CA2474192C

CA2474192C - Nicotinamide derivates useful as p38 inhibitors

Info

Publication number: CA2474192C
Application number: CA2474192A
Authority: CA
Inventors: Nicola Mary Aston; Paul Bamborough; Ann Louise Walker
Original assignee: GlaxoSmithKline LLC
Current assignee: GlaxoSmithKline LLC
Priority date: 2002-02-12
Filing date: 2003-02-10
Publication date: 2011-06-21
Anticipated expiration: 2023-02-10
Also published as: BR0307351A; PL212910B1; CY1107117T1; US7709506B2; ES2400486T3; DK1864975T3; ZA200405602B; EP2258687B1; ES2295553T3; EP1474395A1; US7125898B2; US20050176964A1; PT1474395E; EP1864975A3; RU2309951C2; US7514456B2; AU2003207298B2; NZ533865A; IS2520B; EP1864975B1

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

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 cytokines 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):

0 N-(CH2)m R
(Z), N

Y
wherein R1 is selected from hydrogen, C1-6alkyl optionally substituted by up to three groups selected from C1-6alkoxy, halogen and hydroxy, C2-6alkenyl, C3-7cycloallcyl optionally substituted by one or more C1-6alkyl groups, phenyl optionally substituted by up to three groups selected from R5 and R6, and heteroaryl optionally substituted by up to three groups selected from R5 and R6, R2 is selected from hydrogen, C1_6alkyl and -(CH2)q-C3-7cycloallcyl optionally substituted by one or more C1-6a1ky1 groups, or (CH2)mR1 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 C1-6a11cy1 groups;
R3 is chloro or methyl;
R4 is the group -NH-CO-R7 or -CO-NH-(CH2)q-R8;
R5 is selected from C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, -CONR9R10, -NHCOR10, -SO2NHR9, -(CH2)5NHS02R10, halogen, CN, OH, -(CH2)sNR11R12, and trifluoromethyl;
R6 is selected from C 1-6alkyl, C 1-6alkoxy, halogen, trifluoromethyl and -(CH2)sNR11R12;

R7 is selected from hydrogen, C1-6alkyl, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R13 and/or R14, and -(CH2)rphenyl optionally substituted by R13 and/or R14;
R8 is selected from hydrogen, C1-6a1ky1, C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, CONHR9, phenyl optionally substituted by R13 and/or R14, and heteroaryl optionally substituted by R13 and/or R14;
R9 and R10 are each independently selected from hydrogen and C1-6a1ky1, or R9 and R1 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-R15, wherein the ring may be substituted by up to two C1-6alkyl groups;
R11 is selected from hydrogen, C1-6alkyl and -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, R12 is selected from hydrogen and C1-6alkyl, or Rl I and R12, 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-R15;
R13 is selected from C1-6alkyl, C1_6alkoxy, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1_6alkyl groups, -CONR9R10, -NHCORI0, halogen, CN, -(CH2)sNRl 1R12, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and heteroaryl optionally substituted by one or more R14 groups;
R14 is selected from C1-6alkyl, C1-6alkoxy, halogen, trifluoromethyl and -NR11R12;
R15 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 C1_6alkyl 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):

O N-(CH2)m R1 N

(IA) wherein Rl, R2, R3, R4 and m are as defined above.
According to one embodiment of the present invention, RI is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, phenyl optionally substituted by R5 and/or R6, and heteroaryl optionally substituted by R5 and/or R6, and R2 is selected from hydrogen, C 1 _6alkyl and -(CH2)q-C3-7cycloalkyl.
In a preferred embodiment, R1 is selected from C1-6alkyl, for example methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyl-l-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 C1-6alkoxy, in particular C1-4alkoxy 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 1,1-dimethylbut-2-enyl; C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, optionally substituted by one or two C1-4alkyl groups such as methyl or ethyl; phenyl optionally substituted by up to three groups selected from R5 and R6, for example phenyl optionally substituted by up to three substituents, for example one or two substituents, such as C1-4alkyl, in particular methyl, C1-4alkoxy, in particular methoxy, halogen, in particular fluorine or chlorine, trifluoromethyl, -(CH2)sNR11R12 or -(CH2)sNHSO2R10, located on any position on the ring;
heteroaryl optionally substituted by up to three groups selected from R5 and R6, for example heteroaryl optionally substituted by one or two substituents, in particular a 5-membered heteroaryl such as W, thienyl or thiazolyl optionally substituted by 4alkyl, in particular methyl. Ina particularly preferred embodiment, R1 is C1-6alkyl, for example C2-5 alkyl, such as ethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, n-butyl, isobutyl, 3-methylbutyl or 2-pentyl.
In another preferred embodiment, RI is selected from C3-7cycloalkyl, phenyl optionally substituted by R5 and/or R6, and heteroaryl optionally substituted by R5 and/or R6. In a more preferred embodiment, Rl is selected from C3-6cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, and phenyl optionally substituted by R5 and/or R6. 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 C1-4alkoxy, in particular methoxy, -(CH2) sNR11 1R12, and -(CH2)sNHS02RI 0.
In another preferred embodiment, R1 is selected from C1-6alkyl, for example n-propyl, 1-methylpropyl, isobutyl, 3-methylbutyl or 2,2-dimethylpropyl, and 7cycloalkyl optionally substituted by one or more C1-6alkyl groups, for example cyclopropyl optionally substituted by one or two methyl groups.
In a further preferred embodiment, R1 is selected from C1-6alkyl, for example methyl, ethyl, n-propyl, isopropyl, 1, 1 -dimethylpropyl, 1-ethyl- l -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 C1-6alkoxy, in particular C1-4alkoxy 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 1, 1 -dimethylbut-2-enyl; C3-7cycloalkyl optionally substituted by one or more C1_6alkyl 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 R5 and R6, for example phenyl optionally substituted by up to three substituents such as C1-4alkyl, in particular methyl, C1-4alkoxy, 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 R5 and R6, in particular a 5-membered heteroaryl such as furyl, thienyl or thiazolyl optionally substituted by C1-4alkyl, in particular methyl.
In a preferred embodiment, R2 is selected from hydrogen; C14alkyl, 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, C1-4alkyl and -CH2-cyclopropyl. More preferably R2 is hydrogen.
In a further preferred embodiment, (CH2)mRl 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 C1-6alkyl 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, R4 is the group -CO-NH-(CH2)q-R8.
In one embodiment of the present invention, R5 is selected from C1_6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl, -CONR9R10, -NHCOR10, -SO2NHR9, -(CH2)sNHS02R10, halogen, CN, OH, -(CH2)sNR11R12, and trifluoromethyl.
In a preferred embodiment, R5 is selected from C1-4alkyl, in particular methyl; C1-4alkoxy, in particular methoxy; -(CH2)sNHSO2R10; halogen, in particular chlorine or fluorine; -(CH2)sNR11R12; and trifluoromethyl.
In another preferred embodiment, R5 is selected from C14alkoxy, in particular methoxy, -(CH2)sNR11R12, and -(CH2)sNHS02R10.
In a further preferred embodiment, R5 is selected from C1-4alkyl, in particular methyl; C1-4alkoxy, in particular methoxy; halogen, in particular chlorine or fluorine;
and trifluoromethyl.

In a preferred embodiment, R6 is selected from C1-4alkyl, in particular methyl, ethyl or propyl; C1-4alkoxy, in particular methoxy; halogen, in particular chlorine or fluorine; and trifluoromethyl.
In a further preferred embodiment, R6 is C1-4alkoxy, in particular methoxy.
In one embodiment of the present invention, R7 is selected from hydrogen, C1-6alkyl, -(CH2)q-C3-7cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R13 and/or R14, and -(CH2)rphenyl optionally substituted by R13 and/or R14.
In a preferred embodiment, R7 is selected from C1-6alkyl, -(CH2)q-C3-7cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R13 and/or R14, and -(CH2)rphenyl optionally substituted by C1-6alkyl, C1-6alkoxy, -(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. In another preferred embodiment, R7 is selected from C1-4alkyl, -(CH2)q-C3-6cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R13 and/or R14, and -(CH2)rphenyl optionally substituted by C1_6alkyl, C1_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. In a more preferred embodiment, R7 is -(CH2)rheteroaryl optionally substituted by R13 and/or R14, 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 NR1'R12, furyl or thiophenyl.
In one embodiment of the present invention, R8 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, CONHR9, phenyl optionally substituted by R13 and/or R14, and heteroaryl optionally substituted by R13 and/or R14 In a preferred embodiment, R8 is selected from C3-7cycloalkyl, CONHR9, heteroaryl optionally substituted by R13 and/or R14, and phenyl optionally substituted by C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl, -CONR9R1 0, -NHCOR1 0, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and/or heteroaryl optionally substituted by one or more R14 groups. In another preferred embodiment, R8 is selected from C3-7cycloallcyl, heteroaryl optionally substituted by R13 and/or R14, and phenyl optionally substituted C1-6alkyl, C1_ 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. Ina more preferred embodiment, R8 is selected from C3-6cycloallcyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, heteroaryl optionally substituted by R13 and/or R14, 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. In a particularly preferred embodiment, R8 is selected from C3-6cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl.
In a preferred embodiment, R9 is selected from hydrogen and C1-4alkyl.

In a preferred embodiment, R10 is selected from hydrogen and C1-4alkyl, in particular methyl.
In one embodiment, RI 1 is selected from hydrogen, C1-6alkyl and -(CH2)q-C3-7cycloalkyl optionally substituted by C1-6alkyl.
In a preferred embodiment, Rl 1 and R12, 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-R15.
In one embodiment of the present invention, R13 is selected from C1 _6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl, -CONR9R10, -NHCORIO, halogen, CN, -(CH2)sNR1'R12, trifluoromethyl, phenyl optionally substituted by one or more groups and heteroaryl optionally substituted by one or more R14 groups;
In a preferred embodiment, R13 is selected from C1-4alkyl, in particular methyl, C1-4alkoxy, in particular methoxy, halogen, -(CH2)5NR11R12, phenyl optionally substituted by one or more R14 groups and heteroaryl optionally substituted by one or more R14 groups. Ina more preferred embodiment, R13 is selected from -(CH2)sNR11R12 and heteroaryl optionally substituted by one or more R14 groups, in particular a five or six-membered heteroaryl containing at least one nitrogen atom, for example, pyridyl.
In a preferred embodiment R14 is selected from from C1-4alkyl, in particular methyl, C1-4alkoxy, in particular methoxy, and -NRI 1R12.
In a preferred embodiment, R15 is methyl.
In a preferred embodiment, X and Y are each independently selected from hydrogen, chlorine and fluorine. In a further preferred embodiment, X is fluorine. In another preferred embodiment, Y is hydrogen.
In a preferred embodiment, Z is fluorine.
In one embodiment of the present invention, m is selected from 0, 1, 2, 3 and 4. In 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 C1-6alkyl.
In a preferred embodiment, m is selected from 0, 1, 2 and 3. In 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. In one embodiment, the substituents are preferably one or two methyl groups. In another embodiment, the substituents are preferably one or two fluorine atoms.
In a preferred embodiment, n is selected from 0 and 1. In particular, n is 0.
In a preferred embodiment, q is selected from 0 and 1. In particular, q is 0.
In a preferred embodiment, r is 0.
In 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-(1-cyclopropylethyl)-nicotinamide;
6-(5-cyclopropylcarbamoyl-3 -fluoro-2-methyl-phenyl)-N-(2,2-diinethylpropyl)-nicotinamide;
6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)-nicotinamide; and 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(1-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-methylphenyl}nicotinamide;
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- fluorob enzyl) -6- { 5 - [ (cyc lopropylamino) c arb onyl] -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-[(cyclopropylainino)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-(1,1-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)nicotinainide;
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-(1-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)nicotinainide.
As used herein, the term "allcyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-6alkyl 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 C1-4alkyl 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_6alkenyl 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 1,1-dimethylbut-2-enyl.
As used herein, the term "allcoxy" refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy. A C-1-4alkoxy 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 C3-6cycloalkyl group is preferred, for example, cyclopropyl, cyclopentyl or cyclohexyl. The said cycloalkyl groups may be optionally substituted with one or more C1_6alkyl groups, for example one or two methyl groups. In one embodiment, the cycloalkyl groups may be optionally substituted by up to four C1-6alkyl groups, for example one or two C1-6alkyl groups, in particular one or two C1_4alkyl 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 6alkyl 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, morpholino, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholino.
The said ring may be optionally substituted by one or more substituents independently selected from C 1 _6alkyl 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 term "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-methylglucanine, 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 may be 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) 0 N-(CH2)m R' (Z).
N

W
(II) in which Rl, R2, Z, m and n are as hereinbefore defined and W is halogen, in particular bromine or chlorine, with a compound of formula (III) O,B'O

Y
in which R3, R4, X and Y are as hereinbefore defined, in the presence of a catalyst, for example tetrakis(triphenylphosphine)palladium.
A compound of formula (II) may readily be prepared from a corresponding acid compound of formula (IV) O OH

(Z)n N /

W
(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) N-(CH2)m R1 H
(V) in which Rl, R2 and in 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 (III) may be prepared by reacting a compound of formula (VI) hal Y
(VI) in which R3, R4, X and Y are as hereinbefore defined and hal is halogen, in particular iodine, with bis(pinnacolato)diboron, PdCl2dppf and potassium acetate in a solvent such as DMF.
Alternatively, when R4 is -CO-NH-(CH2)q-R8, a compound of formula (III) may be prepared by reacting an acid compound of formula (VII) hal X I OH
O
(VII) in which R3, hal, X and Y are as hereinbefore defined, with bis(pinnacolato)diboron, PdCl2dppf 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 (1) may also be prepared by reacting a compound of formula (VIII) O O
N /
CI
(VIII) with a compound of formula (III) 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 (1) may be prepared by reacting a compound of (II) as hereinbefore defined with a compound of formula (IX) HO,BOH

Y

(IX) in which R3, R4, 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.

hal hal \ (I) O (~') O. 110 ---6N 'k NH H R7 2 I \ O
/ NAR' O OH O N-(CH2)m R1 1 (iii)/(iv) N N /
Br CI

I
O N-(CH 2)m R1 N

O

H

Scheme 1 i. R7CO2H, HATU, DIPEA, DMF.

ii. Bis(pinnacolato)diboron, PdCl2dppf, KOAc, DMF.
iii. SOC12.

iv. Rl (CH2)mR2NH, Na2CO3, acetone.

v. 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 2 below.

-13-' hal hal (i)/(ii) (iii) \ 011 6,0 OH I / N-(I
H
O O N-(CH2) -R$

O OH O N-(CH2)mR
(iv)/(v) N / N /
Br Cl 0 N-(CH2)q R1 N /

H
N-(CH2)q R8 O

Scheme 2 i. SOCl2.

ii. R8(CH2)qNH2, Na2C03, acetone.
iii. Bis(pinnacolato)diboron, PdCl2dppf, KOAc, DMF.
iv. SOC12.

v. Rl (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.

O
hal O,B0 OH I / OH

O I / N-(CH2)q R8 p O OH O N-(CH2)M -R

(iii)/(iv) (v) \
N / N /
Br CI

0 N-(CH2)m R1 N /

N-(CH2)q R8 O

Scheme 3 i. Bis(pinnacolato)diboron, PdCl2dppf, KOAc, DMF.
ii. R8(CH2)qNH2, HATU, DIPEA, DMF.
iii. SOC12.

iv. R1(CH2)mR2NH, Na2CO3, DCM.

v. Na2CO3, tetralcis(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.

O OH

O O~

\ 011 B110 (i) N

H s H
CI F / N-(CH2)q R F N-(CH2)q O O

(ii) 0 N-(CH2)m R1 N /

F N-(CH2)q O
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.

hal hal (i)/(ii) (iii) \ \ _HOB
F F ~OH
/ OH I / N-(CH2)q R8 O O F N-(CH2)q R8 O OH O N-(CH2)m R1 1 (iv)/(v) I \ (vi) N / N /

Br CI

0 N-(CH2)m R1 N

F N-(CH2)q R8 O
Scheme 5 i. SOC12.
ii. R8(CH2)gNH2, Na2CO3, DCM.
iii. NaH, n-BuLi, THF, (iPrO)3B.
iv. SOC12.
V. Rl(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 iultilamellar 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, polyhydroxypropylmethacrylainide-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 formulations 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.
In 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. In 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. 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.
In 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 p38a, p380, p38yy and/or p386.
In one embodiment, the compounds of the invention selectively inhibit the p38a isoform.
In another embodiment, the compounds of the invention selectively inhibit the p38f isoform. In a further embodiment, the compounds of the invention selectively inhibit the p38a and p380 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. In 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 (1).
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 (1).
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 formula (I) for rheumatoid arthritis therapy include:
immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone; anti-TNFa agents such as etanercept, infliximab, diacerein; tyrosine kinase inhibitors such as leflunomide; kallikrein antagonists such as subreum; interleukin 11 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as (Aventis); interleukin 1 receptor antagonists such as anakinra; CD8 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 3m1/min, Injection Volume of 5 i, at room temperature and UV
Detection Range at 215 to 330nm.

Intermediate 1: 6-Chloro-N-cyclopropylmethylnicotinamide 6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2m1) 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 (4m1), cyclopropylmethylamine (71mg, 0.l0mmol) 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: 6H [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, in).
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, 0.10mmol) 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: 6H [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-methoxybenzyl)nicotinamide 6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2m1) 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 (2m1), 3-methoxybenzylamine (137mg, 0.l0mmol) 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)nicotinamnide. NMR: 8H [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-methylsulphonylaminobenzyl)nicotinamide 6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2m1) 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 (2m1), 3-methylsulphonylaininobenzylamine (200mg, 0.10mmol) 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: 8H [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 5: 6-Chloro-N-[2-(4-methylpiperazin-1-yl)phenyllnicotinamide 6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2m1) 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), 1-(2=aminobenzyl)-4-methylpiperazine (205mg, 0.1Ommol) 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-1-yl)phenyl]nicotinamide. NMR: 8H [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-Methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl-11,3,21 dioxaborolan-2-yl)-benzamide 3-Iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide (Intermediate 7) (83mg, 0.20mmol), bis(pinnacolato)diboron (100mg, 0.39mmol), potassium acetate (97mg, 1.0mmol) 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 (10g, 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-[1,3,2] dioxaborolan-2-yl)-benzamide as a white solid (31mg). LCMS: retention time 3.69min, MH+ 415.

Intermediate 7: 3-lodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide 3-Iodo-4-methylbenzoic acid (154mg, 0.59mmol) was heated at 80 C in thionyl chloride (2m1) 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 (100mg, 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 (1g, 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: 8H CDC13 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-Cvclopropvl-4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2]dioxab orolan-2-yl)-b enzamide N-Cyclopropyl-3-iodo-4-methylbenzamide (Intermediate 9) (1.1g, 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 (30m1) for 4.5hrs. The cooled reaction was absorbed onto silica, applied to a bond-elut (10g, 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: 8H [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-Cyclopropyl-3-iodo-4-methylbenzamide 3-Iodo-4-methylbenzoic acid (1.0g, 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 (0.32m1) 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 (1.1g). NMR: 8H [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-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide 4-Methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2] dioxaborolan-2-yl)-benzoic acid (Intermediate 17) (2.0g, 7.63mmol), DIPEA (4m1, 22.89mmol) and HATU (3.05g, 8.02minol) were dissolved in DMF (20m1) and stirred at room temperature for 15mins. Cyclopropylmethylamine (568mg, 8.01mmol) was added and the reaction stirred at room temperature for 18hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250m1) and water (50m1).
The organic phase was washed with hydrochloric acid (2N, 50m1) and aqueous sodium bicarbonate (1M, 50m1), 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-cyclopropylmethyl-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-benzamide (1.73g).
LCMS:
retention time 3.47min, MH+ 316. NMR: 8H [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-f 1,3,21 dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide 4-Methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0g, 7.63mmol), DIPEA (4m1, 22.89mmol) and HATU (3.05g, 8.02mmol) were dissolved in DMF (20m1) and stirred at room temperature for 15mins. 2-Aminothiazole (801mg, 8.01mmol) was added and the reaction stirred at room temperature for 18hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250m1) and water (50m1). The organic phase was washed with hydrochloric acid (2N, 50m1) 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-[ 1,3,2]
dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzainide (1.72g). LCMS: retention time 3.66min, MH+ 345.
NMR:
OH [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-Methyl-3-(4,4,5,5-tetramethyl-[1,3,21 dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide 4-Methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0g, 7.63mmol), DIPEA (4ml, 22.89mmol) and HATU (3.05g, 8.02mmol) were dissolved in DMF (20m1) and stirred at room temperature for 15mins. 2-Aininothiadiazole (810mg, 8.O1mmol) was added and the reaction stirred at room temperature for 18hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250m1) and hydrochloric acid (2N, 150m1). The aqueous was extracted with ethylacetate (2 x 250m1). 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-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (0.95g). LCMS:
retention time 3.34min, MH+ 346. NMR: SH [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-[1,3,2]dioxaborolan-2-yl)-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 (20m1) were heated at 80 C for 20hrs.
The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, 10g) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum, dissolved in DMF (40ml) and reacted with bis(pinnacolato)diboron (7.76g, 30.57mmol), potassium acetate (3.0g, 30.57mmol) 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 xIOg) 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-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide. LCMS: retention time 3.55min, MH+ 328. NMR: 8H [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-[4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyll thioph ene-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 PdCl2dppf (312mg, 0.38mmol) in DMF (20m1) were heated at 80 C
for 20hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, 10g) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum, dissolved in DMF (20m1) and reacted with bis(pinnacolato)diboron (1.77g, 7.Ommol), potassium acetate (687mg, 7.Ommol) 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, 10g) 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-[ 1,3,2] dioxaborolan-2-yl)-phenyl]thiophene-3-amide. LCMS: retention time 3.65min, MH+ 344. NMR: 8H
[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
(25m1) 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, 75m1), water (75m1) and brine (75m1). 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: SH [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-methylphenyl)thiophene-3-amide Thiophene-3-carboxylic acid (2.75g, 21.45mmol) and HATU (8.15g, 21.45mmol) in DMF (25m1) were stirred at room temperature for 15mins. HOBT
(2.9g, 21.45mmol), 3-iodo-4-methylaniline (5.0g, 21.45mmol) and DIPEA (11.2m1, 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, 75m1), water (75m1) and brine (75m1). 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, MR+ 344. NMR:
SH [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-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-vl)benzoic acid 3-Iodo-4-methylbenzoic acid (10g, 38.16mmol), bis(pinnacolato)diboron (14.5g, 57.24mmol), potassium acetate (18.73g, 190.8mmol) and PdCl2dppf (3.128, 3.8mmol) in DMF (200m1) were heated at 80 C for 21hrs. The solvent was evaporated from the cooled reaction under vacuum, the residue dissolved in ethyl acetate (300m1) and hydrochloric acid (2N, 300m1) and filtered through Celite*. The organic phase was separated and the aqueous extracted with ethyl acetate (2 x 300m1).
The combined organic extracts were washed with brine (500m1) 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-[ 1,3,2]dioxaborolan-2-yl)benzoic acid. LCMS: retention time 3.65min. NMR: SH [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).
* - trade-mark Intermediate 18: N-[4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyll-2-pyrrolidin-1-yl-isonicotinamide Bis(pinacolato)diborane (7.24g, 28.5mmol) was added to a mixture of N-(3-iodo-4-methylphenyl)-2-pyrrolidin-1-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 acetate:cyclohexane). To give N-[4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2] 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: 6H - CDC13 8.27 (1H, d), 7.99 (1H, dd), 7.76 (1H, b), 7.65 (1H, d), 6.20 (1H, d), 6.82 (1H, b), 6.77 (1H, b), 3.52 (4H, apparent t), 2.52 (3H, s), 2.25 (4H, m).

Intermediate 19: N-(3-Todo-4-methylphenyl)-2-pvrrolidin-1-yl-isonicotinamide A solution of N-(3-Todo-4-methylphenyl)-2-chloro-isonicotinamide (Intermediate 20) (7.00g, 18.8mmol) in pyrrolidine (20m1) 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 (20m1). 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, l8mmol). LCMS:
retention time 2.77 min MH+408. NMR: 6H [ZH6] - DMSO 10.29 (1H, s), 8.29 (1H, d), 8.20 (1H, d), 7.71 (1H, dd), 7.72 (1H, dd), 6.97 (1H, brd), 6.88 (1H, 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-Chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide 2-Chloroisonicotinic acid (3.3g, 21mmol), HATU (8.75g, 23mmol), diisopropylethyl amine (10.9m1, 63mmol) and 4-iodo-3-methylaniline (5.00g, 21mmol) in dimethylformamide (50m1) 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 (3xlOOml) and brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetate:cyclohexane) 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: 8H
[ZH6] - DMSO 10.52 (1H, s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87 (1H, dd), 7.70 (1H, dd), 7.34 (1H, d), 2.36 (3H, s).

Intermediate 21: 6-Chloro-N-cyclopropylmethylnicotinamide 6-Bromonicotinic acid (200mg, 0.99mmol) was heated at reflux in thionyl chloride (2m1) 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, 0.10mmol) 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: 8H [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 (100mg, 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 (0.5mrol) and sodium carbonate (100mg) 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.

Compound Amine MH+ Retention time (minutes) Intermediate 22: 6-Chloro-N-(3- 3-methylbutylamine 227 2.92 methylbutyl)nicotinamide Intermediate 23: 6-Chloro-N-(1- 1-cyclopropylethylamine 225 2.65 cyclopropylethyl)nicotinamide Intermediate 24: 6-Chloro-N-(2,2- 2,2-dimethylpropylamine 227 2.82 dimethylpropyl))nicotinamide Intermediate 25: 6-Chloro-N-(2,2- 2,2- 225 2.67 dimethylcyclopropyl)nicotinamide dimethylcyclopropylamine Intermediate 26: 6-Chloro-N- cyclopropylamine 197 2.19 cyclopropylnicotinamide Intermediate 27: 6-Chloro-N- cyclohexylmethylamine 253 3.18 cyclohexylmethylnicotinamide Intermediate 28: 6-Chloro-N- cyclobutylamine 211 2.51 cyclobutylnicotinamide Intermediate 29: 6-Chloro-N-(2- 2-methylpropylamine 213 2.63 methylpropyl)nicotinamide Intermediate 30: 6-Chloro-N- propylamine 199 2.38 propylnicotinamide Intermediate 31: 6-Chloro-N- cyclopentylamine 225 2.70 cyclopentylnicotinamide Intermediate 32: 6-Chloro-N-cyclobutylmethylnicotinamide 6-Chloro-N-cyclobutylmethylnicotinamide was prepared from cyclobutylmethylamine using General Method A.
NMR: SH [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-methylpropyl)nicotinamide 6-Chloro-N-(1-methylpropyl)nicotinamide was prepared from 1-methylpropylamine using General Method A.
NMR: SH [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-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-Fl ,3,21 dioxaborolan-2-yl)-benzamide 3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (Intermediate 35, 900mg), bispinnacolatodiboron (4.5g), potassium acetate (2.1g) and PdCl2dppf (75mg) were mixed in DMF (40m1) and heated at 100 C for 18hours. The cooled reaction was absorbed onto silica and applied to SPE's (Si 2 x l Og). 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-yl)-benzamide (260mg).
LCMS: MH+ 320, retention time 3.39mins.
Intermediate 35: 3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide 3-Fluoro-4-methylbenzoic acid (462mg, 3.Ommol) 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 (200m1) 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 (7m1). Cyclopropylamine (208 1, 3.Ommol), HOBT (405mg, 3.Ommol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (575mg, 3.Ommol) and DIPEA (525 l, 3.Ommol) 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: 8H - 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: d5-[(Cyclopropylamino)carbonyll-3-fluoro-2-methylphenyl}boronic acid N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5g) in THE
(75m1) was cooled to 0 C and sodium hydride (60%, 1.23g) added portionwise over 10minutes. Once effervescence had ceased the reaction was cooled to -75 C and n-butyl lithium (1.6M in hexanes, 20m1) added over 25ininutes maintaining a temperature of <-70 C. Triisopropyl borate (8m1) was added to the reaction over 10minutes 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 (400m1) 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 (30m1) 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 (13m1) 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-[(Cyclopropylamino)carbonyll-3-fluoro-2-methylphenyl}nicotinic acid N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2] dioxaborolan-2-yl)-benzamide (3.2g), methyl 6-chloronicotinate (1.73g), tetralcis(triphenylphosphine)palladium (210mg) and aqueous sodium hydrogen carbonate (1M, 30m1) 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 (1M). 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-Ethylcyclopropyl)methylamine A solution of 2-ethylcyclopropylcarboxamide (250mg, 2.2mmol) in THE was heated to reflux. Borane-dimethylsulphide (1M solution in DCM, 3.2m1, 3.2mmol) was added dropwise over 30minutes and the reaction refluxed for 16hours.
Hydrochloric acid (6N, 0.5m1) was added dropwise and the mixture heated at reflux for 30minutes.
The cooled reaction mixture was diluted with water (20m1), washed with ether (50inl) and basified with sodium hydroxide (6N). The aqueous was extracted with ether (50m1 x 3) and ethyl acetate (50m1). 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: SH [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 (1mg) and aqueous sodium carbonate (0.25m1) in propan-2-ol (lml) were heated at 85 C under nitrogen for 18 hours. The cooled reaction was diluted with ethyl acetate (4m1) and methanol (2ml) and filtered through an SCX bond-elut (1g). 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-I"5-(Cyclopropylmethyl-carbamoyl)-pyridin-2-yll-4-methyl-phenyl)-2-pyrrolidin-1-yl-isonicotinamide O N,,~'-' N i SIN
H I ~N

6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25mg, 0.098mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2] dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-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 (lml) for 18hours. The reaction was absorbed onto silica,applied to a bond-elut (1 Og, 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- 1 -yl-isonicotinamide as a white solid (20mg). LCMS: retention time 2.42min, MH+ 456. NMR: SH [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-[2-methyl-5-(3-pyridin-2-yl-phenylcarb amoyl)-phenyll -nicotin amide N
O ,,,e~' N i ;I H O

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-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) (30mg, 0.072mmo1), aqueous sodium carbonate (2N, 0.5m1) and tetrakis(triphenylphosphine)palladium (4mg) were heated at 90 C in DMF (lml) 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: SH [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-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide O N"
N ~
,o O N

6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5mg, 0.1 Ommol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[
1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) (30mg, 0.10mmol), aqueous sodium carbonate (2N, 0.5ml) and tetralcis(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: SH [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, m).

Example 4: N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyll-nicotinamide O N,,,'!~' N i H
N'I S
O N-N

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-[ 1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS:
retention time 2.79min, MH+ 394. NMR: 8H [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, m), 0.47,(2H, m), 0.27,(2H, m).
Example 5: N-Cvclopropvlmethvl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyll-nicotinamide O N~
N I
-.

NNSD
O

N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2] dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS:
retention time 2.99min, MH+ 393. NMR: 8H [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, m), 0.27,(2H, m).

Example 6: 6-f5-(Cyclopropylmethylcarbamoyl)-2-methyl-phenyll-N-cyclopropylmethyl-nicotinamide N
O ,,e!~' N.
. ' H

6-[5-(Cyclopropylmethyl)carbamoyl-2-methyl-phenyl]-N-cyclopropylmethyl-nicotinamide was prepared from 6-chloro-N-cyclopropylmethyhiicotinamide (Intermediate 1) and N-(cyclopropylmethyl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B.
LCMS: retention time 2.87min, MH+ 364. NMR: 6H [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-f5-(fur-3-ylcarbonylamino)-2-methyl-phenyll-nicotinamide N
O ,,'!~' N ~

H O
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-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.96min, MH+ 376. NMR: 6H [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-Cyclopropylmethyl-6-f2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyll-nicotinamide O N~
N i ~I
H 'S
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-[ 1,3,2] dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS:
retention time 3.07min, MH+ 392. NMR: 8H [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-phenyl)-N-(4-methoxyphenyl)-nicotinamide H
O N
I O.
N~

N
O

6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B.
LCMS: retention time 2.96min, MH+ 402. NMR: 8H [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-f2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyll- nicotinamide H
O N
N

H
NYSE
O N-N

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-[ 1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS:
retention time 3.05min, MH+ 446. NMR: SH [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-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyll- nicotinamide H
O N
N.

zzt, NYD S
O N

N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS:
retention time 3.22min, MH+ 445. NMR: SH [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-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(4-methoxyphenyl)-nicotinamide H
O N
N i H

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-[ 1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B.
LCMS: retention time 3.12min, MH+ 416. NMR: 8H [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-ylcarbonylamino)-2-methyl-phenyll-N-(4-methoxyphenyl)-nicotinamide H
O N~
O=
i N

H O
6-[5-(Fur-3-ylcarbonylainino)-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-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.19min, MH+ 428. NMR: 8H [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-methoxybenzyl)-nicotinamide O N i O.
N
Ne 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-[ 1,3,2]dioxaborolan-2-yl)-benzamide (Intennediate 8) using General Method B.
LCMS: retention time 2.94min, MH+ 416. NMR: 8H [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-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyll- nicotinamide H
O N O.
N

H
NYSE
O N-N

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-[ 1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS:
retention time 3.02min, MH+ 460. NMR: 6H [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-Methoxybenzyl)-6-f2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyll- nicotinamide O N i O
N i NNSD

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-[ 1,3,2] dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS:
retention time 3.20min, MH+ 459. NMR: bH [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-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methoxybenzyl)-nicotinamide H

N i H

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-[1,3,2] dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B.
LCMS: retention time 3.07min, MH+ 430. NMR: 8H [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-phenyll-N-(3-methoxybenzyl)-nicotinamide O N O, N i 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-[ 1,3,2] dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.17min, MH+ 442. NMR: 6H [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-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyll-nicotinamide O N ,00 =
N ~

/I
H 'S
N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl] -nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) 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 3.27min, MH+ 458. NMR: 8H [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, m), 6.94,(2H, m), 6.84,(2H, d), 4.51,(2H, d), 3.75,(3H, s), 2.32,(3H, s).
Example 20: 6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide O N N
H
N i H
0 ,o N

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-[ 1,3,2]dioxaborolan-2-yl)-benzainide (Intermediate 8) using General Method B. LCMS: retention time 2.71min, MH+ 479. NMR: 8H [aH6]-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, m), 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-Methylsulphonylaminobenzyl)-6-f2-methyl-5-(thiadiazol-2-_ylc arb amoyl)-ph enyll -n icotin amid e H
N Qj-0 N=S~
H
N i H
NYSE

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: SH
[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-ylcarb amoyl)-phenyll-nicotin amide H
O N aN=S--H
N

\IONNSD

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-[ 1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.96min, MH+ 522. NMR: 6H [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-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide H
.-0 N,-,(),,,,N
H
N i N,,'~-"

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-[ 1, 3,2] dioxab oro lan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.88min, MH+ 493. NMR: 6H [2H6]-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-methyl-phenyll-N-(3-methylsulphonylaminobenzyl)-nicotinamide O N NS
H
N i H "O

6- [ 5 - (Fur-3 -ylc arb onylamino)-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-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.93min, MH+ 505. NMR: 8H [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-Methylsulphonylaminobenzyl)-6-f5-(thiophen-3-ylcarb onylamino)-2-methyl-phenyll-nicotinamide \\//
O N I
H
N i ~I
H 'S
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: SH [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, in), 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-phenyl)-N- f 2-(4-methylpiperazin-1-ylmethyl)phenyll-nicotinamide ON
H
O N
N~
::111 1 ,o zz" 15 0 N

6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N- [2-(4-methylpiperazin- l -ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.36min, MH+ 484. NMR: 8H [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,(11H, m), 2.13,(3H, s), 0.70,(2H, m), 0.58,(2H, m).

Example 27: N-[2-(4-Methylpiperazin-l-ylmethyl)phenyll-6-[2-methyl-5-(thiadiazol-2-ylcarb amoyl)-phenyll-nicotinamide NJ/
H
O N
N, ~P, H
zzzl' NYSE
O N-N
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- 1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-(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 2.43min, MH+
528.
NMR: 6H [2H6]-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,(11H, m), 2.11,(3H, s).
Example 28: N-[2-(4-Methylpiperazin-1-ylmethyl)phenyll-6-[2-methyl-5-(thiazol-2-ylcarb amoyl)-phenyll -nicotin amide NJN
H
O N
N, N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin- 1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.53min, MH+
527.
NMR: 8H [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,(11H, b), 2.14,(3H, s).

Example 29: 6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-12-(4-methylpiperazin-1-ylmethyl)phenyll-nicotinamide ON
H
O N
N, N
O

6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2] dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.46min, MH+ 498. NMR: SH [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,(11H, m), 1.04,(1H, m), 0.43,(2H, m), 0.23,(2H, m).

Example 30: 6-f5-(Fur-3-ylcarbonylamino)-2-methyl-phenyll-N-f2-(4-methylpiperazin-l-ylmethyl)phenyll-nicotinamide NJN
H
O N I L
N

~I

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-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.53min, MH+ 510. NMR: 8H [2H6]-DMSO 11.64,(1H, b), 10.02,(1H, s), 9.23,(1H, s), 8.38,(2H, in), 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,(11H, m), 2.16,(3H, s).

Example 31: N-[2-(4-Methylpiperazin-1-ylmethyl)phenyll-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyll-nicotinamide NJN/
H
O N
N, H S
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6- [5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin- 1 -ylmethyl)phenyl]nicotinamide (Intermediate 5) 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 2.58min, MH+
526.
NMR: 8H [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,(11H, m), 2.16,(3H, m).

General Method C

The 6-chloronicotinamide (25mg), N-cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 34, 15mg), tetrakis(triphenylphosphino)palladium (2mg) and aqueous sodium hydrogen carbonate (1M, 0.5ml) were mixed in propan-2-ol (2m1) 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.

Compound Structure 6- MH+ Retention Chloronicotinamide time (minutes) Example 32 C 6-Chloro-N- 368 2.78 6-(5- cyclopropylmethyln Cyclopropylcarbamoyl icotinamide -3-fluoro-2-methyl- N (Intermediate 21) phenyl)-N- H,C
cyclopropylmethyl- I q nicotinamide F

Example 33 6-Chloro-N-(3- 384 3.10 6-(5- methylbutyl)nicotin Cyclopropylcarbamoyl NI amide (Intermediate -3-fluoro-2-methyl- V 22) phenyl)-N-(3-methylbutyl)- F
nicotinamide Example 34 C q\,-O 6-Chloro-N- 382 3.01 6-(5- cyclobutylmethylni Cyclopropylcarbamoyl ~ cotinamide -3-fluoro-2-methyl- N - (Intermediate 32) phenyl)-N- H,C
cyclobutylmethyl- I q nicotinamide F

Example 35 C 6-Chloro-N-(1- 382 2.95 6-(5- cyclopropylethyl)ni CH, Cyclopropylcarbamoyl ~ cotinamide -3-fluoro-2-methyl- N (Intermediate 23) phenyl)-N-(1- HC
cyclopropylethyl)- I q nicotinamide F

Example 36 b CH 6-Chloro-N-(2 2- 384 3.01 6-(5- dimethylpropyl))nic Cyclopropylcarbamoyl ~ otinamide -3-fluoro-2-methyl- N - (Intermediate 24) phenyl)-N-(2,2- H3C
dimethylpropyl)- I p nicotinamide F

Example 37 --,7<cH 6-Chloro-N-(2,2- 382 2.90 6-(5- dimethylcyclopropy Cyclopropylcarbamoyl NI 1)nicotinamide -3-fluoro-2-methyl- (Intermediate 25) phenyl)-N-(2,2- H
dimethylcyclopropyl)- F a~
nicotinamide 0 Example 38 6-Chloro-N- 354 2.60 6-(5- cyclopropylnicotina Cyclopropylcarbamoyl NI mide (Intermediate -3-fluoro-2-methyl- 26) phenyl)-N- HNC
cyclopropyl-F
nicotinamide 0 Example 39 6-Chloro-N- 410 3.22 6-(5- b cyclohexylmethylni Cyclopropylcarbamoyl cotinamide -3-fluoro-2-methyl- NI (Intermediate 27) phenyl)-N-cyclohexylmethyl- H,C
I
nicotinamide F

Example 40 6-Chloro-N- 368 2.79 6-(5- cyclobutylnicotina Cyclopropylcarbamoyl NI mide (Intermediate -3-fluoro-2-methyl- 28) phenyl)-N-cyclobutyl- I
nicotinamide F

Example 41 6-Chloro-N-(2- 370 2.86 6-(5- " methylpropyl)nicoti Cyclopropylcarbamoyl I namide -3-fluoro-2-methyl- N i (Intermediate 29) phenyl)-N-(2- H, i methylpropyl)- I
nicotinamide F

Example 42"' 6-Chloro-N-(1- 370 2.84 6-(5- methylpropyl)nicoti Cyclopropylcarbamoyl NI CH, namide -3-fluoro-2-methyl- (Intermediate 33) phenyl)-N-(1- H'0 methylpropyl)- F I b nicotinamide 0 Example 43 6-Chloro-N- 356 2.72 6-(5- propylnicotinamide Cyclopropylcarbamoyl N~ (Intermediate 30) -3-fluoro-2-methyl-phenyl)-N-propyl- N.C
nicotinamide F
O
Example 44 6-Chloro-N- 382 2.92 6-(5- cyclopentylnicotina Cyclopropylcarbamoyl NI mide (Intermediate -3-fluoro-2-methyl- 31) phenyl)-N- N, cyclopentyl- I q F
nicotinamide O
General Method D

Intermediate 38 (40pmo1) in DMF(0.5m1) was treated with HATU (1.l2eq) and DIPEA (3eq). On shaking a solution was formed which was added to a solution of amine (1.2 - 2.Oeq) in DMF (0.5m1). After shaking the reactions were left overnight at room temperature. The solvent was removed in vacuo, the residue dissolved in chloroform (1.Oml) and applied to an SPE (NH2, 0.5g). The product was eluted with chloroform (1.5m1), ethyl acetate (1.5m1) and methanol/ethyl acetate (1:9, 1.5m1). The solvent was evaporated under vacuum from the product fraction.

Compound Amine MH+ Retention time (minutes) Example 45 2-aminomethylthiazole 411 2.79 6-{5-[(cyclopropylamino)carbony l]-3-fluoro-2-methylphenyl } -N-(1, 3 -thiazol-2-ylmethyl)nicotinamide Example 46 2-(2-aminoethyl)thiazole 425 2.78 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-inethylphenyl } -N- [2-(1, 3 -thiazol-2-yl)ethyl]nicotinamide Example 47 2-methylbenzylamine 418 3.26 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(2-methylbenzyl)nicotinamide Example 48 2,4,5-trifluorobenzylamine 458 3.29 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(2,4,5-trifluorobenzyl)nicotinamide Example 49 2,5-difluorobenzylamine 440 3.21 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-(2, 5 -difluorobenzyl)nicotinamide Example 50 3,4-difluorobenzylamine 440 3.24 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(3,4-difluorobenzyl)nicotinamide Example 51 3-chlorobenzylamine 438 3.33 N-(3-chlorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} nicotinamide Example 52 4-chlorobenzylamine 438 3.34 N-(4-chlorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } nicotinamide Example 53 3-chloro-2-fluorobenzylamine 456 3.36 N-(3-chloro-2-fluorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} nicotinamide Example 54 5-fluoro-2-methylbenzylamine 436 3.30 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(5-fluoro-methylbenzyl)nicotinainide Example 55 2-chloro-3,6-difluorobenzylamine 474 3.31 N-(2-chloro-3,6-difluorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} nicotinainide Example 56 2-pentylamine 384 3.14 6-{5-[(cyclopropylainino)carbony 1] -3-fluoro-2-methylphenyl } -N-(1-methylbutyl)nicotinamide Example 57 2,3-difluoro-4-methylbenzylamine 454 3.36 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-(2, 3 -difluoro-4-methylbenzyl)nicotinamide Example 58 2,3,6-tifluorobenzylamine 458 3.29 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(2,3, 5-trifluorobenzyl)nicotinamide Example 59 1,3-dimethylbutylamine 398 3.28 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-(1, 3 -dimethylbutyl)nicotinamide Example 60 3-fluoro-4-methylbenzylamine 436 3.32 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-(3 -fluoro-methylbenzyl)nicotinamide Example 61 5-chloro-2-fluorobenzylamine 456 3.36 N-(5-chloro-2-fluorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-inethylphenyl} nicotinainide Example 62 2-phenylethylamine 418 3.20 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(2-phenylethyl)nicotinamide Example 63 2-methoxy-2-methylpropylamine 400 2.79 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl}-N-(2-methoxy-2-methylpropyl)nicotinamide Example 64 2-methoxyethylamine 372 2.63 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-(2-methoxyethyl)nicotinamide Example 65 3,3-dimethylbutylamine 398 3.30 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methyl henyl}-N-(3,3-dimethylbutyl)nicotinamide Example 66 2-t-butoxyethylamine 414 2.98 N-(2-tert-butoxyethyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } nicotinamide Example 67 1,1-dimethylpropylamine 384 3.17 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(tert-pentyl)nicotinamide Example 68 2-(aminomethyl)-4-methylthiazole 425 2.88 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N- [ (4-methyl-1,3-thiazol-2-yl)methyl]nicotinamide Example 69 1,1-dimethyl-2- 428 3.08 6- {5- hydroxypentylamine [(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(2-hydroxy-1,1-dimethylpentyl)nicotinamide Example 70 2-trifluoromethylbenzylamine 472 3.38 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl}-N-[2-(trifluoromethyl)benzyl]nico tinamide Example 71 2-chlorobenzylamine 438 3.30 N-(2-chlorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methyl henyl}nicotinamide Example 72 4-methylpiperidine 396 3.09 N-cyclopropyl-3 -fluoro-4-methyl-5- {5-[(4-methylpiperidin-l-yl)carbonyl]pyridin-2-yl}benzamide Example 73 N-isobutyl-N-methylamine 384 3.02 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-isobutyl-N-methylnicotinamide Example 74 4-fluorobenzylamine 422 3.19 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(4-fluorobenzyl)nicotinamide Example 75 3,3-diethylazetidine 410 3.24 N-cyclopropyl-3- {5-[(3,3-diethylazetidin-1-yl)carbonyl]pyridin-2-yl} -5-fluoro-4-methylbenzamide Example 76 N-cyclopropyl-N-methylamine 396 3.06 N-cyclopentyl-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-methylnicotinamide Example 77 N-ethyl-N-isopropylamine 384 2.98 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-ethyl-N-isopropylnicotinamide Example 78 2,3,4-trifluorobenzylamine 458 3.30 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(2,3,4-trifluorobenzyl)nicotinamide Example 79 benzylamine 404 3.14 N-benzyl-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } nicotinamide Example 80 2-ethylpiperidine 410 3.17 N-cyclopropyl-3- { 5-[(2-ethylpiperidin-l-yl)carbonyl]pyridin-2-yl} -5-fluoro-4-methylbenzamide Example 81 3-trifluoromethylbenzylamine 472 3.40 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl}-N-[3-(trifluoromethyl)benzyl]nico tinamide Example 82 2-ethyl-2-methylpiperidine 424 3.30 N-cyclopropyl-3- {5-[(2-ethyl-2-methylpiperidin- l -yl)carbonyl]pyridin-2-yl} -5-fluoro-4-methylbenzamide Example 83 1,1-dimethylbutylamine 398 3.30 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(1,1-dimethylbutyl)nicotinamide Example 84 4-chloro-2-fluorobenzylamine 456 3.37 N-(4-chloro-2-fluorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } ni c otinamide Example 85 3,3,3-trifluoropropylamine 410 3.00 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(3,3,3-trifluoropropyl)nicotinamide Example 86 4-trifluoromethylbenzylamine 472 3.41 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-[4-(trifluoromethyl)benzyl]nico tinamide Example 87 3-methoxyaniline 420 3.26 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl}-N-(3-methoxyphenyl)nicotinamid e Example 88 4-methylaniline 404 3.34 6-{5-[(cyclopropylamino)carbony 11-3 -fluoro-2-methylphenyl } -N-(4-methylphenyl)nicotinamide Example 89 3-fluorobenzylamine 422 3.20 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(3-fluorobenzyl)nicotinamide Example 90 2-aminomethyl-5-methylfuran 408 3.09 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-[(5-methyl-2-furyl)methyl] nicotinamide Example 91 3-methylaniline 404 3.36 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl}-N-(3-methylphenyl)nicotinamide Example 92 2,3-difluorobenzylamine 440 3.23 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-m ethylphenyl } -N- (2, 3 -difluorobenzyl)nicotinamide Example 93 2,4-difluorobenzylamine 440 3.23 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(2,4-difluorobenzyl)nicotinamide Example 94 3-chloro-4-fluorobenzylamine 456 3.37 N-(3-chloro-4-fluorobenzyl)-6- {5-[(cyclopropylainino)carbony 1]-3-fluoro-2-methylphenyl } nicotinamide Example 95 4-methylbenzylamine 418 3.27 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(4-methylbenzyl)nicotinamide Example 96 3,4,5-trifluorobenzylamine 458 3.33 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-m ethylp h enyl } -N- (3 , 4, 5 -trifluorobenzyl)nicotinamide Example 97 2-aminomethyl-3-methylthiophene 424 3.21 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N- [ (3 -methylthien-2-yl)methyl]nicotinamide Example 98 3-chloro-2,6-difluorobenzylamine 474 3.35 N-(3-chloro-2,6-difluorobenzyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} nicotinamide Example 99 (2-ethylcyclopropyl)methylamine 396 3.24 6-{5- (Intermediate 39) [(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-[(2-ethylcyclopropyl)methyl]nic otinamide Example 100 2-propylpiperidine 424 3.33 N-cyclopropyl-3-fluoro-4-methyl-5- {5-[(2-propylpiperidin- l -yl)carbonyl]pyridin-2-yl}benzamide Example 101 2-(2-aminoethyl)-4-methylthiazole 439 2.65 6-{5-[(cyclopropylamino)carbony l]-3-fluoro-2-methylphenyl} -N-[2-(4-methyl-1,3 -thiazol-2-yl)ethyl]nicotinamide Example 102 2-fluoro-2-phenylethylamine 436 3.07 6-{5-[(cyclopropylamino)carbony l]-3-fluoro-2-methyl henyl}-N- 2-fluoro-2-phenylethyl)nicotinamide Example 103 2-(2-aminopropyl)thiazole 439 2.70 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-[ 1-methyl-2-(1,3-thiazol-2-yl)ethyl]nicotinamide Example 104 2,4-dimethylpiperidine 410 3.07 N-cyclopropyl-3- {5-[(2,4-dimethylpiperidin-l-yl)carbonyl]pyridin-2-yl} -5-fluoro-4-methylbenzamide Example 105 2,3-dimethylpiperidine 410 3.02 N-cyclopropyl-3- {5-[(2,3-dimethylpiperidin-l-yl)carbonyl]pyridin-2-yl} -5-fluoro-4-methylbenzamide Example 106 3-methylbut-2-enylamine 382 2.97 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl}-N-(3-methylbut-2-enyl)nicotinamide Example 107 N-methyl-N-(1- 410 3.14 6- {5- methylcyclopentyl)amine [(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl } -N-methyl-N-(1-methylcyclopentyl)nicotina mide Example 108 N-(2-cyclopentylethyl)-N- 424 3.26 N-(2-cyclopentylethyl)-6- methylamine {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl}-N-methylnicotinamide Example 109 1,1-dimethylbut-2-enylamine 396 3.06 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-[(2E)-1,1-dimethylbut-2-enyl]nicotinamide Example 110 2,2-dimethyl-3-methyl-pyrrolidine 410 3.07 N-cyclopropyl-3 -fluoro-4-methyl-5- { 5-[(2,2,3-trimethylpyrrolidin- l -yl)carbonyl]pyridin-2-yl}benzamide Example 111 3-ethylpiperidine 410 3.10 N-cyclopropyl-3- {5-[(3-ethylpiperidin-l-yl)carbonyl]pyridin-2-yl} -5-fluoro-4-methylbenzamide Example 112 2-methyl-3,3,3,- 424 3.00 6- {5- trifluoropropylamine [(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(3 ,3 ,3 -trifluoro-2-methylpropyl)nicotinamide Example 113 1-ethyl-l-methylpropylamine 398 3.15 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-(1-ethyl-methylpropyl)nicotinamide Example 114 2-methylpiperidine 396 2.90 N-cyclopropyl-3-fluoro-4-methyl-5- {5-[(2-methylpi eridin-l-yl)carbonyl]pyridin-2-yl} benzamide Example 115 3,3,-dimethylpiperidine 410 3.04 N-cyclopropyl-3- {5-[(3,3-dimethylpiperidin- l -yl)carbonyl]pyridin-2-yl} -5-fluoro-4-methylbenzamide Example 116 3-methylpiperidine 396 2.95 N-cyclopropyl-3-fluoro-4-methyl-5-{5-[(3-methylpiperidin-l-yl)carbonyl]pyridin-2-yl}benzamide Example 117 N-cyclohexyl-N-ethylamine 424 3.18 N-cyclohexyl-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-ethylnicotinamide Example 118 ethylamine 342 2.58 6-{5-[(cyclopropylamino)carbony l]-3-fluoro-2-methylphenyl}-N-ethylnicotinamide Example 119 N-isopropyl-N-inethylamine 370 2.72 6-{5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} -N-isopropyl-N-methylnic otinamide Example 120 3-hydroxy-l-methylpentylamine 414 2.88 6-{5-[(cyclopropylamino)carbony l]-3-fluoro-2-methylphenyl}-N-(2-hydroxy-1-methyl entyl)nicotinamide Example 121 2-fluorobenzylamine 422 3.18 6-{5-[(cyclopropylamino)carbony l]-3-fluoro-2-methylphenyl} -N-(2-fluorobenzyl)nicotinamide Example 122 3-methylbenzylamine 418 3.27 6-{5-[(cyclopropylamino)carbony l]-3-fluoro-2-methylphenyl}-N-(3-methylbenzyl)nicotinamide Example 123 cyclopentylmethylamine 396 3.23 N-(cyclopentylmethyl)-6- {5-[(cyclopropylamino)carbony 1]-3-fluoro-2-methylphenyl} nicotinamide 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 may be demonstrated in the following assays:
p38 Kinase Assay The peptide substrate used in the p38 assay was biotin-IPTSPITTTYFFFRRR-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 3OnM MEK6 protein and 120nM p38 protein in the presence of 1.5uM peptide and 10mM Mg(CH3CO2)2 in I OOmM 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)/(C 1 -C2)), where I was CPM of background, Cl was positive control, and C2 was negative control.

a P38 Fluorescence Polarisation Method a P38 was prepared in house. SB4777790-R Ligand was diluted in HEPES
containing MgC12, CHAPS, DTT and DMSO. This was added to blank wells of a Black NUNC 384 well plate. a 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 M.

Claims

Claims:

1. A compound of formula (I):

wherein R1 is selected from hydrogen, C1-6alkyl optionally substituted by up to three groups selected from C1-6alkoxy, halogen and hydroxy, C2-6alkenyl, C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, phenyl optionally substituted by up to three groups selected from R5 and R6, and heteroaryl optionally substituted by up to three groups selected from R5 and R6, R2 is selected from hydrogen, C1-6alkyl and -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, or (CH2)m R1 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 C1-6alkyl groups;

R3 is chloro or methyl;

R4 is the group -NH-CO-R7 or -CO-NH-(CH2)q-R8;

R5 is selected from C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, -CONR9R10, -NHCOR10, -SO2NHR9, -(CH2)s NHSO2R10, halogen, CN, OH, -(CH2)s NR11R12, and trifluoromethyl;

R6 is selected from C1-6alkyl, C1-6alkoxy, halogen, trifluoromethyl and -(CH2)s NR11R12;

R7 is selected from hydrogen, C1-6alkyl, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, trifluoromethyl, -(CH2)r heteroaryl optionally substituted by R13 and/or R14, and -(CH2)r phenyl optionally substituted by R13 and/or R14;
R8 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, CONHR9, phenyl optionally substituted by R13 and/or R14, and heteroaryl optionally substituted by R13 and/or R14;

R9 and R10 are each independently selected from hydrogen and C1-6alkyl, or R9 and R10, 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-R15, wherein the ring may be substituted by up to two C1-6alkyl groups;

R11 is selected from hydrogen, C1-6alkyl and -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, R12 is selected from hydrogen and C1-6alkyl, or R11 and R12, 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-R15;

R13 is selected from C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, -CONR9R10, -NHCOR10, halogen, CN, -(CH2)s NR11R12, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and heteroaryl optionally substituted by one or more R14 groups;

R14 is selected from C1-6alkyl, C1-6alkoxy, halogen, trifluoromethyl and -NR11R12;
R15 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 C1-6alkyl 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, or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, wherein R1 is selected from C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, phenyl optionally substituted by up to three substituents selected from R5 and R6, heteroaryl optionally substituted by up to three substituents selected from R5 and R6.

3. A compound according to claim 1 or 2, wherein R2 is hydrogen.

4. A compound according to any one of claims 1 to 3, wherein R3 is methyl.

5. A compound according to any one of claims 1 to 4, wherein X is fluorine.

6. A compound according to any one of claims 1 to 5, wherein R7 is selected from C
6alkyl, -(CH2)q-C3-7cycloalkyl, trifluoromethyl, -(CH2)r heteroaryl optionally substituted by R13 and/or R14, and -(CH2)r phenyl optionally substituted by C1-6alkyl, C1-6alkoxy, -(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.

7. A compound according to any one of claims 1 to 6, wherein R8 is selected from C3-7cycloalkyl, CONHR9, heteroaryl optionally substituted by R13 and/or R14, and phenyl optionally substituted by C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl, --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, which is selected from the group consisting of:
6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide;
6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(1-cyclopropylethyl)-nicotinamide;
6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)-nicotinamide;

6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(1-methylpropyl)-nicotinamide.
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-methylphenyl}
nicotinamide;

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-(1,1-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-(1-ethyl-1-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 or a pharmaceutically acceptable salt or solvate thereof.

9. 6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable salt thereof.

10. 6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable solvate thereof.

11. 6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide.

12. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

13. A pharmaceutical composition comprising 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable salt or solvate thereof, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

14. A pharmaceutical composition comprising a pharmaceutically acceptable salt of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

15. A pharmaceutical composition comprising a pharmaceutically acceptable solvate of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

16. A compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, 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.

17. 6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, 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.

18. A pharmaceutically acceptable solvate of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, 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.

19. A pharmaceutically acceptable salt of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, 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.

20. Use of a compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament 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.

21. Use of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, in the manufacture of a medicament 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.

22. Use of a pharmaceutically acceptable salt of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, in the manufacture of a medicament 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.

23. Use of a pharmaceutically acceptable solvate of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, in the manufacture of a medicament 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.

24. A pharmaceutical composition 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, comprising a compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

25. A pharmaceutical composition 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, comprising 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable salt or solvate thereof, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

26. A pharmaceutical composition 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, comprising a pharmaceutically acceptable salt of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

27. A pharmaceutical composition 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, comprising a pharmaceutically acceptable solvate of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2, 2-dimethylpropyl)-nicotinamide, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

28. A process for preparing a compound of formula (I) as claimed in any one of claims I to 7, which comprises:

(a) reacting a compound of formula (II):

in which R1, R2, Z, m and n are as defined in any one of claims 1 to 7, and W
is halogen, with a compound of formula (III):

in which R3, R4, X and Y are as defined in any one of claims to 1 to 7, in the presence of a catalyst; or (b) reacting a compound of formula (VIII):

with a compound of formula (III):

in which R3, R4, X and Y are as defined in any one of claims to 1 to 7, and then reacting the acid thus formed with an amine of formula (V):

in which R1, R2 and m are as defined in any one of claims 1 to 7, under amide forming conditions; or (c) reacting a compound of formula (II):

in which R3, R4, X and Y are as defined in any one of claims to 1 to 7, with a compound of formula (IX):

in which R3, R4, X and Y are as defined in any one of claims 1 to 7, in the presence of a catalyst.