WO2003068747A1 - Nicotinamide derivates useful as p38 inhibitors - Google Patents

Nicotinamide derivates useful as p38 inhibitors Download PDF

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Publication number
WO2003068747A1
WO2003068747A1 PCT/GB2003/000554 GB0300554W WO03068747A1 WO 2003068747 A1 WO2003068747 A1 WO 2003068747A1 GB 0300554 W GB0300554 W GB 0300554W WO 03068747 A1 WO03068747 A1 WO 03068747A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
groups
galkyl
methyl
compound
Prior art date
Application number
PCT/GB2003/000554
Other languages
French (fr)
Inventor
Nicola Mary Aston
Paul Bamborough
Ann Louise Walker
Original Assignee
Smithkline Beecham Corporation
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
Priority claimed from GBGB0203301.7A external-priority patent/GB0203301D0/en
Priority claimed from GB0225385A external-priority patent/GB0225385D0/en
Priority to CA2474192A priority Critical patent/CA2474192C/en
Priority to NZ533865A priority patent/NZ533865A/en
Priority to AU2003207298A priority patent/AU2003207298B2/en
Priority to KR1020047012405A priority patent/KR101058292B1/en
Priority to DK03704769T priority patent/DK1474395T3/en
Priority to DE60316913T priority patent/DE60316913T2/en
Priority to US10/503,968 priority patent/US7125898B2/en
Priority to MXPA04007838A priority patent/MXPA04007838A/en
Priority to BRPI0307351A priority patent/BRPI0307351B8/en
Priority to EP03704769A priority patent/EP1474395B1/en
Priority to SI200331042T priority patent/SI1474395T1/en
Priority to JP2003567878A priority patent/JP4472349B2/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2003068747A1 publication Critical patent/WO2003068747A1/en
Priority to IS7337A priority patent/IS2520B/en
Priority to ZA2004/05602A priority patent/ZA200405602B/en
Priority to IL163090A priority patent/IL163090A/en
Priority to NO20043176A priority patent/NO327418B1/en
Priority to HK05103699A priority patent/HK1070896A1/en
Priority to US11/462,851 priority patent/US7709506B2/en
Priority to US11/462,858 priority patent/US7514456B2/en
Priority to CY20071101642T priority patent/CY1107117T1/en
Priority to US12/713,433 priority patent/US8252818B2/en
Priority to US12/713,448 priority patent/US8575204B2/en

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Definitions

  • This invention relates to novel compounds and their use as pharmaceuticals, particularly as p38 kinase inhibitors, for the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokmes produced by the activity of p38 kinase.
  • R 1 is selected from hydrogen, C ⁇ .galkyl optionally substituted by up to three groups selected from Ci. ⁇ alkoxy, halogen and hydroxy, C2_6 a lkenyl, C3_7cycloalkyl optionally substituted by one or more C ⁇ .galkyl groups, phenyl optionally substituted by up to three groups selected from R ⁇ and R°, and heteroaryl optionally substituted by up to three groups selected from R.5 and R.6, R.2 is selected from hydrogen, Cj.galkyl and -(CH2)q-C3_7cycloalkyl optionally substituted by one or more C ⁇ .galkyl groups, or (CH2) m R. and R.2, together with the nitrogen atom to which they are bound, form a four- to six-membered heterocyclic ring optionally substituted by up to three Ci.galkyl groups; R.3 is chloro or methyl;
  • R 4 is the group -NH-CO-R 7 or -CO-NH-(CH ) q -R 8 ;
  • R5 is selected from C ⁇ . a kyl, Ci.galkoxy, -(CH2)q-C3_7cycloalkyl optionally substituted by one or more Ci .galkyl groups, -CONR ⁇ RlO, -NHCORIO, - SO 2 NI ⁇ R9, -(CH 2 ) s HSO 2 R 10 , halogen, CN, OH, -(CH 2 ) S NR 1 1 R 12 , and trifluoromethyl;
  • R6 is selected from Ci .galkyl, C ⁇ _6alkoxy, halogen, trifluoromethyl and- (CH 2 ) s NRl lRl2;
  • R 7 is selected from hydrogen, Chalky., -(CH2)q-C3_7cycloalkyl optionally substituted by one or more C ⁇ _6al yl groups, trifluoromethyl, -(CH2) r heteroaryl optionally substituted by R 3 and/or R ⁇ 5 and -(CH2) r phenyl optionally substituted by R 1 and/or R 14 ;
  • R 8 is selected from hydrogen, C ⁇ .galkyl, C3_7cycloalkyl optionally substituted by one or more Ci. ⁇ alkyl groups, CONHR ⁇ , phenyl optionally substituted by Rl3 and/or R ⁇ , and heteroaryl optionally substituted by R 3 and/or R 4;
  • R9 and RIO are each independently selected from hydrogen and Ci . ⁇ alkyl, or R and lO, together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R ⁇ , wherein the ring may be substituted by up to two Ci.galkyl groups;
  • RU is selected from hydrogen, Ci.galkyl and -(CH2)q-C3_7cycloalkyl optionally substituted by one or more Ci . ⁇ alkyl groups
  • Ri 2 is selected from hydrogen and C ⁇ . ⁇ alkyl, or Ri 1 and R ⁇ , together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R ⁇ ;
  • Rl3 is selected from C galkyl, C ⁇ alkoxy, -(CH2)q-C3_7cycloalkyl optionally substituted by one or more C galkyl groups, -CONR ⁇ RIO, -NHCOR* 0, halogen, CN, -(CH2) S NR* ⁇ R ⁇ 2 , trifluoromethyl, phenyl optionally substituted by one or more R*4 groups and heteroaryl optionally substituted by one or more R*4 groups;
  • Rl4 is selected from Ci .galkyl, C ⁇ .galkoxy, halogen, trifluoromethyl and - NR n R 12 ;
  • Rl5 is selected from hydrogen and methyl;
  • X and Y are each independently selected from hydrogen, methyl and halogen
  • R is selected from hydrogen, Ci . ⁇ alkyl, C3_7cycloalkyl, phenyl optionally substituted by R ⁇ and/or ⁇ , and heteroaryl optionally substituted by R ⁇ and/or R ⁇
  • R 2 is selected from hydrogen, Ci ⁇ galkyl and -(CH2)q-C3_7cycloalkyl.
  • R is selected from C ⁇ . ⁇ alkyl, for example methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl, 2,2- dimethylpropyl, 1 -ethyl- 1-methyl-propyl, n-butyl, isobutyl, 3-methylbutyl, 1,1- dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2-pentyl or 1-methylpentyl, optionally substituted by up to three groups selected from C ⁇ alkoxy, in particular C ⁇ _4alkoxy groups such methoxy or t-butoxy, halogen, in particular fluorine, and hydroxy; C2-6 a lkenyl, for example C ⁇ galkenyl such as 3-methylbut-2-enyl or 1,1- dimethylbut-2-enyl; C3_7cycloalkyl optionally substituted by one or more C ⁇ . ⁇ alkyl
  • R* is Ci ⁇ galkyl, for example C2.5 alkyl, such as ethyl, n-propyl, isopropyl, 1-methyl ⁇ ropyl, 1,1- dimethylpropyl, 2,2-dimethylpropyl, n-butyl, isobutyl, 3-methylbutyl or 2-pentyl.
  • R is selected from C3_7cycloalkyl, phenyl optionally substituted by R ⁇ and/or R° and heteroaryl optionally substituted by R ⁇ and or R ⁇ .
  • R is selected from C3_gcycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, and phenyl optionally substituted by R ⁇ and/or R ⁇ .
  • the phenyl may be optionally substituted by one or two substituents, located on any position on the phenyl ring.
  • Preferred substituents for the phenyl include C ⁇ _4alkoxy, in particular methoxy, - (CH 2 ) S NR 11 R 12 J and-(CH2)sNHSO 2 R 10 .
  • R* is selected from C ⁇ _6alkyl, for example n-propyl, 1-methylpropyl, isobutyl, 3-methylbutyl or 2,2-dimethylpropyl, and C3_ 7cycloalkyl optionally substituted by one or more Ci.galkyl groups, for example cyclopropyl optionally substituted by one or two methyl groups.
  • R* is selected from Ci.galkyl, for example methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, 1 -ethyl- 1-methyl-propyl, n- butyl, isobutyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2-pentyl or 1- methylpentyl, optionally substituted by up to three groups selected from Ci . ⁇ alkoxy, in particular C ⁇ alkoxy groups such methoxy or t-butoxy, halogen, in particular fluorine, and hydroxy; C2-6 a lkenyl, for example C4_6alkenyl such as 3-methylbut-2- enyl or l,l-dimethylbut-2-enyl; C3_7cycloalkyl optionally substituted by one or more Ci.galkyl groups, for example, cycloprop
  • R 2 is selected from hydrogen; C ⁇ _4alkyl, in particular methyl, ethyl, isopropyl or isobutyl; and -(CH2)q-C3_6cycloalkyl, in particular cyclopropyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl or cyclohexyl.
  • R 2 is selected from hydrogen, C ⁇ _4alkyl and
  • R 2 is hydrogen.
  • (CH2) m R* and R 2 together with the nitrogen atom to which they are bound, form a four- to six-membered heterocyclic ring optionally substituted by up to three Ci.galkyl groups, in particular an azetidinyl, pyrrolidinyl or piperidinyl ring optionally substituted by one or two methyl, ethyl or propyl groups.
  • R3 is methyl
  • R is the group -CO-NH-(CH2)q-R 8 .
  • R ⁇ is selected from Ci. ⁇ alkyl, C ⁇ _ 6 alkoxy, -(CH 2 ) q -C3_7cycloalkyl, -CONR 9 R 10 , -NHCOR 10 , -SO 2 NHR 9 , - (CH 2 ) S NHS02R 10 , halogen, CN, OH, -(CH 2 ) S NR 11 R 12 , and trifluoromethyl.
  • R ⁇ is selected from C ⁇ alkyl, in particular methyl; C ⁇ _4alkoxy, in particular methoxy; -(CH2) s NHSO2R 10 ; halogen, in particular chlorine or fluorine; -(CH2) s NR i lR 12 ; and trifluoromethyl
  • R ⁇ is selected from C ⁇ _4alkoxy, in particular methoxy, -(CH2) s NR ⁇ R 12 and -(CH 2 ) s NHSO2R 10
  • R ⁇ is selected from C ⁇ alkyl, in particular methyl; C ⁇ _4alkoxy, in particular methoxy; halogen, in particular chlorine or fluorine; and trifluoromethyl.
  • R6 is selected from C _4alkyl, in particular methyl, ethyl or propyl; C ⁇ _4alkoxy, in particular methoxy; halogen, in particular chlorine or fluorine; and trifluoromethyl.
  • R ⁇ is C ⁇ _4alkoxy, in particular methoxy.
  • R 7 is selected from hydrogen
  • R 7 is selected from Ci.galkyl, -(CH2) -C3_ 7cycloalkyl, trifluoromethyl, -(CH2) r heteroaryl optionally substituted by R 3 and/or R!4 5 and -(CH2) r phenyl optionally substituted by Ci.galkyl, Ci. ⁇ alkoxy, -(CH2) ⁇ - C3_7cycloalkyl, -CONR 9 R 10 , -NHCOR 10 , halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R 1 ⁇ groups and/or heteroaryl optionally substituted by one or more R 1 ⁇ groups, hr another preferred embodiment, R 7 is selected from C ⁇ _4alkyl, -(CH2)q-C3_6cycloalkyl, trifluoromethyl, -(CH2) r heteroaryl optionally substituted by R 13 and or R ⁇ 5 and -(CH2) r phenyl
  • R 7 is -(CH2) r heteroaryl optionally substituted by R 13 and/or R ⁇ -4, in particular a five or six-membered heteroaryl containing at least one heteroatom selected from oxygen, nitrogen and sulfur, for example, pyridinyl optionally substituted by -NR ⁇ 12 , furyl or thiophenyl.
  • R 8 is selected from hydrogen, Ci. ⁇ alkyl, C3_7cycloalkyl, CONHR 9 , phenyl optionally substituted by R 13 and/or R*4, and heteroaryl optionally substituted by R 3 and/or R 1 ⁇ hi a preferred embodiment, R 8 is selected from C3_7cycloalkyl, CONHR 9 , heteroaryl optionally substituted by R 13 and/or R!4, and phenyl optionally substituted by C ⁇ _ 6 alkyl, C ⁇ _ 6 alkoxy, -(CH2)q-C 3 .
  • R 8 is selected from C3_7cycloalkyl, heteroaryl optionally substituted by R 13 and/or R 1 ⁇ , and phenyl optionally substituted C ⁇ alkyl, C ⁇ _ 6 alkoxy, -(CH 2 )q-C3.
  • R 8 is selected from C3_6"cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, heteroaryl optionally substituted by R 13 and/or R!4, in particular a five or six-membered heteroaryl containing at least one heteroatom selected from nitrogen and sulfur, for example, thiazolyl or thiadiazolyl, and phenyl optionally substituted by heteroaryl.
  • R 8 is selected from C3_5cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl.
  • R 9 is selected from hydrogen and C _4alkyl.
  • R 10 is selected from hydrogen and C ⁇ _4alkyl, in particular methyl.
  • R 1 1 is selected from hydrogen, Ci.galkyl and -(CH2)q- C3_7cycloalkyl optionally substituted by Ci.galkyl.
  • R ! and R 2 together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally further containing one additional heteroatom N-R 1 ⁇ .
  • R 13 is selected from C ⁇ _galkyl, C ⁇ _ 6 alkoxy, -(CH 2 ) q -C 3 _7cycloalkyl, -CONR 9 R 10 , -NHCOR 10 , halogen, CN, - (CH2) S NR 1 ⁇ -R ⁇ , trifluoromethyl, phenyl optionally substituted by one or more R ⁇ 4 groups and heteroaryl optionally substituted by one or more R 1 ⁇ groups;
  • R 13 is selected from Chalky!, in particular methyl, C ⁇ _4alkoxy, in particular methoxy, halogen, -(CH2)sNR 1 1 R 12 , phenyl optionally substituted by one or more R*4 groups and heteroaryl optionally substituted by one or more R*4 groups.
  • R 13 is selected from - (CH2) S NR 1 ⁇ 12 and heteroaryl optionally substituted by one or more R ⁇ groups, in particular a five or six-membered heteroaryl containing at least one nitrogen atom, for example, pyridyl.
  • R 1 ⁇ is selected from from C ⁇ _4alkyl, in particular methyl, C ⁇ _4alkoxy, in particular methoxy, and -NR 1 ⁇ 12 .
  • R 1 ⁇ is methyl
  • X and Y are each independently selected from hydrogen, chlorine and fluorine, hi a further preferred embodiment, X is fluorine, h another preferred embodiment, Y is hydrogen. In a preferred embodiment, Z is fluorine.
  • m is selected from 0, 1, 2, 3 and 4.
  • m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chain may be optionally substituted with up to two groups selected independently from Chalky..
  • m is selected from 0, 1, 2 and 3.
  • m is selected from 0, 1 and 2, in particular 0 and 1.
  • these substituents are preferably one or two methyl groups or fluorine atoms, hi one embodiment, the substituents are preferably one or two methyl groups, h another embodiment, the substituents are preferably one or two fluorine atoms.
  • n is selected from 0 and 1. In particular, n is 0.
  • q is selected from 0 and 1. In particular, q is 0.
  • r is 0. hi a preferred embodiment, s is selected from 0 and 1. It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove.
  • Particular compounds according to the invention include those mentioned in the Examples. Specific examples which may be mentioned include: 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclopropylmethyl- nicotinamide; 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(l-cyclopropylethyl)- nicotinamide;
  • Futher specific examples which may be mentioned include: 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclobutylmethyl- nicotinamide;
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C ⁇ _6alkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, isobutyl, isopropyl and t-butyl.
  • a C _4alkyl group is preferred, for example methyl, ethyl, isopropyl or t-butyl.
  • the said alkyl groups may be optionally substituted with one or more fluorine atoms for example, trifluoromethyl.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and containing at least one double bond.
  • C2_6 a k en y means a straight or branched alkenyl containing at least 2, and at most 6, carbon atoms and containing at least one double bond.
  • alkenyl as used herein include, but are not limited to ethenyl, propenyl, 3-methylbut-2-enyl and l,l-dimethylbut-2-enyl.
  • alkoxy refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2- methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.
  • a C ⁇ _4alkoxy group is preferred, for example methoxy or ethoxy.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms which may optionally contain up to one double bond.
  • C3_7cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms.
  • Examples of "cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a C3_gcycloalkyl group is preferred, for example, cyclopropyl, cyclopentyl or cyclohexyl.
  • the said cycloalkyl groups may be optionally substituted with one or more Ci.galkyl groups, for example one or two methyl groups, hi one embodiment, the cycloalkyl groups may be optionally substituted by up to four C _galkyl groups, for example one or two C ⁇ _galkyl groups, in particular one or two C ⁇ alkyl groups such as methyl or ethyl.
  • heteroaryl ring and “heteroaryl” refer to a monocyclic five- to seven-membered unsaturated hydrocarbon ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur.
  • the heteroaryl ring has five or six ring atoms.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • the said ring may be optionally substituted by one or more substituents independently selected from C ⁇ _ galkyl and oxy.
  • heterocyclic ring or “heterocyclyl” refer to a monocyclic three- to seven-membered saturated hydrocarbon ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur.
  • the heterocyclyl ring has five or six ring atoms.
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, mo holino, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholino.
  • the said ring may be optionally substituted by one or more substituents independently selected from C ⁇ _galkyl and oxy.
  • halogen refers to the elements fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. A particularly preferred halogen is fluorine or chlorine.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
  • the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. All such solvates are included within the scope of the present invention.
  • Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism).
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
  • compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • Salts of the compounds of the present invention are also encompassed within the scope of the invention and may, for example, comprise acid addition salts resulting from reaction of an acid with a basic nitrogen atom present in a compound of formula (I).
  • Salts encompassed within the tenn "pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulf
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • a compound of formula (I) may be prepared by reacting a compound of (II)
  • a compound of formula (H) may readily be prepared from a corresponding acid compound of formula (IV)
  • Suitable amide forming conditions are well known in the art and include treating a solution of the acid of formula (IV), or the activated form thereof, in for example acetone or dichloromethane, with an amine of formula (V) in the presence of sodium carbonate.
  • a compound of formula (IH) may be prepared by reacting a compound of formula (VI)
  • a compound of formula (Ifl) may be prepared by reacting an acid compound of formula (VLI)
  • a compound of formula (I) may also be prepared by reacting a compound of formula (VET)
  • a compound of formula (I) may be prepared by reacting a compound of (fl) as hereinbefore defined with a compound of formula (LX)
  • Scheme 3 i. Bis(pinnacolato)diboron, PdCl 2 dppf, KOAc, DMF. ii. R8(CH 2 )qNH 2 , HATU, DIPEA, DMF. iii. SOCl 2 . iv. R 1 (CH 2 ) m R 2 NH, Na 2 CO 3 , DCM. v. Na CO 3 , tetrakis(triphenylphosphine)palladium, propan-2-ol.
  • a further general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 5 below.
  • the compounds of formula (I) may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration.
  • the pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I).
  • a particularly preferred method of administration, and corresponding formulation, is oral administration.
  • the pharmaceutical composition may take the form of, and be administered as, for example, tablets (including sub-lingual tablets) and capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, emulsions, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the present invention can also be administered in the form of liposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • the present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (I) in combination with a pharmaceutically acceptable carrier.
  • the composition may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intraperitoneal, intraarticular, subcutaneous or intramuscular, inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
  • the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously).
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle.
  • the compounds of the invention may also be formulated as a depot preparation. Such long acting fonnulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the composition may be formulated for topical application, for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
  • Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.
  • Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropan
  • compositions generally are administered in an amount effective for treatment or prophylaxis of a specific condition or conditions.
  • Initial dosing in human is accompanied by clinical monitoring of symptoms, such symptoms for the selected condition, hi general, the compositions are administered in an amount of active agent of at least about 100 ⁇ g/kg body weight. In most cases they will be administered in one or more doses in an amount not in excess of about 20 mg/kg body weight per day. Preferably, in most cases, dose is from about 100 ⁇ g/kg to about 5 mg/kg body weight, daily.
  • the daily dosage level of the active agent will be from 0. 1 mg/kg to 10 mg/kg and typically around 1 mg/kg.
  • optimum dosage will be determined by standard methods for each treatment modality and indication, taking into account the indication, its severity, route of administration, complicating conditions and the like.
  • the physician in any event will determine the actual dosage which will be most suitable for an individual and will vary with the age, weight and response of the particular individual.
  • the effectiveness of a selected actual dose can readily be determined, for example, by measuring clinical symptoms or standard anti-inflammatory indicia after administration of the selected dose.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the present invention provides a compound of formula (I) for use in therapy.
  • the compounds of the present invention are generally inhibitors of the serine/threonine kinase p38 and are therefore also inhibitors of cytokine production which is mediated by p38 kinase.
  • inhibitors of the serine/threonine kinase p38 are included those compounds that interfere with the ability of p38 to transfer a phosphate group from ATP to a protein substrate according to the assay described below.
  • the compounds of the invention may be selective for one or more of the isoforms of p38, for example p38 ⁇ , p38/3, p38 ⁇ and/or p38 ⁇ .
  • the compounds of the invention selectively inhibit the p38c isoform.
  • the compounds of the invention selectively inhibit the p383 isoform.
  • the compounds of the invention selectively inhibit the p38 ⁇ and p38/3 isoforms.
  • Assays for determining the selectivity of compounds for the p38 isoforms are described in, for example, WO 99/61426, WO 00/71535 and WO 02/46158.
  • p38 kinase activity can be elevated (locally or throughout the body), p38 kinase can be incorrectly temporally active or expressed, p38 kinase can be expressed or active in an inappropriate location, p38 kinase can be constitutively expressed, or p38 kinase expression can be erratic; similarly, cytokine production mediated by p38 kinase activity can be occurring at inappropriate times, inappropriate locations, or it can occur at detrimentally high levels.
  • the present invention provides a method for the treatment of a condition or disease state mediated by p38 kinase activity, or mediated by cytokines produced by the activity of p38 kinase, in a subject which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
  • the compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.
  • the present invention also provides a method of inhibiting cytokine production which is mediated by p38 kinase activity in a subject, e.g. a human, which comprises administering to said subject in need of cytokine production inhibition a therapeutic, or cytokine-inhibiting, amount of a compound of the present invention.
  • the compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.
  • the present invention treats these conditions by providing a therapeutically effective amount of a compound of this invention.
  • therapeutically effective amount is meant a symptom-alleviating or symptom-reducing amount, a cytokine- reducing amount, a cytokine-inhibiting amount, a kinase-regulating amount and/or a kinase-inhibiting amount of a compound.
  • Such amounts can be readily determined by standard methods, such as by measuring cytokine levels or observing alleviation of clinical symptoms. For example, the clinician can monitor accepted measurement scores for anti-inflammatory treatments.
  • the compounds of the present invention can be administered to any subject in need of inhibition or regulation of p38 kinase or in need of inhibition or regulation of p38 mediated cytokine production, hi particular, the compounds maybe administered to mammals.
  • mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably, humans.
  • the present invention provides methods of treating or reducing symptoms in a human or animal subject suffering from, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritable bowel syndrome, muscle degeneration, bone resorption diseases, osteoporosis, diabetes, reperfusion injury, graft vs.
  • rheumatoid arthritis arthritis
  • osteoarthritis asthma
  • psoriasis eczema
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, chronic pulmonary inflammation, chronic obstructive pulmonary disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease and epilepsy which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from any type of pain including chronic pain, rapid onset of analgesis, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain associated with osteoarthritis and rheumatoid arthritis, post operative inflammatory pain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia, post- hepatic neuralgia, inflammatory neuropathies and migraine pain which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds of formula (I) may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) and at least one other pharmaceutically active agent.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur separately or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Examples of other pharmaceutically active agents which may be employed in combination with compounds of fonnula (I) for rheumatoid arthritis therapy include: immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone; anti-
  • TNF ⁇ agents such as etanercept, infliximab, diacerein; tyrosine kinase inhibitors such as leflunoniide; kallikrein antagonists such as subreum; interleukin 11 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interleukin 1 receptor antagonists such as anakinra; CD 8 antagonists such as amiprilose hydrochloride; beta amyloid precursor protein antagonists such as reumacon; matrix metalloprotease inhibitors such as cipemastat and other disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine, auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.
  • DMARDs disease modifying anti
  • LCMS was conducted on a column (3.3cm x 4.6mm ID, 3um ABZ+PLUS), at a Flow Rate of 3ml/min, Injection Volume of 5 ⁇ l, at room temperature and UV Detection Range at 215 to 330nm.
  • 6-Bromonicotinic acid 200mg, 0.99mmol was heated at reflux in thionyl chloride (2ml) for 2.5hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (4ml), cyclopropylmethylamine (71mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N- cyclopropylmethylnicotinamide as a cream solid.
  • 6-Bromonicotinic acid 200mg, 0.99mmol was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), p-anisidine (123mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(4- methoxyphenyl)nicotinamide.
  • 6-Bromonicotinic acid 200mg, 0.99mmol was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), 3-methoxybenzylamine (137mg, O.lOmmol) and sodium carbonate
  • 6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), 3-methylsulphonylaminobenzylamine (200mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide.
  • 6-Bromonicotinic acid 200mg, 0.99mmol was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), l-(2-aminobenzyl)-4-methylpiperazine (205mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-[2-(4-methylpiperazin-l-yl)phenyl]nicotinamide.
  • N-Cyclopropyl-3-iodo-4-methylbenzamide (Intermediate 9) (l.lg, 3.64mmol), bis(pinnacolato)diboron (1.85g, 7.28mmol), potassium acetate (1.79g, 18.2mmol) and PdCl 2 dppf (55mg) were heated at 85°C in DMF (30ml) for 4.5hrs. The cooled reaction was absorbed onto silica, applied to a bond-elut (lOg, silica) and eluted with an ethylacetate / cyclohexane gradient (0 to 100%).
  • N-(3-Iodo-4-methylphenyl)-3-furamide (Intermediate 15) (2.5g, 7.64mmol), bis(pinnacolato)diboron (2.13g, 8.41mmol), potassium acetate (825mg, 8.41mmol) and PdCl 2 dppf (312mg, 0.38mmol) in DMF (20ml) were heated at 80°C for 20hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient.
  • the product fractions were concentrated under vacuum, dissolved in DMF (40ml) and reacted with bis(pi ⁇ acolato)diboron (7.76g, 30.57mmol), potassium acetate (3.0g, 30.57mmo ⁇ ) and PdCl 2 dppf (249mg, 0.306mmol) at 80°C for 23 hrs.
  • the cooled reaction was absorbed onto silica and applied to bond-eluts (silica, 2 xlOg) and eluted with a cyclohexane / ethyl acetate gradient.
  • the product fractions were concentrated under vacuum, dissolved in DMF (20ml) and reacted with bis(pi ⁇ acolato)diboron (1.77g, 7.0mmol), potassium acetate (687mg, 7.0mmol) and PdCl 2 dppf (143mg, 0.175mmol) at 80°C for 16 hrs.
  • the cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient.
  • aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml).
  • the organic phase was dried (magnesium sulphate) and absorbed onto silica.
  • the silica was applied to a flash silica column and eluted with cyclohexane / ethyl acetate (3:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)-3-furamide.
  • LCMS retention time 3.52min, MH + 328.
  • 6-Bromonicotinic acid 200mg, 0.99mmol was heated at reflux in thionyl chloride (2ml) for 2.5hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (4ml), cyclopropylmethylamine (71mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N- cyclopropylmethylnicotinamide as a cream solid.
  • 6-Bromonicotinic acid (lOOmg, 0.5mmol) was heated at 95°C in thionyl chloride (0.63ml) for 2hours. The excess thionyl chloride was evaporated under vacuum and the residue dissolved in DCM (2ml). To this solution, amine (0.5mmol) and sodium carbonate (lOOmg) were added and the reaction was stirred at room temperature for 2hours. The reaction was filtered and the residue washed with DCM. The combined filtrate and washings were reduced to dryness to give the desired 6- chloronicotinamide.
  • 6-Chloro-N-cyclobutylmethylnicotinamide was prepared from cyclobutylmethylamine using General Method A.
  • 6-Chloro-N-(l-methylpropyl)nicotinamide was prepared from 1- methylpropylamine using General Method A.
  • N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5g) in THF (75ml) was cooled to 0°C and sodium hydride (60%, 1.23g) added portionwise over lOminutes. Once effervescence had ceased the reaction was cooled to -75°C and n- butyl lithium (1.6M in hexanes, 20ml) added over 25minutes maintaining a temperature of ⁇ -70°C. Triisopropyl borate (8ml) was added to the reaction over lOminutes and the reaction stirred at -70°C for 4hours. The reaction was quenched with water (20ml) and the mixture allowed to warm to 5°C.
  • the residue was mixed with thionyl chloride (30ml) and heated at 100°C for 2.5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ml). Sodium carbonate (25g ) and cyclopropylamine (13ml) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum.
  • 6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (18.5mg, 0.073mmol) and 4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) (30mg, 0.072mmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4mg) were heated at 90°C in DMF (1ml) for 4hours.
  • 6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5mg, 0. lOmmol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)-benzamide (hitermediate 8) (30mg, O.lOmmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4mg) were heated at 90°C in DMF (lml) for 3hours.
  • N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide
  • N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (hitermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiazol-2-yl)-benzamide (Intermediate 11) using General Method B.
  • LCMS retention time 2.99min, MH + 393.
  • 6-[5-(Cyclopropylmethyl)carbamoyl-2-methyl-phenyl]-N-cyclopropylmethyl- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-(cyclopropylmethyl)-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B.
  • N-Cyclopropylmethyl-6-[5-(fur-3-ylcarbonylamino)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl] -3 -furamide (Intermediate 13) using General Method B.
  • LCMS retention time 2.96min, MH + 376.
  • N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide
  • 6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (hitermediate 2) and N-cyclopro ⁇ yl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B.
  • LCMS retention time 2.96min, MH + 402.
  • N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide
  • N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (hitermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiazol-2-yl)-benzamide (hitermediate 11) using General Method B.
  • LCMS retention time 3.22min, MH + 445.
  • Example 12 6-(5-Cy clopropylmethylcarb amoyl-2-methy l-phenyl)-N-(4- methoxyphenvD-nicotinamide
  • 6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B.
  • LCMS retention time 3.12min, MH + 416.
  • 6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl] -3 -furamide (hitermediate 13) using General Method B.
  • LCMS retention time 3.19min, MH + 428.
  • 6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B.
  • N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide
  • N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiazol-2-yl)-benzamide (Intermediate 11) using General Method B.
  • LCMS retention time 3.20min, MH + 459.
  • 6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B.
  • 6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methoxybenzyl)- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]-3-furamide (hitermediate 13) using General Method B.
  • LCMS retention time 3.17min, MH + 442.
  • N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide
  • 6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3- methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropyl-4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B.
  • LCMS retention time 2.71min, MH + 479.
  • N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiadiazol-2- ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5- tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B.
  • LCMS retention time 2.80min, MH + 523.
  • N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)- phenyl] -nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B.
  • LCMS retention time 2.96min, MH + 522.
  • 6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3- methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N- cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzamide (Intermediate 10) using General Method B.
  • LCMS retention time 2.88min, MH + 493.
  • 6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3- methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B.
  • LCMS retention time 2.93min, MH + 505.
  • N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2- methyl-phenyl] -nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3- (4,4,5 , 5-tetramethyl- [1,3,2] dioxaborolan-2-yl)-phenyl] thiophene-3 -amide (Intermediate 14) using General Method B.
  • LCMS retention time 3.03min, MH + 521.
  • 6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-l- ylmethyl)phenyl] -nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin- l-ylmethyl)phenyl]nicotinamide (hitermediate 5) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (rnteraiediate 8) using General Method B.
  • LCMS retention time 2.36min, MH + 484.
  • NMR ⁇ H [ 2 H 6 ]-
  • N- [2-(4-Methylpiperazin- 1 -ylmethyl)phenyl] -6- [2-methyl-5 -(thiadiazol-2- ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4- methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3- (4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B.
  • LCMS retention time 2.43min, MH + 528.
  • Example 28 N-f2-(4-Methylpiperazin-l-yImethvPphenyll-6-f2-methyl-5- (thiazol-2-ylcarb amoyP-phenyll -nicotin amide
  • N-[2-(4-Methylpiperazin-l-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2- ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4- methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (hitermediate 11) using General Method B.
  • LCMS retention time 2.53min, MH + 527.
  • 6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-[2-(4- methylpiperazin-l-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2- (4-methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N- cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzamide (Intermediate 10) using General Method B.
  • LCMS retention time 2.46min, MH + 498.
  • 6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-[2-(4-methylpiperazin-l- ylmethyl)phenyl] -nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin- l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (hitermediate 13) using General Method B.
  • LCMS retention time 2.53min, MH + 510.
  • N-[2-(4-Methylpiperazin-l-ylmethyl)phenyl]-6-[5-(thiophen-3- ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-[2- (4-methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (hitermediate 14) using General Method B.
  • LCMS retention time 2.58min, MH + 526.
  • Examples 32 to 44 may also be prepared using ⁇ 5-[(cyclopropylamino)carbonyl]-3- fluoro-2-methylphenyl ⁇ boronic acid (Intermediate 36) in place of Intermediate 34.
  • the peptide substrate used in the p38 assay was biotin-ff TSPITTTYFFFRRR- amide.
  • the p38 and MEK6 proteins were purified to homogeneity from E.coli expression systems.
  • the fusion proteins were tagged at the N-terminus with Glutathione-S-Transferase (GST).
  • the maximum activation was achieved by incubating 20uL of a reaction mixture of 30nM MEK6 protein and 120nM p38 protein in the presence of 1.5uM peptide and lOmM Mg(CH 3 CO 2 ) 2 in lOOmM HEPES, pH 7.5, added to 15uL of a mixture of 1.5uM ATP with 0.08uCi [g- 33 P]ATP, with or without 15uL of inhibitor in 6%DMSO.
  • the controls were reactions in the presence (negative controls) or absence (positive controls) of 50 mM EDTA. Reactions were allowed to proceed for 60 min at room temperature and quenched with addition of 50uL of 250mM EDTA and mixed with 150uL of Streptavidin SPA beads

Abstract

Compounds of formula (I), are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38.

Description

NICOTINAMIDE DERIVATES USEFUL AS P38 INHIBITORS
This invention relates to novel compounds and their use as pharmaceuticals, particularly as p38 kinase inhibitors, for the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokmes produced by the activity of p38 kinase.
We have now found a group of novel compounds that are inhibitors of p38 kinase.
According to the invention there is provided a compound of formula (I):
Figure imgf000002_0001
(I)
wherein R1 is selected from hydrogen, C^.galkyl optionally substituted by up to three groups selected from Ci.βalkoxy, halogen and hydroxy, C2_6alkenyl, C3_7cycloalkyl optionally substituted by one or more C^.galkyl groups, phenyl optionally substituted by up to three groups selected from R^ and R°, and heteroaryl optionally substituted by up to three groups selected from R.5 and R.6, R.2 is selected from hydrogen, Cj.galkyl and -(CH2)q-C3_7cycloalkyl optionally substituted by one or more C^.galkyl groups, or (CH2)mR. and R.2, together with the nitrogen atom to which they are bound, form a four- to six-membered heterocyclic ring optionally substituted by up to three Ci.galkyl groups; R.3 is chloro or methyl;
R4 is the group -NH-CO-R7 or -CO-NH-(CH )q-R8; R5 is selected from C\. a kyl, Ci.galkoxy, -(CH2)q-C3_7cycloalkyl optionally substituted by one or more Ci .galkyl groups, -CONR^RlO, -NHCORIO, - SO2NIΓR9, -(CH2)s HSO2R10, halogen, CN, OH, -(CH2)SNR1 1R12, and trifluoromethyl;
R6 is selected from Ci .galkyl, Cι_6alkoxy, halogen, trifluoromethyl and- (CH2)sNRl lRl2; R7 is selected from hydrogen, Chalky., -(CH2)q-C3_7cycloalkyl optionally substituted by one or more Cι_6al yl groups, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R 3 and/or R^5 and -(CH2)rphenyl optionally substituted by R1 and/or R14; R8 is selected from hydrogen, C^.galkyl, C3_7cycloalkyl optionally substituted by one or more Ci.βalkyl groups, CONHR^, phenyl optionally substituted by Rl3 and/or R^, and heteroaryl optionally substituted by R 3 and/or R 4;
R9 and RIO are each independently selected from hydrogen and Ci .βalkyl, or R and lO, together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R^, wherein the ring may be substituted by up to two Ci.galkyl groups;
RU is selected from hydrogen, Ci.galkyl and -(CH2)q-C3_7cycloalkyl optionally substituted by one or more Ci .βalkyl groups, Ri 2 is selected from hydrogen and C \ .βalkyl, or Ri 1 and R^, together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R^;
Rl3 is selected from C galkyl, C^alkoxy, -(CH2)q-C3_7cycloalkyl optionally substituted by one or more C galkyl groups, -CONR^RIO, -NHCOR* 0, halogen, CN, -(CH2)SNR* ^R^2, trifluoromethyl, phenyl optionally substituted by one or more R*4 groups and heteroaryl optionally substituted by one or more R*4 groups;
Rl4 is selected from Ci .galkyl, Cι .galkoxy, halogen, trifluoromethyl and - NRnR12; Rl5 is selected from hydrogen and methyl;
X and Y are each independently selected from hydrogen, methyl and halogen;
Z is halogen; m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chain may be optionally substituted with up to two groups selected independently from C .galkyl and halogen; n is selected from 0, 1 and 2; q is selected from 0, 1 and 2; r is selected from 0 and 1 ; and s is selected from 0, 1, 2 and 3. According to a further embodiment of the invention there is provided a compound of formula (IA):
Figure imgf000004_0001
(IA) wherein Rl, R2, R35 R4 and m are as defined above.
According to one embodiment of the present invention, R is selected from hydrogen, Ci .βalkyl, C3_7cycloalkyl, phenyl optionally substituted by R^ and/or ^, and heteroaryl optionally substituted by R^ and/or R^, and R2 is selected from hydrogen, Ci^galkyl and -(CH2)q-C3_7cycloalkyl.
In a preferred embodiment, R is selected from C^.^alkyl, for example methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl, 2,2- dimethylpropyl, 1 -ethyl- 1-methyl-propyl, n-butyl, isobutyl, 3-methylbutyl, 1,1- dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2-pentyl or 1-methylpentyl, optionally substituted by up to three groups selected from C^alkoxy, in particular Cι_4alkoxy groups such methoxy or t-butoxy, halogen, in particular fluorine, and hydroxy; C2-6alkenyl, for example C^galkenyl such as 3-methylbut-2-enyl or 1,1- dimethylbut-2-enyl; C3_7cycloalkyl optionally substituted by one or more C \ .galkyl groups, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, optionally substituted by one or two Cι_4alkyl groups such as methyl or ethyl; phenyl optionally substituted by up to three groups selected from R^ and R^, for example phenyl optionally substituted by up to three substituents, for example one or two substituents, such as Cι_4alkyl, in particular methyl, Cι_4alkoxy, in particular methoxy, halogen, in particular fluorine or chlorine, trifluoromethyl, - (CH2)SNR1 !R12 or -(CH2)s HSO2R1 °, located on any position on the ring; heteroaryl optionally substituted by up to three groups selected from R^ and R° for example heteroaryl optionally substituted by one or two substituents, in particular a 5- membered heteroaryl such as furyl, thienyl or thiazolyl optionally substituted by Cy 4alkyl, in particular methyl. In a particularly preferred embodiment, R* is Ci^galkyl, for example C2.5 alkyl, such as ethyl, n-propyl, isopropyl, 1-methylρropyl, 1,1- dimethylpropyl, 2,2-dimethylpropyl, n-butyl, isobutyl, 3-methylbutyl or 2-pentyl.
In another preferred embodiment, R is selected from C3_7cycloalkyl, phenyl optionally substituted by R^ and/or R° and heteroaryl optionally substituted by R^ and or R^. In a more preferred embodiment, R is selected from C3_gcycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, and phenyl optionally substituted by R^ and/or R^. The phenyl may be optionally substituted by one or two substituents, located on any position on the phenyl ring. Preferred substituents for the phenyl include Cι_4alkoxy, in particular methoxy, - (CH2)SNR11R12 J and-(CH2)sNHSO2R10.
In another preferred embodiment, R* is selected from Cι_6alkyl, for example n-propyl, 1-methylpropyl, isobutyl, 3-methylbutyl or 2,2-dimethylpropyl, and C3_ 7cycloalkyl optionally substituted by one or more Ci.galkyl groups, for example cyclopropyl optionally substituted by one or two methyl groups.
In a further preferred embodiment, R* is selected from Ci.galkyl, for example methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, 1 -ethyl- 1-methyl-propyl, n- butyl, isobutyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2-pentyl or 1- methylpentyl, optionally substituted by up to three groups selected from Ci .βalkoxy, in particular C^alkoxy groups such methoxy or t-butoxy, halogen, in particular fluorine, and hydroxy; C2-6alkenyl, for example C4_6alkenyl such as 3-methylbut-2- enyl or l,l-dimethylbut-2-enyl; C3_7cycloalkyl optionally substituted by one or more Ci.galkyl groups, for example, cyclopropyl, cyclopentyl or cyclohexyl, optionally substituted by one or two ethyl groups; phenyl optionally substituted by up to three groups selected from R^ and R", for example phenyl optionally substituted by up to three substituents such as C1.4a.kyl, in particular methyl, C1.4aU.oxy, in particular methoxy, halogen, in particular fluorine or chlorine and trifluoromethyl, located on any position on the ring; heteroaryl optionally substituted by up to three groups selected from R^ and R", in particular a 5-membered heteroaryl such as furyl, thienyl or thiazolyl optionally substituted by C^alkyl, in particular methyl.
In a preferred embodiment, R2 is selected from hydrogen; Cι_4alkyl, in particular methyl, ethyl, isopropyl or isobutyl; and -(CH2)q-C3_6cycloalkyl, in particular cyclopropyl, -CH2-cyclopentyl, -(CH2)2-cyclopentyl or cyclohexyl. In another preferred embodiment, R2 is selected from hydrogen, Cι_4alkyl and
-CH2-cyclopropyl. More preferably R2 is hydrogen. h a further preferred embodiment, (CH2)mR* and R2, together with the nitrogen atom to which they are bound, form a four- to six-membered heterocyclic ring optionally substituted by up to three Ci.galkyl groups, in particular an azetidinyl, pyrrolidinyl or piperidinyl ring optionally substituted by one or two methyl, ethyl or propyl groups.
In a preferred embodiment, R3 is methyl.
In a preferred embodiment, R is the group -CO-NH-(CH2)q-R8. In one embodiment of the present invention, R^ is selected from Ci.βalkyl, Cι_6alkoxy, -(CH2)q-C3_7cycloalkyl, -CONR9R10, -NHCOR10, -SO2NHR9, - (CH2)SNHS02R10, halogen, CN, OH, -(CH2)SNR11R12, and trifluoromethyl. In a preferred embodiment, R^ is selected from C^alkyl, in particular methyl; Cι_4alkoxy, in particular methoxy; -(CH2)sNHSO2R10; halogen, in particular chlorine or fluorine; -(CH2)sNRilR12; and trifluoromethyl In another preferred embodiment, R^ is selected from Cι_4alkoxy, in particular methoxy, -(CH2)sNRπR12 and -(CH2)sNHSO2R10
In a further preferred embodiment, R^ is selected from C^alkyl, in particular methyl; Cι_4alkoxy, in particular methoxy; halogen, in particular chlorine or fluorine; and trifluoromethyl. In a preferred embodiment, R6 is selected from C _4alkyl, in particular methyl, ethyl or propyl; Cι_4alkoxy, in particular methoxy; halogen, in particular chlorine or fluorine; and trifluoromethyl.
In a further preferred embodiment, R^ is Cι_4alkoxy, in particular methoxy. In one embodiment of the present invention, R7 is selected from hydrogen,
C .galkyl, -(CH2)q-C3_7cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R13 and/or R^, and -(CH2)rphenyl optionally substituted by R13 and/or R14.
In a preferred embodiment, R7 is selected from Ci.galkyl, -(CH2) -C3_ 7cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R 3 and/or R!45 and -(CH2)rphenyl optionally substituted by Ci.galkyl, Ci.βalkoxy, -(CH2)π- C3_7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R1^ groups and/or heteroaryl optionally substituted by one or more R1^ groups, hr another preferred embodiment, R7 is selected from Cι_4alkyl, -(CH2)q-C3_6cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R13 and or R^5 and -(CH2)rphenyl optionally substituted by Cι_6alkyl, Cι_6alkoxy, -(CH2)q-C3_7cycloalkyl5 -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R ^ groups and/or heteroaryl optionally substituted by one or more R1^ groups. In a more preferred embodiment, R7 is -(CH2)rheteroaryl optionally substituted by R13 and/or R^-4, in particular a five or six-membered heteroaryl containing at least one heteroatom selected from oxygen, nitrogen and sulfur, for example, pyridinyl optionally substituted by -NR ^12, furyl or thiophenyl.
In one embodiment of the present invention, R8 is selected from hydrogen, Ci.βalkyl, C3_7cycloalkyl, CONHR9, phenyl optionally substituted by R13 and/or R*4, and heteroaryl optionally substituted by R 3 and/or R1^ hi a preferred embodiment, R8 is selected from C3_7cycloalkyl, CONHR9, heteroaryl optionally substituted by R13 and/or R!4, and phenyl optionally substituted by Cι_6alkyl, Cι_6alkoxy, -(CH2)q-C3.7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R ^ groups and/or heteroaryl optionally substituted by one or more R* groups, hi another preferred embodiment, R8 is selected from C3_7cycloalkyl, heteroaryl optionally substituted by R13 and/or R1^, and phenyl optionally substituted C^alkyl, Cι_ 6alkoxy, -(CH2)q-C3.7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R1^ groups and/or heteroaryl optionally substituted by one or more R*4 groups, hi a more preferred embodiment, R8 is selected from C3_6"cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, heteroaryl optionally substituted by R13 and/or R!4, in particular a five or six-membered heteroaryl containing at least one heteroatom selected from nitrogen and sulfur, for example, thiazolyl or thiadiazolyl, and phenyl optionally substituted by heteroaryl. hi a particularly preferred embodiment, R8 is selected from C3_5cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl. hi a preferred embodiment, R9 is selected from hydrogen and C _4alkyl. h a preferred embodiment, R10 is selected from hydrogen and Cι_4alkyl, in particular methyl.
In one embodiment, R1 1 is selected from hydrogen, Ci.galkyl and -(CH2)q- C3_7cycloalkyl optionally substituted by Ci.galkyl. In a preferred embodiment, R ! and R 2, together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally further containing one additional heteroatom N-R1^.
In one embodiment of the present invention, R13 is selected from Cι_galkyl, Cι_6alkoxy, -(CH2)q-C3_7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, - (CH2)SNR1 ^-R^, trifluoromethyl, phenyl optionally substituted by one or more RΪ4 groups and heteroaryl optionally substituted by one or more R1^ groups;
In a preferred embodiment, R13 is selected from Chalky!, in particular methyl, Cι_4alkoxy, in particular methoxy, halogen, -(CH2)sNR1 1R12, phenyl optionally substituted by one or more R*4 groups and heteroaryl optionally substituted by one or more R*4 groups. In a more preferred embodiment, R13 is selected from - (CH2)SNR1 ^12 and heteroaryl optionally substituted by one or more R ^ groups, in particular a five or six-membered heteroaryl containing at least one nitrogen atom, for example, pyridyl.
In a preferred embodiment R1^ is selected from from Cι_4alkyl, in particular methyl, Cι_4alkoxy, in particular methoxy, and -NR1 ^12.
In a preferred embodiment, R1^ is methyl.
In a preferred embodiment, X and Y are each independently selected from hydrogen, chlorine and fluorine, hi a further preferred embodiment, X is fluorine, h another preferred embodiment, Y is hydrogen. In a preferred embodiment, Z is fluorine. i one embodiment of the present invention, m is selected from 0, 1, 2, 3 and 4. i another embodiment of the present invention, m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chain may be optionally substituted with up to two groups selected independently from Chalky.. hi a preferred embodiment, m is selected from 0, 1, 2 and 3. hi a further preferred embodiment, m is selected from 0, 1 and 2, in particular 0 and 1. When the carbon chain of m is substituted, these substituents are preferably one or two methyl groups or fluorine atoms, hi one embodiment, the substituents are preferably one or two methyl groups, h another embodiment, the substituents are preferably one or two fluorine atoms. h a preferred embodiment, n is selected from 0 and 1. In particular, n is 0. h a preferred embodiment, q is selected from 0 and 1. In particular, q is 0.
In a preferred embodiment, r is 0. hi a preferred embodiment, s is selected from 0 and 1. It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove.
Particular compounds according to the invention include those mentioned in the Examples. Specific examples which may be mentioned include: 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclopropylmethyl- nicotinamide; 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(l-cyclopropylethyl)- nicotinamide;
6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide; 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)- nicotinamide; and
6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(l-methylpropyl)- nicotinamide.
Futher specific examples which may be mentioned include: 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclobutylmethyl- nicotinamide;
6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclobutyl-nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,4,5- trifluorobenzyl)nicotinamide; 6- {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl} -N-(2,5- difluorobenzyl)nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3,4- difluorobenzyl)nicotinamide;
N-(3-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}nicotinamide;
N-(4-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl} nicotinamide;
N-(3-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyljnicotinamide; N-(2-chloro-3,6-difluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl} nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3-difluoro-4- methylbenzyl)nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3,5- trifluorobenzyl)nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3-fluoro-4- methylbenzyl)nicotinamide;
N-(5-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl} nicotinamide; N-(2-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}nicotinamide;
6- {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl} -N-(4- fluorobenzyl)nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3,4- trifluorobenzyl)nicotinamide;
N-benzyl-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[3-
(trifluoromethyl)benzyl]nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(l,l- dimethylbutyl)nicotinamide; N-(4-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl} nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[4-
(trifluoromethyl)benzyl]nicotinamide; 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(5-methyl-2- furyl)methyl]nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3- difluorobenzyl)nicotinamide;
N-(3-chloro-4-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl} nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(4- methylbenzyl)nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(3-methylthien-2- yl)methyl]nicotinamide; N-(3-chloro-2,6-difluorobenzyl)-6- {5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl } nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(l-ethyl-l- methylpropyl)nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2- fluorobenzyl)nicotinamide;
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(tert- pentyl)nicotinamide; and
6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3- methylbenzyl)nicotinamide. As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, Cι_6alkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms.
Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, isobutyl, isopropyl and t-butyl. A C _4alkyl group is preferred, for example methyl, ethyl, isopropyl or t-butyl. The said alkyl groups may be optionally substituted with one or more fluorine atoms for example, trifluoromethyl.
As used herein, the term "alkenyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and containing at least one double bond. For example, C2_6a keny means a straight or branched alkenyl containing at least 2, and at most 6, carbon atoms and containing at least one double bond. Examples of "alkenyl" as used herein include, but are not limited to ethenyl, propenyl, 3-methylbut-2-enyl and l,l-dimethylbut-2-enyl.
As used herein, the term "alkoxy" refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2- methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy. A Cι_4alkoxy group is preferred, for example methoxy or ethoxy.
As used herein, the term "cycloalkyl" refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms which may optionally contain up to one double bond. For example, C3_7cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms. Examples of "cycloalkyl" as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C3_gcycloalkyl group is preferred, for example, cyclopropyl, cyclopentyl or cyclohexyl. The said cycloalkyl groups may be optionally substituted with one or more Ci.galkyl groups, for example one or two methyl groups, hi one embodiment, the cycloalkyl groups may be optionally substituted by up to four C _galkyl groups, for example one or two Cι_galkyl groups, in particular one or two C^alkyl groups such as methyl or ethyl.
As used herein, the terms "heteroaryl ring" and "heteroaryl" refer to a monocyclic five- to seven-membered unsaturated hydrocarbon ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heteroaryl ring has five or six ring atoms. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. The said ring may be optionally substituted by one or more substituents independently selected from Cι_ galkyl and oxy.
As used herein, the terms "heterocyclic ring" or "heterocyclyl" refer to a monocyclic three- to seven-membered saturated hydrocarbon ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heterocyclyl ring has five or six ring atoms. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, mo holino, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholino. The said ring may be optionally substituted by one or more substituents independently selected from Cι_galkyl and oxy.
As used herein, the terms "halogen" or "halo" refer to the elements fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. A particularly preferred halogen is fluorine or chlorine.
As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. All such solvates are included within the scope of the present invention.
Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
Salts of the compounds of the present invention are also encompassed within the scope of the invention and may, for example, comprise acid addition salts resulting from reaction of an acid with a basic nitrogen atom present in a compound of formula (I).
Salts encompassed within the tenn "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. Other salts which are not pharmaceutically acceptable maybe useful in the preparation of compounds of this invention and these form a further aspect of the invention.
The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
A compound of formula (I) may be prepared by reacting a compound of (II)
Figure imgf000011_0001
(H) in which R1, R2, Z, m and n are as hereinbefore defined and W is halogen, in particular bromine or chlorine, with a compound of formula (IH)
Figure imgf000012_0001
in which R3, R , X and Y are as hereinbefore defined, in the presence of a catalyst, for example tetrakis(triphenylphosphine)palladium.
A compound of formula (H) may readily be prepared from a corresponding acid compound of formula (IV)
Figure imgf000012_0002
(IV) in which Z, W and n are as hereinbefore defined, by converting the acid to an activated form of the acid, for example the acid chloride, by treatment with, for example, thionyl chloride, and then reacting the activated acid thus formed with an amine compound of formula (V)
Figure imgf000012_0003
(V) in which R1, R2 and m are as hereinbefore defined, under amide forming conditions.
Suitable amide forming conditions are well known in the art and include treating a solution of the acid of formula (IV), or the activated form thereof, in for example acetone or dichloromethane, with an amine of formula (V) in the presence of sodium carbonate.
A compound of formula (IH) may be prepared by reacting a compound of formula (VI)
Figure imgf000012_0004
(VI) in which R3, R } X and Y are as hereinbefore defined and hal is halogen, in particular iodine, with bis(pinnacolato)diboron, PdCbdppf and potassium acetate in a solvent such as DMF.
Alternatively, when R4 is -CO-NH-(CH2)q-R8, a compound of formula (Ifl) may be prepared by reacting an acid compound of formula (VLI)
Figure imgf000013_0001
(vπ) in which R3, hal, X and Y are as hereinbefore defined, with bis(pinnacolato)diboron, PdCbdppf and potassium acetate in a solvent such as DMF, and then forming an amide by reaction with an amine compound of formula (V) as hereinbefore defined.
A compound of formula (I) may also be prepared by reacting a compound of formula (VET)
Figure imgf000013_0002
(VIE) with a compound of formula (m) as hereinbefore defined and then reacting the acid thus formed with an amine of formula (V) as hereinbefore defined, under amide forming conditions.
Additionally, a compound of formula (I) may be prepared by reacting a compound of (fl) as hereinbefore defined with a compound of formula (LX)
Figure imgf000013_0003
(IX) in which R3, R45 X and Y are as hereinbefore defined, in the presence of a catalyst, for example tetrakis(triphenylphosphine)palladium. For example, one general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 1 below.
Figure imgf000014_0001
Scheme 1 i. R7C02H, HATU, DIPEA, DMF. ii. Bis(pinnacolato)diboron, PdCl2dppf, KOAc, DMF. iii. SOCl2. iv. R1(CH2)mR2NH, Na2CO3, acetone. v. Na C03, tetrakis(triphenylphosphine)palladium, propan-2-ol.
For example, another general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 2 below.
Figure imgf000015_0001
Scheme 2 i. SOCl2. ii. R8(CH2)qNH2, Na2CO3, acetone. iii. Bis(pinnacolato)diboron, PdCl2dppf, KOAc, DMF. iv. SOCl2. v. R1(CH2)mR2NH, Na2CO3, acetone. vi. Na2CO3, tetrakis(triphenylphosphine)palladium, propan-2-ol.
For example, another general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 3 below.
Figure imgf000016_0001
Scheme 3 i. Bis(pinnacolato)diboron, PdCl2dppf, KOAc, DMF. ii. R8(CH2)qNH2, HATU, DIPEA, DMF. iii. SOCl2. iv. R1(CH2)mR2NH, Na2CO3, DCM. v. Na CO3, tetrakis(triphenylphosphine)palladium, propan-2-ol.
For example, another general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 4 below.
Figure imgf000017_0001
Scheme 4 i. NaHCO3, tetrakis(triphenylphosphine)palladium, propan-2-ol. ii. R1(CH2)mR2NH, HATU, DIPEA, DMF.
For example, a further general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 5 below.
Figure imgf000018_0001
Scheme 5
1. SOCl2. ii. R8(CH2)qNH2, Na2CO3, DCM. m NaH, n-BuLi, THF, (iPrO)3B. iv. SOCl2. v. R1(CH2)mR2NH, Na2CO3, DCM. vi NaHCO3, tetrakis(triphenylphosphine)palladium, propan-2-ol. Whilst it is possible for the compounds of the present invention to be administered as the new chemical, the compounds of formula (I) are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I), in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
The compounds of formula (I) may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration. The pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I). A particularly preferred method of administration, and corresponding formulation, is oral administration. For oral administration, the pharmaceutical composition may take the form of, and be administered as, for example, tablets (including sub-lingual tablets) and capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, emulsions, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of the present invention can also be administered in the form of liposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
The present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (I) in combination with a pharmaceutically acceptable carrier. Likewise, the composition may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intraperitoneal, intraarticular, subcutaneous or intramuscular, inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
For transdermal administration, the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative. Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle. The compounds of the invention may also be formulated as a depot preparation. Such long acting fonnulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
Alternatively the composition may be formulated for topical application, for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams. Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation. For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas. h the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
The pharmaceutical compositions generally are administered in an amount effective for treatment or prophylaxis of a specific condition or conditions. Initial dosing in human is accompanied by clinical monitoring of symptoms, such symptoms for the selected condition, hi general, the compositions are administered in an amount of active agent of at least about 100 μg/kg body weight. In most cases they will be administered in one or more doses in an amount not in excess of about 20 mg/kg body weight per day. Preferably, in most cases, dose is from about 100 μg/kg to about 5 mg/kg body weight, daily. For administration particularly to mammals, and particularly humans, it is expected that the daily dosage level of the active agent will be from 0. 1 mg/kg to 10 mg/kg and typically around 1 mg/kg. It will be appreciated that optimum dosage will be determined by standard methods for each treatment modality and indication, taking into account the indication, its severity, route of administration, complicating conditions and the like. The physician in any event will determine the actual dosage which will be most suitable for an individual and will vary with the age, weight and response of the particular individual. The effectiveness of a selected actual dose can readily be determined, for example, by measuring clinical symptoms or standard anti-inflammatory indicia after administration of the selected dose. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. For conditions or disease states as are treated by the present invention, maintaining consistent daily levels in a subject over an extended period of time, e.g., in a maintenance regime, can be particularly beneficial. h another aspect, the present invention provides a compound of formula (I) for use in therapy.
The compounds of the present invention are generally inhibitors of the serine/threonine kinase p38 and are therefore also inhibitors of cytokine production which is mediated by p38 kinase. Within the meaning of the term "inhibitors of the serine/threonine kinase p38" are included those compounds that interfere with the ability of p38 to transfer a phosphate group from ATP to a protein substrate according to the assay described below.
It will be appreciated that the compounds of the invention may be selective for one or more of the isoforms of p38, for example p38α, p38/3, p38γ and/or p38δ. In one embodiment, the compounds of the invention selectively inhibit the p38c isoform. In another embodiment, the compounds of the invention selectively inhibit the p383 isoform. In a further embodiment, the compounds of the invention selectively inhibit the p38α and p38/3 isoforms. Assays for determining the selectivity of compounds for the p38 isoforms are described in, for example, WO 99/61426, WO 00/71535 and WO 02/46158.
It is known that p38 kinase activity can be elevated (locally or throughout the body), p38 kinase can be incorrectly temporally active or expressed, p38 kinase can be expressed or active in an inappropriate location, p38 kinase can be constitutively expressed, or p38 kinase expression can be erratic; similarly, cytokine production mediated by p38 kinase activity can be occurring at inappropriate times, inappropriate locations, or it can occur at detrimentally high levels.
Accordingly, the present invention provides a method for the treatment of a condition or disease state mediated by p38 kinase activity, or mediated by cytokines produced by the activity of p38 kinase, in a subject which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). The compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers. The present invention also provides a method of inhibiting cytokine production which is mediated by p38 kinase activity in a subject, e.g. a human, which comprises administering to said subject in need of cytokine production inhibition a therapeutic, or cytokine-inhibiting, amount of a compound of the present invention. The compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.
The present invention treats these conditions by providing a therapeutically effective amount of a compound of this invention. By "therapeutically effective amount" is meant a symptom-alleviating or symptom-reducing amount, a cytokine- reducing amount, a cytokine-inhibiting amount, a kinase-regulating amount and/or a kinase-inhibiting amount of a compound. Such amounts can be readily determined by standard methods, such as by measuring cytokine levels or observing alleviation of clinical symptoms. For example, the clinician can monitor accepted measurement scores for anti-inflammatory treatments.
The compounds of the present invention can be administered to any subject in need of inhibition or regulation of p38 kinase or in need of inhibition or regulation of p38 mediated cytokine production, hi particular, the compounds maybe administered to mammals. Such mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably, humans.
Thus, the present invention provides methods of treating or reducing symptoms in a human or animal subject suffering from, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritable bowel syndrome, muscle degeneration, bone resorption diseases, osteoporosis, diabetes, reperfusion injury, graft vs. host reaction, allograft rejections, sepsis, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to aquired immune deficiency syndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter's syndrome, traumatic arthritis, rubella arthritis, Crohn's disease, ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, and non articular inflammatory conditions, for example, herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis, tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatory conditions associated with ligamentous sprain and regional musculoskeletal strain, pain, for example that associated with inflammation and/or trauma, osteopetrosis, restenosis, thrombosis, angiogenesis, cancer including breast cancer, colon cancer, lung cancer or prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, chronic pulmonary inflammation, chronic obstructive pulmonary disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease and epilepsy which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from any type of pain including chronic pain, rapid onset of analgesis, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain associated with osteoarthritis and rheumatoid arthritis, post operative inflammatory pain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia, post- hepatic neuralgia, inflammatory neuropathies and migraine pain which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The compounds of formula (I) may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. In particular, in rheumatoid arthritis therapy, combination with other chemotherapeutic or antibody agents is envisaged. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) and at least one other pharmaceutically active agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur separately or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Examples of other pharmaceutically active agents which may be employed in combination with compounds of fonnula (I) for rheumatoid arthritis therapy include: immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone; anti-
TNFα agents such as etanercept, infliximab, diacerein; tyrosine kinase inhibitors such as leflunoniide; kallikrein antagonists such as subreum; interleukin 11 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interleukin 1 receptor antagonists such as anakinra; CD 8 antagonists such as amiprilose hydrochloride; beta amyloid precursor protein antagonists such as reumacon; matrix metalloprotease inhibitors such as cipemastat and other disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine, auranofin, aurothioglucose, gold sodium thiomalate and penicillamine. Examples
The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are commercially available or are prepared according to procedures in the literature.
LCMS was conducted on a column (3.3cm x 4.6mm ID, 3um ABZ+PLUS), at a Flow Rate of 3ml/min, Injection Volume of 5μl, at room temperature and UV Detection Range at 215 to 330nm.
Intermediate 1 : 6-Chloro-N-cvclopropyImethylnicotinamide
6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2ml) for 2.5hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (4ml), cyclopropylmethylamine (71mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N- cyclopropylmethylnicotinamide as a cream solid. NMR: δH [2H6]-DMSO 8.82,(2H, m), 8.23,(1H, dd), 7.63,(1H, d), 3.14,(2H, t), 1.01,(111, m), 0.44,(2H, m), 0.22,(2H, m).
Intermediate 2: 6-Chloro-N-(4-methoxyphenyl)nicotinamide
6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), p-anisidine (123mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(4- methoxyphenyl)nicotinamide. NMR: δH [2H6]-DMSO 10.37,(1H, b), 8.94,(1H, d), 8.34,(1H, dd), 7.70,(1H, d), 7.66,(2H, m), 6.95,(2H, m), 3.75,(3H, s).
Intermediate 3: 6-Chloro-N-(3-methoxybenzvI)nicotinamide
6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), 3-methoxybenzylamine (137mg, O.lOmmol) and sodium carbonate
(500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(3- methoxybenzyl)nicotinamide. NMR: δH [2H6]-DMSO 9.29,(1H, t), 8.88,(1H, d), 8.28,(1H, dd), 7.66,(1H, d), 7.25,(1H, t), 6.90,(2H, m), 6.83,(1H, m), 4.47,(2H, d), 3.74,(3H, s). Intermediate 4 : 6-Chloro-N-(3-methvIsuIphonylammobenzyl)nicotinamide
6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), 3-methylsulphonylaminobenzylamine (200mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide. NMR: δH [2H6]-DMSO 9.30,(1H, t), 8.88,(1H, d), 8.28,(1H, dd), 7.67,(1H, d), 7.23,(1H, t), 7.10,(1H, s), 7.04,91H, d), 6.97,(1H, d), 4.45,(2H, d), 2.90,(3H, s).
Intermediate s: 6-Chloro-N 2-(4-methylpiperazin- -vI)phenyl1nicotinamide
6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2ml), l-(2-aminobenzyl)-4-methylpiperazine (205mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-[2-(4-methylpiperazin-l-yl)phenyl]nicotinamide. NMR: δH [2H6]-DMSO 11.62,(1H, s), 8.95,(1H, d), 8.32,(1H, dd), 8.25,(1H, d), 7.77,(1H, d), 7.34,(1H, m), 7.28,(1H, m), 7.10,(1H, m), 3.73,(2H, s), 2.56-2.20,(8H, b), 2.12,(3H, s).
Intermediate 6 : 4-MethyI-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl- fl,3,21dioxaborolan-2-yl)-benzamide 3-Iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide (Intermediate 7) (83mg,
0.20mmol), bis(pinnacolato)diboron (lOOmg, 0.39mmol), potassium acetate (97mg, l.Ommol) and PdCl2dppf (12mg) were heated at 80°C in DMF (2.5ml) for 4hrs. The cooled reaction was absorbed onto silica, applied to a bond-elut (lOg, silica) and eluted with an ethylacetate / cyclohexane gradient (0 to 100%). The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give 4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide as a white solid (3 lmg). LCMS: retention time 3.69min, MH+ 415.
Intermediate 7 : 3-Iodo-4-methyI-N-(3-pyridin-2-yl-phenyl)benzamide
3-Iodo-4-methylbenzoic acid (154mg, 0.59mmoι) was heated at 80°C in thionyl chloride (2ml) for 3hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (3ml), 2-(3-aminophenyl)pyridine (lOOmg, 0.59mmol) and sodium carbonate (400mg) were added to the solution. The reaction was stirred at room temperature for 11 days, filtered and the filtrate reduced to dryness under vacuum. The residue was dissolved in ether and filtered through a bond-elut (lg, silica), washing with ether. The solvent was evaporated from the combined filtrate and washings to give 3-iodo-4- methyl-N-(3-pyridin-2-yl-phenyl)benzamide as a cream foam. NMR: δH CDCI3 8.70,(1H, dt), 8.33,(1H, d), 8.18,(1H, t), 7.93-7.89,(2H, m), 7.79-7.75,(4H, m), 7.50,(1H, t), 7.35,(1H, d), 7.26,(1H, m), 2.51,(3H, s).
Intermediate 8: N-CyclopropyI-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,21dioxaborolan-2-yl)-benzamide
N-Cyclopropyl-3-iodo-4-methylbenzamide (Intermediate 9) (l.lg, 3.64mmol), bis(pinnacolato)diboron (1.85g, 7.28mmol), potassium acetate (1.79g, 18.2mmol) and PdCl2dppf (55mg) were heated at 85°C in DMF (30ml) for 4.5hrs. The cooled reaction was absorbed onto silica, applied to a bond-elut (lOg, silica) and eluted with an ethylacetate / cyclohexane gradient (0 to 100%). The solvent was evaporated from the product fractions under vacuum and the residue triturated with cyclohexane to give N-cyclopropyl-4-methyl-3 -(4,4, 5 , 5 -tetramethyl- [1,3,2] dioxaborolan-2-yl)-benzamide as a white solid (650mg). NMR: δH [2H6]-DMSO 8.40,(1H, d), 8.06,(1H, d),
7.76,(1H, dd), 7.23,(1H, d), 2.82,(1H, m), 2.48,(3H, s), 1.30,(12H, s), 0.66,(2H, m), 0.56,(2H, m).
Intermediate 9: N-CvclopropyI-3-iodo-4-methylbenzamide 3-Iodo-4-methylbenzoic acid (l.Og, 3.8mmol) was heated at 80°C in thionyl chloride (10ml) for 2hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (10ml), cyclopropylamine (0.32ml) and sodium carbonate (2.0g) were added to the solution. The reaction was stirred at room temperature for 18hrs, filtered and the filtrate reduced to dryness under vacuum. The residue was triturated with ether to give N-cyclopropyl-3-iodo-4-methylbenzamide as a white solid (l.lg). NMR: δH [2H6]- DMSO 8.46,(1H, d), 8.24,(1H, d), 7.74,(1H, dd), 7.38,(1H, d), 2.82,(1H, m), 2.38,(3H, s), 0.67,(2H, m), 0.55,(2H, m).
Intermediate 10 : N-Cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethvI- fl,3,21dioxaborolan-2-yl)-benzamide
4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid (intermediate 17) (2.0g, 7.63mmol), DIPEA (4ml, 22.89mmol) and HATU (3.05g, 8.02mmol) were dissolved in DMF (20ml) and stirred at room temperature for 15mins. Cyclopropylmethylamine (568mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250ml) and water (50ml). The organic phase was washed with hydrochloric acid (2N, 50ml) and aqueous sodium bicarbonate (1M, 50ml), then dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-cyclopropymιethyl-4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (1.73g). LCMS: retention time 3.47min, MH+ 316. NMR: δH [2H6]-DMSO 8.54,(1H, t), 8.11,(1H, d), 7.82,(1H, dd), 7.26,(1H, d), 3.12,(2H, t), 1.32,(12H, s), 1.03,(1H, m), 0.42,(2H, m), 0.22,(2H, m).
Intermediate 11: 4-Methyl-3-(4,4,5,5-tetramethyl-ri,3,21dioxaboroIan-2-yl)-N- (thiazol-2-yl)-benzamide
4-Methyl-3 -(4,4, 5 , 5 -tetramethyl- [1,3,2] dioxaborolan-2-yl)-benzoic acid (2. Og, 7.63mmol), DIPEA (4ml, 22.89mmol) and HATU (3.05g, 8.02mmol) were dissolved in DMF (20ml) and stirred at room temperature for 15mins. 2-Aminothiazole (801mg, 8.01mmol) was added and the reaction stirred at room temperature for lδhours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250ml) and water (50ml). The organic phase was washed with hydrochloric acid (2N, 50ml) and aqueous sodium bicarbonate (1M, 50ml), then dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- N-(thiazol-2-yl)-benzamide (1.72g). LCMS: retention time 3.66min, MH+ 345. NMR: δH [2H6]-DMSO 12.65,(1H, b), 8.32,(1H, d), 8.08,(1H, dd), 7.56,(1H, d), 7.35,(lh, d), 7.28,(1H, d), 2.54,(3H, s), 1.34,(12H, s).
Intermediate 12: 4-MethyI-3-(4,4,5,5-tetramethyl-fl,3,21dioxaborolan-2-yi)-N- (thiadiazol-2-yl)-benzamide 4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid (2.0g,
7.63mmol), DIPEA (4ml, 22.89mmol) and HATU (3.05g, 8.02mmol) were dissolved in DMF (20ml) and stirred at room temperature for 15mins. 2-Aminothiadiazole (810mg, δ.Olmmol) was added and the reaction stirred at room temperature for 18hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250ml) and hydrochloric acid (2N, 150ml). The aqueous was extracted with ethylacetate (2 x 250ml). The combined organic extracts were dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4:1 then 1:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (0.95g). LCMS: retention time 3.34min, MH+ 346. NMR: δH [2H6]-DMSO 13.08,(1H, b), 9.22,(1H, s), 8.35,(1H, d), 8.11,(1H, dd), 7.38,(1H, d), 2.55,(3H, s), 1.34,(12H, s). Intermediate 13: N-[4-Methyl-3-(4,4,5,5-tetramethyl-fl,3,21dioxaborolan-2-vn- phenyll -3-furamide
N-(3-Iodo-4-methylphenyl)-3-furamide (Intermediate 15) (2.5g, 7.64mmol), bis(pinnacolato)diboron (2.13g, 8.41mmol), potassium acetate (825mg, 8.41mmol) and PdCl2dppf (312mg, 0.38mmol) in DMF (20ml) were heated at 80°C for 20hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum, dissolved in DMF (40ml) and reacted with bis(piι acolato)diboron (7.76g, 30.57mmol), potassium acetate (3.0g, 30.57mmoι) and PdCl2dppf (249mg, 0.306mmol) at 80°C for 23 hrs. The cooled reaction was absorbed onto silica and applied to bond-eluts (silica, 2 xlOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum to give N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]-3-furamide. LCMS: retention time 3.55min, MH+ 328. NMR: δH [2H6]- DMSO 9.86,(1H, b), 8.36,(1H, m), 7.86-7.82,(2H, m), 7.77,(1H, t), 7.14,(1H, d), 6.99,(1H, m), 2.41,(3H, s), 1.30,(12H, s).
Intermediate 14: N-r4-MethyI-3-(4,4,5,5-tetramethyI-[l,3,21dioxaborolan-2-yI)- phenyπthiophene-3-amide N-(3-Iodo-4-methylphenyl)thiophene-3-amide (Intermediate 16) (2.64g,
7.64mmol), bis(pinnacolato)diboron (2.13g, 8.41mmol), potassium acetate (825mg, 8.41mmol) and PdCl2dpρf (312mg, 0.38mmol) in DMF (20ml) were heated at 80°C for 20hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum, dissolved in DMF (20ml) and reacted with bis(piι acolato)diboron (1.77g, 7.0mmol), potassium acetate (687mg, 7.0mmol) and PdCl2dppf (143mg, 0.175mmol) at 80°C for 16 hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum to give N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]thiophene-3-amide. LCMS: retention time 3.65min, MH+ 344. NMR: δH [2H6]-DMSO 9.99,(1H, b), 8.35,(1H, s), 7.90,(1H, d), 7.85,(1H, dd), 7.63,(2H, m), 7.14,(1H, d), 2.42,(3H, s), 1.30,(12H, s).
Intermediate 15: N-(3-Iodo-4-methylphenyl)-3-furamide
3-Furoic acid (2.4g, 21.45mmol) and HATU (8.15g, 21.45mmol) in DMF (25ml) were stirred at room temperature for 15mins. HOBT (2.9g, 21.45mmol), 3- iodo-4-methylaniline (5.0g, 21.45mmol) and DIPEA (11.2ml, 64.35mmol) were added and the reaction stirred at room temperature for 16hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane / ethyl acetate (3:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)-3-furamide. LCMS: retention time 3.52min, MH+ 328. NMR: δH [2H6]-DMSO 9.92,(1H, b), 8.36,(1H, d), 8.23,(1H, d), 7.80,(1H, t), 7.66,(1H, dd), 7.29,(1H, d), 6.98,(1H, d), 2.33,(3H, s).
Intermediate 16: N-(3-Iodo-4-methylphenyI)thiophene-3-amide Thiophene-3-carboxylic acid (2.75g, 21.45mmol) and HATU (8.15g,
21.45mmol) in DMF (25ml) were stirred at room temperature for 15mins. HOBT (2.9g, 21.45mmol), 3-iodo-4-methylaniline (5.0g, 21.45mmol) and DIPEA (11.2ml, 64.35mmol) were added and the reaction stirred at room temperature for 16hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane / ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4- methylphenyl)thiophene-3 -amide. LCMS: retention time 3.69min, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), 8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd), 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Intermediate 17: 4-Methyl-3-(4A5,5-tetramethyl-|l.ι3,21dioxaborolan-2- vDbenzoic acid
3-Iodo-4-methylbenzoic acid (lOg, 38.16mmol), bis(pinnacolato)diboron (14.5g, 57.24mmol), potassium acetate (18.73g, 190.8mmol) and PdCl2dppf (3.12g, 3.8mmol) in DMF (200ml) were heated at 80°C for 21hrs. The solvent was evaporated from the cooled reaction under vacuum, the residue dissolved in ethyl acetate (300ml) and hydrochloric acid (2N, 300ml) and filtered through celite. The organic phase was separated and the aqueous extracted with ethyl acetate (2 x 300ml). The combined organic extracts were washed with brine (500ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue absorbed onto silica and applied to a silica flash column. This was eluted with cyclohexane / ethyl acetate (5:1). The product fractions were concentrated under vacuum to give 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid. LCMS: retention time 3.65min. NMR: δH [2H6]-DMSO 12.83,(1H, b), 8.23,(1H, d), 7.89,(1H, dd), 7.29,(1H, d), 2.51,(3H, s), 1.30,(12H, s). Intermediate 18: N-r4-Methyl-3-(4,4,5.5-tetramethvI-fl<3,21dioxaboroIan-2-yl)- phenvπ-2-pyrrolidin-l-yl-isonicotinamide
Bis(pinacolato)diborane (7.24g, 28.5mmol) was added to a mixture of N-(3- iodo-4-methylphenyl)-2-pyrrolidin-l-yl-isonicotinamide (Intermediate 19) (7.73g, 19mmol) in dimethylformamide (100ml) potassium acetate (9.32g, 95mmol) and PdCl2dppf and the reaction was heated under an atmosphere of nitrogen at 80°C for 16 hours. The reaction was cooled and the solvent removed in vacuo. The residue was taken up in chloroform (150ml), washed with water (3x100ml) and brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (20:80 ethyl acetate: cyclohexane to 50:50 ethyl acetatexyclohexane). To give N-[4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-l-yl-isonicotinamide as a white solid (1.5g, 3.7mmol). LCMS: retention time 2.90 min MH+408. NMR: δH - CDC13 8.27 (IH, d), 7.99 (IH, dd), 7.76 (IH, b), 7.65 (IH, d), 6.20 (IH, d), 6.82 (IH, b), 6.77 (IH, b), 3.52 (4H, apparent t), 2.52 (3H, s), 2.25 (4H, m).
Intermediate 19: N-(3-Iodo-4-methyIphenyl)-2-pyrrolidin-l-yl-isonicotinamide
A solution of N-(3-iodo-4-methylphenyl)-2-chloro-isonicotinamide (Intermediate 20) (7.00g, 18.8mmoι) in pyrrolidine (20ml) was heated at 80°C under an atmosphere of nitrogen for 16 hours. Excess pyrrolidine was removed in vacuo and the residue was titurated with dietheyl ether (20ml). The resulting solid was collected by filtration and dried in vacuo to give N-(3-iodo-4-methylphenyl)-2- pyrrolidin-1-yl-isonicotinamide as a pale yellow solid (7.73g, 18mmol). LCMS: retention time 2.77 min MH+408. NMR: δH [2H6] - DMSO 10.29 (IH, s), 8.29 (IH, d), 8.20 (IH, d), 7.71 (IH, dd), 7.72 (IH, dd), 6.97 (IH, brd), 6.88 (IH, b), 3.45 (2H, apparent t), 3.09 (2H, m), 2.35 (3H, s), 1.98 (2H, m), 1.82 (2H, m).
Intermediate 20 : 2-ChIoro-N-(3-iodo-4-methylphenyI)-isonicotinamide
2-Chloroisonicotinic acid (3.3g, 21mmol), HATU (8.75g, 23mmol), diisopropylethyl amine (10.9ml, 63mmol) and 4-iodo-3-methylaniline (5.00g,
21 mmol) in dimethylformamide (50ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150ml). The organic solution was washed with water (3x100ml) and brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetatexyclohexane) to give 2-chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide as a white solid (7.00g, 18.8mmol). LCMS: retention time 3.59 min MH+373. NMR: δH
[2H6] - DMSO 10.52 (IH, s), 8.62 (IH, d), 8.29 (IH, d), 7.99 (IH, b), 7.87 (IH, dd), 7.70 (IH, dd), 7.34 (IH, d), 2.36 (3H, s). Intermediate 21: 6-Chloro-N-cvclopropylmethyInicotinamide
6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2ml) for 2.5hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (4ml), cyclopropylmethylamine (71mg, O.lOmmol) and sodium carbonate (500mg) were added to the solution. The reaction was stirred at room temperature for 4hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N- cyclopropylmethylnicotinamide as a cream solid. NMR: δH [2H6]-DMSO 8.82,(2H, m), 8.23,(1H, dd), 7.63,(1H, d), 3.14,(2H, t), 1.01,(1H, m), 0.44,(2H, m), 0.22,(2H, m).
General Method A
6-Bromonicotinic acid (lOOmg, 0.5mmol) was heated at 95°C in thionyl chloride (0.63ml) for 2hours. The excess thionyl chloride was evaporated under vacuum and the residue dissolved in DCM (2ml). To this solution, amine (0.5mmol) and sodium carbonate (lOOmg) were added and the reaction was stirred at room temperature for 2hours. The reaction was filtered and the residue washed with DCM. The combined filtrate and washings were reduced to dryness to give the desired 6- chloronicotinamide.
Figure imgf000032_0001
Figure imgf000033_0001
Intermediate 32: 6-Chloro-N-cvclobntylmethylnicotinamide
6-Chloro-N-cyclobutylmethylnicotinamide was prepared from cyclobutylmethylamine using General Method A. NMR: δH [2H6] - DMSO 8.81,(1H, d), 8.70,(1H, bt), 8.22,(1H, dd), 7.64,(1H, d), 3.30,(2H, t), 2.52,(1H, m), 1.99,(2H, m), 1.81,(2H, m), 1.73,(2H, m).
Intermediate 33: 6-Chloro-N-(l-methyIpropyl)nicotinamide
6-Chloro-N-(l-methylpropyl)nicotinamide was prepared from 1- methylpropylamine using General Method A.
NMR: δH [2H6] - DMSO 8.82,(1H, d), 8.42,(1H, d), 8.24,(1H, dd), 7.64,(1H, d), 3.91,(1H, m), 1.51,(2H, m), 1.15,(3H, d), 0.87,(3H, t).
Intermediate 34 : N-Cvclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl- [1 ,3.21 dioxaborolan-2-vD-benzamide
3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (Intermediate 35, 900mg), bispinnacolatodiboron (4.5g), potassium acetate (2.1g) and PdCbdppf (75mg) were mixed in DMF (40ml) and heated at 100°C for lδhours. The cooled reaction was absorbed onto silica and applied to SPE's (Si 2 x lOg). The SPE's were eluted with an ethylacetate / cyclohexane gradient (0-6.25% ethylacetate). The solvent was evaporated from the product fractions under vacuum and the residue recrystallised from cyclohexane to give N-cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5- tetramethyl-[ 1 ,3,2]dioxaborolan-2-yι)-benzamide (260mg). LCMS: MFf" 320, retention time 3.39mins.
Intermediate 35 : 3-Bromo-N-cvclopropyl-5-fluoro-4-methylbenzamide
3-Fluoro-4-methylbenzoic acid (462mg, 3.0mmol) was added to a stirred mixture of bromine (2.31ml, 45mmol) and iron powder (252mg, 4.5mmol) under nitrogen. The reaction was stirred at 20°C for 4 hours and then left to stand for 16 hours. Sodium thiosulphate solution (200ml) was added and the product was extracted into ethyl acetate (3 x 150ml). Ethyl acetate extracts were combined and evaporated in vacuo. The crude product (mixture of isomers) was dissolved in dimethylformamide (7ml). Cyclopropylamine (208μl, 3.0mmol), HOBT (405mg, 3.0mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (575mg, 3.0mmol) and DIPEA (525μl, 3.0mmol) were added to the stirred solution. The reaction was stirred for 5 hours at 20°C. Solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. Combined ethyl acetate extracts were washed sequentially with aqueous sodium hydrogen carbonate and hydrochloric acid (0.5M), then dried (magnesium sulphate). The ethyl acetate was evaporated in vacuo and the residue was purified by silica biotage chromatography eluting with cyclohexane: ethyl acetate (6:1) to give 3-bromo-N-cyclopropyl-5-fluoro- 4-methylbenzamide (359mg, 44%).
NMR: δH - CDC13 7.68,(1H, s), 7.39,(1H, d), 6.19,(1H, bs), 2.88,(1H, m), 2.36,(3H, d), 0.88,(2H, m), 0.63,(2H, m). LCMS: MH+ 272.
Intermediate 36: {5-f(Cyclopropylamino)carbonyIl-3-fluoro-2- methylphenyllboronic acid
N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5g) in THF (75ml) was cooled to 0°C and sodium hydride (60%, 1.23g) added portionwise over lOminutes. Once effervescence had ceased the reaction was cooled to -75°C and n- butyl lithium (1.6M in hexanes, 20ml) added over 25minutes maintaining a temperature of <-70°C. Triisopropyl borate (8ml) was added to the reaction over lOminutes and the reaction stirred at -70°C for 4hours. The reaction was quenched with water (20ml) and the mixture allowed to warm to 5°C. The reaction was concentrated under vacuum and the residue partitioned between saturated ammonium chloride and ethyl acetate. The organic phase was washed with saturated ammonium chloride, brine, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in DCM/ethyl acetate and purified by column chromatography on silica eluting with an ethyl acetate/ DCM gradient (5-100% ethyl acetate) and then methanol. The product fractions were combined and the solvent evaporated under vacuum to give {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid. LCMS MH+ 238, retention time 2.19min.
Intermediate 37: N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide N-Iodosuccinimide (22.5g) was added in portions to a solution of 3-fluoro-4- methylbenzoic acid (15.4g) in trifluoromethanesulphonic acid (100ml) at 0°C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ml) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl chloride (30ml) and heated at 100°C for 2.5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ml). Sodium carbonate (25g ) and cyclopropylamine (13ml) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate / cyclohexane gradient (22 - 28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N-cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide. LCMS; MH+ 320, retention time 3.16minutes.
Intermediate 38: 6-{5-r(Cvclopropylamino)carbonvH-3-fluoro-2- methylphenyUnicotinic acid N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzamide (3.2g), methyl 6-chloronicotinate (1.73g), tetrakis(triphenylphosphine)palladium (210mg) and aqueous sodium hydrogen carbonate (IM, 30ml) were mixed in propan-2-ol (100ml) and heated at 90°C for 18hours. The reaction was allowed to cool and the propan-2-ol removed under vacuum. The residue was partitioned between ethyl acetate and aqueous sodiumhydrogen carbonate (IM). The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (x2). The organic extracts were washed with brine, dried (magnesium sulphate) and reduced to dryness under vacuum. The resulting foam was triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3- fluoro-2-methylphenyl}nicotinic acid as a solid. LCMS: MH+315, retention time 2.87mins.
Intermediate 39: (2-Ethylcvclopropyl)methylamine
A solution of 2-ethylcyclopropylcarboxamide (250mg, 2.2mmol) in THF was heated to reflux. Borane-dimethylsulphide (IM solution in DCM, 3.2ml, 3.2mmol) was added dropwise over 30minutes and the reaction refluxed for 16hours. Hydrochloric acid (6N, 0.5ml) was added dropwise and the mixture heated at reflux for 30minutes. The cooled reaction mixture was diluted with water (20ml), washed with ether (50ml) and basified with sodium hydroxide (6N). The aqueous was extracted with ether (50ml x 3) and ethyl acetate (50ml). The combined organic extracts were dried (magnesium sulphate), acidified with hydrogen chloride (3.3M in methanol) and reduced to dryness under vacuum to give (2-ethylcyclopropyl)methylamine (230mg). NMR: δH [2H6]-DMSO 7.85,(3H, b), 2.66,(2H, d), 1.30-1.13,(2H, m), 0.91,(3H, t),
0.77-0.66,(2H, m), 0.46,(1H, m), 0.33,(1H, m). General Method B
The 2-chloropyridine (0.05mmol), phenyl pinnacolborane (0.05mmol), tetrakis(triphenylphosphine) palladium (lmg) and aqueous sodium carbonate (0.25ml) in propan-2-ol (1ml) were heated at 85°C under nitrogen for 18 hours. The cooled reaction was diluted with ethyl acetate (4ml) and methanol (2ml) and filtered through an SCX bond-elut (lg). The product was eluted with 10% ammonia (s.g. 0.88) in methanol. The solvents were evaporated and the residue triturated with ether.
Example 1 : N-(3-[5-(Cyclopropylmethyl-carbamoyl)-pyridin-2-yn-4-methyl- phenyl)-2-pyrrolidin-l-yl-isonicotinamide
Figure imgf000036_0001
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25mg, 0.098mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)- phenyl]-2-pyrrolidin-l-yl-isonicotinamide (Intermediate 18) (30mg, 0.074mmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4mg) were heated at 80°C in DMF (1ml) for lδhours. The reaction was absorbed onto silica,ap lied to a bond-elut (lOg, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%), then acetone and methanol. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-(3-[5-(cyclopropylmethyl-carbamoyl)-pyridin-2-yl]-4-methyl-phenyl)- 2-pyrrolidin-l-yl-isonicotmamide as a white solid (20mg). LCMS: retention time 2.42min, MH+ 456. NMR: δH [2H6]-DMSO 10.32,(1H, s), 9.09,(1H, s), 8.82,(1H, t), 8.28,(1H, m), 8.19,(1H, m), 7.85,(1H, t), 7.76,(1H, m), 7.64,(1H, m), 7.31,(1H, m), 6.98,(1H, m), 6.88,(1H, s), 3.43,(4H, m), 3.18,(2H, m), 2.31,(3H, s), 1.95,(4H, m), 1.07,(1H, m), 0.45,(2H, m), 0.25,(2H, m).
Example 2: N-Cyclopropylmethyl-6-f2-methyl-5-(3-pyridin-2-yl- phenylcarbamoyD-phenyll-nicotinamide
Figure imgf000036_0002
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (18.5mg, 0.073mmol) and 4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) (30mg, 0.072mmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4mg) were heated at 90°C in DMF (1ml) for 4hours. The reaction was absorbed onto silica,applied to a bond-elut (5g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%)) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-cyclopropylmethyl-6-[2- methyl-5-(3-pyridin-2-yl-phenylcarbamoyl)-phenyl]-nicotinamide as a white solid (20mg). LCMS: retention time 3.18min, MH+ 463. NMR: δH [2H6]-DMSO 10.43,(1H, s), 9.14,(1H, s), 8.86,(1H, t), 8.69,(1H, s), 8.53,(1H, s), 8.34,(1H, d), 8.11,(1H, s), 8.01,(1H, d), 7.95-7.89,(3H, m), 7.81-7.78,(2H, m), 7.53-7.46,(2H, m), 7.38,(1H, t), 3.21,(2H, t), 2.44,(3H, s), 1.07,(1H, m), 0.47,(2H, m), 0.27,(2H, m).
Example 3 : 6-(5-CvclopropyIcarbamoyI-2-methyl-phenyl)-N-cyclopropylmethyl- nicotinamide
Figure imgf000037_0001
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5mg, 0. lOmmol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)-benzamide (hitermediate 8) (30mg, O.lOmmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4mg) were heated at 90°C in DMF (lml) for 3hours. The reaction was absorbed onto silica, applied to a bond-elut (5g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to 6-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-N- cyclopropylmethyl-nicotinamide as a cream solid. LCMS: retention time 2.70min, MH+ 350. NMR: δH [2H6]-DMSO 9.11,(1H, s), 8.84,(1H, t), 8.48,(1H, d), 8.31,(1H, dd), 7.88,(1H, s), 7.81,(1H, d), 7.70,(1H, d), 7.41,(1H, d), 3.20,(1H, t), 2.86,(1H, m), 2.37,(3H, s), 1.06,(1H, m), 0.69,(2H, m), 0.57,(2H, m), 0.46,(2H, m), 0.26,(2H, ). Example 4: N-Cvclopropylmethyl-6-F5-(thiadiazoI-2-ylcarbamoyl)-2-methyl~ phenyll-nicotinamide
Figure imgf000038_0001
N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide
(Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.79min, MH+ 394. NMR: δH [2H6]-DMSO 13.14,(1H, b), 9.24,(1H, s), 9.14,(1H, s), 8.86,(1H, t), 8.35,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.82,(1H, d), 7.54,(1H, d), 3.21,(2H, t), 2.46,(3H, s), 1.07,(1H, ), 0.47,(2H, m), 0.27,(2H, m).
Example 5 : N-C ycloprop ylmethyl-6- f 5-(thiazol-2-ylcarb amoy D-2-methyl- phenyll-nicotinamide
Figure imgf000038_0002
N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (hitermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.99min, MH+ 393. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.13,(1H, s), 8.86,(1H, t), 8.34,(1H, d), 8.21,(1H, s), 8.07,(1H, d), 7.81,(1H, d), 7.57,(1H, d), 7.52,(1H, d), 7.29,(1H, d), 3.21,(2H, t), 2.45,(3H, s), 1.07,(1H, m), 0.47,(2H, ), 0.27,(2H, m). Example 6: 6-[5-(Cvclopropylmethylcarbamoyl)-2-methyl-phenyll-N- cyclopropylmethyl-nicotinamide
Figure imgf000039_0001
6-[5-(Cyclopropylmethyl)carbamoyl-2-methyl-phenyl]-N-cyclopropylmethyl- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-(cyclopropylmethyl)-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.87min, MH+ 364. NMR: δH [2H6]-DMSO 9.10,(1H, s), 8.83,(1H, t), 8.60,(1H, t), 8.30,(1H, dd), 7.92,(1H, s), 7.84,(1H, d), 7.71,(1H, d), 7.41,(1H, d), 3.19,(2H, t), 3.13,(2H, t), 2.37,(3H, s), 1.03,(2H, m), 0.44,(4H, m), 0.23,(4H, m).
Example 7: N-Cyclopropylmethyl-6-[5-(fur-3-ylcarbonylaminoV2-methyl- phenyll-nicotinamide
Figure imgf000039_0002
N-Cyclopropylmethyl-6-[5-(fur-3-ylcarbonylamino)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl] -3 -furamide (Intermediate 13) using General Method B. LCMS: retention time 2.96min, MH+ 376. NMR: δH [2H6]-DMSO 9.99,(1H, s), 9.10,(1H, s), 8.83,(1H, t), 8.38,(1H, s), 8.30,(1H, d), 7.80,(2H, s), 7.75,(1H, d), 7.66,(1H, d), 7.30,(1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(2H, m), 0.27,(2H, m). Example 8: N-Cvclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylaminoV phenyll-nicotinamide
Figure imgf000040_0001
N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]- nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide
(Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]thiophene-3 -amide (Intermediate 14) using General Method B. LCMS: retention time 3.07min, MH+ 392. NMR: δH [2H6]-DMSO 10.11,(1H, s), 9.11,(1H, s), 8.83,(1H, t), 8.35,(1H, s), 8.30,(1H, dd), 7.85,(1H, s), 7.78,(1H, d), 7.67-7.63,(3H, m), 7.31,(1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(1H, m), 0.27,(1H, m).
Example 9: 6-(5-Cyclopropylcarbamoyl-2-methyl-phenylVN-(4-methoxyphenyl)- nicotinamide
Figure imgf000040_0002
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (hitermediate 2) and N-cycloproρyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.96min, MH+ 402. NMR: δH [2H6]-DMSO 10.38,(1H, s), 9.20,(1H, s), 8.49,(1H, d), 8.40,(1H, dd), 7.91,(1H, s), 7.82,(1H, d), 7.76,(1H, d), 7.71,(2H, d), 7.43,(1H, d), 6.96,(2H, d), 3.76,(3H, s), 2.87,(1H, m), 2.40,(3H, s), 0.70,(2H, m), 0.58,(2H, m). Example 10: N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)- phenyll- nicotinamide
Figure imgf000041_0001
N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide
(Intermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.05min, MH+ 446. NMR: δH [2H6]-DMSO 13.15,(1H, b), 10.41,(1H, s), 9.24,(2H, m), 8.45,(1H, dd), 8.28,(1H, s), 8.11,(1H, d), 7.88,(1H, d), 7.71,(2H, d), 7.56,(1H, d), 6.97,(2H, d), 3.76,(3H, s), 2.48,(3H, s).
Example 11 : N-(4-Methoxyphen yl)-6- [2-methyl-5-(thiazol-2-ylcarb amovD- phenyll- nicotinamide
Figure imgf000041_0002
N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (hitermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiazol-2-yl)-benzamide (hitermediate 11) using General Method B. LCMS: retention time 3.22min, MH+ 445. NMR: δH [2H6]-DMSO 12.72,(1H, s), 10.40,(1H, s), 9.22,(1H, d), 8.44,(1H, dd), 8.24,(1H, s), 8.09,(1H, d), 7.87,(1H, d), 7.71,(2H, d), 7.58,(1H, d), 7.53,(1H, d), 7.30,(1H, d), 6.97,(2H, d), 3.76,(3H, s), 2.48,(3H, s).
Example 12 : 6-(5-Cy clopropylmethylcarb amoyl-2-methy l-phenyl)-N-(4- methoxyphenvD-nicotinamide
Figure imgf000041_0003
6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 3.12min, MH+ 416. NMR: δH [2H6]-DMSO 10.39,(1H, s), 9.21,(1H, d), 8.63,(1H, t), 8.41,(1H, dd), 7.96,(1H, s), 7.86,(1H, d), 7.79,(1H, d), 7.71,(2H, d), 7.44,(1H, d), 6.96,(2H, d), 3.76,(3H, s), 3.15,(2H, t), 2.41,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Example 13: 6-[5-(Fur-3-ylcarbonylaminoV2-methyl-phenvn-N-(4- methoxyphenyD-nicotinamide
Figure imgf000042_0001
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)- nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl] -3 -furamide (hitermediate 13) using General Method B. LCMS: retention time 3.19min, MH+ 428. NMR: δH [2H6]-DMSO 10.38,(1H, s), 10.00,(1H, s), 9.19,(1H, s), 8.38,(2H, m), 7.83,(1H, s), 7.80,(1H, s), 7.76,(1H, s), 7.73-7.69,(3H, m), 7.32,(1H, s), 7.01,(1H, s), 6.96,(2H, d), 3.76,(3H, s), 2.34,(3H, s).
Example 14: 6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3- methoxybenzyD-nicotinamide
Figure imgf000042_0002
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.94min, MH+ 416. NMR: δH [2H6]-DMSO 9.29,(1H, t), 9.15,(1H, s), 8.48,(1H, d), 8.35,(1H, d), 7.89,(1H, s), 7.81,(1H, d), 7.72,(1H, d), 7.41,(1H, d), 7.26,(1H, t), 6.93,(2H, m), 6.84,(1H, s), 4.51,(2H, d), 3.75,(3H, s), 2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m). Example 15: N-(3-MethoxybenzvP-6-f2-methyl-5-(thiadiazol-2-ylcarbamoyl)- phenyll- nicotinamide
Figure imgf000043_0001
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide
(Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.02min, MH+ 460. NMR: δH [2H6]-DMSO 13.14,(1H, b), 9.32,(1H, t), 9.24,(1H, s), 9.18,(1H, d), 8.40,(1H, dd), 8.26,(1H, s), 8.10,(1H, d), 7.84,(1H, d), 7.55,(1H, d), 7.27,(1H, t), 6.94,(2H, m), 6.84,(1H, d), 4.53,(2H, d), 3.75,(3H, s), 2.46,(3H, s).
Example 16: N-(3-MethoxybenzvP-6-[2-methyl-5-(thiazol-2-ylcarbamovP- phenyll- nicotinamide
Figure imgf000043_0002
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 3.20min, MH+ 459. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.31,(1H, t), 9.17,(1H, d), 8.39,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.83,(1H, d), 7.57,(1H, d), 7.52,(1H, d), 7.29-7.25,(2H, m), 6.94,(2H, m), 6.84,(1H, d), 4.52,(2H, d), 3.75,(3H, s), 2.45,(3H, s). Example 17: 6-(5-Cvclopropylmethylcarbamoyl-2-methyl-phenyP-N-(3- methoxybenzylVnicotinamide
Figure imgf000044_0001
6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 3.07min, MH+ 430. NMR: δH [2H6]-DMSO 9.30,(1H, t), 9.16,(1H, d), 8.62,(1H, t), 8.36,(1H, dd), 7.94,(1H, s), 7.85,(1H, d), 7.74,(1H, d), 7.43,(1H, d), 7.27,(1H, t), 6.94-6.92,(2H, m), 6.84,(1H, d), 4.51,(2H, d), 3.75,(3H, s), 3.14,(2H, t), 2.39,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Example 18: 6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl1-N-(3- methoxybenzyP-nicotinamide
Figure imgf000044_0002
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methoxybenzyl)- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]-3-furamide (hitermediate 13) using General Method B. LCMS: retention time 3.17min, MH+ 442. NMR: δH [2H6]-DMSO 9.99,(1H, s), 9.29,(1H, t), 9.15,(1H, d), 8.38,(1H, s), 8.34,(1H, dd), 7.81,(2H, m), 7.75,(1H, d), 7.67,(1H, d), 7.31-7.25,(2H, m), 7.00.(1H, s), 6.94,(2H, m), 6.84,(1H, d), 4.51,(2H, d), 3.75,(3H, s), 2.32,(3H, s). Example 19: N-(3-MethoxybenzvP-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl- phenyll-nicotinamide
Figure imgf000045_0001
N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]- nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide
(hitermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.27min, MH+ 458. NMR: δH [2H6]-DMSO 10.12,(1H, s), 9.29,(1H, t), 9.15,(1H, d), 8.35-8.32,(2H, m), 7.86,(1H, s), 7.78,(1H, d), 7.68-7.65,(3H, m), 7.32- 7.24,(2H, ), 6.94,(2H, m), 6.84,(2H, d), 4.51,(2H, d), 3.75,(3H, s), 2.32,(3H, s).
Example 20: 6-(5-Cvclopropylcarbamoyl-2-methyl-phenvP-N-(3- methylsulphonylaminobenzvP-nicotinamide
Figure imgf000045_0002
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3- methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropyl-4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.71min, MH+ 479. NMR: δH [2H6]- DMSO 9.33,(1H, t), 9.15,(1H, s), 8.48-8.33,(3H, m), 7.89,(1H, s), 7.81,(1H, d), 7.73,(1H, d), 7.41,(1H, d), 7.31,(1H, t), 7.21,(1H, s), 7.10,(2H, ), 4.51,(2H, d), 2.99,(3H, s), 2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m). Example 21 : N-(3-MethylsulphonylaminobenzvP-6-f2-methyl-5-(thiadiazol-2- ylcarbamovP-phenyll-nicotinamide
Figure imgf000046_0001
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiadiazol-2- ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5- tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.80min, MH+ 523. NMR: δH [2H6]-DMSO 9.35,(1H, t), 9.17,(2H, m), 8.38,(1H, d), 8.26,(1H, s), 8.09,(1H, d), 7.83,(1H, d), 7.52,(1H, d), 7.31,(1H, t), 7.22,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 2.99,(3H, s), 2.46,(3H, s).
Example 22 : N-(3-Methylsulphonylaminobenzyl)-6- [2-methyl-5-(thiazol-2- y lcarb amoyP-phen yll -nicotin amide
Figure imgf000046_0002
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)- phenyl] -nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.96min, MH+ 522. NMR: δH [2H6]- DMSO 10.19,(2H, b), 9.35,(1H, t), 9.17,(1H, s), 8.38,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.84,(1H, d), 7.57,(1H, d), 7.52,(1H, d), 7.31-7.28,(2H, m), 7.22,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 2.99,(3H, s), 2.45,(3H, s). Example 23 : 6-(5-CvclopropylmethylcarbamoyI-2-methyl-phenyl)-N-(3- methylsulphonylaminobenzvD-nicotinamide
Figure imgf000047_0001
6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3- methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N- cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.88min, MH+ 493. NMR: δH [ H6]-DMSO 9.34,(1H, t), 9.16,(1H, d), 8.96,(1H, b), 8.62,(1H, t), 8.35,(1H, dd), 7.94,(1H, s), 7.85,(1H, d), 7.75,(1H, d), 7.43,(1H, d), 7.31,(1H, t), 7.21,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 3.14,(2H, t), 2.99,(3H, s), 2.39,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Example 24: 6-[5-(Fur-3-ylcarbonylamino)-2-methyI-phenyn-N-(3- methylsulphonylaminobenzyP-nicotinamide
Figure imgf000047_0002
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3- methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.93min, MH+ 505. NMR: δH [2H6]- DMSO 9.99,(1H, s), 9.32,(1H, t), 9.15,(1H, d), 8.95,(1H, b), 8.38,(1H, s), 8.33,(1H, dd), 7.81,(2H, d), 7.75,(1H, d), 7.68,(1H, d), 7.33-7.30,(2H, m), 7.21,(1H, s), 7.11,(2H, m), 7.01,(1H, s), 4.51,(2H, d), 2.99,(3H, s), 2.32,(3H, s). Example 25: N-(3-Methylsnlphonylaminobenzyl)-6-F5-(thiophen-3- ylcarbonvIaminoV2-methyl-phenyll-nicotinamide
Figure imgf000048_0001
N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2- methyl-phenyl] -nicotinamide was prepared from 6-chloro-N-(3- methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3- (4,4,5 , 5-tetramethyl- [1,3,2] dioxaborolan-2-yl)-phenyl] thiophene-3 -amide (Intermediate 14) using General Method B. LCMS: retention time 3.03min, MH+ 521. NMR: δH [2H6]-DMSO 10.12,(1H, s), 9.33,(1H, t), 9.15,(1H, s), 8.78,(1H, b), 8.36- 8.32,(2H, m), 7.86,(1H, s), 7.78,(1H, d), 7.69-7.65,(3H, m), 7.31,(2H, m), 7.21,(1H, s), 7.11,(2H, m), 4.51,(2H, d), 2.99,(3H, s), 2.32,(3H, s).
Example 26: 6-(5-Cyclopropylcarbamoyl-2-methyl-phenyP-N-[2-(4- methylpiperazin-l-ylmethvPphenvn-nicotinamide
Figure imgf000048_0002
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-l- ylmethyl)phenyl] -nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin- l-ylmethyl)phenyl]nicotinamide (hitermediate 5) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (rnteraiediate 8) using General Method B. LCMS: retention time 2.36min, MH+ 484. NMR: δH [2H6]-
DMSO 11.70,(1H, b), 9.23,(1H, s), 8.50,(1H, d), 8.38,(1H, d), 8.33,(1H, d), 7.92,(1H, s), 7.83,(2H, m), 7.43,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 2.87,(1H, m), 2.67-2.24,(1 IH, m), 2.13,(3H, s), 0.70,(2H, m), 0.58,(2H, m). Example 27: N-[2-(4-Methylpiperazin-l-ylmethvPphenyll-6-F2-methyl-5- (thiadiazol-2-ylcarbamovP-phenyll-nicotinamide
Figure imgf000049_0001
N- [2-(4-Methylpiperazin- 1 -ylmethyl)phenyl] -6- [2-methyl-5 -(thiadiazol-2- ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4- methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3- (4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.43min, MH+ 528. NMR: δH [1H6]-DMSO 13.07,(1H, b), 11.74,(1H, s), 9.26,(1H, s), 9.21,(1H, s), 8.43,(1H, d), 8.34,(1H, d), 8.29,(1H, s), 8.12,(1H, d), 7.93,(1H, d), 7.56,(1H, d),
7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.78,(2H, s), 2.67-2.26,(1 IH, m), 2.11,(3H, s).
Example 28: N-f2-(4-Methylpiperazin-l-yImethvPphenyll-6-f2-methyl-5- (thiazol-2-ylcarb amoyP-phenyll -nicotin amide
Figure imgf000049_0002
N-[2-(4-Methylpiperazin-l-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2- ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4- methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (hitermediate 11) using General Method B. LCMS: retention time 2.53min, MH+ 527. NMR: δH [2H6]-DMSO 12.73,(1H, b), 11.70,(1H, b), 9.26,(1H, d), 8.43,(1H, dd), 8.33,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.93,(1H, d), 7.58,(1H, d), 7.54,(1H, d), 7.36,(1H, t), 7.30,(2H, m), 7.12,(1H, t), 3.78,(2H, s), 2.67-2.25,(1 IH, b), 2.14,(3H, s). Example 29: 6-(5-Cvclopropylmethylcarbamoyl-2-methyI-phenvP-N-[2-(4- methylpiperazin-l-ylmethyPphenyll-nicotinamide
Figure imgf000050_0001
6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-[2-(4- methylpiperazin-l-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2- (4-methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N- cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.46min, MH+ 498. NMR: δH [2H6]-DMSO 11.67,(1H, b), 9.24,(1H, s), 8.63,(1H, t), 8.39,(1H, d), 8.32,(1H, d), 7.97,(1H, s), 7.88-7.83,(2H, m), 7.45,(1H, d), 7.36,(1H, t), 7.30,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 3.15,(2H, t), 2.70-2.21,(1 IH, m), 1.04,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Example 30: 6-[5-(Fnr-3-ylcarbonylaminoV2-methyl-phenvn-N-f2-(4- methylpiperazin-l-ylmethyPphenyll-nicotinamide
Figure imgf000050_0002
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-[2-(4-methylpiperazin-l- ylmethyl)phenyl] -nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin- l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (hitermediate 13) using General Method B. LCMS: retention time 2.53min, MH+ 510. NMR: δH [2H6]- DMSO 11.64,(1H, b), 10.02,(1H, s), 9.23,(1H, s), 8.38,(2H, m), 8.31,(1H, d), 7.86,(1H, s), 7.80,(1H, s), 7.76,(2H, m), 7.38-7.29,(3H, m), 7.11,(1H, t), 7.01,(1H, s), 3.77,(2H, s), 2.66-2.20,(1 IH, m), 2.16,(3H, s). Example 31 : N-f2-f4-Methylpiperazin-l-ylmethvPphenyll-6-[5-(thiophen-3- ylcarbonylaminoV2-methyl-phenyll-nicotinamide
Figure imgf000051_0001
N-[2-(4-Methylpiperazin-l-ylmethyl)phenyl]-6-[5-(thiophen-3- ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-[2- (4-methylpiperazin-l-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (hitermediate 14) using General Method B. LCMS: retention time 2.58min, MH+ 526. NMR: δH [2H6]-DMSO 11.64,(1H, b), 10.14,(1H, s), 9.23,(1H, s), 8.38,(2H, m), 8.31,(1H, d), 7.91,(1H, s), 7.79-7.75,(2H, m), 7.65,(2H, m), 7.38-7.29,(3H, m), 7.11,(1H, t), 3.77,(2H, s), 2.67-2.24,(1 IH, m), 2.16,(3H, m).
General Method C
The 6-chloronicotinamide (25mg), N-cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 34, 15mg), tetrakis(triphenylphosphino)palladium (2mg) and aqueous sodium hydrogen carbonate (IM, 0.5ml) were mixed in propan-2-ol (2ml) and heated at reflux for 18 hours. The propan-2-ol was evaporated and the residue diluted with ethylacetate / cyclohexane (1 :2). The solution was applied to a SPE (Si, 2g) and eluted with ethylacetate / cyclohexane (1 :2) and then ethylacetate. The solvent was evaporated from the ethylacetate fraction and the residue triturated with ether to give the desired product as a white solid.
Examples 32 to 44 may also be prepared using {5-[(cyclopropylamino)carbonyl]-3- fluoro-2-methylphenyl}boronic acid (Intermediate 36) in place of Intermediate 34.
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
General Method D hitermediate 38 (40μrnol) in DMF(0.5ml) was treated with HATU (1.12eq) and DIPEA (3eq). On shaking a solution was formed which was added to a solution of amine (1.2 - 2.0eq) in DMF (0.5ml). After shaking the reactions were left overnight at room temperature. The solvent was removed in vacuo, the residue dissolved in chloroform (1.0ml) and applied to an SPE (NH2, 0.5g). The product was eluted with chloroform (1.5ml), ethyl acetate (1.5ml) and methanol/ethyl acetate (1:9, 1.5ml). The solvent was evaporated under vacuum from the product fraction.
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Abbreviations
DCM Dichloromethane
DIPEA N,N-Diisopropylethylamine
DME Dimethoxyethane
DMF Dimethylformamide
DMSO Dimethylsulphoxide
HATU O-(7- Azabenzotriazol- 1 -yl)-N,N,N' ,N' -tetramethyluronium hexafluorophosphate
HOBT 1-Hydroxybenzotriazole hydrate
SPE bond-elut (solid phase extraction column)
The activity of the compounds of the invention as p38 inhibitors maybe demonstrated in the following assays:
p38 Kinase Assay
The peptide substrate used in the p38 assay was biotin-ff TSPITTTYFFFRRR- amide. The p38 and MEK6 proteins were purified to homogeneity from E.coli expression systems. The fusion proteins were tagged at the N-terminus with Glutathione-S-Transferase (GST). The maximum activation was achieved by incubating 20uL of a reaction mixture of 30nM MEK6 protein and 120nM p38 protein in the presence of 1.5uM peptide and lOmM Mg(CH3CO2)2 in lOOmM HEPES, pH 7.5, added to 15uL of a mixture of 1.5uM ATP with 0.08uCi [g-33P]ATP, with or without 15uL of inhibitor in 6%DMSO. The controls were reactions in the presence (negative controls) or absence (positive controls) of 50 mM EDTA. Reactions were allowed to proceed for 60 min at room temperature and quenched with addition of 50uL of 250mM EDTA and mixed with 150uL of Streptavidin SPA beads
(Amersham) to 0.5mg/reaction. The Dynatech Microfluor white U-bottom plates were sealed and the beads were allowed to settle overnight. The plates were counted in a Packard TopCount for 60 seconds. IC50 values were obtained by fitting raw data to %I = 100*(1-(I-C2)/(C1-C2)), where I was CPM of background, CI was positive control, and C2 was negative control.
oι P38 Fluorescence Polarisation Method ce P38 was prepared in house. SB4777790-R Ligand was diluted in HEPES containing MgCl2, CHAPS, DTT and DMSO. This was added to blank wells of a Black NUNC 384 well plate, P38 was added to this ligand mixture then added to the remainder of the 384 well plate containing controls and compounds. The plates were read on an LJL Analyst and Fluorescence Anisotropy used to calculate the compound inhibition.
Results
The compounds described in the Examples were tested as described above and had IC50 values of <10 μM.

Claims

Claims:
A compound of formula (I):
Figure imgf000069_0001
(I)
wherein
Ri is selected from hydrogen, Cχ_6alkyl optionally substituted by up to three groups selected from Cχ_galkoxy, halogen and hydroxy, C2-6alkenyl, C3_7cycloalkyl optionally substituted by one or more Cχ_galkyl groups, phenyl optionally substituted by up to three groups selected from R^ and R", and heteroaryl optionally substituted by up to three groups selected from R^ and R^,
R2 is selected from hydrogen, Cx.galkyl and -(CH2)q-C3_7cycloalkyl optionally substituted by one or more C j .βalkyl groups, or (CH2)mR-'- and R2, together with the nitrogen atom to which they are bound, form a four- to six-membered heterocyclic ring optionally substituted by up to three Cj.galkyl groups;
R3 is chloro or methyl; R4 is the group -NH-CO-R7 or -CO-NH-(CH2)q-R8;
R5 is selected from Cχ_6alkyl, Cχ_galkoxy, -(CH2)q-C3_7cycloal yl optionally substituted by one or more Ci.galkyl groups, -CONR^RlO, -NHCOR 0, . S02NHR9, -(CH2)sNHSO2R10, halogen, CN, OH, -(CH2)SNR11R12, and trifluoromethyl; R6 is selected from Cχ_galkyl, Cχ_6alkoxy, halogen, trifluoromethyl and -
(CH2)SNRHR12;
R7 is selected from hydrogen, Ci^galkyl, -(CH2)q-C3_7cycloalkyl optionally substituted by one or more Cχ_galkyl groups, trifluoromethyl, -(CH2)ιheteroaryl optionally substituted by R^ and/or R^, and -(CH2)rPhenyl optionally substituted by R13 and/or R14;
Rβ is selected from hydrogen, Cj.galkyl, C3_7cycloalkyl optionally substituted by one or more Cχ_galkyl groups, CONHR.9, phenyl optionally substituted by Rl3 and/or R^, and heteroaryl optionally substituted by Rl3 and/or R*4; R9 and RlO are each independently selected from hydrogen and Cx.galkyl, or R9 and R*0, together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R^, wherein the ring may be substituted by up to two C \ -galkyl groups;
RU is selected from hydrogen, Cx.galkyl and-(CH2)q-C3_7cycloalkyl optionally substituted by one or more Cχ_5alkyl groups,
Rl2 is selected from hydrogen and Cj.galkyl, or Ri * and ^, together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur andN-R*5;
Rl3 is selected from C _galkyl, Cj.galkoxy, -(CH2)q-C3_7cycloalkyl optionally substituted by one or more Cχ_galkyl groups, -CONR^RlO, -NHCOR!0, halogen, CN, -(CH2)sNRl 1R12} trifluoromethyl, phenyl optionally substituted by one or more R*4 groups and heteroaryl optionally substituted by one or more Rl4 groups;
Rl4 is selected from Cx.galkyl, Cj.galkoxy, halogen, trifluoromethyl and - NRnR12;
R!5 is selected from hydrogen and methyl;
X and Y are each independently selected from hydrogen, methyl and halogen; Z is halogen; m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chain may be optionally substituted with up to two groups selected independently from Cj.galkyl and halogen; n is selected from 0, 1 and 2; q is selected from 0, 1 and 2; r is selected from 0 and 1 ; and s is selected from 0, 1, 2 and 3.
2. A compound according to claim 1 wherein R* is selected from Cχ_6alkyl, C2- galkenyl, C3_7cycloalkyl optionally substituted by one or more Cx.galkyl groups, phenyl optionally substituted by up to three substituents selected from R^ and R^, heteroaryl optionally substituted by up to three substituents selected from R^ and R^.
3. A compound according to claim 1 or claim 2 wherein R2 is hydrogen.
4. A compound according to any one of the preceding claims wherein R3 is methyl.
5. A compound according to any one of the preceding claims wherein X is fluorine.
6. A compound according to any one of the preceding claims wherein R is selected from Cχ_6alkyl, -(CH2)q-C3_7cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R 3 and/or R*4, and -(CH2)rphenyl optionally substituted by
Figure imgf000070_0001
-(CH2)q-C3_7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and/or heteroaryl optionally substituted by one or more R14 groups.
7. A compound according to any one of the preceding claims wherein R is selected from C3_7cycloalkyl, CONHR9, heteroaryl optionally substituted by R13 and or R14, and phenyl optionally substituted by Ci^galkyl, Cχ_6alkoxy, -(CH2)q- C3_7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and/or heteroaryl optionally substituted by one or more R14 groups.
8. A compound according to claim 1 as defined in any one of Examples 1 to 123.
9. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
10. A method for treating a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase comprising administering to a patient in need thereof a compound as claimed in any one of claims 1 to 8.
11. A compound as claimed in any one of claims 1 to 8 for use in therapy.
12. Use of a compound as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in the treatment of a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase.
13. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 8 which comprises
(a) reacting a compound of (U)
Figure imgf000071_0001
(π) in which R1, R2, Z, m and n are as defined in claim 1 and W is halogen, with a compound of formula (in)
Figure imgf000072_0001
(ED) in which R3, R4, X and Y are as defined in claim 1, in the presence of a catalyst, or
(b) reacting a compound of formula (Yin)
Figure imgf000072_0002
(vm) with a compound of formula (JU) as hereinbefore defined and then reacting the acid thus formed with an amine of formula (V)
Figure imgf000072_0003
(V) in which R , R2 and m are as defined in claim 1 , under amide forming conditions, or
(c) reacting a compound of formula (II) as hereinbefore defined with a compound of formula (IX)
Figure imgf000072_0004
(DC) in which R3, R4, X and Y are as defined in claim 1, in the presence of a catalyst.
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