, 2.2 mmol) and /V-methyl morpholine (290 μΙ_, 2.6 mmol) in THF (20 mL) at -78°C was added dropwise a solution of prop-1 -en-2-yl carbonochloridate (280 μΙ_, 2.6 mmol) in THF (10 mL) and on completion of the addition the mixture was warmed to RT. After 16 hr an additional aliquot of /V-methyl morpholine (290 μί, 2.6 mmol) was added, the reaction mixture was cooled to -78°C and a solution of prop-1 -en-2-yl carbonochloridate (280 μί, 2.6 mmol) in THF (5 mL) was added. The reaction mixture was maintained at RT for a further 2 hr and was then quenched by the addition of NH3 in MeOH (7 M, 4.0 mL). After 1 hr the resulting mixture was diluted with EtOAc (30 mL) and was washed with water (30 mL) and brine (30 mL) and then dried and evaporated in vacuo. The residue was triturated with ethyl acetate (20 mL) and was purified by flash column chromatography (Si02, EtOAc in DCM, 20- 50%, gradient elution) to afford prop-1 -en-2-yl 4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-ylcarbamate (76) as an off-white solid (0.60 g, 84% pure by HPLC, 40%) R' 2.78 min (Method 2); m/z 591 (M+H)+ (ES+); 589 (M-H)" (ES").
To a solution of (76) (50 mg, 85 μηηοΙ) and /V-methyl morpholine (1 .0 μί, 9 μηηοΙ) in THF (5.0mL) was added 3-(1 /-/-imidazol-1 -yl)propan-1 -amine (10.6 mg, 85 μηηοΙ) and the reaction mixture heated to 55°C for 16 hr. The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si02, 4 g, MeOH in DCM, 2-5%, gradient elution then Si02, 12 g, 4% [1 % NH3 in MeOH] in DCM, isocratic elution) to afford the title compound, Example 57, as a purple solid (9 mg, 16%): R' 5.37 min (Method 1 basic); m/z 658 (M+H)+ (ES+): 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 1 .85 (2H, m), 2.39 (3H, s), 3.06 (2H, m), 3.95 (2H, m), 6.40 (1 H, s), 6.56 (1 H, dd), 6.86 (1 H, t), 6.89 (1 H, d), 7.16 (1 H, t), 7.31 (1 H, d), 7.37 (2H, d), 7.46 (2H, d), 7.57 (1 H, m), 7.60 (1 H, t), 7.64 (1 H, m), 7.81 (1 H, d), 7.95 (1 H, d), 8.06-8.10 (3H, overlapping m), 8.77 (1 H, s), 9.07 (1 H, s), 9.12 (1 H, s).
Example 58: W-(4-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)-2-(2-methoxyacetamido)acetamide:
Figure imgf000113_0001
To a mixture of 2-(ie f-butoxycarbonylamino)acetic acid [Boc-Gly-OH] (415 mg, 2.37 mmol), PyBOP (1 .23 g, 2.37 mmol) and DIPEA (413 μΙ_, 2.37 mmol) in dry DMF (12 mL) at 0°C under nitrogen was added Intermediate Q (300 mg, 0.592 mmol) and the mixture warmed to 50°C for 16 hr. The resulting mixture was cooled to RT and was partitioned between EtOAc (60 mL) and saturated aq NaHC03 solution (80 mL). The aq layer was extracted with EtOAc (60 mL) and the combined organic extracts were washed with brine (80 mL), dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 40 g, EtOAc in isohexane, 0- 65%, gradient elution) to afford ie/f-butyl 2-(4-(4-(3-(3-fe/f-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-ylamino)-2-oxoethylcarbamate (77) as a purple solid (197 mg, 92% purity, 46%); R' 2.65 min (Method 2); m/z 664 (M+H)+ (ES+).
To a stirred solution of the carbamate (77) (187 mg, 92% pure, 0.259 mmol) in dry DCM (6.0 mL) 0°C under nitrogen was added TFA (2.0 mL) and the reaction mixture maintained at 0°C for 20 min and then warmed to RT for 3 hr. The resulting mixture was evaporated in vacuo and the residue was purified by SCX capture and release to afford 2-amino-/V-(4-(4-(3-(3-ie f-butyl- 1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)acetamide (87) as a brown solid (130 mg, 87%); Rl 1 .82 min (Method 2); m/z 564 (M+H)+ (ES+).
To a solution of (78) (35 mg, 62 μοΙ) and DIPEA (43.3 μΙ, 248 μπιοΙ) in dry THF (2.5 mL) under nitrogen at 0°C was added 2-methoxyacetyl chloride (17.0 μΙ, 186 μηηοΙ) and the reaction mixture maintained at 0°C for 15 min and then warmed to RT. After 1 .75 hr the reaction was quenched by the addition of a 1 % solution of NH3 in MeOH (2.0 mL) and the resulting mixture kept at RT for 1 hr and was then evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product so obtained was purified by flash column chromatography (Si02, 12 g, [5% MeOH in EtOAc] in isohexane, 25-100%, gradient elution) to afford the title compound, Example 58, as a beige solid (14 mg, 34%); R' 2.28 min (Method 2); m/z 636 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1 .28 (9H, s), 2.40 (3H, s), 3.30 (3H, s), 3.82 (2H, s), 3.90 (2H, d), 6.41 (1 H, s), 6.72 (1 H, dd), 7.33 (1 H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (2H, m), 7.64 (1 H, m), 7.83 (1 H, dd), 7.92 (1 H, t), 7.96 (1 H, d), 8.09 (1 H, d), 8.20 (1 H, d), 8.82 (1 H, br s), 9.14 (1 H, br s), 10.59 (1 H, br s).
Example 59: 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 :
Intermediate F
Figure imgf000114_0001
To a solution of Intermediate F (50 mg, 0.094 mmol) in pyridine (1.0 mL) was added trichloroacetylisocyanate (12 μί, 0.103 mmol) and the mixture was stirred at RT until judged to be complete by LC-MS. The solvent was evaporated in vacuo and the resulting residue was subjected to SCX capture and release and then triturated from DCM (10 mL) to give the title compound, Example 59, as an off white solid (25 mg, 44%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-de) δ: 1 .26 (9 H, s), 2.38 (3 H, s), 3.12 (2 H, t), 4.35 (2 H, t), 6.34 (1 H, s), 6.94-6.99 (2 H, m), 7.19 (1 H, dd), 7.33-7.35 (2 H, m), 7.41 -7.50 (5 H, m), 7.52-7.56 (1 H, m), 7.60 (1 H, d), 7.87 (1 H, d), 8.09-8.13 (2 H, m), 8.54 (1 H, s), 8.75 (1 H, s), 9.08 (1 H, s). Example 60: (/?)-/V-(4-(4-(3-(3-ferf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1 -carboxamide:
Figure imgf000115_0001
To a stirred suspension of 2-aminopyridin-4-ol (53.9 g, 489 mmol) in MeCN (500 mL) was added DBU (102 mL, 678 mmol) dropwise over 30 min. The resulting solution was maintained at RT for 30 min and was then treated dropwise with a solution of 1 -fluoro-4-nitronaphthalene (14) (72.0 g, 377 mmol) in acetonitrile (400 mL) over 50 min. The reaction mixture was stirred overnight at RT and was then heated to 50°C for 2 hr. The heating was removed and the stirred mixture was diluted cautiously with water (600 mL) after which it was allowed to cool to RT over 2 hr and was then cooled further to 0°C. The yellow precipitate so produced was collected by filtration and was washed sequentially with a mixture of water and acetonitrile (1 :1 , 2 x 100 mL) and then with water (500 mL) to give the 4-(4-nitronaphthalen-1 -yloxy)pyridin-2 -amine (77), as a yellow solid (76.0 g, 70%): m/z 283 (M+H)+ (ES+).
To a solution of (77) (200 mg, 0.71 mmol) and Et3N (0.20 mL, 1 .42 mmol) in dry THF was added phenyl carbonochloridate (98 μί, 0.78 mmol) and the reaction mixture maintained at RT for 1 hr. An aliquot of (R)-/V,/V-dimethylpyrrolidin-3-amine (270 μί, 2.13 mmol) was added to this mixture and after 15 hr at RT a second aliquot of (R)-/V,/V-dimethylpyrrolidin-3-amine (100 L, 0.79 mmol) was added and the mixture was maintained at RT for a further 1 hr. The resulting mixture was partitioned between aq. NH4CI (10 mL) and DCM (10 mL) and the aq layer was separated and extracted with DCM (3 x 10 mL) The combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 40 g, [5% MeOH in DCM] in DCM, 0-100%, gradient elution and then, 10% [2% NH3 (7M in MeOH) in MeOH] in DCM, isocratic elution and finally, 30% MeOH in DCM, isocratic elution) to afford (R)-3-(dimethylamino)-/V-(4-(4-nitronaphthalen-1 -yloxy)pyridin-2-yl)pyrrolidine-1 - carboxamide, (78), as a yellow/brown solid (250 mg, 81 %); R' 1 .54 min (Method 2); m/z 422 (M+H)+ (ES+).
A solution of (78) (250 mg, 0.593 mmol) in MeOH (40 mL) containing AcOH (4 drops) was subjected to hydrogenation by passage through a Thales H-cube (1 .0 mL min"1, 25°C, 70 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The crude product was partitioned between DCM (20 mL) and aq NaHC03 solution (10 mL) and the organic layer was separated and washed with brine (10 mL), dried and evaporated in vacuo to afford (R)-N- (4-(4-aminonaphthalen-1 -yloxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1 -carboxamide, (79) as a green amorphous solid (200 mg, 78%, 90% pure); R' 1.13 min (Method 2); m/z 392 (M+H)+ (ES+), which was used directly in the next step.
To a solution of CDI (100 mg, 0.370 mmol) in dry DCM (1 .0 mL) was added (5) (85 mg, 0.370 mmol), portionwise, over 20min and the resulting solution maintained at RT for 2.5 hr. A portion of this solution (0.70 mL) was added to a solution of (79) (100 mg, 0.255 mmol) in DCM (1 .0 mL) and the mixture was maintained at RT for 18 hr. The reaction was quenched by the addition of MeOH (3.0 mL) and the mixture was evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 4 g, [5% NH3 (7M in MeOH) in DCM] in DCM, 0-100%, gradient elution) to afford the title compound, Example 60, as a brown glass (52 mg, 30%); R' 4.92 min (Method 1 basic); m/z 647 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 1 .61 (1 H, m), 1 .98 (1 H, m), 2.12 (6H, s), 2.39 (3H, s), 2.58 (1 H, m), 3.03 (1 H, m), 3.25 (1 H, m), 3.49 (1 H, m), 3.58 (1 H, m), 6.41 (1 H, s), 6.60 (1 H, dd), 7.30 (1 H, d), 7.37 (2H, d), 7.44-7.47 (3H, overlapping m), 7.56 (1 H, m), 7.64 (1 H, m), 7.83 (1 H, d), 7.95 (1 H, d), 8.08 (1 H, d), , 8.10 (1 H, d), 8.70 (1 H, s), 8.79 (1 H, s), 9.12 (1 H, s).
Biological Testing
The anti-viral activity of compound Example 1 was compared to that of the neuraminidase inhibitor, zanamivir, which served as a positive control, and to that of BIRB 796, against the Influenza virus strains; H1 N1 (PR8), H1 N1 (A/WSN/33), H3N2 (A/Wuhan/359/95) and Influenza B, using three distinct protocols in MDCK cells:
Assay Method 1: ELISA assay to measure the activity of test compounds to inhibit the virally- induced expression of haemaglutinnin.
Assay Method 2: ELISA assay to measure the activity of test compounds to inhibit the virally- induced expression of nuclear protein.
Assay Method 3: Measurement of the activity of test compounds to inhibit the virally-induced cytopathic effect (CPE) assessed using MTT for detection.
Assay Method 4: Measurement of the activity of test compounds to inhibit the virally-induced cytopathic effect (CPE) assessed using methylene blue for detection.
The anti-viral activity against influenza was then confirmed in primary human epithelial cells. In addition, the effects of compounds were assessed against: (i) virus load following either RSV or HRV-16 infection, (ii) RSV- or HRV-16-induced IL-8 release and (iii) HRV-16-induced ICAM expression.
Experimental Methods
Influenza: cell-based ELISA assay (Methods 1 and 2) As a means of assessing cell associated influenza replication, haemaglutinnin (Method 1 ) or cellular nuclear protein (Method 2) expression was determined using appropriate ELISA assays. Madin-Darby canine kidney (MDCK) cells were infected with influenza virus (H1 N1 , Strain A/PR/8/34, HPA, Salisbury, UK) at an MOI of 0.1 in FCS-free DMEM containing 1.5 μg mL of TPCK treated trypsin and incubated for 1 hr at 37°C for adsorption. The cells were then washed with PBS, fresh media added and the cells were incubated for 2 days (43-50 hr). The cells were fixed with 4% formaldehyde in PBS solution. Where appropriate, cells were pre- incubated with compound for 2 hr, and then added again after washout of non-infected virus. The cells were washed with washing buffer (PBS including 0.5% BSA and 0.05% Tween-20) and incubated with blocking solution (5% milk in PBS including 0.05% Tween-20) for 1 hr. Cells were then washed with washing buffer and incubated for 1 hr at 37°C with anti- Influenza A virus haemagglutinin antibody (mouse monoclonal) (Abeam) or Influenza A virus nuclear protein antibody (rabbit monoclonal; Abeam). After washing, cells were incubated with an HRP- conjugated secondary antibody (Dako) and the resultant signal was determined colorimetrically (OD: 450 nm with a reference wavelength of 655 nm) using TMB substrate (substrate reagent pack supplied by R&D Systems, Inc.). This reaction was stopped by the addition of 50 μΙ_ of 2N H2S04. Cells were then washed with PBS and a 2.5% crystal violet solution applied for 30 min. After washing with PBS, 1 % SDS was added to each well and plates were shaken lightly for 1 hr prior to reading the absorbance at 595 nm. The measured OD450-655 readings were corrected for cell number, determined by crystal violet staining, by dividing the OD450-655 by the OD595 readings. The percentage inhibition for each well was calculated and the IC50 value was determined from the concentration-response curve generated from the serial dilutions of the compound.
Influenza CPE assay (Method 3)
MDCK cells were infected with MOI of 0.1 of influenza (either H1 N1 A/PR/8/34, H1 N1 (A/WSN/33), H3N2 (A/Wuhan/359/95) or Influenza B, HPA, Salisbury, UK) in the FCS-free media containing 1 .5 μg/mL TPCK treated trypsin and incubated for 1 hr at 37°C for adsorption. The cells were then washed with PBS, fresh media added and the cells were incubated for 2 days (44-56 hr). Where appropriate, cells were pre-incubated with compound for 2 hr, and then added again after washout of virus. The cells were then washed with 10% FCS DMEM, and incubated in 10% FCS DMEM containing 0.25 mg/mL of MTT for 2hr. The media were then removed, 200 μΙ_ of DMSO was added to each well and the plates were shaken lightly for 1 hr prior to reading the absorbance at 550 nm.
Inhibition of CPE resulting from treatment, was expressed as a percentage of that achieved by 1 μg/mL of Zanamivir at each concentration of test compound by comparison with vehicle control. The 50% effective concentration value (R-EC50) relative to the effects of 1 μg/mL of Zanamivir was determined from the resultant concentration-response curve for compound Example 1 (Table 1 ). For the characterization of further Examples (Table 3), the percentage inhibition for each well was calculated compared with vehicle. The IC50 value was calculated from the concentration-response curve generated from the serial dilutions of the compound.
Influenza CPE assay (Method 4)
MDCK cells were infected with influenza (H1 N1A/PR/8/34, HPA, Salisbury, UK) at an MOI of 0.1 in FCS-free media containing 1.5 μg mL of TPCK treated trypsin. After incubation for 1 hr at 37°C for adsorption, the cells were washed with FCS-free media and incubated in DMEM containing 1 .5 μg mL of TPCK treated trypsin for 2 days (42-56 hr). Where appropriate, cells were pre-incubated with the test compound for 2 hr, which was added again after washout of virus. The cells were next washed with 10% FCS DMEM, and incubated in 40μΙ_ of methylene blue solution (2% formaldehyde, 10% methanol, 0.175 %, methylene blue in water) for 2 hr. The cells were then washed three times with PBS, and incubated with 200 μΙ_ of PBS for 1 hr at RT. After washing once with PBS, a 1 % SDS solution (100 μΙ_) was added to each well and the plates were shaken gently for 1 hr prior to reading the absorbance at 660 nm.
The percentage inhibition of CPE resulting from treatment with a test compound, was calculated as shown below:
Inhibition % of CPE= 100 x 1 -[(the absorbance value at each concentration of test compound minus the absorbance value of non-infection control) divided by (the absorbance value of infection control minus the absorbance value of non-infection control)]. The 50% inhibitory concentration value (IC50 value) was calculated from the concentration-response curve generated by plotting results for serial dilutions of each compound. Influenza titre assay using 3D cultured bronchial epithelial cells
Primary bronchial epithelial cells, cultured using an air-liquid interface, were purchased from Mattek Corporation (Boston, USA). Fresh, warmed media (30 μΙ_) containing either the test compound at the selected concentration or vehicle (DMSO, final concentration of 0.5%) was transferred to the apical chamber. After incubation for 2 hr, 20 μΙ_ of H1 N1 virus (producing an MOI of approximately 2 at the estimated cell number of 106/well) was added to the apical well and the cells were infected for 1 hr. The apical media was then removed by aspiration and the wells were washed twice with warmed PBS. The plate was incubated at 37°C for 72 hr. PBS (50 μΙ_) was then added to the apical chamber and the preparation left for 10 min. The supernatant was collected from the apical chamber and the virus titre estimated by CPE assay in MDCK cells as follows. An aliquot, (20 μΙ_) of supernatant was collected and 10-fold serial dilutions were prepared in FCS-free DMEM containing 1 .5 μg mL of TPCK treated trypsin. All titrations were performed by infecting confluent MDCK cell monolayers (96 well plates) with the serially diluted supernatant preparations (1/10 - 1/100000). The resultant cytopathic effects were assessed by visual inspection 3 days after infection. The amount of virus required to infect 50% of MDCK cells was calculated for each treatment and is reported as log[TCID50] (υ/20μΙ_).
RSV: In vitro RSA virus load in primary bronchial epithelial cells (F-protein ELISA) NHBEC cells grown in 96 well plates were infected at an MOI of 0.001 with RSV (Strain A2, HPA, Salisbury, UK) in LHC8 Media:RPMI-1640 (50:50) containing 15 mM magnesium chloride. After incubation for 1 hr at 37°C for adsorption, the cells were washed with PBS, fresh media was added and the cells were then incubated for a further 4 days. Cells were pre- incubated with either the test compound or DMSO for 2 hr, which was added again as appropriate after washout of virus.
Cells were initially fixed with 4% formaldehyde in PBS solution for 20 min, washed with WB (washing buffer, PBS including 0.5% BSA and 0.05% Tween-20) and incubated with the blocking solution (5% condensed milk in PBS) for 1 hr. Cells were then washed with WB and incubated for 1 hr at RT with anti- RSV (2F7) F-fusion protein antibody (mouse monoclonal; lot 798760, Cat. No. ab43812, Abeam). After washing, cells were incubated with an HRP- conjugated secondary antibody (lot 00053170, Cat.No. P0447, Dako) before TMB substrate was added (substrate reagent pack, lot 269472, Cat. No. DY999, R&D Systems, Inc.). This reaction was stopped by the addition of 2N H2S04 (50 μΙ_) and the resultant signal was determined colorimetrically (OD: 450 nm with a reference wavelength of 655 nm) using a microplate reader (Varioskan® Flash, ThermoFisher Scientific). Cells were then washed and a 2.5% crystal violet solution (lot 8656, Cat. No. PL7000, Pro-Lab Diagnostics) was applied for 30 min. After washing with WB, 100μΙ_ of 1 % SDS was added to each well, and plates were shaken gently on the shaker for 1 hr prior to reading the absorbance at 595 nm. The measured OD450-655 readings were corrected to the cell number, determined by crystal violet staining, by dividing the OD450-655 by the OD595 readings. The percentage inhibition for each well was calculated and the IC50 value was calculated from the concentration-response curve generated from the serial dilutions of compound.
RSV titre and IL-8 assays using 3D cultured bronchial epithelial cells
Primary bronchial epithelial cells, cultured using an air-liquid interface, were purchased from Epithelia Sari (Geneva, Switzerland). Fresh, warmed media (200 μΙ_) containing either the test compound at the selected concentration or vehicle (DMSO, final concentration of 0.5%) was transferred to the apical chamber, and fresh, warmed media (700 μΙ_) containing either the test compound at the selected concentration or vehicle (DMSO, final concentration of 0.5%) was transferred to the bottom chamber. After incubation for 2 hr, the media in the upper well was carefully removed. The following day, fresh, warmed media (200 μΙ_) containing either the test compound at the selected concentration or vehicle (DMSO, final concentration of 0.5%) was again transferred to the apical chamber, and after 2 hr incubation the media was removed. On the third day, cells were treated in the same manner for 2 hr and the media was removed. The cells in the apical well were infected with RSV Memphis 37 virus (Meridian; MOI of approximately 0.1 ; estimated cell number of 106/well) and incubated for 1 hr. The apical media was then removed by aspiration and the wells were washed twice with warmed PBS and the plate was incubated at 37°C. At 1 hr and 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10 days after infection, warmed PBS (300 μΙ_, 37°C) was added to the apical chamber and the preparation left for 10 min. The supernatant was collected from the apical chamber and stored at -20°C for the IL-8 cytokine assay, and another aliquot (150 μΙ_) was mixed with media (containing 15% sucrose) and then stored (-20°C) for the virus titre assay. IL-8 concentrations were determined with the Duoset ELISA development kit (R&D Systems, Minneapolis, MN). The virus titre was estimated by CPE assay in Hep2 cells as follows of Supernatant (20 μί) was collected and 10-fold serial dilutions were prepared in 5%-FCS DMEM. All titrations were performed by infecting confluent Hep2 cell monolayers (96 well plates) with the serially diluted supernatant preparations (10"1 to 10"5). The resultant CPE was assessed by visual inspection 3 days after infection. The amount of virus required to infect 50% of Hep2 cells was calculated for each treatment and is reported as log[TCID50] (ΙΙ/20μί).
Human rhinovirus: CPE assay using MRC-5 cells MRC-5 cells (human lung fibroblast, ATCC, Manassas, VA) were infected with HRV16 (at MOI of 1 ) in DMEM containing 5% FCS and 1 .5 mM MgCI2. After incubation for 1 hr at 33°C for adsorption, the supernatants were aspirated, fresh media was added and the cells were incubated for a further 4 days. Cells were pre-incubated with either test compound or DMSO for 2 hr, which was added again after washout of virus. Supernatants were aspirated and the cells incubated with methylene blue solution (2% formaldehyde, 10% methanol and 0.175 % methylene blue) for 2 hr at RT. After washing, 1 % SDS was added to each well, and the plates were shaken gently for 1 -2 hr prior to reading the absorbance at 660 nm. The percentage inhibition for each well was calculated. The IC50 value was calculated from the concentration- response curve generated by plotting results obtained from the serial dilutions of each compound.
Human rhinovirus: IL-8 release and ICAM1 expression using BEASE2B cells
Stocks of human rhinovirus (HRV16, obtained from the ATCC, Manassas, VA) were generated by infecting Hela cells with HRV until 80% of the cells were cytopathic. BEAS2B cells were infected with the virus at an MOI of 5 and incubated for 2 hr at 33°C with gentle shaking for adsorption. Test compounds were added 2 hr before HRV infection and 2 hr after infection when residual extracellular HRV was washed out. The cells were then washed with PBS, fresh media was added and the cells were incubated for a further 72 hr. The supernatant was collected for assay of IL-8 concentrations using the Duoset ELISA development kit (R&D Systems, Minneapolis, MN).
The level of ICAM-1 expression on the cell surface was determined by cell-based ELISA. After appropriate incubation, cells were fixed with 4% formaldehyde in PBS. After quenching endogenous peroxidase by adding 0.1 % sodium azide and 1 % hydrogen peroxide, wells were washed with buffer (0.05% Tween in PBS: PBS-Tween). After incubation with the blocking solution (5% milk in PBS-Tween for 1 hr), cells were incubated with anti-human ICAM-1 antibody in 5% BSA PBS-Tween (1 :500) overnight. Wells were then washed with PBS-Tween and incubated with the secondary antibody (HRP-conjugated anti-rabbit IgG, Dako Ltd.). The ICAM-1 signal was detected by adding substrate and the optical densities were read at a wavelength of 450 nm and at a reference wavelength of 655 nm using a spectrophotometer. The wells were then washed with PBS-Tween and total cell numbers in each well were determined by reading the absorbance at 595nm after Crystal Violet staining and elution by 1 % SDS solution. The measured OD 450-655 readings were corrected for cell number by dividing with the OD595 reading in each well.
LPS-induced TNF a release: potency
U937 cells, human monocytic cell line, were differentiated to macrophage-type cells by incubation with phorbol myristate acetate (PMA; 100 ng/mL) for 48 to 72 hr. Where appropriate, cells were pre-incubated with final concentrations of compound for 2 hr. Cells were then stimulated with 0.1 μg mL of LPS (from E. colr'. 01 1 1 :B4, Sigma) for 4 hr, and the supernatant collected for determination of TNFa concentration by sandwich ELISA (Duo-set, R&D systems). The percentage inhibition of TNFa production was calculated as relative values of 10 μg mL BIRB 796 at each concentration of test compound by comparison with vehicle control, and the 50% effective concentration value (R-EC50: Relative-EC50) relative to 10 μg mL BIRB 796 was determined from the resultant concentration-response curve.
MTT Assay in d-U937 cells
Differentiated U937 cells were pre-incubated with compound for 4 hr in 5% FCS or 10% FCS for 24 hr and 72 hr. The supernatant was replaced with 200 μί of new media and 10 μί of MTT stock solution (5 mg/mL) added to each well. After 1 hr incubation, the media were removed, 200 μΙ_ of DMSO added to each well and the plates were shaken lightly for 1 hr prior to reading the absorbance at 550 nm. The percentage loss of cell viability was calculated for each well relative to vehicle (0.5% DMSO)-treatment. Consequently an apparent increase in cell viability for drug treatment relative to vehicle is tabulated as a negative percentage value.
MTT Assay in MDCK cells
MDCK cells were incubated with the compounds for 54 hr in the FCS-free media containing 1.5 μg mL TPCK treated trypsin. The cells were then washed with 10% FCS DMEM, and incubated in 10% FCS DMEM containing 0.25 mg/mL of MTT for 2hr. The media were then removed, 200 L of DMSO was added to each well and the plates were shaken lightly for 1 hr prior to reading the absorbance at 550 nm.
In vivo testing: Influenza virus load in mouse lung
Mice (n = 6 per group) were first exposed to cigarette smoke for 14 days (3 times per day). On day 15 animals were dosed intranasally with influenza (H3N1 Memphis 71 ). Animals were dosed intratracheally, once daily with 2 μg of compound Example 1 or vehicle on days 14, 15, 16, 17 and 18. On day 18 the animals were sacrificed and the lungs taken to estimate the viral titre using a plaque assay. Serial dilutions were added to near confluent monolayers of cells. Following one hr of infection the monolayer was overlaid with molten agarose which sets and the cells incubated with influenza. The cells were then fixed in formaldehyde and subsequently stained with a dye. The plaques were counted and a titre determined in plaque forming units (pfu).
In vivo testing: Mortality resulting from influenza infection in mouse lung. Female BALB/c mice (17-19 g) were obtained from Charles River Laboratories (Wilmington, MA) and quarantined for 48 hr prior to use. Mice were anesthetized by i.p. injection of ketamine/xylazine (50/5 mg/kg) and then infected intranasally (i.n.) with a suspension of influenza virus, A/NWS/33 (H1 N1 ; 90 μΙ_). The infectious inoculation was approximately 135 CCID50/mouse. An aq suspension of compound Example 1 (1 .0 mg/mL, equivalent to 5.5 mg/kg/day) and placebo were administered i.n. (50 μΙ_) twice a day for 6 days starting 24 hr before virus challenge (day -1 to day +4). The dose on day 0 was given 2 hr before virus infection so as to not interfere with the initial infection process. Oseltamivir was administered twice a day orally for the same time period. Ten drug-treated, infected mice and 10 placebo- treated controls were weighed and observed daily until death occurred for 21 days post infection. A normal control group consisting of 10 uninfected, untreated mice was included for body weight comparisons. Pairwise comparisons of survivor numbers were analyzed by the two-tailed Fisher's exact test. Survival curve analysis was performed using the Gehan-Breslow- Wilcoxon test. Results
The data below (Table 1 ) demonstrate that compound Example 1 consistently inhibits CPE with IC50 values in the range of 2-50 nM when cells are treated with the test compound 2 hr before inoculation with influenza virus. The sensitivity of the virus strains to zanamavir showed greater variability, with influenza B being particularly insensitive to the neuraminidase inhibitor. The data further demonstrate that BIRB 796 shows modest activity versus virus-induced haemaglutinnin expression but no consistently-detectable activity against virus-induced nuclear protein expression or CPE. Since compound Example 1 showed equal or better efficacy to Zanamivir in MDCK cells, the efficacy was confirmed in primary human bronchial epithelial cells (Table 2).
Table 1 : Effects of zanamivir, BIRB 796 and compound Example 1 on influenza-induced haemaglutinnin and nuclear protein expression and on CPE.
R-EC5o and [CC5oa] values for Test Compounds (nM)
Viral Strain Assay Zanamivir BIRB 796 Example 1 H1 N1 , PR8 1 b 16 1 18 5
H1 N1 , PR8 2C 43 >2000 1 1
H1 N1 , PR8 3d 45 1368 30
H1 N1 , A WSN/33 3 87 NTe 50
H3N2, A Wuhan/359/95 3 5 >2000 19
Influenza B 3 395 >2000 2
None MTTf [>29000] [9335] [1422] a) 50% cytotoxic concentration; b) expression of haemaglutinnin by ELISA;c) expression of nuclear protein by ELISA; d) virus-induced cytopathic effect (CPE); e) not tested; f) analysis conducted in MDCK cells.
Table 2: Effects of zanamivir and compound Example 1 on influenza viral load in 3D cultured primary bronchial epithelial cells.
Concentration Log TCIDso / 20μΙ_ Statistical analysis
Treatment
(MQ/mL) (Mean ± SEM) p Value3
No infection
H1 N1 control 1 1.0 ±0.61
1 8.2 ±0.60 p<0.001
Compound 0.1 9.2 ±0.62 p<0.05
Example 1 0.01 10.0 ±0.00 NS
0.001 10.6 ±0.20 NS
1 5.3 ±0.33 p<0.001
0.1 7.8 ±0.40 p<0.001
Zanamivir
0.01 8.7 ±0.17 p<0.01
0.001 9.9 ±0.24 NS
a) p value compared with H 1 N1 control (one way Annova, Dunnett's multiple comparison test)
To confirm the relevance of the in vitro studies, the ability of compound Example 1 to inhibit the influenza virus load was evaluated in vivo in the mouse. The results obtained versus the influenza H3N1 , Memphis 71 strain are presented below (Table 3) and demonstrate that treatment led to a decrease in viral load of approximately 80% compared with vehicle controls. The data suggest that treatment with compounds of formula (I) in a once/day dosing regimen may be effective in the treatment of influenza.
Table 3: Effects of treatment with Compound Example 1 on viral load in the mouse lung. Lung viral load
Treatment
pfu / g lung tissue (x 106)
Vehicle 46.6 ± 16.6
Example 1 8.1 ± 1 .9
The activity of other examples of compounds of formula (I) have also been evaluated in these systems and found to share the ability of compound Example (I) to inhibit the propagation of the influenza virus in vitro. The results obtained from these studies are summarised below (Table 4). The protective effects of treatment were not associated with any evidence of toxicity in an MTT assay in MDCK cells. There was no obvious relationship between the potencies of compounds to inhibit influenza-induced CPE and their ability to inhibit LPS-induced TNFa release from d-U937 cells.
Table 4: The effects of test compounds on LPS-induced TNFa release, on influenza-induced CPE and their cellular tolerability
LPS-induced Influenza
Test Compound MTT Assay0
TNFa release3 induced CPEb
Example No R-ECso (nM) ICso (nM) d-U937 cellsd MDCK cells6
1 0.88 6 -ve -ve
2 39 1 1 -ve -ve
16 2.9 166 +ve -ve
17 5.3 64 -ve -ve
20 2.8 486* +ve -ve
40 41 97 -ve -ve
49 1 .6 32 +ve -ve a) assay performed in d-U937 cells; b) see method 3; c) <30% = -ve; >30% = +ve; d) screened at 10 μg mL for 24h; e) screened at 0.2 μg mL; * linear regression.
Furthermore, it was found that a combination treatment comprising of compound Example 1 and the neuraminidase inhibitor, zanamivir, over the concentration range 0.32 - 40 ng/ml for each compound, produces a substantial increase in activity. The extent of the augmentation in anti-viral activity is characteristic of a synergistic interaction between the two agents (see Table 4 and Figure 1 ). The beneficial effects of a combination treatment of compound Example 1 together with zanamivir are particularly noteworthy since both agents can be administered via the inhaled route, so generating an opportunity to formulate the two compounds together, to provide a single combination product. The synergy between compound Example 1 and a neuramindase inhibitor, observed in vitro, has been investigated further in vivo, by evaluating the mortality rate in mice following influenza virus infection (Figure 2). The effectiveness of neuraminidase inhibitors in achieving clinical benefit when used in the treatment of influenza is critically linked to the timing of the onset of dosing relative to infection. This is manifested as a much greater clinical benefit being achieved when drug treatment is given prophylactically, as a rapid diminution of efficacy takes place in the period after infection is established, with delayed onset of treatment.
Table 5: The effect of prophylactic treatment with combinations of compound Example 1 and zanamavir on influenza virus-induced hemagglutinin expression.
[Zanamivir]
(ng/mL) 40 8 1.6 0.32
Inhibition of influenza virus-induced hemagglutinin (%) o 40 100 77 74 60 88
Q.
£
re 8 88 76 72 56 45
x
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3
C 1.6 91 89 84 46 26 3
O
Q. 0.32 87 80 60 36 12
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o
o 0 85 47 54 18 0 In vitro, the time dependence of treatment benefit can be modelled by varying the relative times between virus inoculation and administration of drug. For neuraminidase inhibitors, a marked, time dependent loss of efficacy is revealed as treatment is progressively delayed relative to infection with the virus. In contrast the results disclosed below, (Figure 3) which were obtained using Method 3, indicate that treatment with a compound of formula (I) continues to demonstrate significant benefit when treatment commences 24 hr post exposure to virus. In addition, the results show that a combination of a compound of formula (I) and a neuraminidase inhibitor show markedly superior effects to treatment with either agent alone.
The time dependence of clinical benefit versus the onset of therapeutic dosing can be modelled in the mouse by varying the relative times between inoculation with the virus and the start of drug administration. The results disclosed herein demonstrate that delaying treatment with a neuraminidase inhibitor results in a loss of protection from the adverse effects of viral infection. In contrast treatment with a combination comprising of a compound of formula (I) together with a neuraminidase inhibitor resulted in the maintenance of the protective effect. The data presented below (Table 6) show the profiles of selected examples of compounds of formula (I) versus a virus panel, including RSV and HRV-16, in vitro.
Table 6: In Vitro Activity of Examples of Compounds of Formula (I) Against a Virus Panel.
Values3 (nM) in the Cellular Assay and Virus Indicated
RSV HRV Influenza (PR8)
Example CPEe CPEe
F-ELISAb CPEC IL-8d ICAM-1d
No. (MTT) (MB)
1
41 341 .2 1 .0 >1689 6 7.3
2
nt >346 nt nt 1 1 92
40
102.8 nt nt nt 97 74.0
20
nt >320 nt nt 486 >320
52
nt 2.9 0.019 nt 1 .3 7.9
55
nt 9.5 0.069 nt 1 .7 4.6
54
nt 9.4 0.04 0.098 1 .0 2.4
53
71.7%f 24.0 0.12 0.029 0.79 nt
58
nt 16.0 nt nt 0.72 nt a) Data are presented as the mean of 1-4 replicate observations; b) Experiment performed using NBEC cells and as follows; c) MRC5 cells; d) BEAS2B cells; e) MDCK cells; f) % Inhibition achieved at a concentration of 0.04 μg mL; nt, not tested
The compound Example 1 was found to inhibit IL-8 release from primary 3D nasal epithelial cells infected with RSV (Figure 4) and to inhibit virus load in the same cells (Figure 5).
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.
All patents and patent applications mentioned throughout the specification of the present invention are herein incorporated in their entirety by reference.
The invention embraces all combinations of preferred and more preferred groups and suitable and more suitable groups and embodiments of groups recited above.

Claims

1 . A compound of formula (I):
Figure imgf000127_0001
wherein R1 is Ci-6 alkyl optionally substituted by a hydroxyl group;
R2 is H or Ci-6 alkyl optionally substituted by a hydroxyl group;
R3 is H, Ci-6 alkyl or C0-3 alkylC3-6 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 C2-8 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) 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 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 C3-8 cycloalkyl group,
each aryl, heteroaryl, heterocyclyl or C3-8 cycloalkyl group bearing 0 to 3 substituents selected from halogen, hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, amino, Ci-4 mono or C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, S(0)qCi-6 alkyl, C0-6 alkylC(0)d-6 alkyl or C0-6 alkylC(0)Ci-6 heteroalkyl, with the proviso that the atom linked directly to the carbonyl in -NR3C(0)- is not an oxygen or a sulfur atom; and
b) 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 C2-8 di-alkyl amino, Ci-4 mono or C2-8 di-acyl amino, S(0)qCi-6 alkyl, C0-6 alkylC(0)Ci-6 alkyl, Co-6 alkylC(O)NC0-6 alkyl C0-6 alkyl or C0-6 alkylC(O)C0-6 heteroalkyl; and
p is 0, 1 or 2; q is 0, 1 or 2; or
or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers, tautomers and isotopic derivatives thereof, with the proviso that the compound of formula (I) is not Λ/-(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.
2. A compound according to claim 1 wherein Ar is naphthyl for use in the treatment or prophylaxis of viral infection.
3. A compound according to claim 1 or claim 2 wherein L is -OCH2- or -0-, for use in the treatment or prophylaxis of viral infection.
4. A compound according to any one of claims 1 to 3 wherein X is pyridyl, for use in the treatment or prophylaxis of viral infection.
5. A compound according to any one of claims 1 to 4 wherein Q is:
a. Ci-4alkyl-V-R4, such as Ci-3alkyl-V-R4 wherein:
V is a heteroatom selected from NRV, O or S(0)p;
Rv represents H or d-3 alkyl;
R4 is H or -d-3 alkyl, and p is as defined in claim 1 ,
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; b. Ci-3 alkyl-V-(Ci-3 alkyl-Z-R5)k such as d-3 alkyl-V-(C2-3 alkyl-Z-R5)k wherein:
V is a heteroatom selected from N, NH, O or S(0)p, such as N or NH
(V is N in the case where k = 2, or will be selected from NH, O or S(0)p, in the case where k =1 , in particular NH);
Z is independently selected from NH, O or S(0)p;
R5 is H or -Ci-3alkyl;
k is an integer 1 or 2 (such as 1 ); and
p is as defined in claim 1 ,
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; or c. Ci-s
Figure imgf000128_0001
alkyl-Y-R6, or
Ci-3 alkyl-V-C2-3 alkyl-Z-C2-3 alkyl-Y-R6, wherein
V, Z and Y are independently a heteroatom selected from NH, O or S(0)p, R6 is H or methyl, and
p is as defined in claim 1 ,
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 use in the treatment or prophylaxis of viral infection.
6. A compound according to any one of claims 1 to 4 wherein Q is -NR7R8 and -NR3C(0)Q forms a urea, where R7 and R8 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 and wherein said chain is optionally substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group, a heterocyclyl or C3-8 cycloalkyl group, each aryl, heteroaryl or heterocyclyl group bearing 0 to 3 substituents as defined in claim 1 ;
for use in the treatment or prophylaxis of viral infection.
7. A compound according to any one of claims 1 to 4 wherein Q is -C0-3alkylheterocycle, said heterocyclyl group comprising at least one heteroatom selected from O, N and S, and is optionally substituted by one or two or three groups independently selected from the relevant substituents as defined in claim 1 ; for use in the treatment or prophylaxis of viral infection.
8. A compound according to claim 7 wherein Q is -C0alkylheterocycle, wherein the heterocyclic group is linked through carbon; for use in the treatment or prophylaxis of viral infection.
9. A compound according to claim 7 wherein Q is -C0alkylheterocycle, wherein the heterocyclic group contains one or more N atoms and is linked through N; for use in the treatment or prophylaxis of viral infection.
10. A compound according to any one of claims 1 to 4 wherein Q is:
-CH2OH;
-CH2OCi-6 alkyl, in particular -CH2OCH3;
-CH2CH2OCH3;
-CH20(CH2)2OCH3;
-CH(CH3)OCH3;
-CH2NHCH3 or -CH2N(CH3)2
-CH2NHCH2CH2OCH3 or -CH2NHC(0)CH2OCH3;
-CH2SCH3, -CH2S(0)2CH3 or -CH2NHC(0)CH2S(0)2CH3; or
-CH2NHC(0)CH2;
for use in the treatment or prophylaxis of viral infection.
1 1 . In A compound according to any one of claims 1 to 4 wherein the fragment -NR3C(0)Q in formula (I) is represented by:
-NR3C(0)CH2OH, in particular -NHC(0)CH2OH;
-NR3C(0)CH2OCi-6 alkyl, in particular -NR3C(0)CH2OCH3, especially - NHC(0)CH2OCH3;
-NR3C(0)CH20(CH2)2OCH3, in particular -NHC(0)CH20(CH2)2OCH3;
-NR3C(0)CH(CH3)OCH3 in particular -NHC(0)CH(CH3)OCH3;
-NR3C(0)CH(CH3)NHCi-3alkyl in particular -NHC(0)CH(CH3)NHCH3; -NR3C(0)CH(CH3)N(Ci-3alkyl)2 in particular -NHC(0)CH(CH3)N(CH3)2;
-NR3C(0)C(CH3)2NHCH3 in particular -NHC(0)C(CH3)2NHCH3;
-NR3C(0)(CH2)20Ci-6alkyl, such as -NR3C(0)(CH2)2OCH3, in particular- NHC(0)(CH2)2OCH3;
-NR3C(0)(CH2)3NHCi-3alkyl in particular -NHC(0)(CH2)3NHCH3;
-NR3C(0)(CH2)3N(Ci-3alkyl)2 in particular -NHC(0)(CH2)3N(CH3)2;
-NR3C(0)CH2NHCi-3alkyl in particular -NHC(0)CH2NHCH3;
-NR3C(0)CH2NH(CH2)2OCH3 in particular -NHC(0)CH2NH(CH2)2OCH3;
-NR3C(0)CH2SCH3, in particular -NHC(0)CH2SCH3;
-NR3C(0)CH2S(CH2)2OCH3, in particular -NHC(0)CH2S(CH2)2OCH3;
-NR3C(0)CH2S(CH2)20(CH2)2OCH3, in particular -NHC(0)CH2S(CH2)20(CH2)2OCH3 -NR3C(0)CH2SOCH3, in particular -NHC(0)CH2SOCH3
-NR3C(0)CH2S(0)2CH3, in particular -NHC(0)CH2S(0)2CH3;
-NR3C(0)CH2N[(CH2)2OCH3]2 in particular -NHC(0)CH2N[(CH2)2OCH3]2;
-NR3C(0)NH2 in particular -NHC(0)NH2;
-NR3C(0)NHCi-9 alkyl, such as NR3C(0)NHCi-7 alkyl, in particular -NHC(0)NHCH3 -NR3C(0)N(Ci-4 alkyl)Ci-5 alkyl in particular -NHC(0)N(CH3)2; or
-NR3C(0)NHCH2CONH(CH2)2OCH3 in particular -NHC(0)NHCH2CONH(CH2)2OCH3;
-NHC(0)-(tetrahydropyranyl), such as -NHC(0)-(tetrahydro-2H-pyran-4-yl):
-NHC(0)-(morpholinyl) such as -NHC(0)-(4-morpholinyl) or -NHC(0)-(3-morpholinyl); -NHC(0)-(pyrrolidinyl), such as -NHC(0)-(pyrrolidin-1 -yl);
-NHC(0)-(piperazinyl), such as -NHC(0)-(piperazin-1 -yl);
-NHC(0)-(methylpiperazinyl), such as -NHC(0)-(4-methylpiperazin-1 -yl);
-NHC(0)-[(methoxyethyl)piperazinyl], such as -NHC(0)-[4-(2-methoxyethyl)piperazin-1 - yi];
-NHC(0)-(oxoimidazolidinyl) such as -NHC(0)-(2-oxoimidazolidinyl), in particular - NHC(0)-(2-oxoimidazolidin-1 -yl);
-NHC(0)CH2-(tetrahydropyranyl), such as -NHC(0)CH2-(tetrahydro-2H-pyran-4-yl); -NHC(0)CH2-(morpholinyl), such as -NHC(0)CH2-(4-morpholinyl);
-NHC(0)CH2-(pyrrolidinyl), such as -NHC(0)CH2-(pyrrolidin-1 -yl);
-NHC(0)CH2-(piperazinyl), such as -NHC(0)CH2-(piperazin-1 -yl);
-NHC(0)CH2-(methylpiperazinyl), such as -NHC(0)CH2-(4-methylpiperazin-1 -yl);
-NHC(0)CH2-[(methoxyethyl)piperazinyl], such as -NHC(0)CH2-[4-(2-methoxyethyl) piperazin-1 -yl];
-NHC(0)CH2SCH2CH2-(morpholinyl), such as -NHC(0)CH2SCH2CH2-(4-morpholinyl), or -NHC(0)CH2SCH2CH2-(3-morpholinyl); and
-NHC(0)CH2S02CH2CH2-(morpholinyl), such as -NHC(0)CH2S02CH2CH2-(4- morpholinyl), or -NHC(0)CH2S02CH2CH2-(3-morpholinyl);
in the treatment or prophylaxis of viral infection.
12. A compound selected from: Methyl 4-((4-(3-(3-ie f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin 2-ylurea;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin 2-yl)-2-methoxypropanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin 2-yl)-2-methoxypropanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-(methylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-morpholinoacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-(pyrrolidin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-(4-methylpiperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-(4-(2-methoxyethyl)piperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-(2-methoxyethylamino)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-(dimethylamino)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-(methylamino)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen -1 -yloxy)methy )pyridin-2- yl)-2-((4-methoxybenzyl)(methyl)amino)acetamide;
1 -(4-((3-Methylureidopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ie f-butyl-1 -p-tolyl-1 H-pyrazol 5-yl)urea;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-3- yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-3- yl)-2-(2-methoxyethoxy)acetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-(2-methoxyethoxy)acetamide;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-1 -methyl-3- (pyridin-2-yl)urea;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-3-(pyridin-2- yl)urea;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-(2-methoxyethoxy)acetamide; /V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyrimidin-2- yl)-2-methoxyacetamide;
Λ/-(1 -(2-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)-1 H- imidazol-4-yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfonyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-hydroxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-methyl-2-(methylamino)propanamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin- 2-yl)-2-(methylamino)propanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin- 2-yl)morpholine-3-carboxamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin- 2-yl)morpholine-3-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-methylpiperazine-1 -carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)morpholine-4-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-methoxypropanamide;
2-(3-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)ureido)-/V-(2-methoxyethyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-(dimethylamino)butanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)propanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)-2-oxoimidazolidine-1 -carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfinyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-methoxyethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-(2-methoxyethoxy)ethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylsulfonyl)acetamide;
2-(Bis(2-methoxyethyl)amino)-/V-(4-((4-(3-(3-ie/f-butyl-1-p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2-yl)acetamide; /V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-methoxyacetamide;
N-(4-(2-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)ethoxy)pyridin-2-^ 2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy )-2-methylpropyl) pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propyl)pyridin-2- yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propan-2-yl) pyridin-2-yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 -pyrazol-5-yl)ureido)naphthalen-1 -yloxy )-2-methylpropan-2- yl)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -(4-(hydroxymethyl)phenyl)-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide;
N-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- (methylsulfonyl)acetamide
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
In one embodiment the compound according to the disclosure is:
Methyl4-((4-(3-(3-ie f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) methyl)pyridin- 2-ylurea;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)tetrahydro-2/-/-pyran-4-carboxamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) methyl)pyridin- 2-yl)-2-methoxypropanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin- 2-yl)-2-methoxypropanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfonyl)acetamide
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-hydroxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-methyl-2-(methylamino)propanamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin- 2-yl)-2-(methylamino)propanamide;
(R)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin- 2-yl)morpholine-3-carboxamide;
(S)-/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin- 2-yl)morpholine-3-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-methylpiperazine-1 -carboxamide; /V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)morpholine-4-carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-methoxypropanamide;
2-(3-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)ureido)-/V-(2-methoxyethyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-4-(dimethylamino)butanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)propanamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-3-(methylsulfonyl)-2-oxoimidazolidine-1 -carboxamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-2- yl)-2-(methylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylsulfinyl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-morpholinoacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(pyrrolidin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(4-methylpiperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(4-(2-methoxyethyl)piperazin-1 -yl)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-methoxyethylamino)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(dimethylamino)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(methylamino)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-((4-methoxybenzyl)(methyl)amino)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-methoxyethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-(2-methoxyethoxy)ethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylthio)acetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl)pyridin-2- yl)-2-(2-morpholinoethylsulfonyl)acetamide;
2-(Bis(2-methoxyethyl)amino)-/V-(4-((4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)methyl)pyridin-2-yl)acetamide; 1 -(4-((3-Methylureidopyridin-4-yl)methoxy)naphthalen-1 -yl)-3-(3-ie f-butyl-1 -p-tolyl-1 H-pyrazol- 5-yl)urea;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) methyl) pyridin-3 yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyridin-3- yl)-2-(2-methoxyethoxy)acetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-(2-methoxyethoxy)acetamide;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy )ethyl)-1 -methyl-3- (pyridin-2-yl)urea;
4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy )ethyl)-3-(pyridin-2- yl)urea;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-3- yl)-2-(2-methoxyethoxy)acetamide;
N-(4-(2-(4-(3-(3-ie/f-butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)ethoxy)pyridin-2-yl)- 2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)ethyl)pyridin-2- yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy )-2- methylpropyl)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(2-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propyl)pyridin-2- yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)propan-2- yl)pyridin-2-yl)-2-methoxyacetamide;
Λ/-(4-(1 -(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 -pyrazol-5-yl)ureido)naphthalen-1 -yloxy )-2-methylpropan-2 yl)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie/f-Butyl-1 -(4-(hydroxymethyl)phenyl)-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)methyl) pyrimidin 2-yl)-2-methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- (methylsulfonyl)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2- methoxyethoxy)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)tetrahydro-2/-/-pyran-4-carboxamide; /V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- (methylthio)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-3- methoxypropanamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- hydroxyacetamide;
/V-(4-(4-(3-(3-lsopropyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-Ethyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- methoxyacetamide;
Λ/-(4-(4-(3-(3-(1 -Hydroxy-2-methylpropan-2-yl)-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 yloxy)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-butyl-1 -(2!3!5,6-tetradeutero-4-(trideuteromethyl)phenyl)-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- morpholinoacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)- (dimethylamino)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2 methoxyethylamino)acetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2- ureidoacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2 methoxyacetamido)acetamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)tetrahydro-2/-/-pyran-4-carboxamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)isonicotinamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1-p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-2-(2 (methylsulfonyl)acetamido)acetamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)-3-morpholinopropanamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)morpholine-4-carboxamide;
/V-(2-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- ylamino)-2-oxoethyl)-2,6-difluoro-3-(2-(2-methoxyethoxy)ethoxy)benzamide;
A/-(4-(4-(3-(3-iert-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)phenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-2-methylphenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-3-methylphenoxy)pyridin-2-yl)-2- methoxyacetamide; /V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-2-methoxyphenoxy)pyridin-2-yl^ methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-2,3-dimethylphenoxy)pyridin-2-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)-3-methoxyphenoxy)pyridin-2-yl)-2- methoxyacetamide;
N-Ethyl-N'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyridin-2 ylurea;
4-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2 -ylurea;
/V-Propan-2-yl-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2 -ylurea;
1 -(3-(ie/f-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)-3-(4-((2-(3-phenylureido)pyridin-4- yl)oxy)naphthalen-1 -yl)urea;
1 -(4-((2-(3-Benzylureido)pyridin-4-yl)oxy)naphthalen-1 -yl)-3-(3-(ie/f-butyl)-1 -(p-tolyl)-l H- pyrazol-5-yl)urea;
1 -(4-((2-(3-Cyclopropylureido)pyridin-4-yl)oxy)naphthalen-1 -yl)-3-(3-(ie/f-butyl)-1 -(p-tolyl)-l H- pyrazol-5-yl)urea;
1 -(3-(ie/f-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)-3-(4-((2-(3-(2-methoxyethyl)ureido)pyridin-4- yl)oxy)naphthalen-1 -yl)urea;
1 -(3-(ie/f-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)-3-(4-((2-(3-cyclopentyl)ureido)pyridin-4- yl)oxy)naphthalen-1 -yl)urea;
1 -(3-(ferf-Butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)-3-(4-((2-(3-methyl)ureido)pyridin-4- yl)oxy)naphthalen-1 -yl)urea;
Ethyl 2-(3-(4-((4-(3-(3-(ie/f-butyl)-1 -(p-tolyl)-l H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy)pyridin- 2-yl)ureido)acetate;
4-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)piperidine;
/V-Acetyl 4-(3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin- 2-yl)ureido)piperidine;
2- (2-Methoxyethoxy)-1 -(4-(3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 yloxy)pyridin-2-yl)ureido)piperidin-1 -yl)ethanone;
/V-Methylsulfonyl-4-(3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)ureido)piperidine;
N-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)morpholine-4-carboxamide;
/V-(4-((4-(3-(3-(ie/f-butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy)pyridin-2-ylH methylpiperazine-1 -carboxamide;
3- (4-((4-(3-(3-(ie/f-butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy)pyridin-2-yl)-1 ,1 dimethylurea;
/V-(4-((4-(3-(3-(ie/f-Butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yl)oxy)pyridin-2- yl)piperidine-1 -carboxamide;
/V-Methyl-/V-(2-(morpholin-4-yl)ethyl)-/V'-4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2 -ylurea; /V-(4-(morpholin-4-yl)butyl)-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen- 1 -yloxy)pyridin-2-ylurea;
/V-(2-(morpholin-4-yl)ethyl)-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphm 1 -yloxy)pyridin-2-ylurea;
/V-(3-methylisoxazol-5-yl)methyl-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyridin-2-ylurea;
Λ/-(1 -methyl)piperidin-4-yl-/\/'- 4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 yloxy)pyridin-2-ylurea;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-4- hydroxypiperidine-1 -carboxamide;
/V-(3-(imidazol-1 -yl)propyl)-/V'-4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 yloxy)pyridin-2-ylurea;
/V-(2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetyl)pyrrolidine;
(R)-/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)-3- (dimethylamino)pyrrolidine-l -carboxamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)pyrrolidine-1 -carboxamide;
2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)-/V-methylacetamide;
2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)-/V-(2-morpholinoethyl)acetamide;
2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetyl morpholine;
2- (3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)-/V-(2-(pyridin-4-yl)ethyl)acetamide;
/V-(3-(1 H-lmidazol-1 -yl)propyl)-2-(3-(4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)ureido)acetamide;
1 -(2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetyl)-4-methylpiperazine;
/V-(3-(1 H-lmidazol-1 -yl)propyl)-2-(3-(4-(4-(3-(3-iert-butyl-1 -p-tolyl-1 H-pyrazol-5- yl)ureido)naphthalen-1 -yloxy)pyridin-2-yl)ureido)acetamide;
/V-(6-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido) naphthalen-1 -yloxy)pyrimidin-4-yl)-2- methoxyacetamide;
/V-(6-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)phenoxy)pyrimidin-4-yl)-2- methoxyacetamide;
/V-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-2-yl)-2- methoxyacetamide;
3- (4-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyrimidin-2-yl)urea; 1 -Methyl-3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-2 yl)urea;
1 ,1 -Dimethyl-3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyrimidin-2-yl)urea; 1 -Cyclopropyl-3-(4-(4-(3-(3-ie/f-butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyrimidin-2-yl)urea;
(4-(4-(3-(3-ie f-butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-2- yl)morpholine-4-carboxamide;
3-(6-(4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyrimidin-4-yl)urea; 2-(3-(4-(4-(3-(3-ie/f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 -yloxy)pyridin-2- yl)ureido)acetic acid.
and pharmaceutically acceptable salts thereof, including all stereoisomers, tautomers and isotopic derivatives thereof;
for use in the treatment or prophylaxis of viral infection.
13. A compound for use in the treatment or prophylaxis of viral infection .wherein the compound is /V-(4-((4-(3-(3-ie f-Butyl-1 -p-tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof
14. A method for the treatment or prophylaxis of viral infection, the method comprising administering to a patient in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 13.
15. The method according to claim 14, further comprising administering to the patient an effective amount of an anti-viral agent.
16. The use of a compound as defined in any one of claims 1 to 13 in the preparation of a medicament for the treatment or prophylaxis of viral infection.
17. The use according to claim 16, wherein the medicament further comprises an anti-viral agent.
18. A compound, method or use according to any one of claims 1 to 17, wherein the viral infection is caused by an influenza virus.
19. A compound, method or use according to claim 18, wherein the viral infection is caused by influenza A virus.
20. A compound, method or use according to claim 18 or claim 19, wherein the viral infection is in a patient 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.
21 . A pharmaceutical composition comprising a combination of a compound as defined in any one of claims 1 to 13 and an anti-viral agent, for example a neuraminidase inhibitor.
22. A product comprising a compound as defined in any one of claims 1 to 13 and an antiviral agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prophylaxis of viral infection.
23. A pharmaceutical composition according to claim 21 or a product according to claim 22, wherein the anti-viral agent is oseltamivir, zanamivir, peramivir, amantadine, rimantadine, ribavirin; interferon, acyclovir and/or zidovudine.
24. A pharmaceutical composition or a product according to any one of claims 21 to 23 for nasal administration, topical administration to the lung or oral administration.
25. A pharmaceutical composition or a product according to claim 24 which is in the form of nasal drops or metered spray, an aerosol formulation a non-pressurised formulation such as an aqueous solution or suspension or a dry-powder formulation.
PCT/GB2010/052066 2009-12-11 2010-12-10 Antiviral use of urea compounds WO2011070368A1 (en)

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EP11728920.7A EP2582432B1 (en) 2010-06-17 2011-06-17 Ureido-pyrazole derivatives for use in the treatment of rhinovirus infections
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EP11729150.0A EP2582433B1 (en) 2010-06-17 2011-06-17 Ureido-pyrazole derivatives for use in the treatment of rhinovirus infections
JP2013514787A JP6159251B2 (en) 2010-06-17 2011-06-17 Method
AU2011266797A AU2011266797B2 (en) 2010-06-17 2011-06-17 Methods
JP2013514786A JP2013530179A (en) 2010-06-17 2011-06-17 Ureido-pyrazole derivatives for use in the treatment of respiratory syncytial virus (RSV) infection
US13/805,485 US20130123260A1 (en) 2010-06-17 2011-06-17 Methods
PCT/GB2011/051136 WO2011158039A1 (en) 2010-06-17 2011-06-17 Ureido-pyrazole derivatives for use in the treatment of rhinovirus infections
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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
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