WO2003093248A1 - Heteroaryl substituted biphenyl derivatives as p38 kinase inhibitors - Google Patents

Heteroaryl substituted biphenyl derivatives as p38 kinase inhibitors Download PDF

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Publication number
WO2003093248A1
WO2003093248A1 PCT/GB2003/001834 GB0301834W WO03093248A1 WO 2003093248 A1 WO2003093248 A1 WO 2003093248A1 GB 0301834 W GB0301834 W GB 0301834W WO 03093248 A1 WO03093248 A1 WO 03093248A1
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WIPO (PCT)
Prior art keywords
methyl
biphenyl
optionally substituted
carboxamide
cyclopropyl
Prior art date
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PCT/GB2003/001834
Other languages
French (fr)
Inventor
Richard Martyn Angell
Paul Bamborough
Ian Robert Baldwin
Anne-Marie Li-Kwai-Cheung
Timothy Longstaff
Suzanne Joy Merrick
Kathryn Jane Smith
Stephen Swanson
Ann Louise Walker
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Smithkline Beecham Corporation
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Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to US10/513,095 priority Critical patent/US7425555B2/en
Priority to JP2004501387A priority patent/JP2005535586A/en
Priority to DE60315146T priority patent/DE60315146T2/en
Priority to EP03747504A priority patent/EP1499600B1/en
Priority to AU2003226572A priority patent/AU2003226572A1/en
Publication of WO2003093248A1 publication Critical patent/WO2003093248A1/en

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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

HETEROARYL SUBSTITUTED BIPHENYL DERIVATIVES AS P38 KINASE INHIBITORS.
This invention relates to novel compounds and their use as pharmaceuticals, particularly as p38 kinase inhibitors, for the treatment of conditions or disease states mediated by p38 kinase activity or mediated by 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):
Figure imgf000002_0001
(D wherein
R! is a 5- or 6-membered monocyclic heteroaryl ring containing up to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, which ring is optionally substituted by up to two substituents selected from C^galkyl, -(CH_2)m-C3_ 7cycloalkyl, halogen, cyano, trifluoromethyl, imino, oxo, -(CΗ.2)τfi^ > -(CH_2)mCOR5, -(CH2)mS(O)tR5, -(CH2)mNR5R6 -(CH2)mCON 5R65 -(CH2)mNHCOR5, - (CH2)mSO2NR5R6, -(CH2)mNHSO2R5, and a 5-membered heteroaryl ring optionally substituted by C \ _2 lkyl;
R-2 is selected from hydrogen, methyl, chloro and fluoro;
R3 is selected from methyl and chloro;
R4 is selected from -NH-CO-R? and -CO-NH-(CH2)q-R8;
R5 is selected from hydrogen, Cj.galkyl optionally substituted by up to two OH groups, -(CH2)m-C3_7cycloalkyl, -(CH2)mphenyl optionally substituted by R16 and - (CH2)mheteroaryl optionally substituted by Ri(>,
R6 is selected from hydrogen and Cj.galkyl, or
R-5 and R6, together with the nitrogen atom to which they are bound, foπn a 5- or
Figure imgf000002_0002
R8 is selected from hydrogen, Ci.βalkyl, C3_7cycloalkyl, CONHR12, phenyl optionally substituted by R 0 and/or R 1, and heteroaryl optionally substituted by R^ and/or R 1 ;
R9 is selected from hydrogen and methyl;
RIO is selected from C^alkyl, C^galkoxy, -(CH2)q-C3_7cycloalkyl, - CO R12R13, -NHCOR13, halogen, CN, -(CH2)SNR14R15, trifluoromethyl, phenyl optionally substituted by one or more R groups, and heteroaryl optionally substituted by one or more R! 1 groups;
RU is selected from Ci .galkyl, C^alkoxy, halogen, trifluoromethyl, and - (CH2)sNRl4R15;
Rl2 and R 3 are each independently selected from hydrogen and Cj.galkyl, or
Rl2 and R^3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom independently selected from oxygen, sulfur and N-R- , wherein the ring may be substituted by up to two Cι_6alkyl groups;
Rl4 is selected from hydrogen, C^galkyl and -(CB_2)q-C3_7cycloalkyl optionally substituted by C^galkyl,
R!5 is selected from hydrogen and C^alkyl, or
R!4 and R1^, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R^;
Rl6 is selected from halogen, C^alkyl, hydroxy, C^alkoxy and trifluoromethyl;
U is selected from methyl and halogen;
X and Y are each selected independently from hydrogen, methyl and halogen; m is selected from 0, 1, 2 and 3; n is selected from 0, 1 and 2; q is selected from 0, 1 and 2; r is selected from 0 and 1; s is selected from 0, 1, 2 and 3; and t is selected from 0, 1 and 2.
According to a further embodiment of the invention there is provided a compound of formula (IA):
Figure imgf000003_0001
(IA) wherein Rl, R2, R3 and R4 are as defined above. hi one embodiment, R* is a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, which ring is optionally substituted by up to two substituents selected from C^.galkyl, - (CH2)m"C3-7cycloalkyl, halogen, cyano, trifluoromethyl, -(CH2)mOR^, - (CH2)mNR5R6, -(CH2)mCON 5R65 -(CH2)mNHCOR-5, -(CH2)mS02NR5R65 .
(CH2)mNHSθ2R-\ and a 5-membered heteroaryl ring optionally substituted by C _ 2alkyl.
Representative examples of Rl include 5-membered monocyclic heteroaryl rings containing 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,3,4-triazolyl or tetrazolyl. Further representative examples of Rl include 5- membered monocyclic heteroaryl rings containing up to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur. In one embodiment, R* is a 5-membered monocyclic heteroaryl ring containing 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular thiazolyl, imidazolyl, 1,2,4-oxadiazolyl or 1,3,4- oxadiazolyl. In another embodiment, Rl is pyrrolyl, pyrazolyl, imidazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazolyl or tetrazolyl.
The 5- or 6-membered monocyclic heteroaryl ring maybe optionally substituted by up to two substituents, located on any position on the ring. In one embodiment, the 5- or 6-membered monocyclic heteroaryl ring is optionally substituted by one substituent, located on any position on the ring. Representative examples of the substituents include Chalky!, in particular methyl or ethyl; -(CH2)m-C3_7cycloalkyl, in particular -CH2- cyclopropyl; imino; -(CH2)mOR^, in particular -CH2OH, -CH2OCj_4alkyl such as - CH2OCH3 or -CH2OCH2CH3, and -CH2O(CH2)m-C3_7cycloalkyl such as -CH2OCH2- cyclopropyl; -(CH2)mCOR5, in particular -COCH3; -(CIΪ2)mNR5R6, in particular - NH2, -NHC^alkyl such as -NHCH3, -CH2NH2, -CH2NHCH3, -CH2NHCH2CH3, - CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2NHCH(CH2OH)2, -CH2NH-(CH2)m-C3_ 7cycloalkyl
Figure imgf000004_0001
cyclohexyl, or -(CH2)m R^R^ wherein R-5 and R6, together with the nitrogen atom which they are bound, form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom independently selected from oxygen, sulfur and N-R-9; - (CH2)mNHCOR5, in particular -CH2NHCOR5 wherein R5 is C^al yl optionally substituted by up to two OH groups such as ethyl, 2,2-dimethylpropyl or methyl substituted by OH, -(CH2)m-C3_7cycloalkyl such as -CH2-cyclopropyl, -(CH2)mphenyl optionally substituted by Rl°" such as phenyl or -CH2phenyl, and -(CH2)mheteroaryl optionally substituted by Rl° such as -CH2isoxazole substituted by methyl; - (CH2)mNHSO2 5, in particular -CH2NHSO2R5 wherein R5 is Ci^alkyl such as methyl or -(CH2)mPhenyl optionally substituted by R^ such as -CH2phenyl; and a 5- membered heteroaryl ring optionally substituted by Cj_2 alkyl, in particular pyrrole substituted by methyl. Further representative substituents for the 5- or 6-membered monocyclic heteroaryl ring include C^alkyl, in particular methyl, and -(CH2)mNR5R6.
In a preferred embodiment, Rl is 5-methyl-l,3,4-oxadiazol-3-yl or 5-methyl- 1 ,2,4-oxadiazol-3-yl. In one embodiment, R2 is selected from hydrogen, methyl and chloro. Representative examples of R2 include hydrogen and methyl. In particular, R2 is hydrogen.
A representative example of R3 is methyl. In one embodiment, R^ is selected from hydrogen and C^galkyl optionally substituted by up to two OH groups.
Representative examples of R^ include hydrogen; Cι_4alkyl optionally substituted by up to two OH groups, in particular methyl optionally substituted by OH, ethyl, 2,2-dimethylpropyl or l,3-dihydroxyprop-2-yl; -(CH2)m-C3_7cycloalkyl, in particular cyclopropyl, -CH2-cyclopropyl or cyclohexyl; -(CH2)mphenyl optioanlly substituted by R1^, in particular phenyl or -CH2phenyl; and -(CH2)mheteroaryl optionally substituted by R ^, in particular -CH2isoxazole substituted by methyl. Further representative examples of R^ include hydrogen, Cι_4alkyl, in particular methyl, and C _ 4alkyl substituted by up to two OH groups, in particular l,3-dihydroxyprop-2-yl. Additional representative examples of R^ include hydrogen; Ci _4alkyl optionally substituted by up to two OH groups, in particular methyl optionally substituted by OH, ethyl or 2,2-dimethylpropyl; -(CH2)m_C3-7cycloalkyl, in particular cyclopropyl, -CH2- cyclopropyl or cyclohexyl; -(CH2)mPnenyl optionally substituted by Rl6, in particular phenyl or -GH jphenyl; and -(CH2)mneteroaryl optionally substituted by R16, in particular -CH2isoxazole substituted by methyl.
Representative examples of R^ include hydrogen and C^alkyl, in particular methyl or ethyl. Further representative examples of R" include hydrogen and Cι_4alkyl, in particular methyl. An additional representative example of R" is ethyl. hi one embodiment, R-5 and R", together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally further containing one additional oxygen or sulphur atom, in particular pyrrolidinyl, piperidinyl, morpholino or thiomorpholino. In another embodiment, R^ and R^, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally further containing one additional oxygen atom, in particular pyrrolidinyl, piperidinyl or morpholino. In a further embodiment, R^ and R^, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally further containing one additional sulphur atom, in particular thiomorpholino.
In one embodiment, R? is selected from hydrogen, C1.galkyl, -(CH2)q-C3_ 7cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by Rχ0 and/or R11, and -CH2phenyl optionally substituted by R 0 and/or Rl *■■ . Representative examples of R7 include -(CH2)rheteroaryl optionally substituted by R1^ and/or RU, in particular a 5- or 6-membered heteroaryl containing at least one heteroatom selected from oxygen, nitrogen and sulfur, for example, pyridinyl optionally substituted by -(CH2)SNR14R15_ furyl or thiophenyl. In one embodiment, R8 is selected from hydrogen, Ci .galkyl, C3_7cycloalkyl,
CONHR12, heteroaryl optionally substituted by R10 and/or Rl 1 and, when q is 1 or 2, phenyl optionally substituted by RlO and/or Rl 1. In another embodiment, R8 is selected from C3_7cycloalkyl, phenyl optionally substituted by R^ and/or Rl 1, and heteroaryl optionally substituted by R1 ° and/or R1 -1. In a further embodiment, R8 is selected from
Figure imgf000006_0001
heteroatom selected from oxygen, nitrogen and sulfur, for example, thiazolyl or thiadiazolyl.
Representative examples of RlO and Rl 1 include C^alkoxy, in particular methoxy, and -(CH2)SNR14R15. In one embodiment R*4 and Rl 5, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally further containing one additional oxygen atom, in particular pyrrolidinyl or morpholino. h one embodiment, Rl°" is selected from halogen, in particular fluorine, and C _ galkyl. A representative example of R-*-0" is Cι_4alkyl, in particular methyl. hi 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 one embodiment, n is 0.
In one embodiment, m is selected from 0, 1 and 2, in particular 0 and 1. Representative examples of q are 0 and 1.
A representative example of r is 0.
A representative example of s is 0.
In one embodiment, t is selected from 1 and 2.
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.
Preferred compounds of the invention include: N-Cyclopropyl-2',6-dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)[l, -biphenyl]-3- carboxamide;
6,2' -Dimethyl-4 ' -(5 -methyl- [1,3,4] oxadiazol-2-yl)-biphenyl-3 -carboxylic acid cyclopropyhnethyl-amide;
6,2'-Dimethyl-4'-(5-methyl-[l ,3,4]oxadiazol-2-yl)-biphenyl-3-carboxylic acid thiazol-2- ylamide; 6-Methyl-4' -(5 -methyl- [1 ,3,4]oxadiazol-2-yl)-biphenyl-3-carboxylic acid [ 1 ,3 ,4]thiadiazol-2-ylamide;
Furan-3 -carboxylic acid [6-methyl-4 ' -(5 -methyl- [ 1 ,3 ,4] oxadiazol-2-yl)-biphenyl-3 -yl] - amide;
6-Methyl-4 ' -(5 -methyl- [1,3,4] oxadiazol-2-yl)-biphenyl-3 -carboxylic acid (3 -morpholin-4- yl-phenyl)-amide; and
6-Methyl-4'-(5-methyl-[l,3,4]oxadiazol-2-yl)-biphenyl-3-carboxylic acid cyclopropylamide.
Futher preferred compounds which maybe mentioned include: 4'-(5-Amino-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-5-fluoro-6-methyl-l,r-biphenyl-3- carboxamide;
N-Cyclopropyl-5-fluoro-4'-[5-(methoxymethyl)- 1 ,3,4-oxadiazol-2-yl] -6-methyl- 1,1'- biphenyl-3 -carboxamide; N-Cyclopropyl-4'-{5-[(cyclopropylamino)methyl]-l,3,4-oxadiazol-2-yl}-5-fluoro-6- methyl-1 , 1 '-biρhenyl-3-carboxamide;
4'-[5-(Aminomethyl)-l ,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-l , 1 '- biphenyl-3 -carboxamide;
N-Cyclopropyl-6-methyl-4'-[5-(methylamino)- 1 ,3 ,4-oxadiazol-2-yl] -1,1 '-biphenyl-3- carboxamide;
N-Cycloρropyl-6-methyl-4*-[5-(l-methyl-lH-pyrrol-2-yl)-l,3,4-oxadiazol-2-yl]-l,r- biphenyl-3 -carboxamide;
N-Cyclopropyl-4'-(5 -ethyl- 1 ,3 ,4-oxadiazol-2-yl)-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide;
N-Cyclopropyl-6-methyl-4'-( 1 ,3 ,4-oxadiazol-2-yl)- 1 , 1 '-biphenyl-3 -carboxamide; N-Cyclopropyl-5 -fluoro-6-methyl-4'-(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)- 1 , 1 '-biphenyl-3 - carboxamide;
N-Cyclopropyl-6-methyl-4'- [5 -( { [(3 -methylisoxazol-5 -yl)acetyl] amino} methyl)- 1 ,3 ,4- oxadiazol-2-yl]- 1 , 1 '-biphenyl-3-carboxamide;
N-Cyclopropyl-4'- {5-[(diethylamino)methyl]-l ,3,4-oxadiazol-2-yl} -6-methyl-l , 1 '- biphenyl-3 -carboxamide;
N-Cyclopropyl-4'- { 5-[(cyclopropylamino)methyl] -1,3 ,4-oxadiazol-2-yl} -6-methyl- 1,1'- biphenyl-3 -carboxamide;
N-Cyclopropyl-6-methyl-4'-[5-(thiomorpholin-4-ylmethyl)- 1 ,3 ,4-oxadiazol-2-yl]-l , 1 '- biphenyl-3 -carboxamide; N-Cyclopropyl-4'-(5-{[(3,3-dimethylbutanoyl)amino]methyl}-l,3,4-oxadiazol-2-yl)-6- methyl- 1 , 1 '-biphenyl-3 -carboxamide;
4'-(5- { [(Benzylsulfonyl)amino]methyl} - 1 ,3 ,4-oxadiazol-2-yl)-N-cyclopropyl-6-methyl-
1 , 1 '-biphenyl-3 -carboxamide;
N-Cyclopropyl-4'-{5-[(ethylamino)methyl]-l,3,4-oxadiazol-2-yl}-6-methyl-l,l'-biphenyl- 3 -carboxamide;
N-Cyclopropyl-6-methyl-4'-(5-{[(methylsulfonyl)amino]methyl}-l,3,4-oxadiazol-2-yl)-
1 ,1 '-biphenyl-3-carboxamide;
N-Cyclopropyl-4'-(5-{[(cyclopropylacetyl)amino]methyl}-l,3,4-oxadiazol-2-yl)-6- methyl- 1 , 1 '-biphenyl-3-carboxamide; N-Cyclopropyl-6-methyl-4'-(5- { [(phenylacetyl)amino]methyl} - 1 ,3 ,4-oxadiazol-2-yl)- 1,1'- biphenyl-3-carboxamide;
N-Cyclopropyl-4'-[5-(hydroxymethyl)-l ,3,4-oxadiazol-2-yl]-6-methyl- 1 , 1 '-biphenyl-3- carboxamide;
N-Cyclopropyl-4'-(5-{[(cyclopropylmethyl)amino]methyl}-l,3,4-oxadiazol-2-yl)-6- methyl- 1 , 1 '-biphenyl-3 -carboxamide;
4'-(5 -Amino- 1 ,3 ,4-oxadiazol-2-yl)-N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide;
N-Cyclopropyl-4'-[5-(ethoxymethyl)-l,3,4-oxadiazol-2-yl]-6-methyl-l,r-biphenyl-3- carboxamide; N-Cyclopropyl-4'-[5-(cyclopropylmethyl)-l,3,4-oxadiazol-2-yl]-6-methyl-l,r-biphenyl-3- carboxamide;
N-Cyclopropyl-4'-[5-(methoxymethyl)-l,3,4-oxadiazol-2-yl]-6-methyl-l,l'-biphenyl-3- carboxamide; N-Cyclopropyl-4'-{5-[(cyclopropylmethoxy)methyl]-l,3,4-oxadiazol-2-yl}-6-methyl-l,l'- biphenyl-3-carboxamide; and N-Cyclopropyl-5-fluoro-6-methyl-4'-(tetrazol-5 -yl)- 1 , 1 '-biphenyl-3 -carboxamide.
As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, Ci.galkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n- pentyl, isobutyl, isopropyl and t-butyl. A C^alkyl 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 "alkoxy" refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2- methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy. A Ci _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.
As used herein, the terms "heteroaryl ring" and "heteroaryl" refer to a monocyclic 5- to 7-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 Ci .galkyl and oxy.
As used herein, the terms "heterocyclic ring" or "heterocyclyl" refer to a monocyclic 3- to 7-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, pyraz;olidinyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholino. The said ring may be optionally substituted by one or more substituents independently selected from C . 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 "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 (1) as mixtures with isomers thereof in which one or more chiral centres are inverted. Likewise, it is understood that compounds of formula (1) 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-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. Other salts which are not pharmaceutically acceptable maybe useful in the preparation of compounds of this invention and these form a further aspect of the invention.
The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
A compound of formula (I) may be prepared by reacting a compound of formula
(π)
Figure imgf000010_0001
(π) in which Rl, R2, U and n are as hereinbefore defined and Z is halogen, in particular bromine or iodine, with a compound of formula (IE)
Figure imgf000010_0002
m 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 (ID) may be prepared by, for example, reacting a compound of formula (TV)
Figure imgf000010_0003
(IV) in which R3, R4, X and Y are as hereinbefore defined and W is halogen, in particular bromine or iodine, with bis(pinnacolato)diboron, [l, -bis(diphenylphosphino)ferrocene] dichloropalladium (_T) complex (PdCl2(ppdf)) and potassium acetate in a solvent such as DMF.
When R4 is -NH-CO-R^, a compound of formula (IV) maybe prepared by reacting an amine of formula (V)
Figure imgf000011_0001
(V) in which R3, X, Y and W are as hereinbefore defined, with an acid compound of formula (VI)
R7CO2H
(VI) in which Έ is as hereinbefore defined, under amide forming conditions. Suitable amide forming conditions are well known in the art and include adding a base such as DIPEA to a mixture of the amine of formula (V), the acid of formula (VI), and HATU in a solvent such as DMF.
Alternatively, when R4 is -CO-NH-(CH2)q-R8, a compound of formula (IV) may readily be prepared from a corresponding acid compound of formula (VII)
Figure imgf000011_0002
(vn) in which R3, X, Y and W 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 (VIII)
R8-(CH2)q-NH2
(vm) in which R8 is 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 (NH), or the activated form thereof, in for example DMF, with an amine of formula (VIII) in the presence of a base such as triethylamine. It will be appreciated that in the preparation methods described above, Rl, R2,
R3, R4, U, X and Y may be R.1, R2, R3, R4 U, X and Y as hereinbefore defined or groups convertible to R1, R2 R3, R4, U, X and Y. Conversion of a R1, R2, R3, R4, U, X or Y group may arise if, for example, a protecting group is needed during the reactions described above. A comprehensive discussion of the ways in which such groups maybe protected and methods for cleaving the resulting protected derivatives is given by for example T.W. Greene and P.G.M Wuts in Protective Groups in Organic Synthesis 2nd ed., John Wiley & Son, Inc 1991 and by P.J. Kocienski in Protecting Groups, Georg Thieme Verlag 1994.
Additionally, a further general method comprises final stage modification of one compound of formula (1) into another compound of formula (I). Suitable functional group transformations for converting one compound of formula (I) into another compound of formula (I) are well known in the art and are described in, for instance, Comprehensive Organic Functional Group Transformations, eds. A.R. Katritzky, O. Meth-Cohn and C.W. Rees (Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry, eds. D. Barton and W.D. Ollis (Pergamon Press, Oxford, 1979), and Comprehensive Organic Transformations, R.C. Larock (VCH Publishers Inc., New York, 1989).
For example, one general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 1 below.
Figure imgf000012_0001
(iii)
Figure imgf000012_0002
Scheme 1
(i) HATU, R7CO2H, DIPEA, DMF. (ii) Bis(pinacolato)diboron, KOAc, PdCl2(ppdf), DMF, 80 °C. (iii) R!R2C6H3-Br/I, Pd(PPh3)4, 10% aq Na2CO , DME, 80 °C.
For example, a further general method for preparing the compounds of formula (1) comprises the reactions set out in Scheme 2 below.
Figure imgf000013_0001
Scheme 2
(i) SOCl2, CHC13, 80 °C.
(ii) R8-(CH2)q-NH2, Et3N, DMF, 80 °C.
(iii) Bis(pinacolato)diboron, KOAc, PdCl2(pρdf), DMF, 80 °C.
(iv) R1R2C6H3-Br/I, Pd(PPh )4, 10% aq Na2CO , DME, 80 °C.
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 (1), 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 (1). A particularly preferred method of administration, and corresponding formulation, is oral administration.
For oral administration, the pharmaceutical composition may take the form of, and be administered as, for example, tablets (including sub-lingual tablets) and capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, emulsions, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of the present invention can also be administered in the form of liposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention maybe 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 maybe 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 maybe 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 maybe 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 μg/kg body weight. In most cases they will be administered in one or more doses in an amount not in excess of about 20 mg kg body weight per day. Preferably, in most cases, dose is from about 100 μg/kg to about 5 mg/kg body weight, daily. For administration particularly to mammals, and particularly humans, it is expected that the daily dosage level of the active agent will be from 0. 1 mg kg to 10 mg kg and typically around 1 mg/kg. It will be appreciated that optimum dosage will be determined by standard methods for each treatment modality and indication, taking into account the indication, its severity, route of administration, complicating conditions and the like. The physician in any event will determine the actual dosage which will be most suitable for an individual and will vary with the age, weight and response of the particular individual. The effectiveness of a selected actual dose can readily be determined, for example, by measuring clinical symptoms or standard anti-inflammatory indicia after administration of the selected dose. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. For conditions or disease states as are treated by the present invention, maintaining consistent daily levels in a subject over an extended period of time, e.g., in a maintenance regime, can be particularly beneficial. 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 maybe selective for one or more of the isoforms of p38, for example p38α, p38β, p38γ and/or p38δ. In one embodiment, the compounds of the invention selectively inhibit the p38α isoform. In another embodiment, the compounds of the invention selectively inhibit the p38β isoform. In a further embodiment, the compounds of the invention selectively inhibit the p38α and p38β 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 (T). 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 polymoφhic 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 may be administered to mammals. Such mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably, humans.
Thus, the present invention provides methods of treating or reducing symptoms in a human or animal subject suffering from, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritable bowel syndrome, muscle degeneration, bone resorption diseases, osteoporosis, diabetes, reperfusion injury, graft vs. host reaction, allograft rejections, sepsis, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to aquired immune deficiency syndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter's syndrome, traumatic arthritis, rubella arthritis, Crohn's disease, ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, and non articular inflammatory conditions, for example, herniated ruptured/prolapsed intervertebral disk syndrome, bursitis, tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatory conditions associated with ligamentous sprain and regional musculoskeletal strain, pain, for example that associated with inflammation and/or trauma, osteopetrosis, restenosis, thrombosis, angiogenesis, cancer including breast cancer, colon cancer, lung cancer or prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). A further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, chronic pulmonary inflammation, chronic obstructive pulmonary disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease and epilepsy which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from any type of pain including chronic pain, rapid onset of analgesis, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain associated with osteoarthritis and rheumatoid arthritis, post operative inflammatory pain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia, post-hepatic neuralgia, inflammatory neuropathies and migraine pain which comprises administering to said subject a therapeutically effective amount of a compound of formula (1) 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-TNFα agents such as etanercept, infliximab, diacerein; tyrosine kinase inhibitors such as leflunomide; kallikrein antagonists such as subreum; interleukin 11 agomsts such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (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 (DMA Ds) such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine, auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.
Examples
The following Examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are commercially available or are prepared according to procedures in the literature.
LCMS was conducted on a column (3.3cm x 4.6mm ID, 3um ABZ+PLUS), at a Flow Rate of 3ml/min, Injection Volume of 5μl, at room temperature and UV Detection Range at 215 to 330nm.
4-(4-Bromophenyl)-2-thiazolamine monohydrobromide and 3-iodo-4- methylaniline were purchased from Lancaster.
2-(4-Bromophenyl)-lH-imidazole and 5-(4-iodophenyl)-lH-tetrazole were purchased from Peakdale Fine Chemicals.
2-Chloroisonicotinic acid was purchased from Maybridge Chemicals.
3-(4-Bromo-3-methylphenyl)-5-methyl-l,2,4-oxadiazole was prepared by the procedure described in EP 0 533 268 (Intermediate 1).
2-(4-Bromo-3-methylphenyl)-5-methyl-l,3,4-oxadiazole was prepared by the procedure described in EP 0 533 268 (Intermediate 10).
3-(4-Bromophenyl)-5-methyl-l,2,4-oxadiazole was prepared by the procedure described in WO 97/43262 (Description 11). Intermediate 1: 3-Iodo-4-methylbenzoyl chloride
Figure imgf000020_0001
Thionyl chloride (8.2ml, 112.5mmol) was added to a mixture of 3-iodo-4-methylbenzoic acid (18.5g, 75mmol) in chloroform (100ml) and heated at 61°C for 16 hours. The solvent was removed in vacuo and excess thionyl chloride removed by azeotroping with toluene (3x30ml). The desired product was formed as a beige solid (19.5g 93%) and used in subsequent reactions without further purification. NMR: δΗ [2Η6] - DMSO 8.31 (IH, d), 7.87 (IH, dd), 7.46 (IH, d), 2.43 (3H, s) ppm.
Intermediate 2: 4-(3-Nitrophenyl)morpholine
Figure imgf000020_0002
3-Fluoronitrobenzene (lOg, 71mmol) was added to a solution of moφholine (34ml, 390mmol) in dimethylsulfoxide (120ml) and heated at 110°C for 60 hours. The reaction was cooled and poured onto water (800ml). The desired product precipitated and was collected by filtration. The orange solid was dried in vacuo and used in subsequent reactions without further purification (13.7g, 66mmol).
NMR: δH [2Hβ] - DMSO 7.68 (IH, dd), 7.62 (IH, dd), 7.49 (IH, t), 7.42 (IH, dd), 3.76
(4H, dd), 3.24 (4H, dd) ppm.
Intermediate 3: 3-(4-MorpholinvI)benzenamine
Figure imgf000021_0001
A flask containing 5% palladium on carbon (1.95g) was evacuated and refilled with hydrogen. 4-(3-Nitrophenyl)moφholine (Intermediate 2) (19.5g, 93.75mmol) was introduced into the flask as a solution in ethanol and dimethylformamide (1000ml, 4:1 v/v). The reaction was stirred at room temperature until further uptake of hydrogen ceased (after approximately 7L). The reaction was then filtered through celite and solvent removed in vacuo to yield the desired product (12.6g, 70.6mmol) as a beige solid. NMR: δH [2H6] - DMSO 6.85 (IH, t), 6.12 (2H, m), 6.06 (IH, dd), 4.88 (2H, brs), 3.70 (4H, apparent t), 2.98 (4H, apparent t) ppm. LCMS: retention time 1.08 min MH+179.
Intermediate 4 : 3-Iodo-4-methyl-N- f 3-(4-morpholmyl)phenvIl benzamide
Figure imgf000021_0002
3-Iodo-4-methylbenzoyl chloride (Intermediate 1) (19.5g, 69.6mmol) was added portion- wise to a mixture of triethylamine (48ml, 350mmol) and 3-(4-moφholinyl)benzenamine (Intermediate 3) (12.6g, 70.6mmol) in dimethyl formamide (150ml) and the mixture was heated at 80°C for 16 hours. The solvent was removed in vacuo and the residue taken up in chloroform (200ml). The organic layer was washed with water (2x100ml), 2M sodium hydroxide solution (100ml) and brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The resulting yellow solid was titurated with diethyl ether and collected by filtration to yield the desired product as an off-white solid (20.0g, 47.0mmol). The product was used in subsequent reactions without further purification. NMR: δH [2H6] - DMSO 10.10 (lH,s), 8.39 (IH, d), 7.90 (IH, dd), 7.49 (IH, d), 7.38 (IH, t), 7.28 (IH, brd), 7.19 (IH, t), 6.71 (IH, dd), 3.75 (4H, apparent t), 3.10 (4H, apparent t), 2.44 (3H, s) ppm. LCMS : retention time 3.52 min MH+423. Intermediate 5: 4-MethyI-N-f3-(4-morpholinyl)phenyn-3-(4,4,5,5-tetramethyI- [1 ,3 ,21 -dioxaboroIan-2-vDbenzamide
Figure imgf000022_0001
3-Iodo-4-methyl-N-[3-(4-moφholinyl)phenyl]benzamide (Intermediate 4) (8.00g, 18.9mmol), triethylamine (7.9ml, 56.7mmol) and bis(pinacolato)diboron (4.13ml, 28.4mmol) were added to a solution of [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (1 : 1) (770mg, 945mmol) in dioxane (100ml) and the mixture was heated under nitrogen at 80°C for 3 hours. The reaction was cooled and the solvent removed in vacuo and the residue taken up in dichloromethane (150ml). The organic solution was washed with water (100mlx3), brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (30% ethyl acetate/cyclohexane v:v to 50% ethyl acetate/cyclohexane v:v). The desired product was yielded as a white solid (4.05g, 9.45mmol). ΝMR: δH [2H6] - DMSO 10.11 (1H,S), 8.19 (IH, d), 7.93 (IH, dd), 7.40 (IH, brs), 7.33 (IH, d), 7.28 (IH, brd), 7.19 (IH, t), 6.70 (IH, dd), 3.75 (4H, apparent t), 3.09 (4H, apparent t), 2.54 (3H, s), 1.33 (12H, s) ppm. LCMS: retention time 3.65 min MH+423.
Intermediate 6: Ν-(3-Methoxy-phenyl)-4-methyl-3-(4,4,5,5-tetramethyl- [l,3.,21dioxaborolan-2-vI)-benzamide
Figure imgf000022_0002
4-Methyl-3-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 21) (2g) was dissolved in dimethylformamide (20ml). To this was added 3- methoxyaniline (0.985g), di-isopropylethylamine (4ml) and HATU (3.05g). The mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (250ml) and water (50ml). The organic layer was dried over magnesium sulfate, filtered and removed in vacuo to give the crude material. The product was purified using silica Biotage cartridge (90g) eluting with 1 :4 ethylacetate/cyclohexane to give a white solid (2.06g, 5.61mmol). NMR: δH [2H6] - DMSO 10.20, (IH, s), 8.17, (IH, s), 7.94-7.91, (IH, dd), 7.45, (IH, s), 7.36-7.32, (2H, t), 7.25-7.21, (IH, t), 6.68-6.65, (IH, dd), 3.74, (3H, s), 2.53, (3H, s), 1.32, (12H, s) ppm. LCMS retention time 3.80min MH+ 368.
Intermediate 7: 2-Chloromethyl-5-(4-iodophenyl)-ri,3,41oxadiazole
Figure imgf000023_0001
5-(4-Iodophenyl)-lH-tetrazole (l.OOg, 3.68mmol) and chloroacetic anhydride (3.77g, 22.1mmol) were heated at 95°C for 3 hours. The crude product was purified on a lOg silica SPE cartridge with 5:95 ethyl acetatexyclohexane to 20:80 ethyl acetatexyclohexane. The desired product crystallised spontaneously. The title compound was isolated as white crystals, which were filtered off and washed with cold cyclohexane (690mg, 59%)
NMR: δH CDC13 7.89 (2H, d), 7.80 (2H,d), 4.78 (2H,s) ppm. LCMS: retention time 3.23 min, MH+ 321.
Intermediate 8: 2-(4-Iodophenyl)-5-pyrrolidin-l-ylmethyl-[l,3,41oxadiazoIe
Figure imgf000023_0002
2-Chloromethyl-5-(4-iodophenyl)-[l,3,4]oxadiazole (Intermediate 7) (48mg, 0.15mmol) and potassium iodide (25mg, 0.15mmol) were dissolved in pyrrolidine (2ml) and stirred for 18 hours at 20°C. The amine was then removed in vacuo and the product was purified on a lOg silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetatexyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
NMR: δH [2H6] - DMSO 7.84 (2H, d), 7.62 (2H, d), 3.80 (2H, s), 2.44 (4H, br), 1.57 (4H, br) ppm. LCMS: retention time 2.15 min, MH+ 356.
Intermediate 9; l-f5-(4-Iodophenviyri,3,41oxadiazol-2-ylmethyll-piperidine
Figure imgf000024_0001
2-Chloromethyl-5-(4-iodophenyl)-[l,3,4]oxadiazole (Intermediate 7) (48mg, 0.15mmol) and potassium iodide (25mg, 0.15mmol) were dissolved in piperidine (2ml) and stirred for 18 hours at 20°C. The amine was then removed in vacuo and the product was purified on a lOg silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetatexyclohexane, 100%) ethyl acetate, 95:5 ethyl acetate:methanol).
NMR: δH - CDC13 7.87 (2H, d), 7.80 (2H, d), 3.87 (2H, brs), 2.56 (4H, br), 1.64 (4H, br), 1.45 (2H, br) ppm. LCMS: retention time 2.25 min, MH1" 370.
Intermediate 10: 4- [5-(4-Iodophenyl)- f 1 ,3,41 oxadiazol-2-vImethyll -morpholine
Figure imgf000024_0002
2-Chloromethyl-5-(4-iodophenyl)-[l,3,4]oxadiazole (Intermediate 7) (48mg, 0.15mmol) and potassium iodide (25mg, 0.15mmol) were dissolved in moφholine (2ml) and stirred for 18 hours at 20°C. The amine was then removed in vacuo and the product was purified on a lOg silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetatexyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
NMR: δH - CDC13 7.88 (2H, d), 7.79 (2H, d), 3.89 (2H, s), 3.76 (4H, br), 2.65 (4H, br) ppm. LCMS: retention time 2.73 min, MH+ 372.
Intermediate 11 : f5-(4-Iodophenyl)-[l,3,41oxadiazol-2-yImethyIl-dimethylamine
Figure imgf000025_0001
2-Chloromethyl-5-(4-iodophenyl)-[l,3,4]oxadiazole (Intermediate 7) (48mg, 0.15mmol) and potassium iodide (25mg, 0.15mmol) were dissolved in 2M dimethylamine in tetrahydrofuran (2ml) and stirred for 18 hours at 20°C. The reaction was evaporated to dryness in vacuo and the product was purified on a lOg silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetatexyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
NMR: δH - CDC13 7.87 (2H, d), 7.80 (2H, d), 3.85 (2H, s), 2.42 (6H, s) ppm. LCMS: retention time 2.09 min, MET*" 330.
Intermediate 12: 5-(4-IodophenylV3-methyl-[l,2,41oxadiazole
Figure imgf000025_0002
l,l'-Carbonyldiimidazole (0.49g, 3mmol) was added to a solution of 4-iodobenzoic acid
(0.5g, 2mmol) in dry dimethylformamide (4ml) and stirred at room temperature for 30 minutes. N-hydroxy-acetamidine (0.224g, 3mmol) was added and stirring at room temperature continued for 16 hours. Sodium methoxide in methanol (25% wt solution;
1.1ml, 5mmol) was added and the mixture heated at 80°C for 6 hours. Once cool, ethyl acetate (50ml) and water (50ml) were added. The organic layer was washed with water
(50ml), brine (50ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by silica SPE cartridge (5g) (100% cyclohexane, 20: 1 cyclohexane/ ethyl acetate v:v to 10:1 cyclohexane/ ethyl acetate v:v) to yield the desired product as a white solid (0.15g, 0.52mmol).
NMR: δH -CDC13 7.89, (2H, d), 7.83, (2H, d), 2.48, (3H, s) ppm. LCMS: Retention time 3.33 mins.
Intermediate 13: 4-Iodo-benzoic acid N'-(2,2-dimethyl-propionvI)-hydrazide 4-Iodobenzoic acid (5g, 20.2mmol) was dissolved in dimethylformamide (50ml). To this was added tert-butyl carbazate (2.66g, 20.2mmol), HATU (9.2g, 24.2mmol), 1- hydroxybenzotriazole (2.7g, 20.2mmol) and N,N- diisopropylethylamine (10.5ml, 60.5mmol). The mixture was stirred for 17 hours at room temperature. The solvent was removed in vacuo and the residue partitioned between dichloromethane (75ml) and saturated aqueous sodium bicarbonate solution (75ml). The organic layer was washed with water (100ml), brine (100ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The desired product was obtained as a cream solid (4.6g, 12.7mmol). NMR: δH [2H6] - DMSO 10.25, (IH, s), 8.92, (IH, bs), 7.87, (2H, d), 7.61, (2H, d), 1.41, (9H, s) ppm. LCMS : Retention time 3.06 mins, M-ϊt 361.
Intermediate 14: 4-Iodobenzoic acid hydrazide
Trifluoroacetic acid (10ml) was added to 4-iodo-benzoic acidN'-(2,2-dimethyl- propionyl)-hydrazide (Intermediate 13) (lg, 2.76mmol) and stirred at room temperature for 2 hours. The trifluoroactic acid was removed in vacuo and the residue partitioned between ethyl acetate (50ml) and saturated aqueous sodium bicarbonate solution (50ml).
The organic layer was washed with water (50ml), brine (50ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The desired product was obtained as a white solid (0.55g, 2. lmmol).
NMR: δH [2H6] - DMSO 9.82, (IH, s), 7.82, (2H, d), 7.58, (2H, d), 4.49, (2H, bs) ppm.
LCMS : Retention time 2.34 mins.
Intermediate 15: 2-(4-Iodophenyl)-5-methyl-[l,3,41oxadiazole
Figure imgf000026_0001
Triethyl orthoacetate (10ml) was added to 4-iodo-benzoic acid hydrazide (Intermediate 14) (0.55g, 2. lmmol) and heated under nitrogen at 130 °C for 3 hours. The triethyl orthoacetate was removed in vacuo and the residue partitioned between ethyl acetate
(30ml) and water (30ml). The organic layer was washed with water (50ml), brine (50ml), dried over magnesium sulfate filtered and the solvent removed in vacuo. The residue was purified by silica SPE cartridge (lOg) eluting with 20: 1 cyclohexane/ ethyl acetate v:v to 5:1 cyclohexane/ ethyl acetate v:v. The desired product was obtained as a white solid (0.3 lg, 1. lmmol).
NMR: δH [2H6] - DMSO 7.96, (2H, d), 7.72, (2H, d), 2.56, (3H, s) ppm. LCMS : Retention time 3.02 mins. Intermediate 16: N-Cyclopropyl-3-iodo-4-methylbenzamide
3-Iodo-4-methylbenzoic acid (l.Og, 3.8mmol) was heated at 80°C in thionyl chloride (10ml) for 2hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (10ml), cyclopropylamine (0.32ml) and sodium carbonate (2.0g) were added to the solution. The reaction was stirred at room temperature for lδhrs, filtered and the filtrate reduced to dryness under vacuum. The residue was triturated with ether to give N-cyclopropyl-3- iodo-4-methylbenzamide as a white solid (l.lg). NMR: δH [2H6]-DMSO 8.46,(1H, d), 8.24,(1H, d), 7.74,(1H, dd), 7.38,(1H, d), 2.82,(1H, m), 2.38,(3H, s), 0.67,(2H, m), 0.55,(2H, m).
Intermediate 17: N-Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- ri,3,21dioxaborolan-2-yl)-benzamide N-Cyclopropyl-3-iodo-4-methylbenzamide (Intermediate 16) (l.lg, 3.64mmol), bis(pinnacolato)diboron (1.85g, 7.28mmol), potassium acetate (1.79g, 18.2mmol) and PdCl2dppf (55mg) were heated at 85°C in DMF (30ml) for 4.5hrs. The cooled reaction was absorbed onto silica, applied to a bond-elut (lOg, silica) and eluted with an ethylacetate / cyclohexane gradient (0 to 100%). The solvent was evaporated from the product fractions under vacuum and the residue triturated with cyclohexane to give N- cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide as a white solid (650mg).
NMR: δH [2H6]-DMSO 8.40,(1H, d), 8.06,(1H, d), 7.76,(1H, dd), 7.23,(1H, d), 2.82,(1H, m), 2.48,(3H, s), 1.30,(12H, s), 0.66,(2H, m), 0.56,(2H, m).
Intermediate 18 : 2-Chloro-N-(3-iodo-4-methylphenyI)-isonicotinamide
2-Chloroisonicotinic acid (3.3g, 21mmol), HATU (8.75g, 23mmol), diisopropylethyl amine (10.9ml, 63mmol) and 3-iodo-4-methylaniline (5.00g, 21mmol) in dimethylformamide (50ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150ml). The organic solution was washed with water (3x100ml) and brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetatexyclohexane) to give 2-chloro-N-(3-iodo-4- methylphenyl)-isonicotinamide as a white solid (7.00g, 18.8mmol). LCMS: retention time 3.59 min MH+373. NMR: δH [2H6] - DMSO 10.52 (IH, s), 8.62 (IH, d), 8.29 (IH, d), 7.99 (IH, b), 7.87 (IH, dd), 7.70 (IH, dd), 7.34 (IH, d), 2.36 (3H, s). Intermediate 19: N-(3-Iodo-4-methvIphenyl)-2-pyrrolidin-l-yl-isonicotinamide
A solution of N-(3-iodo-4-methylphenyl)-2-chloro-isonicotinamide (Intermediate 18) (7.00g, 18.8mmol) in pyrrolidine (20ml) was heated at 80°C under an atmosphere of nitrogen for 16 hours. Excess pyrrolidine was removed in vacuo and the residue was titurated with diethyl ether (20ml). The resulting solid was collected by filtration and dried in vacuo to give N-(3-iodo-4-methylρhenyl)-2-pyrrolidin-l-yl-isonicotinamide as a pale yellow solid (7.73g, lδmmol). LCMS: retention time 2.77 min MH+408. NMR: δH [2H6] - DMSO 10.29 (IH, s), 8.29 (IH, d), 8.20 (IH, d), 7.71 (IH, dd), 7.72 (IH, dd), 6.97 (IH, brd), 6.88 (IH, b), 3.45 (2H, apparent t), 3.09 (2H, m), 2.35 (3H, s), 1.98 (2H, m), 1.82 (2H, m).
Intermediate 20 : JV- r4-Methyl-3-(4,4,5,5-tetramethyl-fl ,3,21 -dioxaborolan-2- yI)phenvn-2-(l-pyrrolidinyI)-4-pyridinecarboxamide
Bis(pinacolato)diborane (7.24g, 28.5mmol) was added to a mixture of N-(3-iodo- 4-methylphenyl)-2-pyrrolidin-l-yl-isonicotinamide (Intermediate 19) (7.73g, 19mmol) in dimethylformamide (100ml) potassium acetate (9.32g, 95mmol) and PdCl2dppf and the reaction was heated under an atmosphere of nitrogen at 80°C for 16 hours. The reaction was cooled and the solvent removed in vacuo. The residue was taken up in chloroform (150ml), washed with water (3x100ml) and brine (100ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (20:80 ethyl acetatexyclohexane to 50:50 ethyl acetatexyclohexane) to give N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)phenyl]-2-(l- pyrrolidinyl)-4-pyridinecarboxamide as a white solid (1.5g, 3.7mmol). LCMS: retention time 2.90 min MH+408. ΝMR: δH - CDC13 8.27 (IH, d), 7.99 (IH, dd), 7.76 (IH, b), 7.65 (IH, d), 6.20 (IH, d), 6.82 (IH, b), 6.77 (IH, b), 3.52 (4H, apparent t), 2.52 (3H, s), 2.25 (4H, m), 1.35 (12H, s).
Intermediate 21 : 4-Methyl-3-(4,4,5,5-tetramethvH l,3,21dioxaboroIan-2-vDbenzoic acid 3-Iodo-4-methylbenzoic acid (lOg, 38.16mmol), bis(pinnacolato)diboron (14.5g,
57.24mmol), potassium acetate (18.73g, 190.8mmol) andPdCl2dppf (3.12g, 3.8mmol) in DMF (200ml) were heated at 80°C for 21hrs. The solvent was evaporated from the cooled reaction under vacuum, the residue dissolved in ethyl acetate (300ml) and hydrochloric acid (2Ν, 300ml) and filtered through celite. The organic phase was separated and the aqueous extracted with ethyl acetate (2 x 300ml). The combined organic extracts were washed with brine (500ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue absorbed onto silica and applied to a silica flash column. This was eluted with cyclohexane / ethyl acetate (5:1). The product fractions were concentrated under vacuum to give 4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)benzoic acid. LCMS: retention time 3.65min. NMR: δH [2H6]-DMSO 12.83,(1H, b), 8.23,(1H, d), 7.89,(1H, dd), 7.29,(1H, d), 2.51,(3H, s), 1.30,(12H, s).
Intermediate 22: 4-Methyl-3-(4,4,5,5-tetramethvI-π,3,21dioxaborolan-2-yl)-N- (thiazoI-2-vD-benzamide
4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 21) (2.0g, 7.63mmol), DIPEA (4ml, 22.89mmol) and HATU (3.05g, 8.02mmol) were dissolved in DMF (20ml) and stirred at room temperature for 15mins. 2- Aminothiazole (801mg, 8.01mmol) was added and the reaction stirred at room temperature for lδhours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250ml) and water (50ml). The organic phase was washed with hydrochloric acid (2N, 50ml) and aqueous sodium bicarbonate (1M, 50ml), then dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- (thiazol-2-yl)-benzamide (1.72g).
LCMS: retention time 3.66min, MH+ 345. NMR: δH [2H6]-DMSO 12.65,(1H, b), 8.32,(1H, d), δ.0δ,(lH, dd), 7.56,(1H, d), 7.35,(lh, d), 7.2δ,(lH, d), 2.54,(3H, s), 1.34,(12H, s).
Intermediate 23 : 4-Methyl-3-(4,4,5,5-tetramethyl- [1 ,3,21 dioxaborolan-2-vD-N- (fl,3,41thiadiazol-2-yl)-benzamide
4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 21) (2.0g, 7.63mmol), DIPEA (4ml, 22.δ9mmol) and HATU (3.05g, δ.02mmol) were dissolved in DMF (20ml) and stirred at room temperature for 15mins. 2- Aminothiadiazole (δlOmg, δ.01 mmol) was added and the reaction stirred at room temperature for l hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250ml) and hydrochloric acid (2N, 150ml). The aqueous phase was extracted with ethylacetate (2 x 250ml). The combined organic extracts were dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4:1 then 1:1). The solvent was evaporated from the product fractions under vacuum to give 4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-N-([l,3,4]thiadiazol-2-yl)-benzamide (0.95g).
LCMS: retention time 3.34min, MH+ 346. NMR: δH [2H6]-DMSO 13.0δ,(lH, b), 9.22,(1H, s), δ.35,(lH, d), δ.ll,(lH, dd), 7.38,(1H, d), 2.55,(3H, s), 1.34,(12H, s).
Intermediate 24: N-(3-Iodo-4-methylphenvD-3-furamide 3-Furoic acid (2.4g, 21.45mmol) and HATU (8.15g, 21.45mmol) in DMF (25ml) were stirred at room temperature for 15mins. HOBT (2.9g, 21.45mmol), 3-iodo-4- methylaniline (5.0g, 21.45mmol) and DIPEA (11.2ml, 64.35mmol) were added and the reaction stirred at room temperature for 16hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane / ethyl acetate (3:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)-3-furamide. LCMS: retention time 3.52min, Ml 328. NMR: δH [2H6]-DMSO 9.92,(1H, b), 8.36,(1H, d), δ.23,(lH, d), 7.δO,(lH, t), 7.66,(1H, dd), 7.29,(1H, d), 6.98,(1H, d), 2.33,(3H, s).
Intermediate 25: N-r4-MethyI-3-(4,4,5,5-tetramethvHl,3.21dioxaborolan-2-ylV phenyll -3-furamide
N-(3-Iodo-4-methylphenyl)-3-furamide (Intermediate 24) (2.5g, 7.64mmol), bis(pinnacolato)diboron (2.13g, 8.4 lmmol), potassium acetate (δ25mg, δ.4 lmmol) and PdCl2dppf (312mg, 0.3δmmol) in DMF (20ml) were heated at δ0°C for 20hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum, dissolved in DMF (40ml) and reacted with bis(pinnacolato)diboron (7.76g, 30.57mmol), potassium acetate (3.0g, 30.57mmol) and PdCl2dppf (249mg, 0.306mmol) at δ0°C for 23 hrs. The cooled reaction was absorbed onto silica and applied to bond-eluts (silica, 2 xlOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum to give N-[4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide. LCMS: retention time 3.55min, MH* 328. NMR: δH [2H6]-DMSO 9.86,(1H, b), δ.36,(lH, m), 7.δ6-7.δ2,(2H, m), 7.77,(1H, t), 7.14,(1H, d), 6.99,(1H, m), 2.41,(3H, s), 1.30,(12H, s).
Intermediate 26: N-(3-Iodo-4-methylphenyl)thiophene-3-amide
Thiophene-3-carboxylic acid (2.75g, 21.45mmol) and HATU (δ.l5g, 21.45mmol) in DMF (25ml) were stirred at room temperature for 15mins. HOBT (2.9g, 21.45mmol), 3- iodo-4-methylaniline (5.0g, 21.45mmol) and DIPEA (11.2ml, 64.35mmol) were added and the reaction stirred at room temperature for 16hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane / ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS: retention time 3.69mfn, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), δ.34,(lH, m), δ.29,(lH, d), 7.70,(1H, dd), 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Intermediate 27: N- 4-Methyl-3-(4.4.5,5-tetramethyl-n,3,21dioxaborolan-2-yl)- phenyll thiophene-3-amide
N-(3-Iodo-4-methylphenyl)thiophene-3 -amide (Intermediate 26) (2.64g, 7.64mmol), bis(pinnacolato)diboron (2.13g, δ.41mmol), potassium acetate (δ25mg, 8.41mmol) and PdCl2dppf (312mg, 0.3δmmol) in DMF (20ml) were heated at δ0°C for 20hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum, dissolved in DMF (20ml) and reacted with bis(pinnacolato)diboron (1.77g, 7.0mmol), potassium acetate (6δ7mg, 7.0mmol) and PdCl2dppf (143mg, 0.175mmol) at 80°C for 16 hrs. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum to give N-[4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide. LCMS: retention time 3.65min, MH+ 344. NMR: δH [2H6]-DMSO 9.99,(1H, b), 8.35,(1H, s), 7.90,(1H, d), 7.δ5,(lH, dd), 7.63,(2H, m), 7.14,(1H, d), 2.42,(3H, s), 1.30,(12H, s).
Intermediate 28: N-Cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,21dioxaboroIan-2-yl)-benzamide
4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 21) (2.0g, 7.63mmol), DIPEA (4ml, 22.δ9mmol) and HATU (3.05g, δ.02mmol) were dissolved in DMF (20ml) and stirred at room temperature for 15mins. Cyclopropylmethylamine (568mg, 8.01mmol) was added and the reaction stirred at room temperature for lδhours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250ml) and water (50ml). The organic phase was washed with hydrochloric acid (2N, 50ml) and aqueous sodium bicarbonate (IM, 50ml), then dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (1.73g).
LCMS: retention time 3.47min, MH+ 316. NMR: δH [2H6]-DMSO 8.54,(1H, t), δ.ll,(lH, d), 7.δ2,(lH, dd), 7.26,(1H, d), 3.12,(2H, t), 1.32,(12H, s), 1.03,(1H, m), 0.42,(2H, m), 0.22,(2H, ). Intermediate 29: N-Cvclopropyl-5-fluoro-4,-(hvdrazinocarbonyl)-6-methyl-l,l '- biphenyl-3-carboxamide
A solution of tert-butyl 2-({5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-l,r- biphenyl-4-yl}carbonyl)hydrazinecarboxylate (Intermediate 30) (400mg) in hydrogen chloride (4.0M solution in dioxane, 5ml) was stirred at room temperature under nitrogen for 16hours. Methanol was added to form a solution and the solvents evaporated under vacuum. The residue was partially dissolved in water, basified with sodium hydroxide solution (2N, 10ml) and extracted with ethyl acetate (120ml). The organic phase was dried and the solvent removed under vacuum to give the N-cyclopropyl-5-fluoro-4'- (hydrazinocarbonyl)-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide. LCMS: MH+ 32δ, retention time 2.53minutes.
Intermediate 30: tert-Butyl 2-(f5t-f(cyclopropylamino)carbonyll-3t-fluoro-2t- methyl-l,l,-biphenyl-4-yl|carbonyl)hydrazinecarboxylate N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzamide (Intermediate 32) (3.27g), 4-bromo-benzoic acid N'-(2,2-dimethyl-propionyl)- hydrazide (Intermediate 31) (3.39g), tetrakis(triphenylphosphine)palladium (23δmg) and aqueous sodium hydrogen carbonate (IM, 21.6ml) were mixed in propan-2-ol (20ml) and heated at 90°C under nitrogen for lδhours. The cooled reaction mixture was reduced to dryness under vacuum, the residue partially dissolved in ethyl acetate and filtered. The filtrate was absorbed onto silica and purified by chromatography on silica biotage columns (2x lOOg), eluting with ethyl acetate / cyclohexane (2:3). The product fractions were reduced to dryness under vacuum to give tert-butyl 2-({5'- [(cyclopropylamino)carbonyl] -3 '-fluoro-2'-methyl- 1 , 1 '-biphenyl-4- yl} carbonyljhydrazinecarboxylate.
LCMS: MH+ 42δ, retention time 3.14minutes.
Intermediate 31: 4-Bromo-benzoic acid N'-(2,2-dimethyI-propionyl)-hydrazide t-Butyloxycarbonylhydrazine (1.26g) was added portionwise to a solution of 4- bromobenzoyl chloride (2.0g), and DIPEA (2.37ml) in DCM (20ml) and the reaction stirred at room temperature for l hours. Ammonium chloride solution was added, the organic phase was separated, dried and the solvent evaporated under vacuum to give 4- bromo-benzoic acid N'-(2,2-dimethyl-propionyl)-hydrazide. LCMS: [M-H]" 313/315, retention time 2.97minutes.
Intermediate 32 : N-Cyclopropyl-5-fluoro-4-methyI-3-(4,4,5,5-tetramethyl- [l,3,21dioxaborolan-2-yl)-benzamide
3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (Intermediate 33) (900mg), bispinnacolatodiboron (4.5g), potassium acetate (2.1g) and PdCl2dppf (75mg) were mixed in DMF (40ml) and heated at 100°C for 1 δhours. The cooled reaction was absorbed onto silica and applied to bond-eluts (Si 2 x 10g)and eluted with an ethyl acetate / 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-[l,3,2]dioxaborolan-2-yl)-benzamide (260mg). LCMS: MH+ 320, retention time 3.39mins.
Intermediate 33 : 3-Bromo-N-cvclopropyl-5-fluoro-4-methvIbenzamide
3-Fluoro-4-methylbenzoic acid (462mg, 3.0mmol) was added to a stirred mixture of bromine (2.31ml, 45mmol) and iron powder (252mg, 4.5mmol) under nitrogen. The reaction was stirred at 20°C for 4 hours and then left to stand for 16 hours. Sodium thiosulphate solution (200ml) was added and the product was extracted into ethyl acetate (3 x 150ml). Ethyl acetate extracts were combined and evaporated in vacuo. The crude product (mixture of isomers) was dissolved in dimethylformamide (7ml). Cyclopropylamine (208μl, 3.0mmol), HOBT (405mg, 3.0mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (575mg, 3.0mmol) and DIPEA (525μl, 3.0mmol) were added to the stirred solution. The reaction was stirred for 5 hours at 20°C. Solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. Combined ethyl acetate extracts were washed sequentially with aqueous sodium hydrogen carbonate and hydrochloric acid (0.5M), then dried (magnesium sulphate). The ethyl acetate was evaporated in vacuo and the residue was purified by silica biotage chromatography eluting with cyclohexanexthyl acetate (6: 1) to give 3-bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (359mg, 44%). NMR: δH - CDC13 7.68,(1H, s), 7.39,(1H, d), 6.19,(1H, bs), 2.8δ,(lH, m), 2.36,(3H, d), 0.88,(2H, m), 0.63,(2H, m). LCMS: MH+ 272.
Intermediate 34: 4,-f5-(Chloromethyl)-l,3,4-oxadiazol-2-yll-N-cyclopropyl-5-fluoro- 6-methyl-l ,1 '-biphenyl-3-carboxamide
N-Cyclopropyl-5-fluoro-4'-(hydrazinocarbonyl)-6-methyl- 1 , 1 '-biphenyl-3-carboxamide (Intermediate 29) (5δ0mg) in 2-chloro-l,l,l-triethoxyethane (2.5ml) was heated at δ0°C for 20hours. The reaction was absorbed onto silica and purified by chromatography on a biotage column (silica, 40g), eluting with cyclohexane and then with ethyl acetate / cyclohexane (2:3). The product fractions were reduced to dryness under vacuum to give 4'-[5-(chloromethyl)- 1 ,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-l , 1 '- biphenyl-3 -carboxamide. LCMS: MH+ 3δ5, retention time 3.34minutes.
Intermediate 35: 4'-[5-(Azidomethyl)-l,3,4-oxadiazol-2-yll-N-cvclopropyl-5-fluoro- β-methyl-l '-biphenyl-S-carboxamide
A solution of sodium azide (40mg) in water (3.5ml) was added to (4'-[5-(chloromethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-5 -fluoro-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide (Intermediate 34) (200mg) in DMF (1.5ml) and ethanol (7ml) and the reaction mixture stirred for 5hours at 90°C. The reaction was concentrated under vacuum and the residue partitioned between water (15ml) and chloroform (15ml) and the aqueous extracted with chloroform (2x 15ml). The combined organic extracts were dried (magnesium sulphate), and the solvent evaporated under vacuum to give 4'-[5-(azidomethyl)-l,3,4-oxadiazol-2- yl]-N-cyclopropyl-5-fluoro-6-methyl-l , 1 '-biphenyl-3-carboxamide. LCMS: MH* 392, retention time 3.16minutes.
Intermediate 36: 2-(4-Iodophenyl)-5-(methylamino)-l,3,4-oxadiazole
Phosphorousoxychloride (2ml) was added to benzoic acid, 4-iodo-2- [(methylamino)carbonyl]hydrazide (Intermediate 37) (lOOmg) in acetonitrile (1ml) and the reaction heated at 100°C for l hours. The cooled reaction was poured onto ice/water (60ml) and extracted with ethyl acetate (3x40ml). The combined extracts were reduced to dryness under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient, to give, after evaporation of the solvent 2-(4- iodophenyl)-5-(methylamino)-l,3,4-oxadiazole. LCMS: MH+ 302.
Intermediate 37: Benzoic acid, 4-iodo-2-[(methylamino)carbonyllhvdrazide
4-Methylsemicarbazide (δ9mg), EDC (230mg), HOBt (162mg), 4-iodobenzoic acid (24δmg) and DIPEA (0.21ml) were mixed in DMF (3ml). The reaction was heated at 40°C for 6hours, the DMF was evaporated under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvent, benzoic acid, 4-iodo-2-[(methylamino)carbonyl]hydrazide. LCMS: MH+ 320, retention time 2.29minutes.
Intermediate 38: 2-(4-Iodophenyl)-5-(l-methyl-lH-pyrrol-2-ylVl,3,4-oxadiazole Phosphorousoxychloride (2ml) was added to lH-pyrrole-2-carboxylic acid, l-methyl-2- (4-iodobenzoyl)hydrazide (Intermediate 39) (150mg) in acetonitrile (1ml) and the reaction heated at 100°C for l hours. The cooled reaction was poured onto ice/water (60ml) and extracted with ethyl acetate (3x40ml). The combined extracts were reduced to dryness under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvent, 2-(4-iodophenyl)- 5-(l-methyl-lH-pyrrol-2-yl)-l,3,4-oxadiazole. LCMS: MH+ 352, retention time 3.7minutes.
Intermediate 39: lH-Pyrrole-2-carboxylic acid, l-methyl-2-(4- iodobenzovDhydrazide lH-Pyrrole-2-carboxylic acid, 1-methyl-hydrazide (139mg), EDC (230mg), HOBt (162mg), 4-iodobenzoic acid (24δmg) and DIPEA (0.21ml) were mixed in DMF (3ml). The reaction was heated at 40°C for 6hours, the DMF was evaporated under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvent, lH-pyrrole-2-carboxylic acid, 1-methyl- 2-(4-iodobenzoyl)hydrazide. LCMS: MH* 370, retention time 2.δ4minutes.
Intermediate 40: N-CvclopropyI-4'-(hvdrazinocarbonyl)-6-methyl-l,l'-biphenyl-3- carboxamide A solution of tert-butyl 2-({5'-[(cyclopropylamino)carbonyl]- 2'-methyl-l,l'-biphenyl-4- yl}carbonyl)hydrazinecarboxylate (Intermediate 41) (2.37g) in hydrogen chloride (4.0M solution in dioxane, 20ml) was stirred at room temperature under nitrogen for 6hours. The solvent was evaporated under vacuum, the residue was dissolved in water, basified with sodium hydroxide solution (2N) and extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and the solvent removed under vacuum to give the N- cyclopropyl-4'-(hydrazinocarbonyl)-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide. LCMS: MH+ 310, retention time 2.40minutes.
Intermediate 41: tert-Butyl 2-({5'-f (cyclop ropylaminolcarbonyll -2'-methyl-l,l'- biphenyl-4-yl|carbonyl)hydrazinecarboxylate
3 ' - [(Cyclopropylamino]carbonyl] -6 ' -methyl- 1,1' -biphenyl-4-yl)carboxylic acid ( 1.7g), tert-butylcarbazate (Intermediate 42) (761mg), HOBT (77δmg), DIPEA (1.2ml) and EDC (1.33g) were mixed in DMF (15ml) and stirred at room temperature for l hours. The DMF was evaporated under vacuum, the residue dissolved in ethyl acetate and the solution washed with hydrochloric acid (0.5M, 2x 20ml) and aqueous sodiumhydrogen carbonate (2x 20ml). The organic phase was dried (magnesium sulphate), reduced to dryness under vacuum and purified on a biotage column (silica) eluting with ethyl acetate / cyclohexane (1:1) to give tert-butyl 2-({5'-[(cyclopropylamino)carbonyl] -2'-methyl-l,l'- biphenyl-4-yl} carbonyl)hydrazinecarboxylate . LCMS: MH* 410, retention time 2.90minutes.
Intermediate 42 : 3 '- \ (Cyclopropy laminol carbonyll -6 ' -methy 1-1 ,1 ' -biphenyI-4- vDcarboxylic acid
Methyl 3 ' - [(cyclopropylamino] carbonyl] -6 ' -methyl- 1,1' -biphenyl-4-yl)carboxylate (Intermediate 43) (2.7g, δ.7mmol) and lithium hydroxide monohydrate (0.77g, lδ.3mmol) were mixed in THF (20ml) and water (10ml) and heated at δ0°C for 2h. The THF was evaporated under vacuum and hydrochloric acid (2N) added to the aqueous with vigorous stirring. The solid produced was filtered off, dissolved in methanol and absorbed onto silica. Purified by flash column chromatography eluting with DCM/ethanol ammonia (20:8:1). The product fractions were concentrated under vacuum to give 3 ' -
[(cyclopropylamino] carbonyl] -6' -methyl- l,l'-biphenyl-4-yl)carboxylic acid (2.0g, 78%). LCMS: MH+ 296, retention time 2.94minutes. Intermediate 43: Methyl S'-ffcvclopropylaminolcarbonyll-ό'-methyl-l '-biphenyl- 4-yl)carboxylate
N-Cyclopropyl-3-iodo-4-methylbenzamide (4.7g, 15.6mmol), (4-methoxycarbonylphenyl) boronic acid (3.4g, lδ.7mmol), aqueous sodium carbonate (IM, 50ml) and tetrakis(triphenylphosphine)palladium (l.δg, 0.156mmol) in DME (100ml) were heated at 95°C for lδh. The reaction mixture was absorbed onto silica and purified by flash column chromatography eluting with DCM/ethanol/ammonia (500 : δ : 1 ) . The product fractions were reduced to dryness under vacuum to give methyl 3'- [(cyclopropylamino]carbonyl]-6'-methyl-l,l '-biphenyl-4-yl)carboxylate (2.76g, 57%). LCMS : Wil 310, retention time 3.2 lminutes.
Intermediate 44: 4 5-(Azidomethyl)-l,3,4-oxadiazoI-2-yll-N-cvclopropyl-6-methyl- 1,1 '-biphenyl-S-carboxamide
A solution of sodium azide (14.δmg) in water (1.25ml) was added to 4'-[5- (chloromethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide (Intermediate 45) (40mg) in DMF (0.5ml) and ethanol (2.5ml) and the mixture heated at reflux for 2hours. The solvents were evaporated under vacuum and the residue partitioned between water (20ml) and chloroform (15ml). The aqueous was extracted with chloroform (15ml) and the combined organic phases dried (sodium sulphate) and reduced to dryness in vacuo to give 4'-[5-(azidomethyl)-l,3,4-oxadiazol-2- yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide, LCMS: MH+ 375, retention time 3.11minutes.
Intermediate 45 : 4 '- [5-(Chlorometh yl)-l ,3,4-oxadiazol-2-vn -N-cyclopro yl-6- methyl-l ,1 '-biphenyl-3-carboxamide
N-Cycloproρyl-4'-(hydrazinocarbonyl)-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide (Intermediate 40) (150mg) in 2-chloro-l,l,l-triethoxyethane (5ml) was heated at 150°C for 18hours. The reaction was applied to a biotage cartridge (silica, 90g) and eluted with an ethyl acetate / cyclohexane gradient. The product fractions were reduced to dryness under vacuum to give 4'-[5-(chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6- methyl- 1 , 1 '-biphenyl-3 -carboxamide. LCMS: MH+ 36δ, retention time 3.15minutes.
Intermediate 46: N-CvcIopropyl-4'-f(2-ethanimidoylhydrazino)carbonyll-6-methyl- 1,1 '-biphenyl-3-carboxamide
Sodium (7.5mg) was dissolved in ethanol (3ml), to this solution acetamidine hydrochloride (30.5mg) was added and the reaction stirred at room temperature for 1.5hours. The reaction was filtered and the filtrate added to a solution of N-cyclopropyl - 4'-(hydrazinocarbonyl)-6-methyl-l,r-biρhenyl-3-carboxamide (Intermediate 40) (75mg) in ethanol (1ml). The reaction was stirred for 1 δhours at room temperature and the ethanol evaporated under vacuum to give N-cyclopropyl-4'-[(2- ethanimidoylhydrazino)carbonyl] -6-methyl- 1 , 1 '-biphenyl-3 -carboxamide. LCMS: MH+ 351, retention time 2.13minutes.
Intermediate 47: {5-F(Cvclopropylamino)carbonyl]-3-flnoro-2- methylphenyllboronic acid
N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 4δ) (5g) in THF (75ml) was cooled to 0°C and sodium hydride (60%, 1.23g) added portionwise over lOminutes. Once effervescence had ceased the reaction was cooled to -75°C and n-butyl lithium (1.6M in hexanes, 20ml) added over 25minutes maintaining a temperature of <-70°C. Triisopropyl borate (δml) was added to the reaction over lOminutes and the reaction stirred at -70°C for 4hours. The reaction was quenched with water (20ml) and the mixture allowed to warm to 5°C. The reaction was concentrated under vacuum and the residue partitioned between saturated ammonium chloride and ethyl acetate. The organic phase was washed with saturated ammonium chloride, brine, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in DCM/ethyl acetate and purified by column chromatography on silica eluting with an ethyl acetate/ DCM gradient (5-100%) ethyl acetate) and then methanol. The product fractions were combined and the solvent evaporated under vacuum to give {5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}boronic acid. LCMS MH " 23δ, retention time 2.19min.
Intermediate 48: 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 trifluoromethanesulphomc acid (100ml) at 0°C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ml) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl chloride (30ml) and heated at 100°C for 2.5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ml). Sodium carbonate (25g ) and cyclopropylamine (13ml) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate / cyclohexane gradient (22 - 28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N- cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide. LCMS; MH+ 320, retention time 3.16minutes. General Method A
The following method was used to prepare the Examples described below:
Tetrakis(triphenylphosphine)palladium(0) (20mg) was added to the desired aromatic halide (0.147mmol) and the desired boronic ester ( 0.147mmol) dissolved in 1,2- dimethoxyethane (3ml) and 10% w:v aqueous sodium carbonate (2ml). The reaction was heated under nitrogen at 80°C for 18 hours. The solvent was removed in vacuo. The crude material was purified by silica Biotage chromatography (lOg), silica SPE cartridge or mass directed HPLC to give the desired product.
Example 1 : 4'-(2-Aιnino-4-thiazolyI)-6-methyl-N-[3-(4-morpholinyl)phenyl1 [1,1 '- biphenyIl-3-carboxamide
Figure imgf000038_0001
Example 1 was prepared using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and 4-methyl-N-[3-(4-moφholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-
2-yl)benzamide (Intermediate 5) .
ΝMR: δH [2H6] - DMSO 10.09 (IH, s), 7.91 (2H, d), 7.88 (2H, m), 7.47 (IH, d), 7.43 (2H, d), 7.40 (IH, brs), 7.30 (IH, brd), 7.18 (IH, t), 7.09 (2H, brs), 6.70 (IH, dd), 3.74
(4H, apparent t), 3.09 (4H, apparent t), 2.34 (3H, s) ppm. LCMS: retention time 3.39 min
MH+471.
Example 2: 2,,6-Dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-vn-N-r3-(4- morpholinyllphenyll [1,1 '-biphenyll-3-carboxamide
Figure imgf000038_0002
Example 2 was prepared using 2-(4-bromo-3-methylphenyl)-5 -methyl- 1, 3 ,4-oxadiazole and 4-methyl-N-[3-(4-moφholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[ 1 ,3,2]-dioxaborolan- 2-yl)benzamide (Intermediate 5) . NMR: δH [2H6] - DMSO 10.05 (IH, s), 7.98 (IH, brs), 7.95 (IH, dd), 7.90 (IH, brd), 7.78 (IH, d), 7.51 (IH, d), 7.36 (2H, m), 7.30 (IH, brd), 7.18 (IH, t), 6.70 (IH, dd), 3.74 (4H, apparent t), 3.09 (4H, apparent t), 2.61 (3H,s), 2.13 (3H, s), 2.09 (3H, s) ppm. LCMS: retention time 3.26 min MH+469.
Example 3: 6-Methyl-4'-(5-methvI-l,2,4-oxadiazol-3-yl)-N-r3-(4- morpholinvDphenyll [1,1 '-biphenyll-3-carboxamide
Figure imgf000039_0001
Example 3 was prepared using 3 -(4-bromophenyl)-5 -methyl- 1,2,4-oxadiazole and 4- methyl-N-[3-(4-moφholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2- yl)benzamide (Intermediate 5) .
ΝMR: δH [2H6] - DMSO 10.10 (IH, s), 8.11 (2H, d), 7.91 (IH, d), 7.90 (IH, s), 7.65 (2H, d), 7.50 (IH, d), 7.39 (IH, brs), 7.30 (IH, brd), 7.19 (IH, t), 6.71 (IH, dd), 3.74 (4H, apparent t), 3.09 (4H, apparent t), 2.70 (3H, s), 2.35 (3H, s) ppm. LCMS: retention time
3.46 min MH+455.
Example 4: 4'-(l_H-Imidazol-2-yl)-6-methyl-N-[3-(4-morpholinyllphenyll [1,1 '- biphenyll-3-carboxamide
Figure imgf000039_0002
Example 4 was prepared using 2-(4-bromophenyl)-lH-imidazole and 4-methyl-N-[3-(4- moφholinyl)phenyl] -3 -(4,4,5 , 5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)benzamide (Intermediate 5) .
ΝMR: δΗ [1H6] - DMSO 12.70 (1Η, brs), 10.09 (1Η, s), 8.05 (2Η, d), 7.89 (2H, m), 7.51 (2H, d), 7.48 (IH, d), 7.40 (IH, brs), 7.30 (IH, brd), 7.19 (3H, apparent t), 6.71 (IH, dd), 3.74 (4H, apparent t), 3.09 (4H, apparent t), 2.35 (3H, s) ppm. LCMS: retention time 2.47 min MH+439. Example 5: 4,-(2-Amino-4-thiazolyl)-N-cvclopropyl-6-methyl[l,l '-biphenvIl-3- carboxamide
Figure imgf000040_0001
Example 5 was prepared using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)benzamide
(Ihtermediate 17).
ΝMR: δH [2H6] - DMSO 8.42 (IH, s), 7.87 (2H, d), 7.74 (2H, dd), 7.7 (IH, d), 7.4 (2H, d), 7.38 (IH, d), 7.12 (IH, s), 2.85 (IH, m), 2.3 (3H, s), 0.67 (2H, m), 0.56 (2H, m) ppm.
LCMS: retention time 2.99min MH* 350.
Example 6: iV-Cvclopropyl-2',6-dimethyl-4'-(5-methyI-l,3,4-oxadiazoI-2-yl)fl,l>- biphenyll-3-carboxamide
Figure imgf000040_0002
Example 6 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-l,3,4-oxadiazole andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
ΝMR: δH [2H6] - DMSO 8.43 (IH, d), 7.95 (IH, s), 7.85 (IH, dd), 7.8(1H, dd), 7.6 (IH, s), 7.4 (IH, d) 7.3 (IH, d), 2.85 (IH, m), 2.6 (3H, s), 2.1 (3H, s), 2.05 (3H, s), 0.67 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.93min MH+348.
Example 7: N-Cvclopropyl-6-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)[l,l'- biphenyl1-3-carboxamide
Figure imgf000041_0001
Example 7 was prepared using 3-(4-bromophenyl)-5-methyl-l,2,4-oxadiazole and N- cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17). ΝMR: δH [1H6] - DMSO 8.43 (IH, d), 8.10 (2H, d), 7.78 (IH, dd), 7.72(1H, d), 7.58 (2H, d), 7.4 (IH, d), 2.85 (IH, m), 2.7 (3H, s), 2.3 (3H, s), 0.67 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 3.24min MH+334.
Example 8: N-Cyclopropyl-4'-(lH-imidazol-2-yl)-6-methyl-[l,l '-biphenyll-3- carboxamide
Figure imgf000041_0002
Example 8 was prepared using 2-(4-bromophenyl)-lH-imidazole and N-cyclopropyl-4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17). ΝMR: δΗ [2Η6] - DMSO 12.6 (IH, s), 8.45 (IH, d), 8.05 (2H, d), 7.75 (IH, d), 7.7(1H, s), 7.45(2H, d), 7.4 (IH, d), 7.15 (bd, 2H), 2.85 (IH, m), 2.3 (3H, s), 0.67 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.17min MH^lδ.
Example 9: iV-r4,-(2-Amino-4-thiazolvn-6-methyl-fl.l,-biphenyll-3-yll-2-(l- pyrroIidinyl)-4-pyridinecarboxamide
Figure imgf000041_0003
Example 9 was prepared using using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l ,3,2]-dioxaborolan-2- yl)phenyl]-2-(l-pyrrolidinyl)-4-pyridinecarboxamide (Intermediate 20). ΝMR: δH [2H6] - DMSO 10.3 (IH, s), 8.2 (IH, d), 7.85 (2H, d), 7.7 (IH, dd), 7.65(1H, d), 7.35(2H, d), 7.3 (IH, d), 7.1(2H,s), 7.05 (IH, s), 6.95 (IH, d), 6.85 (IH, s), 3.4 (4H, m), 2.25 (3H, s), 1.95 (4H, m)ppm. LCMS: retention time 2.68min MH+456.
Example 10: N-^'^-DimethyM'-fS-methyl-l^^-oxadiazoI^-ylMlJ'-biphenyll-S- yll-2-(l-pyrrolidinyl)-4-pyridinecarboxamide
Figure imgf000042_0001
Example 10 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-l,3,4-oxadiazole and N-[4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)ρhenyl]-2-(l- pyrrolidinyl)-4-pyridinecarboxamide (Intermediate 20) .
ΝMR: δH [2H6] - DMSO 10.3 (IH, s), 8.2 (IH, d), 7.95 (IH, s), 7.85 (IH, d), 7.7 (IH, dd), 7.55(1H, d), 7.3(2H, dd), 6.95(1H, d), 6.85 (IH, s), 3.45 (4H, m), 2.6 (3H, s), 2.15 (3H, s), 2.0 (3H, s), 1.95 (4H, m)ppm. LCMS: retention time 2.71min MH+454.
Example 11 : N-r6-Methyl-4,-(5-methyl-l,2,4-oxadiazol-3-vn[l,l'-biphenvIl-3-yll-2- (1 -p yrrolidinvD-4-pyridinecarb oxamide
Figure imgf000042_0002
Example 11 was prepared using 3 -(4-bromophenyl)-5 -methyl- 1,2,4-oxadiazole and N-[4- methyl-3 -(4,4,5 ,5 -tetramethyl- [ 1 ,3 ,2] -dioxaborolan-2-yl)phenyl] -2-( 1 -pyrrolidinyl)-4- pyridinecarboxamide (Intermediate 20).
ΝMR: δH [2H6] - DMSO 10.3 (IH, s), 8.2 (IH, d), 8.1 (2H, d), 7.75 (2H, m), 7.55(2H, d), 7.3 (IH, d), 6.95(1H, d), 6.85 (IH, s), 3.45 (4H, m), 2.7 (3H, s), 2.25 (3H, s), 1.95 (4H, m)ppm. LCMS: retention time 2.90min MH+440. Example 12 : 6-Meth yl-4 '-(5-pyrroϋdin-l -ylmethyl- [1 ,3,41 oxadiazol-2-vD-biphenyl- 3-carboxylic acid cyclopropylamide
Figure imgf000043_0001
Example 12 was prepared from 2-(4-iodophenyl)-5-pyrrolidin-l-ylmethyl-
[l,3,4]oxadiazole (Intermediate 8) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
ΝMR: δH [2H6] - DMSO 8.45 (lH,d), 8.09 (2H, d), 7.78 (IH, dd), 7.73 (IH, s), 7.62 (2H, d), 7.42 (IH, d), 3.98 (2H, brs), 2.85 (IH, m), 2.61 (4H, br), 2.30 (3H, s), 1.73 (4H, br), 0.69 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.28 min, MH+ 403.
Example 13: 6-Methyl-4'-(5-piperidin-l-ylmethyl-[l,3.41oxadiazol-2-yl)-biphenyl-3- carboxylic acid cyclopropylamide
Figure imgf000043_0002
Example 13 was prepared from l-[5-(4-iodophenyl)-[l,3,4]oxadiazol-2-ylmethyl]- piperidine (Intermediate 9) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]- dioxaborolan-2-yl)benzamide (Intermediate 17).
ΝMR: δH [2H6] - DMSO δ.45 (lH,d), 8.09 (2H, d), 7.78 (IH, dd), 7.73 (IH, s), 7.63 (2H, d), 7.42 (IH, d), 3.87 (2H, brs), 2.84 (IH, m), 2.50 (4H, br), 2.30 (3H, s), 1.52 (4H, br), 1.38 (2H, br), 0.69 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.40 min, MH÷ 417. Example 14: 6-Methyl-4t-(5-morpholin-4-ylmethyl-[l,3,41oxadiazol-2-yl)-biphenyl-3- carboxylic acid cyclopropylamide
Figure imgf000044_0001
Example 14 was prepared from 4-[5-(4-iodophenyl)-[l,3,4]oxadiazol-2-ylmethyl]- moφholine (Intermediate 10) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[ 1,3,2]- dioxaborolan-2-yl)benzamide (Intermediate 17).
ΝMR: δH [2H6] - DMSO 8.46 (IH, d), 8.09 (2H, d), 7.77 (IH, dd), 7.73 (lH,s) , 7.63 (2H, d), 7.42 (lH,d), 3.92 (2H, s), 3.61 (4H, t), 2.84 (IH, m), 2.55 (4H, br), 2.30 (3H, s), 0.69 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.70 min, MH+ 419.
Example 15 : 6-Methyl-4 '-(5-methylaminomethyl- [1 ,3,4] oxadiazol-2-vD-biphen yI-3- carboxylic acid cyclopropylamide
Figure imgf000044_0002
2-Chloromethyl-5-(4-iodophenyl)-[l,3,4]oxadiazole (Intermediate 7) (48mg, 0.15mmol) and potassium iodide (25mg, 0.15mmol) were dissolved in 2M methylamine in tetrahydrofuran (2ml) and stirred for 18 hours at 20°C. The reaction was evaporated to dryness in vacuo and the product was purified on a lOg silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetatexyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol). The resulting material was dissolved in 1,2 dimethoxyethane (4ml) with tetrakis(triphenylphosphine)palladium(0) (16mg, 0.014mmol), N-cyclopropyl-4- methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 17) (0.15mmol) and IM aqueous sodium carbonate (0.15ml, 0.15m ol). The reaction was heated under nitrogen at 80°C for 18 hours. The solvent was removed in vacuo and the residue was purified by silica biotage chromatography eluting with 95:5 ethyl acetate:methanol. NMR: δH [2H6] - DMSO 8.45 (lH,d), 8.09 (2H, d), 7.78 (IH, dd), 7.74 (IH, s), 7.63 (2H, d), 7.42 (IH, d), 3.96 (2H, s), 2.85 (IH, m), 2.35 (3H, s), 2.30 (3H, s), 0.69 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.20 min, MH+ 363.
Example 16: 4'-(5-Dimethylaminomethyl-fl,3,4]oxadiazoI-2-yl)-6-methyl-biphenyl-3- carboxylic acid cyclopropylamide
Figure imgf000045_0001
Example 16 was prepared from [5-(4-iodophenyl)-[l,3,4]oxadiazol-2-ylmethyl]- dimethylamine (Intermediate 11) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17). ΝMR: δH [2H6] - DMSO 8.45 (lH,d), 8.09 (2H, d), 7.78 (IH, dd), 7.74 (IH, s), 7.63 (2H, d), 7.42 (IH, d), 3.89 (2H, s), 2.85 (IH, m), 2.32 (6H, s), 2.30 (3H, s), 0.69 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.27 min, MH+ 377.
Example 17: 4'-{5-[(2-Hydroxy-l-hvdroxymethyl-ethylamino)-methyll- fl,3,41oxadiazol-2-yl}-6-methyl-biphenyl-3-carboxyIic acid cyclopropylamide
Figure imgf000046_0001
2-Chloromethyl-5-(4-iodophenyl)-[l,3,4]oxadiazole (Intermediate 7) (48mg, 0.15mmol), serinol (206 mg, 2.25mmol) and potassium iodide (25mg, 0.15mmol) were dissolved in dimethylformamide (1ml) and stirred for 18 hours at 20°C. The reaction was evaporated to dryness in vacuo and the product was flushed through a lOg silica SPE cartridge, eluting with 95:5 ethyl acetate methanol, to remove inorganic material. Without further purification the crude product was dissolved in 1,2 dimethoxyethane (4ml). Tetrakis(triphenylphosphine)palladium(0) (16mg, 0.014mmol), N-cyclopropyl-4-methyl- 3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 17) (0.15mmol) and IM aqueous sodium carbonate (0.15ml, 0.15mmol) were added. The reaction was heated under nitrogen at 80°C for 18 hours. Solvent was removed in vacuo and the residue was purified by mass-directed HPLC to yield the desired product. ΝMR: δH [2H6] - DMSO 8.45 (lH,d), 8.09 (2H, d), 7.78 (IH, dd), 7.74 (IH, s), 7.63 (2H, d), 7.42 (IH, d), 4.51 (2H, t) 4.13 (2H, s), 3.42 (2H, m), 3.36 (2H, m), 2.85 (IH, m), 2.62 (IH, q), 2.30 (3H, s), 0.69 (2H, m), 0.56 (2H, m) ppm. LCMS: retention time 2.22 min, MH+423.
Example 18 : 6,2 ,-Dimethyl-4 ' -(5-methyl- [1 ,3,41 oxadiazol-2-y D-biphenyl-3-carboxyIic acid cyclopropylmethyl-amide
Figure imgf000046_0002
The title compound was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl- [l,3,4]oxadiazole andN-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]- dioxaborolan-2-yl)benzamide (Intermediate 17). NMR: δH - CD3OD 8.55, (IH, t), 7.96, (IH, s), 7.85, (2H, m), 7.64, (IH, s), 7.43, (IH, d), 7.34, (IH, d), 3.11, (2H, m), 2.75, (3H, s), 2.10, (3H, s), 2.01, (3H, s), 1.01, (IH, m), 0.41, (2H, m), 0.21, (2H, m) ppm. LCMS : Retention time 3.19 mins MH+ 362.
Example 19: 6,2,-Dimethyl-4,-(5-methyl-[l,3,41oxadiazol-2-yl)-biphenyl-3-carboxylic acid thiazol-2-ylamide
Figure imgf000047_0001
Example 19 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[l,3,4]oxadiazole and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl-N-(thiazol-2-yl)-benzamide (Intermediate 22).
NMR: δH - CD3OD 12.65, (IH, s), 8.03, (IH, d), 7.97, (IH, s), 7.63, (2H, m), 7.58, (2H, m), 7.35, (IH, d), 7.24, (IH, d), 2.61, (3H, s), 2.13, (3H, s), 2.10, (3H, s) ppm. LCMS : Retention time 3.23 mins MH+ 391.
Example 20: 6,2,-Dimethyl-4,-(5-methvI-fl,3,41oxadiazol-2-yll-biphenyl-3- carboxylic acid (3-methoxy-phenyl)-amide
Figure imgf000047_0002
Example 20 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[l,3,4]oxadiazole and N-(3-methoxy-ρhenyl)-4-methyl-3-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)- benzamide (Intermediate 6).
NMR: δH - CD3OD 10.15, (IH, s), 7.93, (3H, m), 7.78, (IH, d), 7.51, (IH, d), 7.45, (IH, s), 7.37, (2H, d), 7.23, (IH, t), 6.67, (IH, d), 3.74, (3H, s), 2.61, (3H, s), 2.13, (3H, s), 2.10, (3H, s) ppm. LCMS : Retention time 3.40 mins MH+ 414.
Example 21: 6,2'-Dimethyl-4,-(5-methyl-fl,3,41oxadiazol-2-yll-biphenyl-3-carboxylic acid π.3.41thiadiazol-2-ylamide
Figure imgf000048_0001
Example 21 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[l,3,4]oxadiazole and 4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-([l,3,4]thiadiazol-2-yl)- benzamide (Intermediate 23).
NMR: δH - CD3OD 9.22, (IH, s), 8.07, (IH, d), 7.98, (IH, s), 7.90, (2H, m), 7.57, (2H, m), 7.36, (IH, d), 2.61, (3H, s), 2.14, (3H, s), 2.12, (3H, s) ppm. LCMS : Retention time 3.11 MH" 392.
Example 22: Furan-3-carboxylic acid [6,2'-dimethyl-4,-(5-methyl-[l,3,41oxadiazoI-2- vD-bipheπyl-3-yll-amide
Figure imgf000048_0002
Example 22 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[l,3,4]oxadiazole and N- [4-methyl-3 -(4,4,5 ,5 ,-tetramethyl- [1,3,2] dioxaborolan-2-yl)-phenyl] -3-furamide (Intermediate 25).
NMR: δH - CD3OD 9.91, (IH, s), 8.35, (IH, s), 7.94, (IH, s), 7.87, (IH, d), 7.79, (IH, s), 7.67, (IH, d), 7.48, (IH, s), 7.32, (2H, m), 6.98, (IH, s), 2.60, (3H, s), 2.13, (3H, s), 1.99, (3H, s) ppm. LCMS : Retention time 3.21 mins MH+ 374.
Example 23: Thiophene-3-carboxylic acid [6,2'-dimethyl-4,-(5-methyl- [l,3,41oxadiazol-2-yl)-biphenyl-3-yll-amide
Figure imgf000049_0001
Example 23 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[l,3,4]oxadiazole and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3- amide (Intermediate 27).
NMR: δH - CD3OD 10.04, (IH, s), 8.32, (IH, s), 7.95, (IH, s), 7.86, (IH, d), 7.71, (IH, d), 7.62, (2H, m), 7.53, (IH, s), 7.32, (2H, m), 2.60, (3H, s), 2.14, (3H, s), 1.99, (3H, s) ppm. LCMS : Retention time 3.33 mins MH+ 390.
Example 24: 6-Methyl-4'(3-methyI-[l,2,41oxadiazol-5-yl -biphenyl-3-carboxyIic acid cyclopropylamide
Figure imgf000049_0002
Example 24 was prepared using 5-(4-iodophenyl)-3-methyl-[ 1 ,2,4]oxadiazole
(Intermediate 12) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzamide (Intermediate 17) using DMF as the solvent.
ΝMR: δH [2H6] - DMSO 8.43, (IH, d), 8.17, (2H, d), 7.78, (IH, d), 7.73, (IH, s), 7.64, (2H, d), 7.41, (IH, d), 2.85-2.δ2, (IH, bm), 2.44, (3H, s), 2.29, (3H, s), 0.70-0.65, (2H, bm), 0.54, (2H, bm) ppm. LC/MS : Retention time 3.16 mins MH+ 334.
Example 25: Furan-3-carboxylic acid [6-methyl-4'-(3-methyl-[l,2,41oxadiazol-5-yl)- biphenyl-3-yll-amide
Figure imgf000050_0001
Example 25 was prepared using 5-(4-iodophenyl)-3-methyl-[l,2,4]oxadiazole (Intermediate 12) and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl] -3-furamide (Intermediate 25) using DMF as the solvent. NMR: δH [2H6] - DMSO 9.94, (IH, s), 8.35, (IH, s), 8.16, (2H, d), 7.78, (IH, s), 7.70- 7.61, (4H, bm), 7.30, (IH, d), 6.98, (IH, s), 2.43, (3H, s), 2.23, (3H, s) ppm. LCMS : Retention time 3.45 mins MH* 360.
Example 26: Thiophene-3-carboxylic acid [6-methyl-4,-(3-methyl-[l,2,41oxadiazol-5- yl)-biphenyl-3-yll -amide
Figure imgf000050_0002
Example 26 was prepared using 5-(4-iodophenyl)-3-methyl-[l,2,4]oxadiazole (Intermediate 12) and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]thiophene-3-amide (Intermediate 27) using DMF as the solvent. NMR: δH [2H6] - DMSO 10.07, (IH, s), 8.33, (IH, s), 8.17, (2H, d), 7.73-7.61, (6H, bm), 7.32-7.29, (IH, bd), 2.43, (3H, s), 2.22, (3H, s) ppm. LCMS : Retention time 3.64 mins MH+ 376.
Example 27: 6-MethyI-4,(3-methyl-[l,2,41oxadiazol-5-vI)-biphenyl-3-carboxylic acid [l,3,41thiadiazoI-2-ylamide
Figure imgf000051_0001
Example 27 was prepared using 5-(4-iodophenyl)-3-methyl-[l,2,4]oxadiazole (Intermediate 12) and 4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- ([l,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23) using DMF as the solvent. NMR: δH [2H6] - DMSO 13.11, (IH, s), 9.22, (IH, s), 8.20, (2H, d), 8.10, (IH, s), 8.04, (IH, d), 7.73, (2H, d), 7.54, (IH, d), 2.44, (3H, s), 2.37, (3H, s) ppm. LCMS : Retention time 3.35 mins MH1" 378.
Example 28: 6-Methyl-4'(3-methyl-[l,2,41oxadiazoI-5-yl)-biphenyl-3-carboxylic acid (3-morpholin-4-yl-phenvD-amide
Figure imgf000051_0002
Example 2δ was prepared using 5-(4-iodophenyl)-3-methyl-[l,2,4]oxadiazole (Intermediate 12) and 4-methyl-N-(3-moφholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 5) with propan-2-ol as the solvent. NMR: δH [2H6] - DMSO 10.08, (IH, s), 8.19, (2H, d), 7.92, (IH, d), 7.89, (IH, s), 7.70, (2H, d), 7.50, (IH, d), 7.38, (IH, s), 7.28, (IH, d), 7.17, (IH, t), 6.70, (IH, d), 3.73, (4H, t), 3.07, (4H, t), 2.44, (3H, s), 2.34, (3H, s) ppm. LCMS : Retention time 3.50 mins MH+ 455.
Example 29: 6,2,-Dimethyl-4'-(5-methyl-[l,2,41oxadiazol-3-yl)-biphenyl-3-carboxylic acid cyclopropylamide
Figure imgf000052_0001
Example 29 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[l,2,4]oxadiazole and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (intermediate 17) using DMF as the solvent.
NMR: δH [2H6] - DMSO 8.36, (IH, d), 7.95, (IH, s), 7.86, (IH, d), 7.76, (IH, d), 7.58, (IH, s), 7.39, (IH, d), 7.27, (IH, d), 2,81, (IH, m), 2.67, (3H, s), 2.05, (6H, br), 0.65, (2H, m), 0.54, (2H, m) ppm. LCMS : Retention time 3.22 mins MH^ 348.
Example 30: Furan-3-carboxylic acid [6,2'-dimethyl-4'-(5-methyl-[l,2,41oxadiazol-3- yl -biphenyl-3-yll -amide
Figure imgf000052_0002
Example 30 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[l,2,4]oxadiazole and N- [4-methyl-3 -(4,4,5 ,5 ,-tetramethyl-[ 1 ,3,2] dioxaborolan-2-yl)-phenyl] -3 -furamide (Intermediate 25) using DMF as the solvent.
NMR: δH [2H6] - DMSO 9.89, (IH, s), 8.34, (IH, s), 7.95, (IH, s), 7.88, (IH, d), 7.77, (IH, s), 7.67, (IH, d), 7.46, (IH, s), 7.28, (2H, t), 6.96, (IH, s), 2.67, (3H, s), 2.11, (3H, s), 1.98, (3H, s) ppm. LCMS : Retention time 3.55 mins MH+ 374.
Example 31: Thiophene-3-carboxylic acid [6,2'-dimethyl-4,-(5-methyl- fl,2,41oxadiazol-3-yl)-biphenyl-3-yn-amide
Figure imgf000053_0001
Example 31 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[l,2,4]oxadiazole andN-[4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3- amide (Intermediate 27) using DMF as the solvent. NMR: δH [2H6] - DMSO 10.03, (IH, s), 8.31, (IH, s), 7.95, (IH, s), 7.87, (IH, d), 7.69, (IH, d), 7.64-7.59, (2H, m), 7.52, (IH, d), 7.30-7.27, (2H, m), 2.67, (3H, s), 2.12, (3H, s), 1.98, (3H, s) ppm. LCMS : Retention time 3.67 mins MH " 390.
Example 32: 6,2,-Dimethyl-4,-(5-methyl-[l,2,41oxadiazol-3-yl)-biphenyl-3-carboxyIic acid (3-morpholin-4-yl-phenyl)-amide
Figure imgf000053_0002
Example 32 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[l,2,4]oxadiazole and 4-methyl-N-(3 -moφholin-4-yl-phenyl)-3 -(4,4, 5 ,5 -teframethyl- [1,3,2] dioxaborolan-2- yl)-benzamide (Intermediate 5) with propan-2-ol as the solvent.
NMR: δH [2H6] - DMSO 10.01, (IH, s), 7.98, (IH, s), 7.93-7.89, (2H, m), 7.77, (IH, s), 7.49, (IH, d), 7.36, (IH, s), 7.34-7.28, (2H, m), 7.17, (IH, t), 6.69, (IH, d), 3.73, (4H, t), 3.07, (4H, t), 2.68, (3H, s), 2.11, (3H, s), 2.09, (3H, s) ppm. LCMS : Retention time 3.60 mins Mtf" 469.
Example 33 : 6-Methyl-4 ' -(5-methyl- [1 ,3,41 oxadiazol-2-yl)-biphenyl-3-carboxylic acid [l,3,41thiadiazol-2-ylamide
Figure imgf000054_0001
Example 33 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole (Intermediate 15) and 4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)-N- ([1 ,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23) with propan-2-ol as the solvent.
NMR: δH [2H6] - DMSO 9.24, (IH, s), 8.06, (4H,bm), 7.71, (2H, d), 7.55, (2H, d), 2.62, (3H, s), 2.38, (3H, s) ppm. LCMS : Retention time 3.03 mins MH+ 378.
Example 34: Thiophene-3-carboxylic acid [6-methyl-4,-(5-methyl-[l,3,41oxadiazol-2- vD-biphenyl-3-yll-amide
Figure imgf000054_0002
Example 34 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole (Intermediate 15) and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]thiophene-3-amide (Intermediate 27) with propan-2-ol as the solvent. NMR: δH [2H6] - DMSO 10.08, (IH, s), 8.34, (IH, s), 8.06, (2H, m), 7.65, (6H, bm) 7.31, (IH, s), 2.61, (3H, s), 2.24, (3H, s) ppm. LCMS : Retention time 3.35 mins MH* 376.
Example 35: Furan-3-carboxylic acid [6-methyI-4,-(5-methyl-[l,3,4]oxadiazol-2-yl)- biphenyl-3-yll -amide
Figure imgf000055_0001
Example 35 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole (Intermediate 15) and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenyl]-3-furamide (Intermediate 25) with propan-2-ol as the solvent.
NMR: δH [2H6] - DMSO 9.94, (IH, s), 8.37, (IH, s), 8.06, (2H, d),7.79, (IH, s), 7.76- 7.68, (IH, m), 7.65, (IH, s), 7.59, (2H, d), 7.31, (IH, d), 6.99, (IH, s), 2.60, (3H, s), 2.22, (3H, s) ppm. LCMS : Retention time 3.21 mins Mtf" 360.
Example 36: 6-Methyl-4,-(5-methyl-[l,3,41oxadiazol-2-yI)-biphenyl-3-carboxylic acid (3-morpholm-4-yl-phenvD-amide
Figure imgf000055_0002
Example 36 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole
(Intermediate 15) and 4-methyl-N-(3-moφholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 5) with propan-2-ol as the solvent. NMR: δH [2H6] - DMSO 10.08, (IH, s), 8.07, (2H, d), 7.90, (2H, m), 7.66, (2H, d), 7.49, (IH, d), 7.38, (IH, s), 7.27, (IH, d), 7.17, (IH, t), 6.70, (IH, d), 3.73, (4H, t), 3.07, (4H, t), 2.60, (3H, s), 2.33, (3H, s) ppm. LCMS : Retention time 3.29 mins MH+ 455.
Example 37: 6-Methyl-4,-(5-methyl-[l,3,4Ioxadiazol-2-yl)-biphenyl-3-carboxylic acid (3-methoxy-phenvD-amide
Figure imgf000056_0001
Example 37 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole (Intermediate 15) and N-(3-methoxy-phenyl)-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) with propan-2-ol as the solvent. NMR: δH [2H6] - DMSO 10.19, (IH, s), 8.07, (2H, d), 7.90, (2H, m), 7.66, (2H, d), 7.50, (IH, d), 7.45, (IH, s), 7.36, (IH, d), 7.23, (IH, t), 6.67, (IH, d), 3.74, (3H, s), 2.60, (3H, s), 2.34, (3H, s) ppm. LCMS : Retention time 3.39 mins MH+400.
Example 38: 6-Methyl-4'-(5-methyl-[l,3,41oxadiazoI-2-yl)-biphenyl-3-carboxylic acid thiazol-2-yIamide
Figure imgf000056_0002
Example 38 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole (Intermediate 15) and 4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl-N- (thiazol-2-yl)-benzamide (Intermediate 22) with propan-2-ol as the solvent. NMR: δH [2H6] - DMSO 12.69, (IH, s), 8.07, (3H, m), 8.01, (IH, d), 7.69, (2H, d), 7.55, (IH, d), 7.51, (IH, d), 7.28, (IH, d), 2.61, (3H, s), 2.36, (3H, s) ppm. LCMS : Retention time 3.16 mins MH+ 377.
Example 39: 6-Methyl-4,-(5-methyl-[l,3,4]oxadiazol-2-yl)-biphenyl-3-carboxylic acid cyclopropylamide
Figure imgf000057_0001
Example 39 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole (Intermediate 15) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 17) with propan-2-ol as the solvent. NMR: δH [2H6] - DMSO 8.44, (IH, d), 8.05, (2H, d), 7.77, (IH, d), 7.72, (IH, s), 7.60, (2H, d), 7.40, (IH, d), 2.83, (IH, m), 2.60, (3H, s), 2.29, (3H, s), 0.6δ-0.65, (2H, m), 0.57- 0.53, (2H, m) ppm. LCMS : Retention time 2.δ6 mins MH+ 334.
Example 40: 6-Methyl-4,-(5-methyl-[l,3,41oxadiazol-2-yl)-biphenyl-3-carboxylic acid cyclopropylmethylamide
Figure imgf000057_0002
Example 40 was prepared using 2-(4-iodophenyl)-5-methyl-[l,3,4]oxadiazole (Intermediate 15) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 28) with propan-2-ol as the solvent. NMR: δH [2H6] - DMSO 8.59, (IH, t), 8.07, (2H, d), 7.80, (IH, d), 7.77, (IH, s), 7.62, (2H, d), 7.42, (IH, d), 3.12, (2H, m), 2.60, (3H, s), 2.30, (3H, s), 1.01, (IH, m), 0.43-0.39, (2H, m), 0.22-0.19, (2H, m) ppm. LCMS : Retention time 3.03 mins MH+ 34δ.
Example 41 : 4'-(5-Amino-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-5-fluoro-6-methyl- 1,1 '-biphenyl-3-carboxamide
Figure imgf000057_0003
N-Cyclopropyl-5-fluoro-4'-(hydrazinocarbonyl)-6-methyl-l,l'-biphenyl-3-carboxamide (Intermediate 29) (150mg) and a mixture of di(benzotriazolyl)methanimines (121mg, Synthesis 6, 2001, δ97-903) were dissolved in THF (10ml) and the solution heated at reflux for 6hours. The cooled reaction was absorbed onto silica and applied to a silica biotage column (40g) and eluted with an ethyl acetate / cyclohexane gradient (50-100% ethyl acetate). The product fractions were combined and evaporated to dryness to give 4'- (5-amino-l ,3,4-oxadiazol-2-yl)-N-cyclopropyl-5-fluoro-6-methyl-l , 1 '-biphenyl-3- carboxamide.
NMR: δH [2H6] - DMSO 8.53,(1H, d), 7.90,(2H, d), 7.65-7.55,(4H, m), 7.31,(2H, b), 2.85,(1H, m), 2.20,(3H, d), 0.70,(2H, m), 0.57,(2H, m). LCMS: MH+ 353, retention time 2.δ0minutes.
Example 42: N-Cvclopropyl-5-fluoro-4t-[5-(methoxymethyl)-l,3,4-oxadiazol-2-yll-6- methyl-1 ,1 '-biphenyl-3-carboxamide
Figure imgf000058_0001
Freshly prepared sodium methoxide in methanol (0.2M, O.δml) was added to a solution of (4'- [5 -(chloromethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-5-fluoro-6-methyl- 1,1'- biphenyl-3 -carboxamide (Intermediate 34) (50mg) in methanol (1ml) and the reaction stirred at room temperature for lδhours. Further sodium methoxide in methanol (0.2M, 1.6ml) was added and the reaction continued for 72hours. The reaction was reduced to dryness under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was reduced to dryness and loaded onto a bond-elut (silica, lOg). Eluted with an ethyl acetate / cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-5-fluoro-4'-[5-(methoxymethyl)- 1 ,3, 4-oxadiazol-2-yl] -6-methyl- 1 , 1 '-biphenyl-3 -carboxamide.
NMR: δH [2H6] - DMSO 8.55,(1H, d), 8.12,(2H, d), 7.65,(4H, m), 4.76,(2H, s), 3.41,(3H, s), 2.86,(1H, m), 2.20,(3H, d), 0.70,(2H, m), 0.57,(2H, m). LCMS: MH+ 3δ2, retention time 3.01minutes.
Example 43 : N-Cyclopropyl-4'- 5-[(cyclopropylamino)methyll-l,3,4-oxadiazol-2- yll-5-fluoro-6-methyl-l ,1 '-biphen yl-3-carboxamide
Figure imgf000058_0002
4'-[5-(Chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-l,l'- biphenyl-3 -carboxamide (Intermediate 34) (50mg) and potassium iodide (22mg) were stirred in cyclopropylamine (2ml) for 4δhours. The reaction was absorbed onto silica and purified by chromatography on a biotage column (silica, 9g), eluting with DCM / methanol (99: 1). The product fractions were reduced to dryness under vacuum to give N- cyclopropyl-4'- {5-[(cyclopropylamino)methyl]- 1 ,3 ,4-oxadiazol-2-yl} -5-fluoro-6-methyl- 1 , 1 '-biphenyl-3-carboxamide.
NMR: δH [2H6] - DMSO 8.55,(1H, d), 8.1 l,(2H,d), 7.65,(4H, m), 4.04,(2H, d), 3.14,(1H, m), 2.86,(1H, m), 2.20,(3H, d), 0.70,(2H, m), 0.57,(2H, m), 0.39,(2H, m), 0.26,(2H, m). LCMS: MH+ 407, retention time 2.56minutes.
Example 44 : N-Cyclopropyl-4 '- f 5-(ethoxymethvD-l ,3 ,4-oxadiazol-2-yll -5-fluoro-6- methyl-U'-biphenyl-S-carboxamide
Figure imgf000059_0001
Freshly prepared sodium ethoxide in ethanol (0.2M, 0.8ml) was added to a solution of (4'-[5-(chloromethyl)-l ,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-l , 1 '- biphenyl-3 -carboxamide (Intermediate 34) (50mg) in ethanol (1ml) and the reaction stirred at room temperature for 1 δhours. The reaction was reduced to dryness under vacuum and the residue partitioned between ethyl acetate and water. The organic phase dried (magnesium sulphate) and reduced to dryness under vacuum. The residue was purified by HPLC to give N-cyclopropyl-4'-[5-(ethoxymethyl)-l,3,4-oxadiazol-2-yl]-5- fluoro-6-methyl- 1 , 1 '-biphenyl-3-carboxamide. NMR: δH [2H6] - DMSO δ.56,(lH, d), 8.12,(2H, d), 7.65,(4H, m), 4.79,(2H, s), 3.62,(2H, q), 2.86,(1H, m), 2.20,(3H, d), 1.17,(3H, t), 0.70,(2H, m), 0.57,(2H, m). LCMS: MH+396, retention time 3.17minutes.
- 5δ Example 45: 4l-[5-(Aminomethyl ,3,4-oxadiazoI-2-yll-N-cyclopropyI-5-fluoro-6- methyl-l.l'-biphenyl-3-carboxamide
Figure imgf000060_0001
4'-[5-(Azidomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-l,l'- biphenyl-3 -carboxamide (Intermediate 35) (20δmg) and palladium on carbon (10%w/w, 21mg) in ethanol (10ml) were hydrogenated imder lAtm. of hydrogen for 24hours at room temperature. The reaction was filtered through celite and the filtrate reduced to dryness under vacuum. The residue was applied to a bond-elut (silica, lOg) and eluted with an ethyl acetate / cyclohexane gradient (50-100%) ethyl acetate) and then with methanol in ethyl acetate (0-50%). The solvent was evaporated from the product fractions under vacuum to give 4'-[5-(aminomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl- 5 -fluoro-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide.
NMR: δH CDC13 8.12,(2H, d), 7.49-7.42,(4H, m), 6.36,(111, b), 4.1δ,(2H, s), 2.90,(1H, m), 2.22,(3H, d), 0.88,(2H, m), 0.63,(2H, m). LCMS: MH+367, retention time 2.22minutes.
Example 46: N-Cyclopropyl-5-fluoro-4'-[5-(hvdroxymethyl)-l,3,4-oxadiazol-2-yll-6- methyl-l,l'-biphenyl-3-carboxamide
Figure imgf000060_0002
A solution of 4'-[5-(aminomethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-5-fluoro-6- methyl-l,l'-biphenyl-3 -carboxamide (Example 45) (96mg) in acetic acid / water (1:1 v/v, 7ml)was cooled to 0°C. Sodium nitrite (206mg) was added and the solution stirred for 30minutes at 0°C and then for a further lόhours at room temperature. Concentrated sodium hydroxide solution (10ml) was added to the reaction and the mixture extracted with ether (3x 40ml) and then chloroform (40ml). The organic phases were combined, dried and reduced to dryness under vacuum. The residue was dissolved in 5% potassium hydroxide in methanol and stirred at room temperature for 90minutes. The methanol was removed in vacuo, the residue partitioned between ethyl acetate / chloroform (1:1) / water and the organic phase dried and reduced to dryness under vacuum. This material was purified by chromatography on a bond-elut (silica, 2g), eluting with an ethyl acetate / cyclohexane gradient to give after evaporation of the solvent N-cyclopropyl-5-fluoro-4'- [5-(hydroxymethyl)-l,3,4-oxadiazol-2-yl]-6-methyl-l,r-biphenyl-3-carboxamide. NMR: δH [2H6] - DMSO 8.55,(1H, d), 8.11,(2H, d), 7.65,(4H, m), 5.99,(1H, t),
4.75,(2H, d), 2.86,(1H, m), 2.20,(3H, d), 0.70,(2H, m), 0.57,(2H, m). LCMS: MET 367, retention time 2.77minutes.
Example 47: N-CycIopropyl-6-methyl-4'-[5-(methyIamino)-l,3,4-oxadiazol-2-yll- 1,1 '-biphenyI-3-carboxamide
Figure imgf000061_0001
2-(4-Iodophenyl)-5-(methylamino)-l,3,4-oxadiazole (Intermediate 36) (30mg), N- cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (33mg), tetrakis(triphenylphosphine)palladium (13mg) and aqueous sodium carbonate (IM, 0.11ml) in DME (3ml) were mixed and heated at δ0°C for 1 δhours. The reaction was purified by HPLC to give N-cyclopropyl-6-methyl-4'-[5-(methylamino)- 1,3,4- oxadiazol-2-yl] -1,1 '-biphenyl-3 -carboxamide. LCMS: MH+ 349, retention time 2.76minutes.
Example 48: N-Cvclopropyl-6-methyl-4'-[5-(l-methyI-lH-pyrrol-2-yl)-l,3,4- oxadiazol-2-yIl-l,l'-biphenvI-3-carboxamide
Figure imgf000062_0001
2-(4-Iodophenyl)-5-(l-methyl-lH-pyrrol-2-yl)-l,3,4-oxadiazole (Intermediate 38) (35mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (33mg), tetrakis(triphenylphosphine)palladium (13mg) and aqueous sodium carbonate (IM, 0.11ml) in DME (3ml) were mixed and heated at 80°C for l hours. The reaction was purified by bond-elut (silica), eluting with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvent, N-cyclopropyl-6-methyl-4'-[5-(l-methyl-lH-pyrrol- 2-yl)- 1 ,3 ,4-oxadiazol-2-yl] -1,1 '-biphenyl-3 -carboxamide.
NMR: δH [2H6] - DMSO 8.46,(1H, d), δ.l6,(2H, d), 7.79,(1H, dd), 7.75,(1H, d), 7.64,(2H, d), 7.42,(1H, d), 7.21,(1H, m), 7.01,(1H, dd), 6.27,(1H, dd), 4.04,(3H, s), 2.86,(1H, m), 2.31,(3H, s), 0.69,(2H, m), 0.56,(2H, m). LCMS: MH* 399, retention time 3.41minutes.
Example 49: N-Cyclopropyl-4'-(5-ethyl-l,3,4-oxadiazol-2-yl)-6-methyl-l,l '- biphenyl-3-carboxeamide
Figure imgf000062_0002
N-Cyclopropyl-4'-(hydrazinocarbonyl)-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide (Intermediate 40) (50mg) in triethylorthopropionate (5ml) was heated at 150°C for 18hours. The excess triethylorthopropionate was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate / cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N- cyclopropyl-4'-(5-ethyl-l,3,4-oxadiazol-2-yl)-6-methyl-l,r-biphenyl-3-carboxamide. NMR: δH [2Hg] - DMSO 8.44,(1H, d), 8.08,(2H, d), 7.78,(1H, dd), 7.73,(1H, d), 7.61,(2H, d), 7.42,(1H, d), 2.97,(2H, q), 2.84,(1H, m), 2.30,(3H, s), 1.35,(3H, t), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 34δ, retention time 3.04minutes.
Example 50: N-Cvclopropyl-6-methyl-4,-(l,3,4-oxadiazol-2-yl)-l,l'-biphenyl-3- carboxamide
Figure imgf000063_0001
N-Cyclopropyl-4'-(hydrazinocarbonyl)-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide (Intermediate 40) (50mg) in triethylorthoformate (5ml) was heated at 150°C for 5hours.
The excess triethylorthoformate was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate / cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-4'-(l,3,4- oxadiazol-2-yl)-6-methyl-l , r-biphenyl-3-carboxamide. NMR: δH [2H6] - DMSO 9.39,(1H, s), 8.45,(1H, d), 8.12,(2H, d), 7.79,(1H, dd),
7.74,(1H, d), 7.64,(2H, d), 7.42,(1H, d), 2.85,(1H, m), 2.30,(3H, s), 0.69,(2H, m),
0.57,(2H, m). LCMS: MH+ 320, retention time 2.82minutes.
Example 51 : N-CvclopropyI-5-fluoro-6-methyl-4'-(5-methyI-l,3,4-oxadiazol-2-yI)- 1 ,1 '-biphenyl-3-carboxamide
Figure imgf000063_0002
N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzamide (32mg), 2-(4-Iodophenyl)-5-methyl-[l,3,4]oxadiazole (29mg), tetrakis(triphenylphosphine)palladium (2mg) and aqueous sodiumhydrogen carbonate (0.5ml) in propan-2-ol (2ml) were heated at 85°C for lδhours. The cooled reaction was diluted with ethyl acetate (6ml) and applied to a bond-elut (silica, 5g) and eluted with ethyl acetate. The eluent was reduced to dryness under vacuum, the residue applied to a bond-elut (silica, lg) and eluted with ether and then ethyl acetate. The solvent was removed from the ethyl acetate fraction under vacuum to give N-cyclopropyl-5-fluoro-6- methyl-4'-(5-methyl- 1 ,3,4-oxadiazol-2-yl)- 1 , 1 '-biphenyl-3-carboxamide. NMR: δH [2H6] - DMSO 8.55,(1H, d), 8.08,(2H, d), 7.64,(4H, m), 2.86,(1H, m), 2.61,(3H, s), 2.20,(3H, s), 0.70,(2H, m), 0.57,(2H, m). LCMS: MH1" 352, retention time 3.04minutes.
Example 52 : 4'-{5-[(Benzoylamino)methyll-l,3,4-oxadiazol-2-yl}-N-cvclopropyI-6- methyl-1 ,1 '-biphenyl-3-carboxamide
Figure imgf000064_0001
A solution of benzoyl chloride (6.3μl) in THF (1ml) was added dropwise to 4'-[5- (aminomethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide (Example 53) (lδ.δmg) and triethylamine (7.5μl) in THF (4ml),. The reaction was stirred at room temperature for lόhours, the solvent evaporated, the residue dissolved in water (10ml) and extracted with DCM (2x 10ml). The combined organics were reduced to dryness under vacuum, the residue dissolved in methanol and the solution applied to a bond-elut (aminopropyl, lg), eluting with further methanol. The eluent was reduced to ca.l0ml in vacuo and passed through a bond-elut (SCX, 2g), eluting with methanol. The solvent was evaporated from the eluent under vacuum. The residue was applied to a bond-elut (silica, 2g) and eluted with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvent 4'-{5-
[(benzoylamino)methyl] -1,3 ,4-oxadiazol-2-yl} -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide.
NMR: δH MeOD 7.δ9,(2H, d), 7.69,(2H, d), 7.51,(1H, dd), 7.46,(1H, s), 7.37-7.25,(5H, m), 7.17,(1H, d), 4.69,(2H, s), 2.61,(1H, m), 2.09,(3H, s), 0.57,(2H, m), 0.41,(2H, m). LCMS : MH*" 453, retention time 3.05minutes. Example 53: 4,-[5-(Aminomethyl)-l,3,4-oxadiazol-2-yll-N-cyclopropyl-6-methyl-l,l '- biphenyl-3-carboxamide
Figure imgf000065_0001
4'- [5 -(Azidomethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide (Intermediate 44) (27.8mg) and palladium on carbon (10% w/w, 5mg) in ethanol (5ml) were hydrogenated under 1 Atm. of hydrogen for 2hours. The reaction was filtered through celite, the filtrate reduced to dryness under vacuum and the residue applied to a bond-elut (silica, 4g). The column was eluted with chloroform, ether, ethyl acetate, and methanol. The methanol fraction was reduced to dryness under vacuum to give 4'-[5-(aminomethyl)-l ,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l , 1 '-biphenyl-3- carboxamide. LCMS: MH+ 349, retention time 2.16minutes.
Example 54: N-Cvclopropyl-6-methyl-4'-{[(cycIopropylacetyl)aminolmethv -l,3.4- oxadiazol-2-vIl-l,l'-biphenyl-3-carboxamide
Figure imgf000065_0002
4'- [5 -(Aminomethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide (Example 53) (30mg), EDC (19.8mg), HOBt (11.7mg), cyclopropylacetic acid (7.4mg) and DIPEA (0.02ml) were mixed in DCM (5ml). The reaction was stirred at room temperature for 4δhours, the reaction was washed with water (2x 10ml) and the DCM was evaporated under vacuum. The residue was dissolved in methanol and filtered through a bond-elut (SCX, 2g). The solvent was evaporated from the filtrate and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvent, N-cyclopropyl-6-methyl-4'- { [(cyclopropylacetyl)amino]methyl} -1,3 ,4-oxadiazol-2-yl] -1,1 '-biphenyl-3 -carboxamide. NMR: δH CDC13 δ.09,(2H, d), 7.66,(1H, dd), 7.61,(1H, d), 7.45,(2H, d), 7.34,(1H, d), 6.45,(1H, bt), 6.27,(1H, bs), 4.δ2,(2H, d), 2.91,(1H, m), 2.30,(3H, s), 1.50,(1H, m), 1.06,(2H, m), 0.δ6,(4H, m), 0.62,(2H, m). LCMS: MH+ 417, retention time 2.82minutes.
Example 55: N-CvcIopropyl-6-methyl-4'-[5-(f[(3-methyIisoxazol-5- yl)acetyl1amino]methyl)-l,3,4-oxadiazol-2-yll-l,l'-biphenyI-3-carboxamide
Figure imgf000066_0001
4'-[5-(Aminomethyl)-l ,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l , 1 '-biphenyl-3- carboxamide (Example 53) (30mg), EDC (19.8mg), HOBt (11.7mg), 3-methyl-5- isoxazoleacetic acid (12.2mg) and DIPEA (0.02ml) were mixed in DMF (5ml). The reaction was stirred at room temperature for 4δhours, the DMF evaporated under vacuum and the residue dissolved in DCM. The solution was washed with water (2x 10ml) and the DCM was evaporated under vacuum. The residue was dissolved in methanol and filtered through a bond-elut (SCX, 2g). The solvent was evaporated from the filtrate and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvent, N-cyclopropyl-6-methyl-4'-[5-({[(3- methylisoxazol-5-yl)acetyl]amino}methyl)- 1 ,3,4-oxadiazol-2-yl]- 1 , 1 '-biphenyl-3- carboxamide. NMR: δH [2H6] - DMSO 9.05,(1H, t), δ.46,(lH, d), 8.06,(2H, d), 7.79,(1H, d), 7.74,(1H, s), 7.63,(2H, d), 7.42,(1H, d), 6.23,(1H, s), 4.66,(2H, d), 2.84,(1H, m), 2.30,(3H, s),
2.19,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: Mtf 472, retention time 2.δlminutes. Example 56: N-Cyclopropyl-4'-{5-[(diethyIamino)methyll-l,3,4-oxadiazol-2-yll-6- methyl-l,l'-biphenyl-3-carboxamide
Figure imgf000067_0001
4'-[5-(Chloromethyl)- 1 ,3 ,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3- carboxamide (Intermediate 45) (37mg) and potassium iodide (5mg) were mixed in diethylamine (3ml) and the reaction stirred at room temperature for lδhours. The excess amine was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate / cyclohexane gradient. After evaporation of the solvent this gave N-cyclopropyl-4'- {5-[(diethylamino)methyl]-l ,3,4-oxadiazol-2-yl}-6-methyl- 1,1'- biphenyl-3-carboxamide.
NMR: δH [2H6] - DMSO 8.46,(1H, d), 8.08,(2H, d), 7.79,(1H, d), 7.73,(1H, s), 7.63,(2H, d), 7.42,(1H, d), 4.00,(2H, s), 2.85,(1H, m), 2.57,(4H, q), 2.30,(3H, s), 1.05,(6H, t), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH1" 405, retention time 2.37minutes.
Example 57: N-Cvclopropyl-4l-{5-f(cyclopropylamino)methyl]-l,3,4-oxadiazol-2- yl}-6-methyI-l,l'-biphenyl-3-carboxamide
Figure imgf000067_0002
4'-[5-(Chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cycloρropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Intermediate 45) (37mg) and potassium iodide (5mg) were mixed in cyclopropylamine (3ml) and the reaction stirred at room temperature for l hours. The excess amine was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate / cyclohexane gradient. After evaporation of the solvent this gave N-cyclopropyl-4'-{5-[(cyclopropylamino)methyl]-l,3,4-oxadiazol-2-yl}-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide. NMR: δH [2H6] - DMSO 8.46,(1H, d), 8.09,(2H, d), 7.79,(1H, dd), 7.74,(1H, s), 7.63,(2H, d), 7.42,(1H, d), 4.04,(2H, s), 2.85,(1H, m), 2.30,(3H, s), 2.20,(1H, m), 0.69,(2H, m), 0.57,(2H, m), 0.39,(2H, m), 0.26,(2H, m). LCMS: MH+ 3δ9, retention time 2.53minutes.
Example 58: N-CvcIopropyl-6-methyl-4'-[5-(thiomorpholin-4-ylmethyl)-l,3,4- oxadiazol-2-yll-l,l'-biphenyl-3-carboxamide
Figure imgf000068_0001
4'-[5-(Chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Intermediate 45) (37mg) and potassium iodide (5mg) were mixed in thiomoφholine (2ml) and DMF (2ml) and the reaction stirred at room temperature for 1 δhours. The solvents were evaporated under vacuum and the residue purified by bond- elut (silica), eluting with an ethyl acetate / cyclohexane gradient. After evaporation of the solvent this gave N-cyclopropyl-6-methyl-4'-[5-(thiomoφholin-4-ylmethyl)-l,3,4- oxadiazol-2-yl] -1,1 '-biphenyl-3 -carboxamide.
NMR: δH [ H6] -DMSO 8.46,(1H, d), 8.09,(2H, d), 7.78,(1H, d), 7.74,(1H, s), 7.63,(2H, d), 7.42,(1H, d), 3.97,(2H, s), 2.84-2.δO,(5H, m), 2.66,(4H, m), 2.30,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 435, retention time 2.96minutes. Example 59: 4'-{5-[(Cvclohexylamino)methyn-l,3,4-oxadiazol-2-yl}-N-cvclopropyl- 6-methyl-l ,1 '-biphenyI-3-carboxamide
Figure imgf000069_0001
4'- [5-(Chloromethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3- carboxamide (Intermediate 45) (37mg) and potassium iodide (5mg) were mixed in cyclohexylamine (2ml) and DMF (2ml) and the reaction stirred at room temperature for 18hours. The solvents were evaporated under vacuum and the residue purified by bond- elut (silica), eluting with an ethyl acetate / cyclohexane gradient. After evaporation of the solvent this gave 4'-{5-[(cyclohexylamino)methyl]-l,3,4-oxadiazol-2-yl}-N-cyclopropyl- 6-methyl- 1 , r-biphenyl-3-carboxamide.
NMR: δH [2H6] - DMSO 8.46,(1H, d), 8.14,(1H, s), 8.09,(2H, d), 7.79,(1H, d), 7.74,(1H, s), 7.64,(2H, d), 7.42,(1H, d), 4.17,(2H, s), 2.85,(1H, m), 2.60,(1H, m), 2.30,(3H, s), l.δ9,(2H, m), 1.70,(2H, m), 1.56,(1H, m), 1.26-1.05,(5H, m), 0.69,(2H, m), 0.57,(2H, m). LCMS : MH+ 432, retention time 2.43minutes.
Example 60: N-Cvclopropyl-4,-(5-{f(3,3-dimethylbutanoyl)aminolmethv -l,3,4- oxadiazol-2-yl)-6-methyl-l,l'-biphenyl-3-carboxamide
Figure imgf000069_0002
t-Butylacetic acid (lOmg) and HATU (33mg) in DMF (1ml) were stirred for lOminutes at room temperature. To this solution was added HOBt (11.6mg), DIPEA (.0.45ml) and 4'- [5-(aminomethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide (Example 53) (30mg) in DMF (3ml) and the reaction stirred at room
- 6δ - temperature for 72hours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2x5ml). The organic phase was reduced to dryness and the residue purified by bond-elut (silica, 5g) eluting with an ethyl acetate / cyclohexane gradient and then by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4'-(5- {[(3,3-dimethylbutanoyl)amino]methyl} - 1 ,3,4-oxadiazol-2- yl)-6-methyl- 1 , 1 '-biphenyl-3 -carboxamide. LCMS: MH" 44δ, retention time 3.07minutes.
Example 61 : N-Cyclopropyl-4'-(5-[(glvcoloylamino)methyll-l,3,4-oxadiazol-2-yl}-6- methyl-l,l'-biphenyl-3-carboxamide
Figure imgf000070_0001
4'-[5-(Aminomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Example 53) (30mg), HOBt (11.7mg), EDC (19.δmg), DIPEA (0.018ml) and glycolic acid (6.6mg) were mixed in DCM (6ml) and methanol (1ml) and the reactions stirred at room temperature for 96hours. The reaction was reduced to dryness under vacuum and the residue partitioned between DCM and water. The organic phase was evaporated and the residue purified by bond-elut (silica, 5g) eluting with an ethyl acetate / cyclohexane gradient and then by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4'- {5-[(glycoloylamino)methyl]-l,3,4-oxadiazol-2-yl}-6- methyl- 1 , 1 '-biphenyl-3 -carboxamide.
NMR: δH [ H6] - DMSO 8.60,(1H, t), 8.46,(1H, d), 8.05,(2H, d), 7.79,(1H, dd), 7.74,(1H, d), 7.63,(2H, d), 7.43,(1H, d), 5.67,(1H, b), 4.64,(2H, d), 3.92,(3H, s), 2.δ5,(lH, m), 2.30,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 407, retention time 2.56minutes.
Example 62: 4'-(5-{[(BenzvIsulfonvI)amino]methyl}-l,3,4-oxadiazol-2-yl)-N- cyclopropyl-6-methyl-l,l'-biphenyl-3-carboxamide
Figure imgf000071_0001
4'-[5-(Aminomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Example 53) (30mg) was mixed with α-toluenesulphonyl chloride (33mg) in pyridine (6ml) at 0°C and the reaction stirred at room temperature for 72hours. Further α-toluenesulphonyl chloride (66mg) in pyridine (3ml) was added and stirring continued for lδhours. The reaction was diluted with DCM and washed with hydrochloric acid (2N, 4x5ml) and then water (5ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents 4'-(5-{[(benzylsulfonyl)amino]methyl}-l,3,4-oxadiazol-2-yl)- N-cyclopropyl-6-methyl-l,l'-biphenyl-3-carboxamide.
NMR: δH [2H6] - DMSO 8.46,(1H, d), 8.08,(2H, d), 7.79,(1H, dd), 7.74,(1H, d), 7.65,(2H, d), 7.43-7.37,(5H, m), 4.50,(4H, m), 2.85,(1H, m), 2.30,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 503, retention time 3.11minutes.
Example 63 : N-Cvclopropyl-4'-{5-[(ethylamino)methyll-l,3,4-oxadiazol-2-yl}-6- methyl-1 ,1 '-biphenyI-3-carboxamide
Figure imgf000071_0002
4'-[5-(Chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Intermediate 45) (37mg) and potassium iodide (5mg) were mixed in ethylamine in THF (2M, 3ml) and the reaction stirred at room temperature for lδhours. The excess amine was evaporated under vacuum and the residue purified by preparative HPLC. After evaporation of the solvent this gave N-cyclopropyl-4'- {5- [(ethylamino)methyl] - 1 ,3 ,4-oxadiazol-2-yl} -6-methyl- 1 , 1 '-biphenyl-3 -carboxamide. NMR: δH [2H6] - DMSO 8.46,(1H, d), 8.18,(1H, s), 8.09,(2H, d), 7.79,(1H, dd), 7.74,(1H, d), 7.63,(2H, d), 7.42,(1H, d), 4.01,(2H, s), 2.85,(1H, m), 2.62,(2H, q), 2.30,(3H, s), 1.04,(3H, t), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 377, retention time 2.25minutes.
Example 64: N-CycIopropyl-6-methyI-4'-(5-{[(methylsuIfonyl)aminolmethyl}-l,3,4- oxadiazol-2-yl)-l,l'-biphenyl-3-carboxamide
Figure imgf000072_0001
4'-[5-(Aminomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,r-biphenyl-3- carboxamide (Example 53) (30mg) was mixed with methanesulphonyl chloride (0.02ml) and pyridine (0.034ml) in DCm (3ml) and the reaction stirred at room temperature for 1 δhours. The reaction was washed with water (4x4ml) and then hydrochloric acid (2N, 5ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents N-cyclopropyl-6-methyl-4'-(5- { [(methylsulfonyl)amino]methyl} - 1 ,3 ,4-oxadiazol-2-yl)- 1 , 1 '-biphenyl-3 -carboxamide. NMR: δH [2H6] - DMSO 8.46,(1H, d), 8.09,(2H, d), 8.03,(1H, b), 7.79,(1H, dd), 7.74,(1H, d), 7.64,(2H, d), 7.42,(1H, d), 4.5δ,(2H, s), 3.05,(3H, s), 2.85,(1H, m), 2.30,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 427, retention time 2.7δminutes.
Example 65: N-CvclopropyI-6-methyl-4,-{5-f(propionyIamino)methyIl-l,3,4- oxadiazol-2-yI}-l,l,-biphenyl-3-carboxamide
Figure imgf000072_0002
Propionic acid (6.4mg) and HATU (33mg) in DMF (1ml) were stirred for lOminutes at room temperature. To this solution was added HOBt (11.6mg), DIPEA (.0.45ml) and 4'- [5-(aminomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Example 53) (30mg) in DMF (2ml) and the reaction stirred at room temperature for lδhours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2x4ml). The organic phase was reduced to dryness and the residue purified by bond-elut (SCX, 5g) eluting with methanol and then by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-6-methyl- 4'- { 5 -[(propionylamino)methyl] - 1 ,3 ,4-oxadiazol-2-yl} -1,1 '-biphenyl-3 -carboxamide. NMR: δH [2H6] - DMSO 8.62,(1H, t), 8.46,(1H, d), 8.05,(2H, d), 7.79,(1H, dd), 7.74,(1H, d), 7.63,(2H, d), 7.42,(1H, d), 4.60,(2H, d), 2.85,(1H, m), 2.30,(3H, s), 2.20,(2H, q), 1.04,(3H, t), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 405, retention time 2.74minutes.
Example 66: N-Cyclopropyl-4,-(5-{f(cyclopropyIacetyllaminolmethyl]-l,3,4- oxadiazol-2-yl)-6-methyI-l ,1 '-biphenyI-3-carboxamide
Figure imgf000073_0001
Cyclopropylacetic acid (δ.6mg) and HATU (33mg) in DMF (1ml) were stirred for 1 Ominutes at room temperature. To this solution was added HOBt (11.6mg), DIPEA (.0.45ml) and 4'-[5-(aminomethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1,1'- biphenyl-3 -carboxamide (Example 53) (30mg) in DMF (2ml) and the reaction stirred at room temperature for lδhours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2x4ml). The organic phase was reduced to dryness and the residue purified by bond-elut (SCX, 5g) eluting with methanol and methanolic ammonia. The methanolic ammonia fraction was further purified by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4'-(5- { [(cyclopropylacetyl)amino]methyl} - 1 ,3 ,4-oxadiazol-2-yl)-6-methyl- 1 , 1 '-biphenyl-3- carboxamide. NMR: δH [2H6] - DMSO δ.58,(lH, t), 8.45,(1H, d), 8.04,(2H, d), 7.77,(1H, d), 7.72,(1H, s), 7.62,(2H, d), 7.40,(1H, d), 4.60,(2H, d), 2.δ4,(lH, m), 2.2δ,(3H, s), 2.09,(2H, d), 0.9δ,(lH, m), 0.6δ,(2H, m), 0.55,(2H, m), 0.44,(2H, m), 0.15,(2H, m). LCMS: MH* 431, retention time 2.δδminutes. Example 67: N-Cvclopropyl-6-methyl-4'-(5-{[(phenyIacetyl)aminolmethyU-l,3,4- oxadiazol-2-yl)-l ,1 '-biphenyI-3-carboxamide
Figure imgf000074_0001
Phenylacetic acid (12mg) and HATU (33mg) in DMF (1ml) were stirred for lOminutes at room temperature. To this solution was added HOBt (11.6mg), DIPEA (.0.45ml) and 4'- [5 -(aminomethyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide (Example 53) (30mg) in DMF (2ml) and the reaction stirred at room temperature for lδhours. The solvent was evaporated under vacuum and the residue dissolved in DMSO (0.25ml), methanol (0.25ml) was added and the precipitate produced isolated by filtration to give N-cyclopropyl-6-methyl-4'-(5-
{[(phenylacetyl)amino]methyl} - 1 ,3 ,4-oxadiazol-2-yl)- 1 , 1 '-biphenyl-3 -carboxamide. NMR: δH [2H6] - DMSO 8.93,(1H, t), 8.46,(1H, d), 7.98,(2H, d), 7.79,(1H, d), 7.74,(1H, s), 7.62,(2H, d), 7.42,(1H, d), 7.32,(4H, m), 7.25,(1H, m), 4.63,(2H, d), 3.53,(2H, s), 2.85,(1H, m), 2.30,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 467, retention time 3.04minutes.
Example 68: N-Cvclopropyl-4'-[5-(hvdroxymethyl)-l,3,4-oxadiazol-2-yll-6-methyl- 1,1 '-biphenyI-3-carboxamide
Figure imgf000074_0002
A solution of 4'-[5-(aminomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl -6-methyl- 1,1'- biphenyl-3-carboxamide (Example 53) (30mg) in acetic acid / water (1:1 v/v, 3ml)was cooled to 0°C. Sodium nitrite (68mg) was added and the solution stirred 24hours at room temperature. Concentrated sodium hydroxide solution was added to the reaction and the mixture extracted with ether (3x 20ml). The combined organic phases were treated with potassium hydroxide in methanol (5%, 3ml) for 2hours, washed with water, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in 5% potassium hydroxide in methanol and stirred at room temperature for 90minutes. The methanol was removed in vacuo, the residue partitioned between ethyl acetate / chloroform (1:1) / water and the organic phase dried and reduced to dryness under vacuum. This material was purified by HPLC, to give, after evaporation of the solvent, N-cyclopropyl-4'-[5 -(hydroxymethyl)- 1 ,3 ,4-oxadiazol-2-yl] -6-methyl- 1 , 1 '-biphenyl-3 - carboxamide. NMR: δH [2H6] - DMSO 8.46,(1H, d), 8.09,(2H, d), 7.79,(1H, dd), 7.74,(1H, d), 7.64,(2H, d), 7.42,(1H, d), 6.01,(1H, b), 4.75,(2H, s), 2.85,(1H, m), 2.30,(3H, s), 0.69,(2H, M), 0.57,(2H, m). LCMS: MH+ 350, retention time 2.70minutes.
Example 69: N-Cyclopropyl-4'-(5-{f(cvclopropylmethyl)aminolmethv -l,3,4- oxadiazol-2-vD-6-methyl-l ,1 '-biphenyl-3-carboxamide
Figure imgf000075_0001
4'-[5-(Chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Intermediate 45) (37mg) and potassium iodide (5mg) were mixed in cyclopropylmethylamine (3ml) and the reaction stirred at room temperature for 1 δhours. The excess amine was evaporated under vacuum and the residue purified by preparative HPLC. After evaporation of the solvent this gave N-cyclopropyl-4'-(5- { [(cyclopropylmethyl)amino]methyl} - 1 ,3 ,4-oxadiazol-2-yl)-6-methyl- 1 , 1 '-biphenyl-3 - carboxamide. NMR: δH [2H6] - DMSO δ.46,(lH, d), 8.14,(1H, s), 8.09,(2H, d), 7.79,(1H, dd), 7.74,(1H, d), 7.64,(2H, d), 7.42,(1H, d), 4.1δ,(2H, s), 2.δ5,(lH, m), 2.60,(2H, d), 0.93,(1H, m), 0.69,(2H, m), 0.57,(2H, m), 0.46,(2H, m), 0.1δ,(2H, m). LCMS: MH*" 403, retention time 2.36minutes. Example 70: 4'-(5-Amino-l,3,4-oxadiazol-2-yl)-N-cyclopropyI-6-methyl-l,l'- biphenyl-3-carboxamide
Figure imgf000076_0001
N-Cyclopropyl-4'-(hydrazinocarbonyl)-6-methyl-l, -biphenyl-3-carboxamide (Intermediate 40) (35mg) and a mixture of di enzotriazolyl)methanimines (30mg, Synthesis 6, 2001, δ97-903) were dissolved in THF (1.5ml) and the solution heated at reflux for3hours. The cooled reaction was absorbed onto silica and applied to a bond-elut (silica, lOg) and eluted with an ethyl acetate / cyclohexane gradient. The product fractions were combined and evaporated to dryness to give 4'-(5-amino-l,3,4-oxadiazol- 2-yl)-N-cyclopropyl-6-methyl- 1 , 1 '-biphenyl-3-carboxamide.
NMR: δH [2H6] - DMSO 8.44,(1H, d), 7.88,(2H, d), 7.77,(1H, d), 7.72,(1H, s), 7.55,(2H, d), 7.40,(1H, d), 7.30,(2H, s), 2.85,(1H, m), 2.30,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH1" 335, retention time 2.71minutes.
Example 71 : N-CvcIopropyl-4'-[5-(ethoxymethyl)-l,3,4-oxadiazol-2-yll-6-methyl- U'-biphenyl-S-carboxamide
Figure imgf000076_0002
4'-[5-(Chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biρhenyl-3- carboxamide (Intermediate 45) (50mg) was added to a freshly prepared sodium ethoxide solution (0.0δ7M, 2ml), and the reaction stirred at room temperature for 72hours. The reaction was partitioned between ethyl acetate and water, the organic phase dried (sodium sulphate) and reduced to dryness under vacuum. The residue was purified by HPLC to give, after evaporation of the solvent, N-cyclopropyl-4'-[5-(ethoxymethyl)-l,3,4- oxadiazol-2-yl] -6-methyl- 1 , 1 '-biphenyl-3 -carboxamide.
NMR: δH CDC13 8.13,(2H, d), 7.6δ,(lH, dd), 7.63,(1H, d), 7.46,(2H, d), 7.34,(1H, d), 6.39,(1H, b), 4.7δ,(2H, s), 3.69,(2H, q), 2.91,(1H, m), 2.31,(3H, s), 1.29,(3H, t), 0.δ7,(2H, m), 0.63,(2H, m). LCMS: MH+ 37δ, retention time 3.09minutes.
Example 72: N-Cvclopropyl-4'-[5-(cyclopropylmethyl)-l,3,4-oxadiazoI-2-yll-6- methyl-l,l'-biphenyl-3-carboxamide
Figure imgf000077_0001
4'-[5-(Azidomethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,l'-biphenyl-3- carboxamide (Intermediate 44) (40mg), triethylamine (0.051ml) and ethyl 2- cyclopropylethanimidate hydrochloride (23mg) in ethanol (3ml) were heated at δ0°C for 16hours. The ethanol was removed under vacuum, the residue applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient. Evaporation of the solvent from the product fractions gave N-cyclopropyl-4'-[5-(cyclopropylmethyl)-l,3,4- oxadiazol-2-yl] -6-methyl- 1 , 1 '-biphenyl-3 -carboxamide.
NMR: δH CDC13 δ.ll,(2H, d), 7.67,(1H, dd), 7.63,(1H, d), 7.46,(2H, d), 7.35,(1H, d), 6.30,(1H, b), 2.94-2.86,(3H, m), 2.31,(3H, s), 1.25,(1H, m), 0.8δ,(2H, m), 0.69-0.66,(4H, m), 0.3δ,(2H, m). LCMS: MH+ 374, retention time 3.25minutes.
Example 73 : N-Cvclopropyl-4'-[5-(methoxymethyl)-l,3,4-oxadiazol-2-vIl-6-methyl- 1,1 '-biphenyl-3-carboxamide
Figure imgf000078_0001
4'-[5-(Chloromethyl)- 1 ,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l , 1 '-biphenyl-3- carboxamide (Intermediate 45) (50mg) was added to a freshly prepared sodium methoxide solution (0.08M, 12ml), and the reaction stirred at room temperature for 96hours. The reaction was partitioned between ethyl acetate and water, the organic phase dried (sodium sulphate) and reduced to dryness under vacuum. The residue was applied to a bond-elut (silica, 5g) and eluted with an ethyl acetate / cyclohexane gradient. The product fractions were reduced to dryness under vacuum and further purified by HPLC, to give after evaporation of the solvent, N-cyclopropyl-4'-[5-(methoxymethyl)- 1,3,4- oxadiazol-2-yl] -6-methyl- 1 , 1 '-biphenyl-3-carboxamide. NMR: δH [2H6] - DMSO 8.46,(1H, d), δ.l0,(2H, d), 7.79,(1H, dd), 7.74,(1H, d), 7.63,(2H, d), 7.42,(1H, d), 4.76,(2H, s), 3.41,(3H, s), 2.85,(1H, m), 2.30,(3H, s), 0.69,(2H, m), 0.56,(2H, m). LCMS: MH1" 364, retention time 2.95minutes.
Example 74: N-Cvclopropyl-4'-(5-[(cyclopropylmethoxy)methyll-l,3,4-oxadiazoI-2- yl}-6-methyI-l,l'-biphenyl-3-carboxamide
Figure imgf000078_0002
4'-[5-(Chloromethyl)-l,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-l,r-biphenyl-3- carboxamide (Intermediate 45) (50mg) was added to a freshly prepared sodium cyclopropyhnethoxide solution (0.08M, 6ml), and the reaction stirred at room temperature for 26hours. The reaction was concentrated under vacuum and the residue applied to a bond-elut (silica, lOg) and eluted with an ethyl acetate / cyclohexane gradient. The product fractions were reduced to dryness under vacuum, to give, N-cyclopropyl-4'- {5- [(cyclopropylmethoxy)methyl]- 1 , 3 ,4-oxadiazol-2-yl} -6-methyl- 1 , 1 '-biphenyl-3 - carboxamide.
NMR: δH [2H6] - DMSO 8.45,(1H, d), 8.09,(2H, d), 7.77,(1H, dd), 7.73,(1H, d), 7.62,(2H, d), 7.41,(lH,d), 4.80,(2H, s), 3.41,(2H, d), 2.δ4,(lH, m), 2.29,(3H, s), 1.04,(1H, m), 0.6δ,(2H, m), 0.56,(2H, m), 0.48,(2H, m), 0.21,(2H, m). LCMS: MH+ 404, retention time 3.24minutes.
Example 75: N-Cyclopropyl-6-methyl-4'-(5-methyl-l,3,4-triazol-2-yl)-l,l '-biphenyl- 3-carboxamide
Figure imgf000079_0001
N-Cyclopropyl-4'- [(2-ethanimidoylhydrazino)carbonyl] -6-methyl- 1 , 1 '-biphenyl-3 - carboxamide (Intermediate 46) (80mg) in xylene (15ml) was heated at 190°C under Dean- Stark conditions for 4hours. The xylene was decanted from the precipitated solid and the solid washed with cyclohexane. The solid was applied to a bond-elut (silica) and eluted with an ethyl acetate / cyclohexane gradient to give, after evaporation of the solvents under vacuum, N-cyclopropyl-6-methyl-4'-(5-methyl- 1 ,3,4-triazol-2-yl)- 1 , 1 '-biphenyl-3- carboxamide.
NMR: δH [ H6] - DMSO 13.74,(1H, b), δ.43,(lH, d), 8.05,(2H, d), 7.76-7.72,(2H, m),
7.46,(2H, d), 7.39,(1H, d), 2.δ5,(lH, m), 2.41,(3H, s), 2.30,(3H, s), 0.6δ,(2H, m), 0.56,(2H, m). LCMS: MH+ 333, retention time 2.74minutes.
7δ - Example 76: 4'-(4-Acetyl-5-imino-4,5-dihydro-l,3,4-oxadiazoI-2-yl)-N-cycIopropyl- 6-methyl-l ,1 '-biphenyl-3-carboxamide
Figure imgf000080_0001
Acetyl chloride (5.1μl) was added to a solution of 4'-(5-amino-l,3,4-oxadiazol-2-yl)-N- cyclopropyl-6-methyl-l,l'-biphenyl-3-carboxamide (20mg) and triethylamine (0.01ml)in THF (2ml) and the reaction stirred at room temperature for lδhours. The solvent was evaporated from the reaction and the residue purified by HPLC to give, after evaporation of the solvent, 4'-(4-acetyl-5-imino-4,5-dihydro- 1 ,3,4-oxadiazol-2-yl)-N-cyclopropyl-6- methyl- 1 , 1 '-biphenyl-3 -carboxamide.
ΝMR: δH [2H6] - DMSO 8.45,(1H, d), 7.99,(2H, d), 7.78,(1H, d), 7.73,(1H, s), 7.61,(2H, d), 7.42,(1H, d), 2.85,(1H, m), 2.30,(3H, s), 2.16,(3H, s), 0.69,(2H, m), 0.57,(2H, m). LCMS: MH+ 377, retention time 2.65minutes.
General Method B
Aryl halide (20mg), {5-[(Cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 47) (22mg), tetrakis(triphenylphosphine) palladium (2mg), sodiumhydrogen carbonate (0.25ml) and propan-2-ol (1ml) were mixed in a sealed vessel and heated in a microwave at 150°C for lOminutes. Methanol (5ml) was added, the mixture filtered, and the solvent evaporated in vacuo. The mixture was purified by mass- directed autoprep and the solvents evaporated to give the desired product.
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000082_0001
Abbreviations
DCM Dichloromethane
DIPEA N,N-Diisopropylethylamine
DME Dimethoxyethane
DMF Dimethylformamide
DMSO Dimethylsulphoxide
EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HATU O-(7- Azabenzotriazol- 1 -yl)-N,N,N' ,N' -tetramethyluronium hexafluorophosphate
HOBT 1-Hydroxybenzotriazole hydrate
SPE Solid phase extraction using bond elute cartridges available from Varian
THF Tetrahydrofuran
The activity of the compounds of the invention as p3δ inhibitors may be demonstrated in the following assays:
p38 Kinase Assay The peptide substrate used in the p3 δ assay was biotin-IPTSPITTTYFFFRRR- amide. The p3δ and MEK6 proteins were purified to homogeneity from E.coli expression systems. The fusion proteins were tagged at the N-terminus with Glutathione-S- Transferase (GST). The maximum activation was achieved by incubating 20uL of a reaction mixture of 30nM MEK6 protein and 120nM p3δ protein in the presence of 1.5uM peptide and lOmM Mg(CH3CO2)2 in lOOmM HEPES, pH 7.5, added to 15uL of a mixture of 1.5uM ATP with O.OδuCi [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 δl - 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. IC5o values were obtained by fitting raw data to %I = 100*(1-(I-C2)/(C1-C2)), where I was CPM of background, CI was positive control, and C2 was negative control.
P38 α Fluorescence Polarisation Method
P38 α was prepared in house. SB4777790-R Ligand was diluted in HEPES containing MgCl2, CHAPS, DTT and DMSO. This was added to blank wells of a Black NUNC 384 well plate. P38 α was added to this ligand mixture then added to the remainder of the 384 well plate containing controls and compounds. The plates were read on an LJL Analyst and Fluorescence Anisotropy used to calculate the compound inhibition.
Results
The compounds described in the Examples were tested as described above and had IC50 values of <10 μM.

Claims

Claims:
A compound of formula (I):
Figure imgf000084_0001
(I) wherein
Rl is a 5- or 6-membered monocyclic heteroaryl ring containing up to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, which ring is optionally substituted by up to two substituents selected from Cj.galkyl, -(CH2)m-C3_ 7cycloalkyl, halogen, cyano, trifluoromethyl, imino, oxo, -(CH2)mOR- , -(CH2)mCOR5, -(CH2)mS(O)tR5, -(CH2)mNR5R65 -(CH2)mCONR5R6 -(CH2)mNHCOR5, - (CH2)mSO2NR5R6, -(CH2)mNHSO2R5, and a 5-membered heteroaryl ring optionally substituted by C \ _2alkyl;
R2 is selected from hydrogen, methyl, chloro and fluoro;
R3 is selected from methyl and chloro;
R4 is selected from -NH-CO-R? and -CO-NH-(CH2)q-R8;
R-5 is selected from hydrogen, Cj.galkyl optionally substituted by up to two OH groups, -(CH2)m-C3_7cycloalkyl, -(CH2)I11phenyl optionally substituted by Rl 6 and - (CH2)mheteroaryl optionally substituted by R*6,
R^ is selected from hydrogen and Cj.galkyl, or
R-5 and R6, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom independently selected from oxygen, sulfur and N-R-^;
R7 is selected from hydrogen, Cχ_6alkyl, -(CH2)q-C3_7cycloalkyl, trifluoromethyl, -(CH2)rheteroaryl optionally substituted by R* 0 and/or Rl , and - (CH2)rphenyl optionally substituted by RlO and/or R11;
R8 is selected from hydrogen, Cχ_6alkyl, C3_7cycloalkyl, CONHRl2, phenyl optionally substituted by Rl 0 and/or R 1 , and heteroaryl optionally substituted by R 0 and/or RU;
R9 is selected from hydrogen and methyl;
R ° is selected from Cχ_6alkyl, C galkoxy, -(CH2)q-C3_7cycloalkyl, - CONRl2Rl3, -NHCOR13, halogen, CN, -(CH2)SNR14R15, trifluoromethyl, phenyl optionally substituted by one or more Rl 1 groups, and heteroaryl optionally substituted by one or more Rl 1 groups;
Rl 1 is selected from Cχ_6alkyl, Cχ_6alkoxy, halogen, trifluoromethyl, and - (CH2)sNRl4Rl5; Rl and Rl3 are each independently selected from hydrogen and Cχ_galkyl, or
Rl2 and Rl3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom independently selected from oxygen, sulfur and N-R-^, wherein the ring may be substituted by up to two Cx.galkyl groups; R*4 is selected from hydrogen, Cχ_6alkyl and -(CH2)q-C3_7cycloalkyl optionally substituted by Cχ_6alkyl,
R!5 is selected from hydrogen and Cχ_galkyl, or
Rl4 and Rl5, together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R9;
Rl6 is selected from halogen, C _6alkyl, hydroxy, Cx.galkoxy and trifluoromethyl;
U is selected from methyl and halogen;
X and Y are each selected independently from hydrogen, methyl and halogen; m is selected from 0, 1, 2 and 3; n is selected from 0, 1 and 2; q is selected from 0, 1 and 2; r is selected from 0 and 1; s is selected from 0, 1, 2 and 3; and t is selected from 0, 1 and 2.
2. A compound according to claim 1 wherein Rl is a 5-membered monocyclic heteroaryl ring containing 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, optionally substituted by up to two substituents selected from Cχ_ 4alkyl, -(CH2)m-C3_7cycloalkyl, imino, -(CH2)mOR5, -(CH2)mCOR5, -
(CH2)mNR5R6, -(CH2)mNHCOR5, -(CH2)mNHSO R5 and a 5-membered heteroaryl ring optionally substituted by Cχ_2alkyl.
3. A compound according to claim 1 or claim 2 wherein R2 is hydrogen.
4. A compound according to any one of the preceding claims wherein R3 is methyl.
5. A compound according to any one of the preceding claims wherein X is fluorine.
6. A compound according to any one of the preceding claims wherein R^ is (CH2)rheteroaryl optionally substituted by R*^ and/or Rl 1.
7. A compound according to any one of the preceding claims wherein R8 is selected from C3_6cycloalkyl, phenyl optionally substituted by R 0 and/or Rl 1 and heteroaryl optionally substituted by Rl 0 and/or Rl 1.
δ. A compound according to claim 1 as defined in any one of Examples 1 to 81.
9. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
10. A method for treating a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase comprising administering to a patient in need thereof a compound as claimed in any one of claims 1 to δ.
11. A compound as claimed in any one of claims 1 to 8 for use in therapy.
12. Use of a compound as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in the treatment of a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p3δ kinase.
13. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to δ which comprises reacting a compound of formula (H)
Figure imgf000086_0001
(D) in which Rl, R2, U and n are as defined in claim 1 and Z is halogen, with a compound of formula (HI)
Figure imgf000086_0002
(W) in which R3, R4, X and Y are as defined in claim 1, in the presence of a catalyst.
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012241A2 (en) * 2003-07-25 2005-02-10 Novartis Ag p-38 KINASE INHIBITORS
JP2007519692A (en) * 2004-01-30 2007-07-19 スミスクライン ビーチャム コーポレーション Fused heteroaryl derivatives for use as p38 kinase inhibitors
JP2007519693A (en) * 2004-01-30 2007-07-19 スミスクライン ビーチャム コーポレーション Fused heteroaryl derivatives and their use as P38 kinase inhibitors
JP2008516989A (en) * 2004-10-19 2008-05-22 コンパス ファーマシューティカルズ リミティド ライアビリティ カンパニー Compositions and their use as antitumor agents
US7425555B2 (en) 2002-04-30 2008-09-16 Smithkline Beecham Corporation Heteroaryl substituted biphenyl derivatives as p38 kinase inhibitors
WO2009009041A2 (en) * 2007-07-06 2009-01-15 Kinex Pharmaceuticals, Llc Compositions and methods for modulating a kinase cascade
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WO2009051848A1 (en) * 2007-10-20 2009-04-23 Kinex Pharmaceuticals, Llc Pharmaceutical compositions for modulating a kinase cascade and methods of use thereof
US7572790B2 (en) 2003-04-09 2009-08-11 Smithkline Beecham Corporation Biphenyl carboxylic amide p38 kinase inhibitors
US7626055B2 (en) 2003-04-09 2009-12-01 Smithkline Beecham Corporation Biphenyl-carboxamide derivatives and their use as p38 kinase inhibitors
WO2010001365A1 (en) * 2008-07-04 2010-01-07 Institut National De La Sante Et De La Recherche Medicale (Inserm) Nitrogen heterocycle derivatives as proteasome modulators
US7683097B2 (en) * 2004-05-27 2010-03-23 Propharmacon Inc. Topoisomerase inhibitors
US7838540B2 (en) 2003-08-11 2010-11-23 Glaxosmithkline Llc 3-aminocarbonyl, 6-phenyl substituted pyridine-1-oxides as p38 kinase inhibitors
US7935697B2 (en) 2006-12-28 2011-05-03 Kinex Pharmaceuticals, Llc Compositions for modulating a kinase cascade and methods of use thereof
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US11452713B2 (en) 2016-02-29 2022-09-27 University Of Florida Research Foundation, Incorporated Chemotherapeutic methods for treating low-proliferative disseminated tumor cells

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0124931D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124936D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124934D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
MXPA04007838A (en) * 2002-02-12 2004-10-15 Smithkline Beecham Corp Nicotinamide derivates useful as p38 inhibitors.
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
GB0308185D0 (en) * 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0402137D0 (en) * 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
GB0402140D0 (en) * 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
US20080051416A1 (en) * 2004-10-05 2008-02-28 Smithkline Beecham Corporation Novel Compounds
GB0512429D0 (en) * 2005-06-17 2005-07-27 Smithkline Beecham Corp Novel compound
GB0612026D0 (en) 2006-06-16 2006-07-26 Smithkline Beecham Corp New use
AU2007281774A1 (en) 2006-08-04 2008-02-14 Astrazeneca Ab Human antibodies to ErbB 2
JP2021519334A (en) 2018-03-26 2021-08-10 クリア クリーク バイオ， インコーポレイテッド Compositions and Methods for Inhibiting Dihydroorotoic Acid Dehydrogenase

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015920A1 (en) * 1992-12-30 1994-07-21 Glaxo Group Limited Benzanilide derivatives as 5-ht1d-antagonists
WO1995015954A1 (en) * 1993-12-07 1995-06-15 Smithkline Beecham Plc Heterocyclic biphenylylamides useful as 5ht1d antagonists
WO2003032987A1 (en) * 2001-10-17 2003-04-24 Glaxo Group Limited 2'-methyl-5'-(1,3,4-oxadiazol-2-yl)-1,1'-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
WO2003033482A1 (en) * 2001-10-17 2003-04-24 Glaxo Group Limited Oxadiazolyl-biphenylcarboxamides and their use as p38 kinase inhibitors
WO2003032986A1 (en) * 2001-10-17 2003-04-24 Glaxo Group Limited 2' -methyl-5-(1,3,4-oxadiazol-2-yl)-1,1'-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2179254T3 (en) * 1996-11-04 2003-01-16 Bayer Cropscience Sa 1-PESTICIDE POLYARILPIRAZOLES.
PE20020506A1 (en) * 2000-08-22 2002-07-09 Glaxo Group Ltd PIRAZOLE DERIVATIVES FUSED AS PROTEIN KINASE INHIBITORS
GB0119863D0 (en) * 2001-08-14 2001-10-10 Cancer Res Campaign Tech DNA-PK inhibitors
GB0124939D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124934D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124941D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124933D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124928D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
MXPA04007838A (en) 2002-02-12 2004-10-15 Smithkline Beecham Corp Nicotinamide derivates useful as p38 inhibitors.
GB0209891D0 (en) 2002-04-30 2002-06-05 Glaxo Group Ltd Novel compounds
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015920A1 (en) * 1992-12-30 1994-07-21 Glaxo Group Limited Benzanilide derivatives as 5-ht1d-antagonists
WO1995015954A1 (en) * 1993-12-07 1995-06-15 Smithkline Beecham Plc Heterocyclic biphenylylamides useful as 5ht1d antagonists
WO2003032987A1 (en) * 2001-10-17 2003-04-24 Glaxo Group Limited 2'-methyl-5'-(1,3,4-oxadiazol-2-yl)-1,1'-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
WO2003033482A1 (en) * 2001-10-17 2003-04-24 Glaxo Group Limited Oxadiazolyl-biphenylcarboxamides and their use as p38 kinase inhibitors
WO2003032986A1 (en) * 2001-10-17 2003-04-24 Glaxo Group Limited 2' -methyl-5-(1,3,4-oxadiazol-2-yl)-1,1'-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors

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US7626055B2 (en) 2003-04-09 2009-12-01 Smithkline Beecham Corporation Biphenyl-carboxamide derivatives and their use as p38 kinase inhibitors
US7572790B2 (en) 2003-04-09 2009-08-11 Smithkline Beecham Corporation Biphenyl carboxylic amide p38 kinase inhibitors
EP2251333A1 (en) * 2003-07-25 2010-11-17 Novartis AG Biphenyl derivatives as P-38 kinase inhibitors
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US7700622B2 (en) 2003-07-25 2010-04-20 Novartis Ag p-38 kinase inhibitors
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US7754726B2 (en) 2003-07-25 2010-07-13 Novartis Ag Benzamide derivatives as p-38 kinase inhibitors
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US7683097B2 (en) * 2004-05-27 2010-03-23 Propharmacon Inc. Topoisomerase inhibitors
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US8598169B2 (en) 2004-12-28 2013-12-03 Kinex Pharmaceuticals, Llc Biaryl compositions and methods for modulating a kinase cascade
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