Title of Invention

"2-(2,4-DICHLOROPHENYLAMINO)-4-TRIFLUOROMETHYLPYRIMIDINE-5-CARBOXYLIC ACID (TETRAHYDROPYRAN-4-YLMETHYL)-AMIDE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF "

Abstract 2-(2,4-Dichlorophenylarnino)-4-trifluorornethylpyrirnidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide  or  a  pharmaceutically  acceptable  salt thereof of the kind such as herein described.
Full Text Compounds
The present invention relates to novel pyrimidine derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of diseases, particularly pain, which diseases are caused directly or indirectly by an increase or decrease in activity of the cannabinoid receptor.
Cannabinoids are a specific class of psychoactive compounds present in Indian cannabis (Cannabis sativa), including about sixty different molecules, the most representative being cannabinol, cannabidiol and several isomers of tetrahydrocannabinol. Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of China, where, 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecological disorders. These uses later became so established that, around 1850, cannabis extracts were included in the US Pharmacopaeia and remained there until 1947.
Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, euphoria, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects related to bronchial constriction, immunomodulation, and inflammation have also been observed. The capability of cannabinoids to reduce intraocular pressure and to affect respiratory and endocrine systems is also well documented. See e.g. L.E. Hollister, Health Aspects of Cannabis, Pharmacological Reviews. Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune responses and exhibit anti-inflammatory properties. Wirth et al., Antiinflammatory Properties of Cannabichrome, Life Science. Vol. 26, pp. 1991-1995, (1980).
In spite of the foregoing benefits, the therapeutic use of cannabis is controversial, both due to its relevant psychoactive effects (causing dependence and addiction), and due to manifold side effects that have not yet been completely clarified. Although work in this field has been ongoing since the 1940's, evidence indicating that the peripheral effects of cannabinoids are directly mediated, and not secondary to a CNS effect, has been limited by the lack of receptor characterisation, the lack of information concerning an endogenous cannabinoid ligand and, until recently, the lack of receptor subtype selective compounds.
The first cannabinoid receptor was found to be mainly located in the brain, in neural cell lines, and, only to a lesser extent, at the peripheral level. In view of its location, it was called the central receptor ("CB1"). See Matsuda et al., "Structure of a Cannabinoid Receptor and Functional Expression of the Cloned cDNA," Nature. Vol. 346, pp. 561-564 (1990. The second cannabinoid receptor ("CB2") was identified in the spleen, and was assumed to modulate the non psychoactive effects of the cannabinoids. See Munro et el., "Molecular Characterization of a Peripheral Receptor for Cannabinoids," Nature. Vol. 365, pp. 61-65 (1993).
Recently, some compounds have been prepared which are capable of acting as agonists on both the cannabinoid receptors. For example, use of derivatives of dihydroxypyrrole-(l,2,3-d,e)-l,4-benzoxazine in the treatment of glaucoma and the use of derivatives of 1,5-diphenyl-pyrazole as immunomodulators or psychotropic agents in the treatment of various neuropathologies, migraine, epilepsy, glaucoma, etc are known. See U.S. Patent No. 5,112,820
and EP S76357, respectively. However, because these compounds are active on both the CBl and CB2 receptor, they can lead to serious psychoactive effects.
The foregoing indications and the preferential localisation of the CB2 receptor in the immune system confirms a specific role of CB2 in modulating the immune and anti-inflammatory response to stimuli of different sources.
The total size of the patient population suffering from pain is vast (almost 300 million), dominated by those suffering from back pain, osteo-arthritic pain and post-operative pain. Neuropathic pain (associated with neuronal lesions such as those induced by diabetes, HTV, herpes infection, or stroke) occurs with lower, but still substantial prevalence, as does cancer pain.
The pathogenic mechanisms that give rise to pain symptoms can be grouped into two main categories:
- those that are components of inflammatory tissue responses (Inflammatory Pain);
- those that result from a neuronal lesion of some form (Neuropathic Pain). Chronic inflammatory pain consists predominantly of osteo-arthritis, chronic low back
pain and rheumatoid arthritis. The pain results from acute and on-going injury and/or inflammation. There may be both spontaneous and provoked pain.
There is an underlying pathological hypersensitivity as a result of physiological hyperexcitability and the release of inflammatory mediators which further potentiate this hyperexcitability. CB2 receptors are expressed on inflammatory cells (T cells, B cells, macrophages, mast cells) and mediate immune suppression through inhibition of cellular interaction/ inflammatory mediator release. CB2 receptors may also be expressed on sensory nerve terminals and therefore directly inhibit hyperalgesia.
The role of CB2 in immunomodulation, inflammation, osteoporosis, cardiovascular, renal and other disease conditions is now being examined. In light of the fact that cannabinoids act on receptors capable of modulating different functional effects, and in view of the low homology between CB2 and CBl, the importance of developing a class of drugs selective for the specific receptor sub-type is evident. The natural or synthetic cannabinoids currently available do not fulfil this function because they are active on both receptors.
Based on the foregoing, there is a need for compounds which are capable of selectively modulating the receptor for cannabinoids and, therefore, the pathologies associated with such receptors. Thus, CB2 modulators offer a unique approach toward the pharmacotherapy of immune disorders, inflammation, osteoporosis, renal ischemia and other pathophysiological conditions.
The present invention provides novel pyrimidine derivatives of formula (I) and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions containing these compounds or derivatives, and their use as CB2 receptor modulators, which are useful in the treatment of a variety of disorders.
The present invention further comprises a method for treating disease mediated by CB2 receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
The invention provides compounds of formula (I):

R6
(Formula Removed)
wherein: O
(I) Y is phenyl, optionally substituted with one, two or three substituents;
R1 is selected from hydrogen, Q* alkyl, C34 cycloalkyl and halosubstitutedCi-6 alkyl;
R2 is (CH2)mR3 where m is 0 or 1;
or R1 and R2 together with N to which they are attached form an optionally substituted 4-to 8- membered non-aromatic heterocyclyl ring;
R3 is an optionally substituted 4- to 8- membered non-aromatic heterocyclyl group, an optionally substituted C3.8 cycloalkyl group, an optionally substituted straight or branched CM0 alkyl, a Cs.7 cycloalkenyl or R5;
R4 is selected from hydrogen, C alkyl, C3.6 cycloalkyl, or halosubstitutedCi^ alkyl, COCH3,and S02Me;
Rsis
(Formula Removed)
wherein p is 0,1 or 2 and X is CH2 or O;
R6 is methyl, chloro or CHxFn wherein n is 1,2, or 3, x is 0,1 or 2 and n and x add up to
3;
R7 is OH, Q-salkoxy, NR^R1*, NHCOR9, NHS02R9, SOqR9;
R8,isHorCMalkyl;
R^isHorCfialkyl;
R9 is C1.6alkyl;
q is 0,1 or 2;
and pharmaceutically acceptable derivatives thereof.
In one particular embodiment Y is a substituted phenyl.
In one particular embodiment Y is substituted by 1 or 2 substituents. If mono-substituted, in one particular embodiment the substituent is in the 3 position. If di-substituted, in one particular embodiment the substituents are in the 2- and 4- positions.
When Y is substituted, the substituent or substituents are preferably selected from Cw alkyl, halosubstitutedCi.6 alkyl, Ci_6 alkoxy, a hydroxy group, a cyano group, halo, a Ci_ 6alkylsulfonyl group, -CONH2, -NHCOCH3 and -COOH. Furthermore the substituent or substituents can be selected from halosubstitutedCi_6 alkoxy, and S02NR8*R8b wherein R8* and R8b are as defined above. Additionally the substituent or substiuents can be SCi^alkyl.
In one particular embodiment Y is substituted by chloro, fluoro, bromo, cyano, CF3, methyl, CF30- or SCH3 and methoxy; more particularly halo, cyano or methoxy.
In one particular embodiment the compound of formula (I) is a compound of formula (la)

(Formula Removed)
wherein;
R1 is selected from hydrogen, Ci_6 alkyl, C3^cycloalkyl and halosubstitutedC].6 alkyl;
R2 is (CI^mR3 where m is 0 or 1;
or R1 and R2 together with N to which they are attached form a 4- to 8- membered non-aromatic ring selected from azetidinyl, pyrrolidinyl, morpholinyl, piperizinyl, piperidinyl, tetrahydropyridinyl, azapine, oxapine, azacyclooctanyl, azaoxacyclooctanyl and azathiacyclooctanyl any of which can be unsubstituted or substituted by one, two or three substituents selected from Ci.6 alkyl, C^ alkoxy, a hydroxy group, a cyano group, halo, sulfonyl group, methylsulfonyl, NR^R1*, NHCOCH3, (=0), and -CONHCH3.
R3 is 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide, thioxetanyl-s.s-dioxide, dioxalanyl, pyrrolidinyl, tefrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, azapine, oxapine, azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl, a C3.8 cycloalkyl group, a straight or branched CMO alkyl, a C5.7 cycloalkenyl or Rs, any of which can be unsubstitutedor substituted by one, two or three substituents selected from CM alkyl, Ci-e alkoxy, a hydroxy group, a cyano group, halo, sulfonyl group, methylsulfonyl, NRtaR8b, NHCOCH3, (=0),and-CONHCH3;
R10 is selected from Ci_6 alkyl, halosubstitutedCi^ alkyl, C\^ alkoxy, a hydroxy group, a cyano group, halo, a Ci.6alkyl sulfonyl group, -CONH2, -NHCOCH3, -COOH, halosubstitutedCw alkoxy, SC^alkyl and S02NR8,R8b;
R4is selected from hydrogen, Ci-e alkyl, C3^ cycloalkyl, or halosubstitutedCi^ alkyl, C0CH3,and S02Me;
Rsis
wherein p is 0,1 or 2 and X is CH2 or O;
R6 is methyl, chloro or CHxFn wherein n is 1,2, or 3, x is 0,1 or 2 and n and x add up to
R7 is OH, C^alkoxy, NR8*R8b, NHCOR9, NHS02R9, SOqR9;
R^isHorC-salkyl;
R8bisHorCwalkyl;
R9 is C^alkyl;
q is 0,1 or 2;
d is 0,1,2 or 3
and pharmaceutically acceptable derivatives thereof.
In one particular embodiment R1 is hydrogen.
In one particular embodiment R4 is Ci^alkyl or hydrogen, more preferably methyl or hydrogen even more preferably hydrogen.
Alternatively R1 and R2 together with N to which they are attached form an optionally substituted 5- or 6- membered non-aromatic heterocyclyl ring.
When R1 and R2 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl ring which is substituted, or when R3 is substituted, the substituent or substituents are preferably selected from: Q-6 alkyl, Cj.6 alkoxy, a hydroxy group, a cyano group, halo or a sulfonyl group. Additionally the optional substituent(s) can be choosen from methylsulfonyl, NR'V, NHCOCH3, (=0), or -CONHCH3.
In one particular embodiment R6 is CHxFn, for example CF3, CHFa, CH2F, more preferably CF3.
In one particular embodiment R5 is
(Formula Removed)
wherein p is 0,1 or 2;
In one particular embodiment R7 is OH.
In one particular embodiment R3 is an optionally substituted 4- to 8- membered non-aromatic heterocyclyl group, an optionally substituted C3.g cycloalkyl group, an optionally substituted straight or branched CMO alkyl or Rs.
In one particular embodiment when R3 is an optionally substituted C3.8cycloalkyl group or an optionally substituted 4- to 8- membered nonaromatic heterocyclyl, m is 1.
In one particular embodiment R3 is an optionally substituted Q^cycloalkyl group or an optionally substituted 4- or 6- membered nonaromatic heterocyclyl.
hi one particular emobodiment R1 and R2 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl ring which is selected from pyrrolidinyl, morpholinyl, piperizinyl, piperidinyl and tetrahydropyridinyl.
In one particular embodiment when R3 is nonaromatic heterocyclyl it is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl.
In one particular embodiment the compound of formula (I) is a compound of formula (lb)
(Formula Removed)
wherein;
R3 is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, a C3-8 cycloalkyl group, any of which can be unsubstitutedor substituted by one, two or three substituents selected from C^ alkyl, C^ alkoxy, a hydroxy group, a cyano group, halo, sulfonyl group, methylsulfonyl, NR8*R8b, NHCOCH3, (=0), and -CONHCH3;
R10 is selected from chloro, fluoro, bromo, cyano, CF3, methyl, CF3O- or SCH3 and methoxy;
R4is selected from hydrogen or methyl;
R8g is H or C^alkyl;
R^isHorCsalkyl;
m is 0 or 1
d is 0,1,2 or 3 and
and pharmaceutically acceptable derivatives thereof.
In one particular embodiment m is 1.
In one particular embodiment the compound of formula (I) is a compound of formula (Ic)
B4

(Formula Removed)
wherein;
R1 and R2 together with N to which they are attached form a 5- to 6- membered non-aromatic ring selected from pyrrolidinyl, morpholinyl, piperizinyl, piperidinyl and tetrahydropyridinyl, any of which can be unsubstituted or substituted by one, two or three substituents selected from C^ alkyl, Ci_6 alkoxy, a hydroxy group, a cyano group, halo, sulfonyl group, methylsulfonyl, NR^R*, NHCOCH3, (=0), and -CONHCH3.
R10 is selected from chloro, fluoro, bromo, cyano, CF3, methyl, CF30- or SCH3 and methoxy;
R4 is hydrogen or methyl;
R8" is H or Ci^alkyl;
R* is H or Cwalkyl;
disO, 1,2 or 3 and
and pharmaceutically acceptable derivatives thereof.
In one particular embodiment the compounds are selective for CB2 over CB1. Preferably the compounds are 100 fold selective i.e. compounds of formula (I) have an ECSO value at the cloned human cannabinoid CB2 receptor of at least 100 times the ECSO values at the cloned humna cannabinoid CB1 receptor or have less than 10% efficacy at the CB1 receptor.
The invention is described using the following definitions unless otherwise indicated.
The term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, salt of such ester or solvate of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
It will be appreciated by those skilled in the art that compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds, and that the compounds of formula (I) may be derivatised at more than one position.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiological acceptable salts thereof. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sri., 1977,66,1-19. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable nontoxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropyl amine, tromefliamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
Preferred examples of pharmaceutically acceptable salts include the ammonium, calcium, magnesium, potassium, and sodium salts, and those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.
The terms "halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
The term 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1 -dimethylethyl, or combinations thereof.
The term 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
The term 'cycloalkyl' means a closed non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
The term 'cycloalkenyl" as a group or part of a group means a non-aromatic ring, containing at least one CH=CH moiety for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
When R1 and R2 taken together with the N to which they are attached form an optionally substituted heterocyclyl ring, the ring may optionally contain 1,2,3 or 4 further heteroatoms. The ring may be saturated or unsaturated. Preferably the further heteroatoms are selected from oxygen, nitrogen or sulphur. An example of a 4- membered heterocyclyl ring is azetidinyl. Examples of 5- membered heterocyclyl rings include pyrrolidinyl. Examples of 6-membered heterocyclyl rings are morpholinyl, piperizinyl or piperidinyl. An additional example is tetrahydropyridinyl. Examples of a 7- membered heterocyclyl ring are azapine or oxapine. Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
When R3 is an optionally substituted non-aromatic heterocyclyl group, the ring may contain 1,2,3, or 4 heteroatoms. Preferably the heteroatoms are selected from oxygen, nitrogen or sulphur. Examples of 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide, thioxetanyl-s,s-dioxide. Examples of 5- membered heterocyclyl groups in this instance include dioxalanyl, pyrrolidinyl or tetrahydrofuranyl or tetrahydrothiophenyl. Examples of 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl or thiomorpholinyl-s,s-dioxide. An additional example is tetrahydropyridinyl. Examples of a 7- membered heterocyclyl ring are azapine or oxapine. Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, or thiacyclooctanyl.
In one particular embodiment compounds of the present invention can be selected from: 1 -[2-(3-Chlorophenylamino)-4-trifluoromemylpyrimidin-5-yl]-1 -piperidin-1 -ylmethanone; 2-(3-Oilorophenylamino)-4-trifluoromethylpyriniidine-5-carboxylicacidcyclopentylmethyl-amide;
l-[2-(3-Chlorophenylammo)-4-trifluoromemylpyrinu^
2-(3-C%lorophenylammo)-4-trifluoromemylpyrirnidine-S-carboxylic acid cyclohexylmethyl-amide;
2-Phenylamino-4-trifluoromethylpyrimidine-S-carboxylicacidcyclohexylmethyl-amide; l-[2-(2,3-Dichlorophenylamino)-4-1rifluoromemylpyrimidin-5-yl]-l-morpholm-4-yl-methanone; l-[2-(2,4-Dichlorophenylamino)-4-trifluoromemylpyrirnidin-5-yl]-l-moipholm-4-yl-me1hanone; l-[2-(3,4-Dichlorophenylainmo)-4-1rifluoromemylpy^^ l-[2-(2,5-Dichlorophenylainmo)-4-1rifluoromemylpyri^
l-[2-(3-Fluorophenylammo)-4-trifluoromemylpyrimidin-5-yl]-l-morpholm-4-yl-methanone; l-[2-(3-Bromophenylamino)-4-1rifluoromemylpyrimidm-5-yl]-l-moipholm-4-yl-methanone; 1 -[2-(3-Bromophenylammo)-4-1rifluoromemylpyrimidin-5-yl]-1 -piperidin-4-yl-methanone; l-[2-(3,5-DicMorophenylarmno)-4-1rifluoromem^
2-(3-CMorophenylammo)-4-trifluoromemylpyrimidin-5-carboxylic acid cyclopentylamide; 2-(2,3-Dichlorophenylaniino)-4-trifluoromethylpyrimidine-5-carboxylicacidcyclohexylmethyl-amide;
2-(2,4-IMchloTophenylamino)-4-1rifluoromemylpyrimidine-5-carboxylicacidcyclohexylmethyl-amide;
2-(3,4-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acidcyclohexylmethyl-amide;
2-(3,5-Dichloropheiiylainino)-4-trifluoromethylpyrimidine-5-carboxylicacidcyclohe^^ amide;
2-(3-Fliiorophenylan]ino)-4-1riflucTomethylpyrimidme-5-carboxylicacidcyclohexylmeihyl-amide;
2-(3-Bromophenylammo)-4-trifluoromethylpyrimidine-5-carboxylic acid cyclohexylmethyl-amide;
2-(2,6-DichlorophenyIarnmo)-4-trifluoromethylpyrimidine-5-carboxylicacidcyclohexyImethyl-amide;
2-(3-CWorophenylammo)^-1rifluorome1hylpyiinidmc-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide;
2-(3-C^lorophenylamino)-4-trifluoromethylpyrimidin-5-carboxylicacidcyclobutylamide; 2-(3-Fluorophenylamino)-4-trifluoromethylpyriinidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide;
2-(3-Bromophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide;
2-(2,3-DicMorophraylammo)-4-1rifluoromethyl^
ylmefbyl)-amide;
1 ^^(2,4-Dichlorophenylamino^4jjtrifluoromelhyJtori acid (tetrahydropyran-4-
L ylmethv])-n"'^ftr
2-(2,5-Dichlorophenylammo)-4-trifluoromethylpyrimidine-5-carboxylic acid (tetrahydropyran-4-
ylmethyl)-amide;
2-(3,5-DichloTophenylammo)-4-trifluorome1hylpyrimidine-5-carboxylic acid (tetrahydropyran-4-
ylmethyl)-amide;
2-(3-Methoxyphenylamino)-4-1rifluoromethylpyrimidine-5-carboxylic acid (tetrahydrcpyran-4-
ylmethyl)-amide;
2-(3-nuorophenylamino)-4-trifluoromethylpyrimidme-5-carboxylicacid(cyclopentylmethyl)-
amide;
2-(3-Bromophenylamino)^-1rifluoromemylpyrim
amide;
2-(2,3-Dichlorophenylammo)-4-1rifluoromemylpyrimidine-5-carboxylicacidcycloperitylmeihyl-
amide;
.2-(24-DicMoTOT?henylaxruno)-4-trifluoromelhyto^
•issz. ~ "" yvy -r-7^—
2-(2,5-Dichlon>phenylammo)-4-trifluoromethylpyrimidme-5-carboxylic acid cyclopentylmethyl-
amide;
2-(2,6-Dichlorophenylammo)-4-trifluoromemylpyriiriidine-5-carboxylic acid cyclopentylmethyl-
amide;
2-(3,4-IMcbJorophenylainmo)-4-trifluoromethylpyrimidine-5-carboxylic acid cyclopentylmethyl-
amide;
2-(3,5-DicUorophenylammo)^-trifluoromethylpyriinidine-5-carboxylicacidcyclopentylmethyl-
amide;
2-(3-Methoxyphenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acidcyclopentylmethyl-amide;
2-(3-Bromophenylamino)^-1rifluoromethylpyrimidine-5-carboxylicacidcyclobutylamide; 2-(2,3-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acidcyclobutylamide; 2-(2,4-Dichlorophenylamino)-4-1rifluoromethylpyrimidine-5-carboxylicacidcyclobutylamide; 2-(2,5-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acidcyclobutylamide; 2-(2,6-Dichlorophenylamino)^-trifluoromethylpyrimidine-5-carboxylic acidcyclobutylamide; 2-(3,5-DicUorophenylanimo)^-trifluoromemylpyrinudme-5-carboxylic acidcyclobutylamide; 2-(3-Memoxyphenylammo)^-trifluoromemylpyrimidine-5-carboxylic acidcyclobutylamide; 2-(3-ChlOTophenylanuno)^-trifluoromemylpyrimidme-5-carboxylicacidcyclobutylmethyl-amide;
2-(2s6-DichlcTophenylamino)^-trifluoromemyl-pyrimidine-5-carboxylicacid(tctrahydro-pyran-4-ylmethyl)-amide;
2-(3,4-DichlcTophenylamino)^-trifluoromemylpyrimidine-5-carboxylicacid(te1rahydro-pyran-4-ylmethyl)-amide;
l-[2-(3,4-Dichlorophenylammo)-4-trifluoromethylpyrimidin-5-yl]-l-(morpholin-4-yl)-methanone;
2-(3-Memoxyphenylamino)-4-trifluoromemyl-pyri^ amide;
2-(3-Chlorophenylammo)^-1rifluoromemyl-pyrimidine-5-carboxylicacid(l-hydroxy-cyclohexylmethyl)-amide;
2-(3-Bromophenylammo)^-trifluoromemyl-pyrimidine-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
2-(3-CbJoro-4-fluorophenylamino)-4-trifluoromethyl-pyrimidme-5-carboxylicacid cyclohexylmethyl-amide;
2-(3-CUoro-2-fluorophenylanimo)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide;
2-(5-QUOTC-2-fluorophenylanmo)-4-trifluoromemyl-pyriinidine-5-carboxylicacid cyclohexylmethyl-amide;
2-(3,5-Difluorophenylammo)-4-trifluoromethyl-pyrimidine-5-carboxylicacidcyclohexylmethyl-amide;
2-(4-CWoro-2-Mfluoromemylphenylammo)-4-trifluoTDmemyl-pyrimidme-5-carboxylicacid cyclohexylmethyl-amide;
2-(3-C^anophenylamino)-4-trifluoromethyl-pyrimidin-5-carboxylic acid cyclohexylmethyl-amide;
2-(3-Cyanophenylamino)-4-trifluoromethyl-pyrimidine-S-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide;
2-(3-C^anophenylammo)-4-trifluoromemyl-pyiimidine-S-carboxylicacidcyclopentylmethyl-amide;
2-(4-Cyanophenylammo)-4-trifluoromemyl-pyrimidine-S-carboxylic acid cyclohexylmethyl-amide;
2-(4-Cyanophenylammo)-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide;
2-(4-Cyanophenylamino)^-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-
amide;
2-(3-Memoxy-5-(trifluoromemyl)phenylaimno)-4-1rifluoromethyl-pyrimidine-5-carboxylic acid
(tetrahydropyran-4-ylmethyl)-amide;
2^3,5-Bis-trifluoromethyl-pheny]anuno)^-trifluoTcmeAyl-pyrimidine-5-carboxylicacid
(tctrahydropyran-4-ylmethyl)-amide;
2-(3-Bromo-5-(1rifluoromethyl)phenylamino)-4-1rifluoromethyl-pyrimidine-5-carboxylicacid
(tetrahydropyran-4-ylmethyl)-amide;
2-(3-Fluoro-5-(trifluoromethyl)phenylamino)-4-1rifluoromethyl-pyrimidine-5-carboxylic acid
(tetrahydropyran-4-ylmeihyl)-amide;
2-(2-Fluoro-3-(1rifluoTomethyl)phenylaimno)-4-trifluoTomethyl-pyrimidine-5-carboxylicacid
(te1rahydropyran-4-ylmethyl)-amide;
2-(2-Methylmio-3-(trifluoromemyl)phenylamino)-4-1rifl^^
(tetrahydropyran-4-ylmethyl)-amide;
2-(5-Chloro-2-methylphenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylicacid
(cyclopentylmethyl)-amide;
2-(3-CWoro^-me1hylphenylainino)-4-1rifluorome1hyl-pyrimidine-5-carboxylicacid
(tetrahydropyran-4-ylmethyl)-amide;
2-(3-CUoro-2-me1hylphenylamino)^1rifluorome1hyl-pyrimidine-5-carboxylicacid
(tetrahydropyran-4-ylmethyl)-amide;
2-(4-Chloro-3-methoxyphenyIamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid
(tetrahydropyran-4-ylmethyl)-amide;
2-(4-Chloro-3-me&ylphenylamino)^-trifluoromethyl-pyrimidine-5-carboxylicacid
(tetrahydropyran-4-ylmethyl)-amide;
2-(3-CWoTophenylamino)^-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-
methyl-amide;
2-(3-CMorophenylanimo)-4-trifluonmethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-methyl-
amideGW848546X;
2-(3-Chlorophenylamino)^trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-
methyl-amide GW848556X;
2-(5-ChloTO-2-fluorophenylamino)^trifluoromethyl-pyrimidine-5-carboxylicacid
cyclobutylmethyl-amide GW 849408X;
2-(3,5-Difluorophenylamino)-4-trifluoromeihyl-pyrimidine-5-carboxylic acidcyclobutylmethyl-
amide GW 849409X;
2-(3- cyclobutylmethyl-amide;
2-(3-Chloro-4-fluorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylicacid cyclobutylmethyl-amide GW 850297X;
2-(3-CMoro-2-fluorophenylaimno)-4-trifluoromemyl-pyriimdme-5-carboxylicacid cyclobutylmethyl-amide;
2-(3-Fluoro-4-trifluorome1hylphenylamino)-4-trifluorometiiyl-pyrimidine-5-carboxylicacid cyclobutylmethyl-amide;
2-(3-Chloro-4-cyanophenylamino)^trifluoromethyl-pyrimidine-5-carboxylicacid cyclobutylmethyl-amide GW 850315X;
2-(3-Fluorophenylamino)-4-trifluoromemyl-pyiiiudine-5-carboxyHcacidpyclobu1ylmethyl-amide GW 850629X;
2-(3-Bromophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide;
2-(2,3-Dichlorophenylammo)-4-trifluoTomemyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide;
2-(2,4-DicMorophenylanimo)-4-1iifluoromemyl-pyriimdme-S-carboxylic acid cyclobutylmethyl-amide GW 850632X;
2-(2,5-DicMorophenylammo)-4-1rifluoromemyl amide;
2-(2,6-Dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acidcyclobutylmethyl-amide GW 850634X;
2-(3,4-Diclilorophenylammo)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide GW 850635X;
2-(3-Memoxyphenylammo)-4-trifluoromemyl-pyrimid4ne-S-carboxylic acid cyclobutylmethyl-amide;
2-(3,5-Dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide GW 850642X;
2-(3-Bromophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylamide GW 853718X;
2-(2,4-DichloTophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylamide GW 853719X;
2-(3-Chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopropylamide GW 842159X:;
2-(3-Chlorophenylammo)-4-trifluoromethyl-pyrimidine-5-carboxylicacid (3,3-dimethylbutyl)-amideGW847199X;
2-(3-Chlorophenylammo)-4-trifluoromethyl-pyrimidine-5-carboxylicacidmethyl-(tetrahydro-pyran-4-ylmethyl)-amide GW 851353X:;
2-(2-Fluoro-3-cUoro-phenylamino)-4-trifluoromemyl-pyrimidine-5-carboxylicacid(tetrahydro-pyran-4-ylmethyl)-amide GW 851360X;
2-(2-nuoro-5-chloro-phenylamino)-4-trifluoromemyl-pyrimidine-5-carboxylicacid(tetrahydro-pyran-4-ylmethyl)-amide GW 851361X:; 2-(3,5-DifluorophenyIammo)-4-trifluoromemyl-pyri^ 4-ylmethyl)-amide GW 851362X:; 2-(4-Fluoro-3-chloro-phenylammo)-4-trifluorom pyran-4-ylmethyl)-amide GW 851363X:;
2-(4-Trifluoromemoxy-3-chloro-phenylamino)-4-trifluoromemyl-pyrmudme-5-carboxylicacid (tetrahydro-pyran-4-ylmeihyl)-amide GW 851365X:;
2-(4-Cyano-3-cMoro-phenylanuno)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-
pyran-4-ylmethyl)-amide GW 851366X:;
2-(4-Trifluoromethyl-3-fluoro-phenylainino)^-trifluoromethyl-pyrimidine-5-carboxylic acid
(tetrahydro-pyran-4-ylmethyl)-amide GW 851367X:; ' 2-(4-C^ano-3-cWoro-phenylamino)^1rifluoromethyl-pyrmudine-5-carboxylic acid
cyclopentylmethyl-amide GW 856462X:;
2-(2,4-Dichlon>-phenylaniino)^-trifluoTome1hyl-pyrimidine-5-carboxylic acid (1,1-dioxo-
hexahydro-1 Z6 - thiopyran-4-yl)-amide GW 864873X:;
2-(2,4-I^uorc-phenylamino)^-1rifluorcmethyl-pyrimidine-5-carboxylicacidcyclohexy ' amide GW865283X;
2-(2-Chloro^-fluoro-phenylamino)^-lrifluoromethyl-pyrimidine-5-carboxylicacid
cyclohexylmefliyl-amide GW 865286X:;
2-(2,4-Difliioro-phenylamino)^trifluoromethyl-pyrimidine-5-carboxylicacidc^clobutylmethyl-
amide GW 865291X:;
2-(2-Chloro^-fluoro-phenylamino)^-trifluoromethyl-pyrimidine-5-carboxylic acid
cyclobutylmethyl-amide GW 865294X:;
2-(2-Chloro^-bromo-phenylamino)^-1rifluoromethyl-pyrimidine-5-carboxylicacid
cyclohexylmethyl-amide GW 866677X:;
2-(2-Riioro^-cMoro-phenylammo)-4-trifluorome1hyl-pyrimidine-5-carboxylicacid
cyclohexylmethyl-amide GW 866678X:;
2-(2-Chloro-4-bromo-phenylammo)-4-1rifluoromethyl-pyrimidine-5-carboxylicacid
cyclobutylmethyl-amide GW 867720X:;
2-(2-Fluoro-4-chloro-phenylaim^o)-4-trifluoromethyl-pyrimidine-S-carboxylicacid
cyclobutylmethyl-amide GW 867723X:;
2-(2-Fluoro-4-bromo-phenylanu^o)-4-trifluoromemyl-pyrimidine-5-carboxylicacid
cyclobutylmethyl-amide GW 867725X:;
2-(2-Biomo-4-chloro-phenylammo)-4~lTifluon>memyl-pyrimidine-S-carboxylicacid
cyclobutylmethyl-amide GW 867780X:;
2-(2-Fluoro-4-bromo-phenylanuno)-4-trifluoromemyl-pyrimidine-S-carboxylic acid
cyclohexylmethyl-amide GW 867784X:;
2-(2-Fluoro-4-bromo-phenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-
pyran-4-ylmethyl)-amide GW 867785X:;
2-(2-Chloro-4-fluoro-phenylammo)-4-trifluoromefcyl-pyriniidine-5-carboxylic acid (tetrahydro-
pyran-4-ylmethyl)-amide;
2-(2-Chloro^-bromo-phenylammo)-4-trifluoromethyl-pyrimidine-5-carboxy]ic acid (tetrahydro-
pyran-4-ylmethyl)-amide;
2-(2-CWoio-4-cyano-phenylammo)-4-1rifluoromemyl-pyriniidine-5-carboxylic acid (tetrahydro-
pyran-4-ylmethyl)-amide;
2-(2-Chloro-4-1rifluoromethyl-phenylamino)-4-trifluoromethyl-pyrimid,me-S-carboxylic acid
(1etrahydro-pyran-4-ylmethyl)-amide;
2-(2-Chloro-4-cyano-phenylamino)-4-lrifluorome1hyl-pyriimd^e-5-carboxylicacid
cyclohexylmethyl-amide;
2-(2-Bromo^-chloro-phenylamino)^-trifluoromethyl-pyiimidine-5-carboxylicacid
cyclohexylmethyl-amide;
2-(2-Bromo-4-chloro-phenylamino)^-trifluoromethyl-pyrimidine-5-carboxylicacid(tetrahydro-
pyran-4-ylmethyl)-amide; GW 870000X: J 2-(3-Bromophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopropylmethyl-
amide;
2-(2,4-Dichlorophenylamino)^1rifluoromethyl-pyrimidme-5-carboxylicacidcyclo
amide GW 871909X:;
2-(2,3-Difluorophenylammo)^trifluoromethyl-pyrimidine-5-carboxylicacidcyclohexylmethyl-) amide;
2-(2-Fluoro-3-trifluoromemyl-phenylamino)-4-trifluoromemyl-pyriinidine-5-carboxylicacid
cyclohexylmethyl-amide;
2-(2-QUoro-4-memylphenylamino)-4-trifluoromemyl-pyrimidine-5-carboxylicacid
cyclohexylmethyl-amide;
2-(4-Chloro-3-methoxyphenylamino)-4-trifluoTomethyl-pyrimidine-5-carboxylic acid
cyclohexylmethyl-amide;
2-(5-Oiloro-2-memylphenylamino)-4-1rifIuo«>memyl-pyrimidine-5-carboxylic acid
cyclohexylmethyl-amide;
2-(3-Chloro-4-fluoro-phenylamino)-4-1rifluoromethyl-pyrimidine-5-carboxylicacid l cyclopentylmethyl-amide GW 848814X;
2-(3-C^loro-2-fluoTO-phenylamino)-4-1rifluoromemyl-pyrimidme-5-carboxylicacid
cyclopentylmethyl-amide GW 848815X;
2-(2- cyclopentylmethyl-amide GW 871627; i GW 842170X 2-(3,4-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid
(tetrahydro-pyran-4-ylmethyl)-amide;
2-(Phenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-amide GW
855149X
2-(2-Fluoro-3-trifluoromemyl-phenylammo)-4-trifluoromethyl-pyrimidine-5-carboxylicacid
cyclobutylmethyl-amide; GW 873896X
2-(2-Trifluoromemyl-4-bromo-phenylammo)-4-trifluoromemyl-pyrimidine-5-carboxylicacid
(tetrahydro-pyran-4-ylmethyl)-amide; GW 874234X
2-(3-Chlorophenylamino)-4-1rifluoromethyl-pyrimidine-5-carboxylicacid(tetrahydrothiopyran-4-
ylmethyl) amide; GW875763X
2-(2,4-DicMorophenylamino)-4-trifluoFomethyl-pyrimidine-S-carboxylicacid
(tetrahydrothiopyran-4-ylmethyl) amide;
and pharmaceutically acceptable derivatives thereof.
Compounds of formula (I) can be prepared as set forth in the following schemes:
Scheme 1:
(Scheme Removed)
sherein L is a leaving group, for example halo, PG is a protecting group for example methyl, ethyl or benzyl, X is a leaving group for example halo, OCi^alkyl, e.g. O-methyl or O-ethyl or
NRaRb wherein Ra and Rb are independently selected from Ci.6 alkyl, e.g. methyl, and R1, R?, R4, R6 and Y are as defined for compounds of formula (I). Scheme 2:
(Formula Removed)
wherein Li and L2 are leaving groups independently selected from halo, for example chloro, R1, R2, R4, R6 and Y are as defined for compounds of formula (I).
It is to be understood that the present invention encompasses all isomers of compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formulas I and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, nC, ,4C, 18F, 123I and 12SI.
Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, I4C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. nC and 8F isotopes are particularly useful in PET (positron emission tomography), and ,2SI isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
The compounds of the invention bind selectively to the CB2 receptor, and are therefore useful in treating CB2 receptor mediated diseases.
In view of their ability to bind to the CB2 receptor, the compounds of the invention may be useful in the treatment of the disorders that follow. Thus, the compounds of formula (I) may be useful as analgesics. For example they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteo-arthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
The compounds of the invention may also be useful disease modification or joint structure preservation in multiple sclerosis, rheumatoid arthritis, osteo-arthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
The compounds of the invention may be particularly useful in the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; nonspecific lower back pain; multiple sclerosis pain; fibromyalgia; HTV-related neuropathy; postherpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
The compounds of formula (I) may also be useful in the treatment of fever.
The compounds of formula (I) may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac'disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastro esophageal reflux disease); organ
transplantation; other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, tendinitis, bursitis, and Sjogren's syndrome.
. The compounds of formula (I) are also useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation. The compounds of formula (I) are also effective in increasing the latency of HTV infection.
The compounds of formula (I) are also useful in the treatment of diseases of abnormal platelet function (e.g. occlusive vascular diseases).
The compounds of formula (I) are also useful for the preparation of a drug with diuretic action.
The compounds of formula (I) are also useful in the treatment of impotence or erectile dysfunction.
The compounds of formula (I) are also useful for attenuating the hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSATD's) and cyclooxygenase-2 (COX-2) inhibitors.
The compounds of formula (I) are also useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment. The compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and neuroinflamation.
The compounds of formula (I) are also useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
The compounds of formula (I) are also useful in the treatment of tinnitus.
The compounds of formula (I) are also'useful in the treatment of psychiatric disease for example schizophrenia, depression (which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc), anxiety disorders (including generalised anxiety disorder and social anxiety disorder), panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnesic disorders and age-associated memory impairment, disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sexual dysfunction, sleep disorders (including disturbances
of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse
of drugs such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine
(phencyclidine-like compounds), opiates (e.g. heroin, morphine), amphetamine or
amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof.
The compounds of formula (I) are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence - inducing agent. Examples of dependence inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
The compounds of formula (I) are also useful in the treatment of kidney dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer.
It is to be understood that references to treatment includes both treatment of established symptoms and prophylactic treatment unless explicitly stated otherwise.
According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.
According to another aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by the activity of cannabinoid 2 receptors.
According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from a condition which is mediated by the activity of cannabinoid 2 receptors which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
According to a further aspect of the invention we provide a method of treating a human or animal subject suffering from an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof. Preferably the pain is selected from inflammatory pain, viseral pain, cancer pain, neuropathic pain, lower back pain, muscular sceletal, post operative pain, acute pain and migraine. More preferably the inflammatory pain is pain associated with rheumatoid arthritis or osteoarthritis.
According to another aspect of the invention is provided the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment or prevention of a condition such as an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis
Preferably the pain is selected from inflammatory pain, viseral pain, cancer pain, neuropathic pain, lower back pain, muscular sceletal, post operative pain, acute pain and migraine. More preferably the inflammatory pain is pain associated with rheumatoid arthritis or osteoarthritis.
In order to use a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention is provided a pharmaceutical composition comprising a compound of
formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
As used herein, "modulator" means both antagonist, full or partial agonist and inverse agonist. Inone embodimentof the present modulators are agonists.
The term "treatment" or "treating" as used herein includes the treatment of established disorders and also includes the prophylaxis thereof. The term " prophylaxis" is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrence of symptoms in an afflicted subject and is not limited to complete prevention of an afflication.
Compounds of formula (Q and their pharmaceutically acceptable derivatives may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parentarally, sub-lingually, dermally, intranasally, transdermally, rectally, via inhalation or via buccal administration.
Compositions of formula (I) and their pharmaceutically acceptable derivatives which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of a compound or derivative in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichloro'difluoromethane or trichlorofluoromethane.
A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable derivative thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
Typical dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
Each dosage unit for oral administration contains suitably from O.Olmg/Kg to 500 mg/Kg for example 0.1 mg to 500 mg/Kg, and preferably from 0.01 mg to 100 mg/Kg for example lmg/Kg to lOOmg/Kg, and each dosage unit for parenteral administration contains suitably from
0.1 mg to 100 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable derivative thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 5.0% of a compound of formula 00.
The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable derivative thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable derivative thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
It may be advantageous to prepare the compounds of the present invention as nanoparticles. This may improve the oral bioavailability of the compounds. For the purposes of the present invention "nanoparticulate" is defined as solid particles with 50% of the particles having a particle size of less than lpm, more preferably less than 0.75um
The particle size of the solid particles of compound Q) may be determined by laser diffraction. A suitable machine for determining particle size by laser diffraction is a Lecotrac laser particle size analyser, using an HELOS optical bench fitted with a QUDflEL dispersion unit.
Numerous processes for the synthesis of solid particles in nanoparticulate form are known. Typically these processes involve a milling process, preferably a wet milling process in the presence of a surface modifying agent that inhibits aggregation and/or crystal growth of the nanoparticles once created. Alternatively these processes may involve a precipitation process, preferably a process of precipitation in an aqueous medium from a solution of the drug in a nonaqueous solvent.
Accordingly, in a further aspect, the present invention provides a process for preparing compound (I) in nanoparticulate form as hereinbefore defined, which process comprises milling or precipitation.
Representative processes for the preparation of solid particles in nanoparticulate form are described in die patents and publications listed below.
U.S. Patent No. 4,826,689 to Violanto & Fischer, U. S. Patent No. 5,145,684 to Liversidge et al U.S Patent No. 5,298,262 to Na & Rajagopalan, U.S. Patent No. 5,302,401 Liversidge et al U.S. Patent No. 5,336,507 to Na & Rajagopalan, U.S. Patent No. 5,340,564 to Illig & Sarpotdar U.S. Patent No. 5,346,702 to Na Rajagopalan, U.S. Patent No. 5,352,459 to Hollister et al U.S. Patent No. 5,354,560 to Lovrecich, U.S. Patent No. 5,384,124 to Courteille et al, U.S. Patent No. 5,429,824 to June, U.S. Patent No. 5,503,723 to Ruddy et al, U.S. Patent No. 5,510 118 to Bosch et al, U.S. Patent No. 5,518 to Bruno et al, U.S. Patent No. 5,518,738 to Eickhoff et al, U.S. Patent No. 5,534,270 to De Castro, U.S. Patent No. 5,536,508 to Canal et al, U.S. Patent No. 5,552,160 to Liversidge et al, U.S. Patent No. 5,560,931 to Eickhoff et al, U.S. Patent No. 5,560,932 to Bagchi et al, U.S. Patent No. 5,565,188 to Wong et al, U.S. Patent No. 5,571,536 to Eickhoff et al, U.S. Patent No. 5,573,783 to Desieno & Stetsko, U.S Patent No. 5,580,579 to Ruddy et al, U.S. Patent No 5,585,108 to Ruddy et al, U.S. Patent No. 5,587,143 to Wong, U.S. Patent No. 5,591456 to Franson et al, U.S. Patent No. 5,622,938 to Wong, U.S. Patent No 5,662,883 to Bagchi et al, U.S. Patent No. 5,665,331 to Bagchi et al, U.S Patent No. 5,718,919 to
Ruddy et al, U.S. Patent No. 5,747,001 to Wiedmann et al, WO93/25190, W096724336, WO 97/14407, WO 98/35666, WO 99/65469, WO 00/18374, WO 00/27369, WO 00/30615 and WO 01/41760.
Such processes may be readily adapted for the . preparation of compound (I) in nanoparticulate form. Such processes form a further aspect of the invention.
The process of the present invention preferably uses a wet milling step carried out in a mill such as a dispersion mill in order to produce a nanoparticulate form of the compound. The present invention may be put into practice using a conventional wet milling technique, such as that described in Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling" p.45 (1986).
In a further refinement, WO02/00196 (SmithKline Beecham pic) describes a wet milling procedure using a mill in which at least some of the surfaces are made of nylon (polyamide) comprising one or more internal lubricants, for use in the preparation of solid particles of a drug substance in nanoparticulate form.
In another aspect the present invention provides a process for preparing compounds of the invention in nanoparticulate form comprising wet milling a suspension of compound in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising a lubricated nylon, as described in WO02/00196.
The suspension of a compound of the invention for use in the wet milling is typically a liquid suspension of the coarse compound in a liquid medium. By "suspension" is meant that the compound is essentially insoluble in the liquid medium. Representative liquid media include an aqueous medium. Using the process of the present invention the average particle size of coarse compound of the invention may be up to 1mm in diameter. This advantageously avoids the need to pre-process the compound.
In a further aspect of the invention the aqueous medium to be subjected to the milling comprises compound (0 present in from about 1% to about 40% w/w, preferably from about 10% to about 30% w/w, more preferably about 20% w/w.
The aqueous medium may further comprise one or more pharmaceutically acceptable water-soluble carriers which are suitable for steric stabilisation and the subsequent processing of compound (I) after milling to a pharmaceutical composition, e.g. by spray drying. Pharmaceutically acceptable excipients most suitable for steric stabilisation and spray-drying are surfactants such as poloxamers, sodium lauryl sulphate and polysorbates etc; stabilisers such as celluloses e.g. hydroxypropylmethyl cellulose; and carriers such as carbohydrates e.g. maimitol.
In a further aspect of the invention the aqueous medium to be subjected to the milling may further comprise hydroxypropylmethyl cellulose (HPMC) present from about 0.1 to about 10% w/w.
The process of the present invention may comprise the subsequent step of drying compound of the invention to yield a powder.
Accordingly, in a further aspect, the present invention provides a process for preparing a pharmaceutical composition contain a compound of the present invention which process comprises producing compound of formula (I) in nanoparticulate form optionally followed by drying to yield a powder.
A further aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable deriviate thereof in which the
compound of formula (I) or a pharmaceutically acceptable deriviate thereof is present in solid particles in nanoparticulate form, in admixture with one or more pharmaceutically acceptable carriers or excipients.
By "drying" is meant the removal of any water or other liquid vehicle used during the process to keep compound of formula (I) in liquid suspension or solution. This drying step may be any process for drying known in the art, including freeze drying, spray granulation or spray drying. Of these methods spray drying is particularly preferred. All of these techniques are well known in the art. Spray drying/fluid bed granulation of milled compositions is carried out most suitably using a spray dryer such as a Mobile Minor Spray Dryer [Niro, Denmark], or a fluid bed drier, such as those manufactured by Glatt, Germany.
In. a further aspect the invention provides a pharmaceutical composition as hereinbefore defined, in the form of a dried powder, obtainable by wet milling solid particles of compound of formaula (I) followed by spray-drying the resultant suspension.
Preferably, the pharmaceutical composition as hereinbefore defined, further comprises HPMC present in less than 15% w/w, preferably in the range 0.1 to 10% w/w.
The CB2 receptor compounds for use in the instant invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib or COX-189; 5-lipoxygenase inhibitors; NSAID's, such as aspirin, diclofenac, indomethacin, nabumetone or ibuprofen; leukotriene receptor antagonists; DMARD's such as methotrexate; adenosine Al receptor agonists; sodium channel blockers, such as lamotrigine; NMDA receptor modulators, such as glycine receptor antagonists; gabapentin and related compounds; tricyclic antidepressants such as amitriptylme; neurone stabilising antiepileptic drugs; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; SHTi agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletnptan, frovatriptan, almotriptan or rizatriptan; EPi receptor ligands, EP4 receptor ligands; EP2 receptor ligands; EP3 receptor ligands; EP4 antagonists; EP2 antagonists and EP3 antagonists; bradykinin receptor ligands and vanilloid receptor ligand, antirheumatoid arthritis drugs, for example anti TNF drugs e.g. enbrel, remicade, anti-EL-1 drugs, or DMARDS e.g. leflunamide. When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995 US5.633.272; US5.466.823, US6.310.099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, WO99/12930, WO00/26216, WO00/52008, WO00/38311, WO01/58881 andWO02/18374.
The compound of the present invention may be administered in combination with other -active substances such as 5HT3 antagonists, NK-1 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic1 antidepressants and/or dopaminergic antidepressants.
Suitable 5HT3 antagonists which may be used in combination of the compound of the inventions include for example ondansetron, granisetron, metoclopramide.
Suitable serotonin agonists which may be used in combination with the compound of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compound of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRIs which may be used in combination with the compound of the invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
It will be appreciated mat the compounds of any of the above combinations or compositions may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
Determination of cannabinoid CB1 Receptor Agonist Activity
The cannabinoid CB1 receptor agonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.
Experimental Method
Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CB1 receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23. This cassette consisted of DNA sequence encoding the human CB1 receptor flanked by the yeast GPD promoter to the 5' end of CB1 and a yeast transcriptional terminator sequence to the 3' end of CB1. MMY23 expresses a yeast/mammalian chimeric G-protein alpha submit in which the C-terminal 5 amino acids of Gpal are replaced with the C-terminal S amino acids of human Gcci3 (as described in Brown et al. (2000), Yeast 16:11-22). Cells were grown at 30°C in liquid Synthetic Complete (SC) yeast media (Guthrie and Fink (1991), Methods in Enzymology, Vol. 194) lacking uracil, tryptophan, adenine and leucine to late logarithmic phase (approximately 6 OD6oo/ml).
Agonists were prepared as 10 mM stocks in DMSO. EC50 values (the concentration required to produce 50% maximal response) were estimated using dilutions of between 3- and 5-fold (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume)

were transferred into black, clear bottom, microtitre plates from NUNC (96- or 3 84-well). Cells were suspended at a density of 0.2 ODeoofml in SC media lacking hisudine, uracil, tryptophan, adenine and leucine and supplemented with lOmM 3-aminotriazole, 0.1M sodium phosphate pH 7.0, and 20uM fluorescein di-|3-D-glucopyranoside (FDGlu). This mixture (SOul per well for 384-well plates, 200ul per well for 96-well plates) was added to agonist in the assay plates (Multidrop 384, Labsystems). After incubation at 30°C for 24 hours, fluorescence resulting from degradation of FDGlu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist-stimulated cell growth, was determined using a Spectrofluor microtitre plate reader (Tecan; excitation wavelength: 485nm; emission wavelength: 535nm). Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value. Efficacy (Ew) was calculated from the equation
Enax = MaXfcompouaj x] - Mh^compound X] / MaX[HU210]" MinpnniO] X 100%
where Max[compouI1dx] and Min[conipoundx] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and Maxpamo] and Minpnoio] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l ,1'-Dimethylheptyl)-6a,7,10,1 Oa-tetrahydro-1 -hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol (HU210; available from Tocris). Equieffective molar ratio (EMR) values were calculated from the equation
EMR = EC50 [compound X] / EC50 [HU210]
Where EC50 [compound x] is the EC50 of compound X and ECSO[HU2io]is the ECsoof HU210. Compounds of the Examples tested according to this method had ECSo values >2000nM and/or efficacy values of Determination of cannabinoid CB2 Receptor Agonist Activity
The cannabinoid CB2 receptor agonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.
Experimental Method
Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CB2 receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23. This cassette consisted of DNA sequence encoding the human CB2 receptor flanked by the yeast GPD promoter to the 5' end of CB2 and a yeast transcriptional terminator sequence to the 31 end of CB2. MMY23 expresses a yeast/mammalian chimeric G-protein alpha subunit in which the C-terminal 5 amino acids of Gpal are replaced with the C-terminal 5 amino acids of human Gai3 (as described in Brown et al. (2000), Yeast 16:11-22). Cells were grown at 30°C in liquid Synthetic Complete (SC) yeast media (Guthrie and Fink (1991), Methods in Enzymology, Vol. 194) lacking uracil, tryptophan, adenine and leucine to late logarithmic phase (approximately 6 ODoWml).
Agonists were prepared as 10 mM stocks in DMSO. EC50 values (the concentration required to produce 50% maximal response) were estimated using dilutions of between 3- and 5-fold (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black, clear bottom, microtitre plates from NUNC (96- or 3 84-well). Cells were suspended at a density of 0.2 OD^o/ml in SC media lacking histidine, uracil, tryptophan,
adenine and leucine and supplemented with lOmM 3-aminotriazole, 0.1M sodium phosphate pH 7.0, and 20M fluorescein di-(3-D-glucopyranoside (FDGlu). This mixture (SOul per well for 384-well plates, 200ul per well for 96-well plates) was added to agonist in the assay plates (Multidrop 384, Labsystems). After incubation at 30°C for 24 hours, fluorescence resulting from degradation of FDGlu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist-stimulated cell growth, was determined using a Spectrofluor microtitre plate reader (Tecan; excitation wavelength: 485nm; emission wavelength: 535nm). Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value. Efficacy (Emu) was calculated from the equation Enax ** Max[comp0undx] - Min[conv)U„dx] / Maxpnnio] - Min[HU2io] x 100% where Max[compoundx] and Min[compoun EMR = ECso [compound X] / EC50 [HU210]
Where EC50 [compound x] is the ECS0 of compound X and EC50 pnnio] is the EC50 of HU210.
Compounds of Examples 1 to 23,31 to 56,68,163 - 256 tested according to this method had ECso values 20 to 300 nM and efficacy values of >50% at the cloned human cannabinoid CB2 receptor.
Compounds of Examples 24 to 30 and 73-113, and 257-259 tested according to this method had EC50 values 300 to lOOOnM or efficacy values of > 50% at the cloned human cannabinoid CB2 receptor.
Compounds of Examples 57-67,69-72,114-162, and 260-265 tested according to this method had ECS0 values > lOOOnM or efficacy values of The following examples are illustrative, but not limiting of the embodiments of the present invention.
All NMR experimental data was recorded at 400MHz.
Conditions. Hardware, and Software used for Mass-directed Autopurification
Hardware
Waters 600 gradient pump, Waters 2700 Sample Manager, Waters Reagent Manager, Micromass
ZMD mass spectrometer, Gilson 202 - fraction collector, Gilson Aspec - waste collector.
Software
Micromass Masslynx version 3.5
Column
The column used is typically a Supelco ABZ+ column whose dimensions are 10mm internal
diameter by 100mm in length. The stationary phase particle size is 5um.
Solvents
A. Aqueous solvent = Water +0.1% Formic Acid
B. Organic solvent = MeCN: Water 95:5 +0.05% Formic Acid
Make up solvent = MeOH: Water 80:20 +50mMol Ammonium Acetate Needle rinse solvent = MeOH: Water: DMSO 80:10:10
Methods
Five methods are used depending on the analytical retention time of the compound of interest.
They all have a flow rate of 20ml/min and a 15-minute runtime, which comprises of a 10-minute
gradient followed by a 5-minute column flush and re-equilibration step.
Method 1 MDP 1.5-2.2 = 0-30%B
Method 2 MDP 2.0-2.8 = 5-30% B
Method 3 MDP 2.5-3.0 = 15-55%B
Method 4 MDP 2.8-4.0 = 30-80% B
Method 5 MDP 3.8-5.5 = 50-90% B
Reference Example 1: 2-(3-CMorophenvlammo)-4-trifluoromemvlp\TTmidine-5-carboxviic acid benzvlamide (GW8262253Q
(a). To a solution of benzyl 2-chloro-4-trifluoromethylpyrimidine-5-carboxylate (0.50 g, ex Maybridge) in 1,4-dioxan (5 ml) was added 3-chloroaniline (0.85 ml) and the solution stirred at room temperature for 15 h. 1,4-Dioxan was removed under reduced pressure and ethyl acetate (15 ml) added. The solution was washed sequentially with 2N hydrochloric acid (10 ml) and water (3 x 10 ml), dried (MgS04), evaporated and triturated with hexane to afford benzyl 2-(3-cWorophenylammo)-4-trifluoromemylpyrimidine-5-carboxylate (524 mg, GW824019X). NMR (DMSO-d6) F1577 6 5.35 (2H, s), 7.14 (1H, d), 7.35-7.45 (6H, m), 7.68 (1H, m), 7.98 (1H, s), 9.13 (lH,s), 10.95 (lH,s). LC/MS CF100425-1, t = 3.70 min, \MH+] 408 and 410.
(b). To a solution of benzyl 2-(3-cUorophenylammo)-4-trifluoromethyl-pyrimidine-5-carboxylate (0.50 g) in ethanol (15 ml) was added a solution of potassium hydroxide (205 mg) in ethanol (10 ml) and the solution stirred at reflux for 15 h. Ethanol was removed under reduced pressure and water (15 ml) added. The solution was washed with ether and concentrated hydrochloric acid added to adjust the acidity to pH 1. The precipitated solid was filtered, washed with water and dried in vacuo at 50°C to afford 2-(3-cMorophenylammo)-4-trifluoromethylpyrimidine-5-carboxylic acid (366 mg, GW836224X).
NMR (DMS0-d6) F1711 8 7.49 (IH, d), 7.71 (IH, t), 7.98 (IH, d), 8.33 (IH, s), 9.42 (IH, s),
11.15 (lH,s), 14.0 (lH,brs).
LC/MS CF100569-1, t = 3.44 min, [MH+] 318 and 320.
(Figure Removed)
(c). To a solution of 2-(3-chlorophenylaniino)^-trifluoromethylpyrimidine-5-carboxylic acid (35 mg) in dimethylformamide (2 ml) was added successively N-ethylmorpholine (42 ul), benzylamine (15ul), 1-hydroxybenzotriazole hydrate (23 mg) and l-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (25 mg). The solution was stirred for 3 h and allowed to stand overnight. Dimethylformamide was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 5% sodium bicarbonate solution (2.5 ml), water (2.5 ml), 5% citric acid solution (2.5 ml) and brine (2 x 2.5 ml), dried (MgS04) and evaporated to afford the title compound (45 mg).
Example 1: l-r2-(3-ChlorophenvlaminoV4-1rifluoromethvlpvrimidin-5-vl1-l-piperidin-l-vlmethanone (GW833967X)
NMR (DMSO-d6) F1920 8 4.47 (2H, d), 7.10 (IH, d), 7.25 (IH, m), 7.36 (5H, m), 7.69 (IH, d), 7.98 (IH, s), 8.89 (IH, s), 9.12 (IH, t), 10.65 (IH, s). LC/MS CF100768-1, t = 3.23 min, [MH+] 407 and 409.
(Figure Removed)
In a manner similar to Reference Example 1(c) . 2-(3-chlorophenylamino)-4-
trifluoromethylpyrimidine-5-carboxylic acid (35 mg) and piperidine (13 ul) afforded the title
compound (38 mg).
NMR (DMSO-d6) F3513 8 1.3-1.65 (6H, m), 3.28 (2H, s), 3.6 (2H, br s), 7.10 t), 7.68 (IH, d), 7.96 (IH, s), 8.78 (IH, s), 10.55 (IH, s).
LC/MS CF102572-1, t = 3.63 min, [MH4! 385 and 387.
Example 2:2-f3-Chlorophenvlammo)-4-trifluoromemvlpvrmiidine-S-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
Li a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (100 mg) and cyclopentylmethylamine hydrochloride (63 mg, prepared as described in Kelley et al., J. Med. Chem., 40,3207, (1997) ) afforded the title compound (80 mg). NMR (DMSO-d6) 8 1.20-1.26 (2H, m), 1.48-1.67 (4H, m), 1.67-1.73 (2H, m), 2.06-2.10 (IH, quintuplet), 3.15-3.18 (2H, t), 7.09 (IH, dt), 7.37 (IH, q), 7.67 (IH, d), 7.96 (IH, d), 8.60-8.63 (IH, t), 8.79 (IH, s), 10.60 (IH, s). LC/MS, t = 3.73 min, [MH4] 399.
Example 3: l-r2-(3-ChlorophenvlammoM-trifluoromemvlpvrimidin-5-vl1-l-morpholin-4-vl-methanone (GW833968X)
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-
trifluoromethylpyrimidine-5-carboxylic acid (35 mg) and morpholine (11.5 }il) afforded the title
compound (43 mg).
NMR (DMSO-d6) F3514 S 3.4-3.75 (8H, m), 7.10 (IH, d), 7.38 (IH, t), 7.68 (IH, d), 7.98 (IH,
s), 8.80 (IH, s), 10.60 (IH, s).
LC/MS CF102580-1, t = 3.29 min, [MH+] 387 and 389.
Example 4:2-f3-Chlorophenvlamino')-4-1rifluoromethvlpvrimidine-5-carboxvlic acid cvclohexvlmethvlamide fGW8348473Q
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (35 mg) and cyclohexanemethylamine (15 mg) afforded the title compound (27 mg).
NMR (DMSO-d6) F3834 S 0.85-1.0 (2H, m), 1.1-1.3 (3H, m), 1.5 (IH, m), 1.55-1.8 (5H, m), 3.06 (2H, t), 7.09 (IH, d), 7.37 (IH, t), 7.68 (IH, d), 7.97 (IH, s), 8.58 (IH, t), 8.79 (IH, s), 10.6 (IH, s).
LC/MS CF102892-1, t = 3.87 min, [MH+] 413 and 415.
Example 5:2-Phenvlamino-4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclohexvl-methvl-amide(GW835126»
In a manner similar to Reference Example 1(c) 2-phenylamino-4-trifluoromethylpyrimidine-5-
carboxylic acid (32 mg) and cyclohexanemethylamine (15 mg) afforded the title compound (33
mg).
NMR (DMSO-d6) F3834 5 0.85-1.0 (2H, m), 1.05-1.3 (3H, m), 1.5 (IH, m), 1.55-1.8 (5H, m),
3.08 (2H, t), 7.06 (IH, d), 7.35 (2H, t), 7.76 (2H, d), 8.56 (IH, t), 8.74 (IH, s), 10.4 (IH, s).
LC/MS CF102995-2, t = 3.66 min, [MH+] 379.
Example 6: l-r2-(2.3-DichloTophenvlamino)-4-trifluoromethvlpvrimidin-5-vl"|-l-morpholin-4-vl-methanone (GW8361833Q
ci In a manner similar tp Reference Example 1(c) 2-(2,3-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (24 mg) and morpholine (10 |xl) afforded the title compound (17 mg).
NMR (DMSO-d6) F4055 5 3.4-3.8 (8H, m), 7.40 (IH, t), 7.54 (IH, d), 7.60 (IH, d), 8.78 (IH, s), 10.15 (lH,s). LC/MS CF103118-1, t = 3.32 min, [MH+] 421 and 423.
In a manner similar to Reference Example 1(c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) and morpholine (10 fil) afforded the title compound (31 mg).
Example 7: l-r2-f2.4-Dichlorophenvlamino)-4-trifluoromemvlpvrimidin-5-vl|-l-morpholin-4-vl-methanone (GW836185X)
(Figure Removed)
NMR (DMSO-d6) F4130 8 3.3-3.8 (8H, m), 7.52 (1H, d of d), 7.68 (1H, d), 7.76 (IH, d), 8.73
(1H, s), 10.05 (IH, s).
LC/MS CF103090-1, t = 3.37 min, [MH+] 421 and 423.
Example 8: l-r2-(3.4-I^chlon>phenvlaminoM-trifluoromemvlpvrinu'din-5-vll-l-morpholin-4-vl-methanone fGW83618730
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3,4-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (30 mg) and morpholine (10 jxl) afforded the title compound (36
mg).
NMR (DMSO-d6) F4135 5 3.35-3.8 (8H, m), 7.67 (IH, d), 7.76 (IH, d of d), 8.22 (IH, s), 8.90
(IH, s), 10.80 (IH, s).
LC/MS CF103106-1, t - 3.45 min, [MH+] 421 and 423.
Example 9: l-r2-f2.5-DicMorophenvlarm^o)^-1rifluoromemvlpvrimidm-5-vl1-l-morpholin-4-vl-methanone (GW83681430
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,5-dichlorophenylamino)-4-trifluoromemyl-
pyrimidine-5-carboxylic acid (35 mg) and morpholine (14.5 jul) afforded the title compound (27
mg).
NMR (DMSO-d6) F4240 8 3.4-3.75 (8H, m), 7.32 (IH, d of d), 7.66 (IH, d), 7.78 (IH, d), 8.71
(IH, s), 10.05 (IH, s).
LC/MS CF103313-3, t = 3.31 min, [MH+] 421 and 423.
Example 10: l-r2-f3-Huon>phenvlammoV4-trifluoromemvlpvrimidin-5-vl1-l-morpholin-4-vl-methanone (GW836825X)
In a manner similar to Reference Example 1(c) 2-(3-fluorophenylamino)-4-trifluoromemylpyrimidine-5-carboxylic acid (35 mg) and morpholine (12 \il) afforded the title compound (31 mg).
NMR(DMS0-d6) F4231 8 3.4-3.8 (8H, m), 6.85 (lH,tof d), 7.37 (IH, q), 7.52(IH, d), 7.77 (IH, d oft), 8.80 (IH, s), 10.65 (IH, s). LC/MS CF103273-1, t = 3.06 min, [MH+] 371.
Example 11: l-r2-(3-Bromophenvlamino)-4-1rifluoromethvlpyrimidin-5-vll-l-morpholin-4-vl-metnanone fGW836831X)
H
In a manner similar to Reference Example 1(c) 2-(3-bromophenylamino)-4-
trifluoromethylpyrimidine-5-carboxylic acid (35 mg) and morpholine (10 uJ) afforded the title
compound (31 mg).
NMR (DMSO-d6) F4249 8 3.4-3.8 (8H, m), 7.22 (IH, d), 7.30 (IH, t), 7.71 (IH, d), 8.11 (IH, s),
8.81 (lH,s), 10.60 (lH,s).
LC/MS CF103286-1, t = 3.25 min, [MH+] 431 and 433.
Example 12: l-f2-(3-Bromophenvlammo)-4-trifluoromemvlpyrmiid!m-5-vl1-l-piperidin-4-vlmethanone (GW836835X)
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-bromophenylamino)-4-
trifluoromethylpyrimidme-5-carboxylic acid (35 mg) and piperidine (12 u.1) afforded the title
compound (31 mg).
NMR (DMSO-d6) F4252 8 1.3-1.7 (6H, m), 3.26 (2H, s), 3.60 (2H, br s), 7.21 (IH, d), 7.30 (IH,
t), 7.70 (IH, d), 8.11 (IH, s), 8.78 (IH, s), 10.55 (IH, s).
LC/MS CF103290-1, t= 3.57 min, [MH+] 429 and 431.
Example 13: l-r2-(3.5-DichlorophenvlaminoM-trifluoromethvlpvrimidin-5-vl1-l-morpholin-4-vl-methanone (GW836842X) H In a manner similar to Reference Example 1(c) 2-(3,5-dichIorophenyIamino)-4-trifIuoromethyI-pyrimidine-5-carboxylic acid (35 mg) and morpholine (14.5 u.1) afforded the title compound (42 mg).
NMR (DMSO-d6) F4264 8 3.4-3.75 (8H, m), 7.35 (IH, s), 7.89 (2H, s), 8.87 (IH, s), 10.80 (IH,
s).
LC/MS CF103346-3, t = 3.52 min, [MH+] 421 and 423.
Example 14:2-(3-ChlorophenvlanmoV4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclopentvlamide (GW837350X
In a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (35 mg) and cyclopentylamine (13 ul) afforded the title compound (34 mg).
NMR (DMSO-d6) F4407 8 1.5 (4H, m), 1.65 (2H, m), 1.85 (2H,m), 4.15 (IH, m), 7.09 (IH, d), 7.36 (IH, t), 7.67 (IH, d), 7.97 (IH, s), 8.55 (IH, d), 8.79 (IH, s), 10.60 (IH, s). LC/MSCF103478-1, t - 3.55 min, [MH+] 385 and 387.
Example 15: 2-(2.3-DichlorophenvlaminoV4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide (GW837356X)
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,3-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and cyclohexanemethylamine (16 jxl) afforded the title
compound (30 mg).
NMR (DMSO-d6) F4419 8 0.85-1.0 (2H, m), 1.1-1.3 (3H, m), 1.45 (IH, m), 1.55-1.8 (5H, m),
3.05 (2H, t), 7.40 (IH, t), 7.55 (2H, d), 8.53 (IH, t), 8.65 (IH, s), 10.15 (IH, s).
LC/MS CF103536-1, t - 3.84 min, [MH+] 447 and 449.
Example 16:2-(2.4-DicMoiophenvlammo)-4-1rifluoromemvlpvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide (GW837357X)
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (35 mg) and cyclohexanemethylamine (16 ul) afforded the title compound (14 mg).
NMR (DMSO-d6) F4420 8 0.85-1.0 (2H, m), 1.1-1.3 (3H, m), 1.45 (IH, m), 1.55-1.75 (5H, m), 3.05 (2H, t), 7.46 (IH, d), 7.57 (IH, d), 7.72 (IH, s), 8.53 (IH, t), 8.64 (IH, s), 10.00 (IH, s). LC/MS CF103536-2, t = 3.90 min, [MH+] 447 and 449.
Example 17: 2-f3.4-DicMorophenvlammo)-4-1rifluoromemvlrATimidme-5-carboxvlic acid
cvclohexvlmethvl-amide
(GW837359X)
(figure Removed)
In a manner similar to Reference Example 1(c) 2-(3,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (35 mg) and cyclohexanemethylamine (16 ul) afforded the title compound (31 mg).
NMR (DMSO-d6) F4424 5 0.8-1.0 (2H, m), 1.1-1.3 (3H, m), 1.5 (IH, m), 1.55-1.8 (5H, m), 3.06 (2H, t), 7.62 (IH, d), 7.69 (IH, d), 8.18 (IH, s), 8.59 (IH, t), 8.82 (IH, s), 10.70 (IH, s). LC/MS CF103537-1, t = 4.01 min, [MH+] 447 and 449.
Example 18:2-f3.5-Dichlorophenvlamino)-4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide (GW837360X)
In a manner similar to Reference Example 1(c) 2-(3,5-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and cyclohexanemethylamine (16 JJ.1) afforded the title
compound (30 mg).
NMR (DMSO-d6) F4425 8 0.85-1.0 (2H, m), 1.1-1.3 (3H, m), 1.5 (IH, m), 1.55-1.8 (5H, m),
3.07 (2H, t), 7.26 (IH, s), 7.89 (2H, s), 8.58 (IH, t), 8.86 (IH, s), 10.80 (IH, s).
LC/MS CF103537-2, t = 4.08 min, [MH+] 447 and 449.
Example 19: 2-(3-Fluorophenvlamino)-4-1rifluoromethvlpvrimidine-5-carboxvIic acid cvclohexvlmethvl-amide (GW837804X) a manner similar to Reference Example 1(c) 2-(3-fluoTophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and cyclohexanemethylamine (18 ul) afforded the title
compound (38 mg).
NMR (DMSO-d6) F4461 8 0.85-1.0 (2H, m), 1.1-1.3 (3H, m), 1.5 (IH, m), 1.55-1.8 (5H, m),
3.09 (2H, t), 6.87 (IH, t of d), 7.39 (IH, q), 7.53 (IH, d), 7.78 (IH, d oft), 8.59 (IH, t), 8.80 (IH,
s), 10.60 (IH, s).
LC/MS CF103528-1, t = 3.68 min, [MH+397.
Example 20: 2-f3-Bromophenvlamino')-4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-bromophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (35 mg) and cyclohexanemethylamine (15 ul) afforded the title compound (36 mg).
NMR (DMSO-d6) F4480 8 0.85-1.0 (2H, m), 1.1-1.3 (3H, m), 1.5 (IH, m), 1.55-1.8 (5H, m), 3.08 (2H, t), 7.23 (IH, d), 7.31 (IH, t), 7.71 (IH, d), 8.10 (IH, s), 8.57 (IH, t), 8.80 (IH, s), 10.60 (lH,s). LC/MS CF103564-1, t = 3.85 min, [MH+] 457 and 459.
Example 21: 2-(2.6-DichlorophenvlaminoV4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide (GW838944X)
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,6-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (33 mg) and cyclohexanemethylamine (15 ul) afforded the title compound (9 mg).
NMR (DMSO-d6) F4419 8 0.85-1.0 (2H, m), 1.05-1.25 (3H, m), 1.46 (IH, m), 1.55-1.8 (5H, m), 3.04 (2H, t), 7.39 (IH, t), 7.59 (2H, d), 8.56 (2H, m), 10.10 (IH, (Scheme Removed)
LC/MS CF103536-1, t = 3.84 min, [MH4 ] 447 and 449.
Example 22: 2-f3-Chlorophenvlammo)-4-trifluoromemvlpvrimidine-5-carboxvlic acid ftetrahydro-pyran^-vlmethvlVamide (GW840415X)
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (30 mg) and 4-aminomethyltetrahydropyran (13 mg) afforded the
title compound (25 mg).
NMR (DMSO-d6) F5027 8 1.15-1.3 (2H, m), 1.62 (2H, d), 1.74 (IH, m), 3.13 (2H, t), 3.27 (2H,
t), 3.86 (2H, d), 7.10 (IH, d), 7.37 (IH, t), 7.66 (IH, d), 7.97 (IH, s), 8.63 (IH, t), 8.82 (IH, s),
10.60 (IH, s).
LC/MS CF104182-1, t = 3.22 min, [MH+] 415 and 417.
Example 23: 2-(3-Chlorophenvlammo^-trifluoromemvlpvrimidine-5-carboxvlic acid cvclobutvl-amide (GW8404163O
H
In a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and cyclobutylamine (10 |xl) afforded the title compound
(28 mg).
NMR (DMSO-d6) F5028 8 1.6-1.75 (2H, m), 1.9-2.05 (2H, m), 2.2-2.3 (2H, m), 4.32 (IH, m),
7.10 (IH, d), 7.37 (IH, t), 7.67 (IH, d), 7.96 (IH, s), 8.82 (2H, s), 10.60 (IH, s).
LC/MS CF104199-1, t - 3.45 min, [MH+] 371 and 373.
Examples 24 to 30
Table 1) gives examples 24 to 30, column 1 gives the precursors that were reacted with methyl 2-chloro-4-trifluoromethyl-pvrimidine-5-carboxylate in a manner similar to that in Reference example 1(a). In a manner similar to that in Reference example 1(b), the carboxylic acid of the resultant ester was prepared. Finally, in a manner similar to that of Reference example 1(c), the resultant acid product was reacted with the precursor of column 2 to provide the final product of column 3.
Table 1
(Table Removed)
Example 31: 2-(3-FluorophenvlammoM-trifluoromemvlpvrimidine-5-carboxvlic acid ftetrahvdropvran-4-vlmethvDamide
In a manner similar to Reference Example 1(c) 2-(3-fluorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and 4-aminomethyltetrahydropyran (16 mg) afforded the title
compound (38.,mg).
NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.63 (2H, d), 1.75 (1H, m), 3.15 (2H, t), 3.29 (2H, t), 3.86
(2H, d), 6.88 (1H, td), 7.38 (1H, q), 7.51 (lH,d), 7.76 (1H, dt), 8.64 (1H, t), 8.82 (1H, s), 10.60
(1H, s).
LC/MS, t = 3.08 min, [MH+] 399.
Example 32: 2-(3-Bromophenvlamino')-4-trifluoromethylpvrimidine-5-carboxvlic acid ftetrahvdropvran^-vlmethvDamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-bromophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and 4-aminomethyltetrahydropyran (13 5 mg) afforded the title
compound (36 mg).
NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.62 (2H, d), 1.74 (1H, m), 3.13 (2H, t), 3.27 (2H, t), 3.86
(2H, d), 7.23 (1H, d), 7.31 (1H, t), 7.71 (1H, d), 8.11 (1H, s), 8.63 (1H, t), 8.82 (1H, s), 10.60
(lH,s).
LC/MS, t = 3.26 min, [MH+] 459 and 461.
Example 33: 2-(2.3-DichlorophenvlaminoV4-trifluoromethvlpvrimidine-5-carboxvlic acid ftetrahvdropvran-4-vlmethvl')amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,3-dichlorophenylammo)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) and 4-aminomethyltetrahydropyran (12 mg) afforded the title compound (25 mg)
NMR (DMSO-d6) S 1.1-1.25 (2H, m), 1.60 (2H, d), 1.72 (IH, m), 3.11 (2H, t), 3.26 (2H, t), 3.85 (2H, d), 7.40 (IH, t), 7.55 (2H, d), 8.60 (IH, t), 8.66 (IH, s), 10.10 (IH, s). LC/MS, t = 3.29 min, [MH+] 449 and 451.
Example 34: 2-(2.4-Dichlorophenvlamino)-4-trifluoromethvlpvrinudine-5-carboxvlic acid (tetrahvdropvran-4-vfaethvl)amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) and 4-aminomethyltetrahydropyran (12 mg) afforded the title compound (34 mg).
NMR (DMSO-d6) 8 1.1-1.25 (2H, m), 1.59 (2H, d), 1.72 (IH, m), 3.11 (2H, t), 3.26 (2H, t), 3.85 (2H, d), 7.47 (IH, dd), 7.57 (IH, d), 7.72 (IH, s), 8.60 (IH, t), 8.65 (IH, s), 10.05 (IH, s). LC/MS, t = 3.33 min, [MH+] 449 and 451.
Additional synthesis of Example 34: GW 842166X2-(2.4-Dichlorophenvlammo)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid ftetrahvdro-pvran-4-vlmethvlVamide
(a). To a solution of methyl 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylate (0.50 g, ex Maybridge) in 1,4-dioxan (5 ml) was added 2,4-dichloroaniline (1.7 g) and the solution stirred under reflux for 7 h. 1,4-Dioxan was removed under reduced pressure and ethyl acetate (15 ml) ided. The solution was washed sequentially with 2N hydrochloric acid (10 ml) and water (3x10 Med (MgS04), evaporated and triturated with hexane to afford methyl 2-(2,4-
'mylammo)-4-trifluoromemylpyriimdine-5-carboxylate GW 836235X (358 mg,
6 3.95 (3H, s), 7.30 (IH, dd), 7.45 (IH, d), 8.00 (IH, s), 8.5 (IH, d), 9.05
" min, [MH+] 366..
(Figure Removed)
/-trifluoromethyl-pyrimidine-5-.don of potassium hydroxide (190 mg) in n. Ethanol was removed under reduced s washed with ether and concentrated , to pH 1. The precipitated solid was filtered, , to afford 2-(2,4-dichlorophenylamino)-4-,id (262 mgGW836224X) GW 836246X.
NMR(DMSO-d6) F1711 5 7.48 (1H, dd), 7.60 (1H, d), 7.73 (1H, d), 8.95 (1H, s), 10.3 (1H, s), 13.6 (lH,s).
(Figure Removed)
(c). To a solution of 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid GW 836246X (30 mg) in dimethylformamide (2 ml) was added successively N-ethylmorpholine (33 ul), 4-aminomethyltetrahydropyran (12mg), 1-hydroxybenzotriazole hydrate (18 mg) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (20 mg). The solution was stirred for 3 h and allowed to stand overnight. Dimethylformamide was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 5% sodium bicarbonate solution (2.S ml), water (2.S ml), 5% citric acid solution (2.5 ml) and brine (2 x 2.5 ml), dried (MgS04) and evaporated to afford the title compound (34 mg) GW 842166X. NMR (DMSO-d6) F1920 8 1.20 (2H, m), 1.58 (2H, d), 1.70 (1H, m), 3.10 (2H, t), 3.23 (2H, t), 3.84 (2H, dd), 7.46 (1H, dd), 7.57 (1H, d), 7.71 (1H, d), 8.59 (1H, t), 8.63 (1H, s), 10.00 (1H, s). LOMS CF100768-1, t = 3.33 min, [MH+] 449.
(Figure Removed)
Additional synthesis of Example 34: GW 842166X2-(2.4-Dichlorophenvlamino)-4-trifluoromefovl-pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmethvl)-amide
solution of methyl 2-cUoro-4-trifluoromethylpyrimidine-5-carboxylate (70 g, ex
"•«?, ex Fluorochem 48g) in 1,4-dioxan (100 ml) was added 2,4-dichloroaniline (142 - stirred under reflux for 10.5 h. 1,4-Dioxan was partially removed (approx -essure and 2N HC1 (800ml) added. The mixture was stirred with overhead "Hng solid filtered onto a sinter. The solid was washed with 2N HC1 (2. "* then dried over sodium hydroxide in vacuo at 50°C to afford N 4-trifluoromethyl-pyrimidine-5-carboxylate GW 836235X. 4- dichloroaniline.
, dd), 7.49 (1H, d), 7.74 (1H, d), 8.96 (1H, s),
ylammo)-4-trifluorometiiyl-pyrimidine-5- 0 ml) was added a solution of potassium .ution stirred at reflux for 24 h. Methanol wasml) added. The solution was washed with ether
,4-dichloroaniline) and concentrated hydrochloric precipitated solid was filtered, washed with 2N HC1
and water until the pH of the filtrate was neutral. The solid was dried in vacuo at 50°C to afford
2-(2,4-dichlorophenylamino)^-trifluoromethyl-pyrimidine-5-carboxylic acid (86.9 g) GW
836246X. GW836224X
NMR (DMSO-d6) F1711 5 7.48 (IH, dd), 7.60 (IH, d), 7.73 (IH, d), 8.95 (IH, s), 10.3 (IH, s),
13.6 (IH, s).
LC/MS CF100425-1, t = 4.35 min, [MH+] 352 CF100425-1
(c). To a solution of 2-(2,4-dichIorophenylamino)^trifluoromethyl-pyrimidine-5-carboxyIic acid GW 836246X (86 g) in dimethylformamide (800 ml) was added successively N-ethylmorpholine (93ml), 4-aminomethyltetrahydropyran (29.5g), 1-hydroxybenzotriazole hydrate (51.5g) and l-(3-dimemylammo-propyl)-3-emylcarbodiimide hydrochloride (56.2g). The solution was stirred for 24h. Dimethylformamide was partially removed (approx 650ml) under reduced pressure and 5% sodium bicarbonate solution added (3 x 500 ml, added portionwise to control the release of carbon dioxide). The mixture was stirred with overhead stirring for 3h and the resulting solid filtered onto a sinter. The solid was washed with 5% sodium bicarbonate (4 x 400ml) and water (3 x 400ml) then dried over sodium hydroxide in vacuo at 50°C to afford the title compound (109.1g) GW 842166X.
NMR (DMSO-d6) F1920 8 1.20 (2H, m), 1.58 (2H, d), 1.70 (IH, m), 3.10 (2H, t), 3.23 (2H, t), 3.84 (2H, dd), 7.46 (IH, dd), 7.57 (IH, d), 7.71 (IH, d), 8.59 (IH, t), 8.63 (IH, s), 10.00 (IH, s). LQMS CF100768-1, t= 3.41 min, [MH+] 449.
Example 35: 2-f2.5-DicMorophenvlamino)-4-trifluoromemvlpvrimidine-5-carboxvlic acid ftetrahvdropvran-4-vlmethvl)-amide
(Figure Removed)
CI In a manner similar to Reference Example 1(c) 2-(2,5-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and 4-aminomethyltetrahydropyran (25 mg) afforded the title compound (63 mg).
NMR (DMSO-d6) 5 1.15-1.3 (2H, m), 1.60 (2H, d), 1.72 (IH, m), 3.12 (2H, t), 3.27 (2H, t), 3.85 (2H, d), 7.35 (IH, dd), 7.59 (IH, d), 7.73 (IH, s), 8.62 (IH, t), 8.70 (IH, s), 10.05 (IH, s). LC/MS, t - 3.30 min, [MH+] 449 and 451.
Example 36:2-(3.5-DicMorophenvlarnmoM-trifluoromemvlpvrimidine-5-carboxvlic acid (tetrahvdropvran-4-vlmethvD-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3,5-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and 4-aminomethyltetrahydropyran (25 mg) afforded the title compound (68 mg).
NMR (DMSO-d6) 8 1.15-1.35 (2H, m), 1.62 (2H, d), 1.72 (IH, m), 3.14 (2H, t), 3.28 (2H, t), 3.86 (2H, d), 7.25 (IH, s), 7.88 (2H, s), 8.66 (IH, t), 8.88 (IH, s), 10.75 (IH, s).
Example 37: 2-0-MethoxvphenvlaminoV4-trifluoromethvlpvrimidine-5-carboxvlic acid (tetrahvdropvran-4-vlmethvlVamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-methoxyphenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (32 mg) and 4-aminomethyltetrahydropyran (14.5 mg) afforded the title compound (29 mg).
NMR (DMSO-d6) 5 1.1-1.25 (2H, m), 1.61 (2H, d), 1.74 (IH, m), 3.13 (2H, t), 3.27 (2H, t), 3.74 (3H, s), 3.86 (2H, d), 6.63 (IH, d), 7.25 (2H, m), 7.53 (IH, s), 8.62 (IH, t), 8.76 (IH, s), 10.35 (IH, s). LC/MS, t = 2.97 min, [MH+] 411.
Example 38: 2-(3-Fluorophenvlammo)-4-1rifluoromemvlpvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-fluorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) and cyclopentylmethylamine hydrochloride (17 mg, prepared as described in Kelley et al., J. Med. Chem., 40, 3207, (1997) ) afforded the title compound (17 mg). NMR (DMSO-d6) 8 1.20-1.30 (2H, m), 1.45-1.68 (4H, m), 1.68-1.77 (2H, m), 2.1 (IH, quintuplet), 3.19 (2H, t), 6.89 (IH, dt), 7.40 (IH, q), 7.54 (IH, d), 7.78 (IH, d), 8.64 (IH, t), 8.80 (IH, s), 10.70 (IH, s). LC/MS, t = 3.53 min, [MH+] 383.
Example 39: 2-G-BromophenvlaminoV4-trifluoromethvlpvritnidine-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-bromophenylarnino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (36.5 mg) and cyclopentylmemylamine hydrochloride (17 mg) afforded
the title compound (28 mg).
NMR (DMSO-d6) 8 1.39-1.52 (2H, m), 1.69-1.90 (4H, m), 1.90- 2.02 (2H, m), 2.34 (IH,
quintuplet), 3.4 (2H, t), 7.48 (IH, d), 7.57 (IH, t), 7.95 (IH, d), 8.37 (IH, s). 8.86 (IH, t), 9.02
(IH, s), 10.80 (IH, s).
LC/MS, t = 3.33 min, [MH+] 443 and 445.
Example 40:2-(2.3-DichloroDhenvlamino')-4-trifluoromethvbvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,3-dicMorophenylammo)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (32 mg) and cyclopentylmethylamine hydrochloride (15 mg) afforded
the title compound (30 mg).
NMR (DMSO-d6) 8 1.15-1.30 (2H, m), 1.44-1.78 (6H, m), 2.10 (IH, quintuplet), 3.16 (2H, t),
7.41 (2H, t), 7.54 (IH, m), 8.58 (IH, br t), 8.78 (IH, s), 10.10 (IH, s).
LC/MS, t = 3.71 min, [MH+] 433 and 435.
Example 41:2-f2.4-DicMorophenvlamino)-4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-
pyrirnidine-5-carboxylic acid (32 mg) and cyclopentylmethylamine hydrochloride (15 mg) afforded
the title compound (27 mg).
NMR (DMSO-d6) 8 1.2-1.3 (2H, m), 1.4-1.79 (6H, m), 2.10 (IH, quintuplet), 3.17 (2H, t), 7.50 (IH,
d), 7.60 (IH, d), 7.75 (IH, d), 8.68 (IH, t), 8.78 (IH, s), 10.10 (IH, s).
LC/MS, t = 3.76 min, [MH4} 433 and 435.
Example 42:2-f2.5-KchloroDhenvlamino')-4-lrifluoromethvlpvrirnidme-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,5-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylicacid (32 mg) and cyclopentylmethylamme hydrochloride (IS mg) afforded
the title compound (23 mg).
NMR (DMSO-d6) 8 1.15-1.30 (2H, m), 1.45-1.79 (6H, m), 2.08 (1H, quintuplet), 3.18 (2H, t), 7.38
(1H, d), 7.62 (1H, d), 7.75 (1H, s), 8.61 (1H, br t), 8.71 (1H, s), 10.05 (1H, s).
LC/MS, t = 3.76 min, \MH+] 433 and 435.
Example 43:2-f2.6-KcMorophenvlarnmo)-4-trifluoromethvlpvrirmdine-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,6-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (32 mg) and cyclopentylmethylamine hydrochloride (IS mg) afforded
the title compound (25 mg).
NMR (DMSO-d6) 6 1.15-1.30 (2H, m), 1.45-1.78 (6H, m), 2.08 (1H, quintuplet), 3.15 (2H, t), 7.4
(1H, t), 7.6-7.68 (2H, m), 8.5-8.7 (2H, m), 10.20 (1H, s).
LC/MS, t = 3.49 min, [MH+] 433 and 435.
Example 44: 2-f3.4-DicMcTOphenvlammo)-4-trifluoromemvlp\Timidine-S-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
m a manner similar to Reference Example 1(c) 2-(3,4-dichlorophenylamino)-4-trifluoromethyl-
pvrimidine-5-carboxylic acid (32 mg) and cyclopentylmethylamine hydrochloride (15 mg) afforded
the title compound (29 mg).
NMR (DMSO-d6) 8 1.12-1.3 (2H, m), 1.44-1.8 (6H, m), 2.1 (1H, quintuplet). 3.17 (2H, t), 7.62
(1H, br d), 7.72 (1H, d), 8.18 (1H, d), 8.60-8.69 (1H, br t), 8.83 (1H, s), 10.80 (1H, s).
LC/MS, t = 3.87 min, [MH+] 433 and 435.
Example 45: 2-f3.S-DicMoropheTiY1a^mo)-4-1rifluoromemvlpvrirnidme-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3,5-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (32 mg) and cyclopentylmethylamine hydrochloride (15 mg) afforded
the title compound (27 mg).
NMR (DMSO-d6) 1.14-1.34 (2H, m), 1.45-1.8 (6H, m), 2.10 (1H, quintuplet), 3.20 (2H, t), 7.28
(1H, s), 7.91 (2H, s), 8.6-8.7 (1H, br t), 8.9 (1H, s), 10.75 (1H, s).
LC/MS, t = 3.94 min, [MH+] 433 and 435.
Example 46: 2-(3-Methoxvphenvlamino')-4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-methoxyphenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (32 mg) and cyclopentylmethylamine hydrochloride (17 mg) afforded the title compound (21 mg).
NMR(DMSO-d6) 1.25-1.38 (2H,m), 1.50-1.85 (6H, m), 2.15 (1H, quintuplet), 3.25 (2H, t), 3.85 (3H, s), 6.70 (1H, br d), 7.26-7.37 (2H, m), 7.60 (1H, m), 8.68 (1H, t), 8.80 (1H, s), 10.50 (1H, s). LC/MS, t = 3.46 min, [MH+] 395.
Example 47: 2-(3-BromophenvlaininoM-trifluoromethvlpvriinidine-5-carboxvlic acid cvclobutvlamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-bromophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and cyclobutylamine (10 |d) afforded the title compound (30
nig)-
NMR (DMSO-d6) S 1.70 (2H, m), 1.97 (2H, m), 2.22 (2H, m), 4.32 (1H, m), 7.22-7.33 (2H, m),
7.70 (1H, d), 8.10 (1H, s), 8.81-8.83 (2H, m), 10.60 (1H, s).
LC/MS, t = 3.47 min, [MH*] 415 and 417.
Example 48: 2-f2.3-DicrJorophenvlammoV4-trifluoromethvlpvrimidine-5-carboxvlic acid cvclobutvlamide


(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,3-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (25 mg) and cyclobutylamine (10 ul) afforded the title compound (20
mg).
NMR (DMSO-d6) 8 1.70 (2H, m), 1.97 (2H, m), 2.22 (2H, m), 4.32 (1H, m), 7.38-7.56 (3H, m),
8.65 (1H, s), 8.80 (1H, d), 10.10 (1H, s).
LC/MS, t = 3.48 min, [MET] 405 and 407.
Example 49: 2-(2.4-IMcMorophenvlamino)^-1rifluorome1hvlpvrirnidine-5-carboxvlic acid
cvclobutvlamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (30 mg) and cyclobutylamine (10 ul) afforded the tide compound (26
mg).
NMR (DMSO-d6) 8 1.70 (2H, m), 1.97 (2H, m), 2.22 (2H, m), 4.32 (1H, m), 7.46-7.72 (3H, m),
8.64 (1H, s), 8.80 (1H, d), 10.00 (1H, s).
LC/MS, t = 3.54 min, [MH+] 405 and 407.
Example 50: 2-(2,5-DicMon)phenvlammoM-trifluoromemylpvrimidine-5-carboxvlic acid cvclobutvlamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,5-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (50 mg) and cyclobutylamine (19 ul) afforded the title compound (56
mg).
NMR (DMSO-d6) 8 1.70 (2H, m), 1.97 (2H, m), 2.22 (2H, m), 4.30 (1H, m), 7.33-7.73 (3H, m),
8.70 (1H, s), 8.80 (1H, d), 10.00 (1H, s).
LC/MS, t = 3.52 min, [MH*] 405 and 407.
Example 51: 2-(2.6-DicMorophenvlammo)-4-trifluoromemvlpviAm'dine-5-carboxvlic acidN-cvclobutvlamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,6-dichlorophenylamino)-4-trifluoromeuiyl-pyrimidine-5-carboxylic acid (30 mg) and cyclobutylamine (10 ul) afforded the title compound (34
mg).
NMR (DMSO-d6) 8 1.70 (2H, m), 1.97 (2H, m), 2.22 (2H, m), 4.30 (1H, m), 7.36-7.60 (3H, m),
8.59 (1H, s), 8.80 (1H, d), 10.15 (1H, s).
LC/MS, t = 3.24 min, [MH*] 405 and 407.
Example 52: 2-f3.5-DichlorophenvlaminoV4-1rifluoromemvlpvrirm'dme-5-carboxvlic acid cvclobutvlamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3,5-dichIorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (50 mg) and cyclobutylamine (19 ul) afforded the title compound (56
mg).
NMR (DMSO-d6) 8 1.70 (2H, m), 1.97 (2H, m), 2.22 (2H, m), 4.32 (1H, m), 7.25-7.87 (3H, m),
8.85 (1H, d), 8.88 (1H, s), 10.80 (1H, s).
LC/MS, t = 3.73 min, [MlT] 405 and 407.
F/Kflmple 53:2-f3-Memoxvphenvlamino)-4-trifluoromemvlT?vrimidine-5-carboxvlic acid cvclobutvlamide
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-methoxyphenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (32 mg) and cyclobutylamine (10.5 ul) afforded the title compound (27
mg).
NMR (DMSO-d6) 8 1.70 (2H, m), 1.97 (2H, m), 2.22 (2H, m), 3.75 (3H, s), 4.32 (1H, m), 7.53-
7.87 (4H, m), 8.76 (1H, s), 8.81 (1H, d), 10.40 (1H, s).
LC/MS, t = 3.20 min, [MH4] 367.
Example 54:2-G-CMorophenvlaminoV4-nifluoromemvlpvrirnidine-5-carboxvlic acid cvclobutvlmethvl-amide
(a) A solution.of borane-tetrahydrofuran complex (1M in tetrahydrofuran, 120ml) was added over lOmin to a solution of cyclobutane carbonitrile (8.1g) [Lancaster] in dry tetrahydrofuran (20ml) under nitrogen at room temperature. The solution was refluxed overnight then cooled to 20°. Methanol (150ml) was added dropwise over 15mins keeping the temperature below 25°, men the mixture was cooled to 0° and dry hydrogen chloride was bubbled through for 30min. The resulting mixture was refluxed for 90min, evaporated and the residue re-evaporated twice from methanol. Ether (150ml) was added and the resulting solid was filtered off. It was taken up in hot isopropanol (50ml), filtered, and hot acetonitrile (30ml) added. The mixture was cooled and the solid filtered off to give the C-cyclobutylmethylamine hydrochloride (5.7g) NMR (400 MHz, DMSO-d6) F6382 1.8 (4H, m), 2.0 (2H, m), 2.54 (1H, m), 2.80 (2H, d), 8.0 (3H,brs).
(b) In a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (32 mg) and C-cyclobutylmethylamine hydrochloride (13 mg) afforded the title compound (28 mg).
NMR (DMSO-d6) 8 1.70 (2H, m), 1.82 (2H, m), 2.00 (2H, m), 2.50 (1H, m), 3.26 (2H, m), 7.08-7.95 (4H, m), 8.55 (1H, t), 8.77 (1H, s), 10.60 (1H, s). LC/MS, t = 3.56 min, [MH*] 385.


(Figure Removed)
Example 55: 2-(2.6-Dichlorophenvlamino)-4-1rifluoromemvl-pvrimidine-5-carboxvlic acid ftetrahvdro-pvran-4-vlmethvD-amide GW842168


(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(2,6-dichlorophenylamJno)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (30mg) and 4-aminomethyltetrahydropyran (20mg, ex
CombiBlocks) afforded the title compound (32mg).
NMR (DMSO-d6) S 1.16-1.22 (2H, m), 1.58 (2H, d), 1.70 (1H, m), 3.09 (2H, t), 3.23 (2H, m),
3.84 (2H, d), 7.38 (1H, t), 7.59 (2H, d), 8.61 (2H, m), 10.10 (1H, s)
LC/MS, t = 3.02 min, Molecular ion observed (MH4) = 449 consistent with the molecular formula
CI8HI735C12F3N402
Example 56GW 842170X : 2-f3.4-DichlorophenvlammoM-trifluoromemvlpyrimidine-5-carboxvlic acid (tetrahvdro-pvran^-vlmethvlVamide
In a manner similar to Reference Example 1(c) 2-(3>4-dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (30mg) and 4-aminomethyltetrahydropyran (20mg, ex
CombiBlocks) afforded the title compound (38mg).
NMR (DMSO-d6) 8 1.18-1.25 (2H, m), 1.62 (2H, d), 1.74 (IH, m), 3.1 (2H, t), 3.25 (2H, m), 3.85
(2H, d), 7.60 (IH, t), 7.69 (IH, m), 8.16 (IH, dd), 8.64 (IH, t), 8.84 (IH, s), 10.70 (IH, s)
LC/MS, t = 3.45 min, Molecular ion observed (MH*) = 449 consistent with the molecular formula
C1gH17N40235Cl2F3
Example 68: GW 836187X l-r2-G.4-Dichlorophenvlamino')-4-trifluoromethvlDvrimidin-5-vll-l-fmorpholin-4-vD-methanone
In a manner similar to Reference Example 1(c) 2-(3,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30mg) and morpholine (15mg, ex Aldrich) afforded the title compound (36mg). NMR (DMSO-d6) 8) 3.7 (8H, s), 7.65 (IH, d), 7.75 (IH, dd), 8.2 (IH, d), 8.9 (IH, s), 10.80 (IH,
s)
LC/MS, t = 3.45 min, Molecular ion observed (MH*) = 421 consistent with the molecular formula
CI6H13N40235C12F3
Table 2:
Example 57-67 and 69-73 were prepared in a corresponding fashion to the above compounds.
(Table Removed)
Table 3
Compounds 74 to 87 were prepared according to the conditions described for table 1, and
purified by the method given in column P as follows:
Method A: refers to the procedure in part (b) of Example 166.
Method B: Mass-directed autopuriflcation using the procedures detailed at the beginning of the
experimental
Method C: Purification using Biotage Chromatography over Merck 9385 Silica Gel ( 25g)
eluting with 1-2% methanol in dichloromethane.
Intermediate A: 4-Aminomethvltetrahvdropvran-4-ol hydrochloride (GW877062A)


(Figure Removed)
To a solution of l.OM lithium aluminium hydride in tetrahydrofuran (20 ml) was added under
a nitrogen atmosphere a solution of 4-hydroxytetra-hydropyran-4-carbonitrile (0.50 g,
prepared as described in Eiden et al., Arch. Pharm., 320.348, (1987) ) in tetrahydrofuran (2
ml) and the solution stirred at reflux for 6 hours. Water (1 ml) and 2N sodium hydroxide
solution (1 ml) were added cautiously and the resultant solid filtered and washed with ether.
The filtrate was dried (MgS04), evaporated and the residue dissolved in ethanol (3 ml) and
concentrated hydrochloric acid (0.5 ml) added. Solvent was removed under reduced pressure
and the resultant solid washed with ether and dried in vacuo at 40°C to afford the title
compound (234 mg).
NMR ( DMSO-d6) 1.45-1.6 (4H, m), 2.78 (2H, q), 3.61 (4H, m). 5.07 (IH, br s), 7.89 (3H, br
s).
(Table Removed)
Table 4
In the following table 4, column 2 gives precursors R2NH2 that were reacted with 2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride in a manner similar to that in part (a) of Example 166 GW847367X. The resultant product was reacted with the precursor YNH2 of column 3 in a manner similar to that in part (b) of Example 166 GW847367X, to provide the final product in column 4.
Preparation Method A: refers to the procedure give in part (b) of Example 166. GW 847367XPreparation Method B: This is exemplified by the by Example 109, 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)amide ( SO mg) and 2-chloro-2-cyanoaniline (118mg) were irradiated in a microwave apparatus (the model used was the 'Creator1, supplied by Personal Chemistry", operating at 300 Watts), at 190°C for 30 min. For examples using this method, the equivalents of substituted aniline YNH2 used, and duration of irradiation follow in brackets after the method B.
The column entitled "Prep" refers to the preparation method used.
The product was then purified according to on of the following methods described below. The column entitled "Pure" refers to the purification method used
Purification method A: refers to the procedure give in part (b) of Example 166 GW 847367X Purification method B: mass directed autopurification using the procedures detailed at the beginning of the experimental.
Purification method C: The reaction was worked up as for part (b) of Example 166 GW 8473 67X, and the crude product further purified by Biotage chromatography over Merck 93 85 silica gel, eluting with isohexane/ethyl acetate.

Table 4
(Table Removed)
In Example 103 - Preparation Method B (S equiv, IS min) N.B. Reaction mixture also contained 0.5 ml MeCN and purification method C The product was purified by trituration with isohexane after this.
5 Method C - As for method B, but the solvent used was 1,4-dioxan not MeCN
Table 5
Compounds 114 to 145 were prepared as set out for table 2 and purified as follows:
Purification Method A: as for reference example lc,
Purification Method C: The reaction was worked up as in example lc, and the product purified by Biotage chromatography using the following solvent systems:
Sol 1 ethyl acetate
Sol 2 1% methanol in dichloromethane
Sol 3 2% methanol in dichloromethane

(Table Removed)
Preparation Method A: refers to the procedure give in part (b) of Example 166. GW 847367X Preparation Method B: Exemplified by Example 154: A mixture of 2-chloro-4-trifluoromethyl-pyrimidin-S-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (SO mg), 3,5-dicyanoaniline (69mg), and acetonitrile ( 0.5ml) was irradiated in a microwave apparatus (the model used was the 'Creator', supplied by "Personal Chemistry", operating at 300 Watts), at 180°C for 60 min. The temperature, duration of irradiation, and number of equivalents of the substituted-aniline used are given after the method in the table.
Preparation Method C: exemplified by Example 162: A mixture of 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-yhnethyl)-amide (80 mg) and 4-fluoro-2-(trifluoromethyl)aniline (11 lmg) was irradiated in microwave apparatus (the model used was the 'Creator', supplied by "Personal Chemistry", operating at 300 Watts), at 190°C for 45 min.
Purification was carried out as detailed in the table to give the product.
Purification Method A: refers to the procedure give in part (b) of Example 166. GW 847367X
Purification Method B: mass directed autopurification using the procedures detailed at the beginning of the experimental.
Purification Method C: The reaction was worked up as for part (b) of Example 166GW 847367X, and the crude product further purified by Biotage chromatography over Merck 9385 silica gel, ehiting with isohexane/ethyl acetate (7:3
(Table Removed)
Example 163 2-f3-MemoxvDhenvlammo^-trifluoromeihvl-t>vrimidine-5-carboxvlic acid cvclohexvlmethvl-amide (GW843786X)
(Figure Removed
hi a manner similar to Reference Example 1(c) 2-(3-methoxyphenylamino)-4-trifluoro-methylpyrimidine-5-carboxylic acid (32 mg) and cyclohexanemethanamine (16 JJ.1, ex Lancaster) afforded the title compound (28 mg).
NMR (DMSO-d6) 8 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.5 (IH, m), 1.55-1.75 (5H, m), 3.06 (2H, t), 3.74 (3H, s), 6.63 (IH, d), 7.2-7.3 (2H, m), 7.54 (IH, s), 8.57 (IH, t), 8.74 (IH, s), 10.35 (IH, s).
LC/MS, t = 3.57 min, Molecular ion observed [MH+] = 409 consistent with the molecular formula C20H23F3N4O2.
Example 164:2-(3-CMorophenvlammo)-4-1rifluoromethvl-pvi^idine-5-carboxvlic acid (1-hvdroxvcvclohexvlmethvn-amideGW845232X(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-chlorophenylamino)-4-trifluoro-methylpyrimidine-5-carboxylic acid (32 mg) and 1-aminomethyl-l-cyclohexanol hydrochloride (20 mg, ex Aldrich) afforded the title compound (29 mg).
NMR ( DMSO-d6) 8 1.3 (IH, m), 1.4-1.5 (7H, m), 1.6 (2H, m), 3.28 (2H, d), 4.34 (IH, s), 7.16 (IH, d), 7.43 (IH, t), 7.73 (IH, d), 8.04 (IH, t), 8.51 (IH, t), 8.91 (IH, s), 10.65 (IH, s). LC/MS, t = 3.39 min, Molecular ion observed [M-H]" = 427 consistent with the molecular formula QsHao^CUySUCfe.
Example 165: 2-(3-BromophenvlammoM-1rifluoromemvl-Pvrimidine-5-carboxYlic acidfl-hvdroxvcvclohexvlmethvD-amide GW845236X
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-bromophenylamino)-4-trifJuoro-methylpyrimidine-5-carboxylic acid (36.5 mg) and 1-aminomethyl-l-cyclohexanol hydro-4-chloride (20 mg, ex Aldrich) afforded the title compound (28 mg).
NMR (DMSO-d6) 8 1.25 (IH, m), 1.35-1.45 (7H, m), 1.6 (2H, m), 3.23 (2H, d), 4.28 (IH, s), 7.23 (IH, d), 7.31 (IH, t), 7.71 (IH, d), 8.12 (IH, s), 8.45 (IH, t), 8.85 (IH, s), 10.55 (IH, s).
LC/MS, t = 3.43 min, Molecular ion observed [M-H]" = 471 consistent with the molecular formula QsHjo^BrFaN^.
Example 166:2-f3-Chloro-4-fluorophenvlammo)-4-trifluoromemvl-Pvrimidine-S-carboxvlic acid cvclohexvlmethvl-amide GW847367X
(a). To a solution of 2-chloro-4-1rifluoromemyl-pyrimidin-5-carbonyl chloride (750 mg, ex
Maybridge) in dichloromethane (IS ml) at -40° was added dropwise over 30 minutes a solution of
cyclohexanemethanamine (0.35 ml, ex Lancaster) and triethylamine (0.41 ml) in dichloromethane
(IS ml). Dichloromethane was removed under reduced pressure and ethyl acetate (20 ml) added.
The solution was washed sequentially with water, 5% sodium bicarbonate solution and water,
dried (MgS04), evaporated and triturated with ethenhexane to afford 2-chloro-4-trifluoromethyl-
pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (GW877061A, 666 mg).
NMR (DMSO-d6) 8 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.5 (1H, m), 1.55-1.75 (5H, m), 3.12
(2H, t), 8.75 (1H, t), 9.18 (1H, s).
LC/MS, t = 3.31 min, Molecular ion observed [MH+] = 322 consistent with the molecular
formula C13H,535C1F3N30.
(b). To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (100 mg) in 1,4-dioxan (1 ml) was added 3-chloro~4-fluoroaniline (228 mg, ex Lancaster) and the solution stirred at reflux for 4 hours. Dioxan was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 2N hydrochloric acid (2 x 3 ml) and water (3x3 ml), dried (MgS04), evaporated and triturated with isohexane to afford the title compound (107 mg).
NMR (DMSO-d6) 8 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.45 (1H, m), 1.6-1.75 (5H, m), 3.06 (2H, t), 7.25 (1H, t), 7.43 (1H, t), 7.56 (1H, t), 8.56 (1H, t), 8.69 (1H, s), 10.20 (1H, s). LC/MS, t = 3.81 min, Molecular ion observed [MH4"] = 431 consistent with the molecular formula Cft^ClFJSUO.
H
Tframple 167: 2-f3-CMoro-2-fluorophenvlanTinoM-trifluoromemvl-PvrimiQ^e-5-carboxvlic acid cvclohexvlmethvl-amide GW847369X


(Figure Removed)
In a manner similar to Example 166(b),GW847367X 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclohexylmethyl-amide (100 mg) and 3-chloro-2-fluoroaniline (230 mg, ex
Acros) afforded the title compound (101 mg).
NMR (DMSO-d6) 5 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.5 (IH, m), 1.6-1.8 (5H, m), 3.08 (2H,
t), 7.43 (IH, t), 7.67 (IH, m), 8.07 (IH, d), 8.58 (IH, t), 8.80 (IH, s), 10.60 (IH, s).
LC/MS, t = 3.71 min, Molecular ion observed IMff1"] =431 consistent with the molecular
formula CBH1S^CIF^O.
Example 168:2-(5-CMoro-2-fluorophenvlamino)-4-trifluoixmiemvl-pvrimidme-5-carboxvlic acid cvclohexvlmethvl-amide
GW847667X
(Figure Removed)

In a manner similar to Example 166(b), GW847367X 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (100 mg) and 5-chloro-2-fluoroaniline (230 mg, ex Avocado) afforded the title compound (116 mg).
NMR (DMSO-d6) 8 0.85-LO (2H, m), 1.1-1.25 (3H, m), 1.5 (IH, m), 1.6-1.75 (5H, m), 3.07 (2H, t), 7.29 (IH, m), 7.36 (IH, t), 7.77 (IH, d of d), 8.57 (IH, t), 8.72 (IH, s), 10.15 (IH, s). LC/MS, t = 3.73 min, Molecular ion observed [MH4"] = 431 consistent with the molecular formula CwH^CligSUO.
Example 169:2-(3.5-IMfluorophenvlamino)-4-trifluoromethvl-pvrimidin-5-carboxvlic acid cvclohexvlmethvl-amide GW848199X
(Figure Removed)
in a manner similar to Example 166GW847367X(b) 2-cMoro-4-1rifluoromemyl-pyrimidine-5-
carboxylic acid cyclohexylmethyl-amide (100 mg) and 3,5-difluoroaniline (200 mg, ex Lancaster)
afforded the title compound (110 mg).
NMR (DMSO-d6) 8 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.5 (IH, m), 1.6-1.75 (5H, m), 3.09 (2H,
t), 6.89 (IH, t), 7.54 (2H, d), 8.60 (IH, t), 8.85 (IH, s), 10.80 (IH, s).
LC/MS, t = 3.74 min, Molecular ion observed [MH+] = 415 consistent with the molecular
formula C19H19F5N4O.
Example 170: 2-(4-CMoro-2-trifluoTomemvlphenvlamino)^-trifluoromethvl-Dvrimidine-5-
carboxvlic acid cvclohexvlmethvl-amide
(Figure Removed)
in a manner similar to Example 166GW847367X(b) 2-cMoro-4-trifluoromemyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (80 mg) and 4-chloro-2-trifluoromethylaniline (107 mg, ex Lancaster) afforded, after purification by mass-directed autopreparation technique, the title compound (6 mg).
NMR (DMSO-d6) 5 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.5 (1H, m), 1.55-1.75 (5H, m), 3.06 (2H, t), 7.76 (1H, d), 7.88 (1H, d), 7.97 (1H, s), 8.56 (1H, t), 8.70 (1H, s), 10.15 (1H, s). LC/MS, t = 3.97 min, Molecular ion observed [MH4! = 481 consistent with the molecular formula C2oH1935ClF6N40.
Example 171: 2-f3-CVanophenvlammoM-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide GW850212X

(Figure Removed)
To a solution of 2-chloro-4-trifluoromemyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (50 mg) in acetonitrile (0.5 ml) was added 3-aminobenzonitrile (92 mg, ex Aldrich) and the solution heated at 200°C under microwave conditions for 45 minutes. Acetonitrile was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 2N hydrochloric acid (2x3 ml) and water (3x3 ml), dried (MgS04), evaporated and the residue purified using silica gel chromatography with 1:1 ethyl acetate:isohexane to afford the title compound (37 mg).
NMR (DMSO-d6) 8 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.5 (1H, m), 1.6-1.8 (5H, m), 3.08 (2H, t), 7.50 (1H, d), 7.57 (1H, t), 8.00 (1H, d), 8.25 (1H, s), 8.59 (1H, t), 8.83 (1H, s), 10.75 (1H, s). LC/MS, t = 3.51 min, Molecular ion observed [Mff*"] = 404 consistent with the molecular formula C20H20F3N5O.
Example 172: 2-f3-CVanophenvlammoV4-1rifluoromemvl-pvrinudine-5-carboxvlic acid
rtetrahvdropvran-4-vlmethvn-amide GW851296X
(Figure Removed)
in a manner similar to Reference Example 1(c) 2-(3-cyanophenylamino)-4-trifluoro-
methylpyrimidine-5-carboxylic acid (32 mg) and 4-aminomethyltetrahydropyran(14 mg, ex
Combi Blocks) afforded the title compound (26 mg).
NMR (DMSO-d6) 8 1.15-1.25 (2H, m), 1.62 (2H, d), 1.74 (IH, m), 3.14 (2H, t), 3.27 (2H, t), 3.86
(2H, d of d), 7.50 (IH, d), 7.57 (IH, t), 8.00 (lH.d), 8.26 (IH, s), 8.65 (IH, t), 8.85 (IH, s), 10.70
(IH, s).
LC/MS, t = 2.94 min, Molecular ion observed [MH*] = 406 consistent with the molecular
formula C19H18F3N5O2.
Example 173:2-(3-CvanophenvlammoM-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide GW851298X
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(3-cyanophenylamino)-4-trifluoro-methylpyrimidine-5-carboxylic acid (32 mg) and cyclopentanemethanamine hydrochloride (17 mg) afforded the title compound (16 mg).
NMR (DMSO-d6) 8 1.20-1.30 (2H, m), 1.45-1.6 (4H, m), 1.65-1.75 (2H, m), 2.08 (IH, quintuplet), 3.19 (2H, t), 7.50 (IH, d), 7.57 (IH, t), 8.00 (IH, d), 8.25 (IH, s), 8.63 (IH, t), 8.82 (IH, s), 10.70 (IH, s).
LC/MS, t = 3.42 min, Molecular ion observed [MH"1"] = 390 consistent with the molecular formula C19H18F3N5O.
Example 174:2-(4-CvanophenvlaminoV4-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide GW851391X
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(4-cyanophenylamino)-4-trifluoro-
methylpyrimidine-5-carboxylic acid (32 mg) and cyclohexanemethanamine (16 ul, ex Lancaster)
afforded the title compound (18 mg).
NMR (DMSO-d6) 8 0.85-1.0 (2H, m), 1.1-1.25 (3H, m), 1.5 (IH, m), 1.6-1.8 (5H, m), 3.08 (2H,
t), 7.81 (2H, d), 7.97 (2H, d), 8.61 (IH, t), 8.85 (IH, s), 10.90 (IH, s).
LC/MS, t = 3.51 min, Molecular ion observed [MH4] = 404 consistent with the molecular
formula C20H20F3N5O.
Example 175:2-f4-CVanophenvlanunoM-trifluoromemvl-pvrimidine-5-carboxvlic acid ftetrahvdropvran-4-vlmethvn-amide GW851392X
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(4-cyanophenylamino)-4-trifiuoro-
methylpyrimidine-5-carboxylic acid (32 mg) and 4-aminomethyltetrahydropyran (14 mg, ex
Combi Blocks) afforded the title compound (6 mg).
NMR (DMSO-d6) S 1.15-1.25 (2H, m), 1.60 (2H, d), 1.75 (IH, m), 3.14 (2H, t), 3.27 (2H, t), 3.86
(2H, d), 7.82 (2H, d), 7.97 (2H, d), 8.67 (IH, t), 8.87 (IH, s), 10.85 (IH, s).
LC/MS, t = 2.92 min, Molecular ion observed [MH4] = 406 consistent with the molecular
formula C19H18F3N5O2.
Example 176:2-(4-CVanophenvlammoM-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide GW851393X
(Figure Removed)
In a manner similar to Reference Example 1(c) 2-(4-cyanophenylamino)-4-trifluoro-methylpyrimidine-5-carboxylic acid (32 mg) and cyclopentanemethanamine hydrochloride (17 mg) afforded the title compound (22.5 mg).
NMR (DMSO-d6) 8 1.15-1.30 (2H, m), 1.45-1.65 (4H, m), 1.65-1.75 (2H, m), 2.08 (IH, quintuplet), 3.17 (2H, t), 7.82 (2H, d), 7.97 (2H, d), 8.64 (IH, t), 8.84 (IH, s), 10.90 (IH, s). LC/MS, t = 3.40 min, Molecular ion observed [MH+] = 390 consistent with the molecular formula C19H18F3N5O.
Example 177:2-(3-Memoxv-5-(trifluoiiomemvl)phenvlamino)-4-trifluoromemvl-pvrirmdine-S-carboxvlic acid (tetrahvdropvran-4-vlmethvl)-amide GW867012X
(a). To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carbonyl chloride (1.5 g) in dichloromethane (20 ml) at -2° was added a dropwise a solution of 4-aminomethyltetrahydropyran (0.70 g, ex Combi Blocks) and triethylamine (1.05 ml) in dichloromethane (10 ml) and the solution stirred at 0° for 1 hour. Dichloromethane was removed under reduced pressure and ethyl acetate (30 ml) added. The solution was washed with 2N hydrochloric acid (3 x 20 ml), dried (MgS04), evaporated and the residue purified using silica gel chromatography with 1:1 ethyl acetate:isohexane to afford 2-chloro-4-trifluoromemyl-pyrirnidin-5-carboxylic acid (tetrahydropyran-4-yl-methyl)-amide (GW877060A, 1.20 g).
NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.61 (2H, d), 1.74 (IH, m), 3.17 (2H, t), 3.25 (2H, t), 3.86 (2H, d of d), 8.81 (IH, t), 9.20 (IH, s).
LC/MS, t = 2.54 min, Molecular ion observed [MH"1"] = 324 consistent with the molecular formula CzH^^ClFjNaOz. .

(Formula Removed)
(b). In a manner similar to Example 166(b), GW847367X 2-cUoro-4-trifluoromemyl-pyrimidin-
5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg) and 3-methoxy-5-
(trifluoromethyl)aniline (148 mg, ex Aldrich) afforded after stirring at reflux for 24 hours the title
compound (51 mg).
NMR (DMSO-d6)8 1.15-1.3 (2H, m), 1.62 (2H, d), 1.74 (IH, m), 3.13 (2H, t), 3.27 (2H, t), 3.83
(3H, s), 3.86 (2H, d), 6.92 (IH, s), 7.73 (IH, s), 7.80 (lH,s), 8.64 (IH, t), 8.85 (IH, s), 10.65 (IH,
s).
LC/MS, t = 3.38 min, Molecular ion observed [MH4^ = 479 consistent with the molecular
formula C20H20F6N4O3.
(Figure Removed)
Example 178: 2-(3.5-Bis-trifluoromethvlphenvlaminol-4-trifluoromethvl-pvrirnidine-5-carboxvlic acid ftelrahvdiopvran-4-vlmethvlVamide GW867013X
(Figure Removed)
Li a manner similar to Example 166GW847367X(b) 2-chloro-4-trifluorornethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg) and 3,5-bis(thfluoromethyl)aniline (177 mg, ex Aldrich) afforded, after stirring at reflux for 80 hours and purification by mass-directed autopreparation technique, the title compound (24.5 mg).
NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.62 (2H, d), 1.75 (IH, m), 3.14 (2H, t), 3.28 (2H, t), 3.86 (2H, d), 7.72 (IH, s), 8.49 (2H, s), 8.67 (IH, t), 8.93 (IH, s), 11.05 (IH, s). LC/MS, t = 3.62 min, Molecular ion observed [MH4] = 517 consistent with the molecular formula C20H17F9N4O2.
Example 179: 2-(3-Bromo-5-ftrifluoromemvl)phenvlammo)-4-1rifluoromemvl-PVi™idine-5-
carboxvlic acid (teJrahvdropvran-4-vlmemvlVamide GW867014X
(Figure Removed)
in a manner similar to Example 166GW847367X(b) 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg) and 3-bromo-5-(trifluoro-methyl)aniline (185 mg, ex Avocado) afforded, after stirring at reflux for 80 hours and purification by mass-directed autopreparation technique, the title compound (28 mg). NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.62 (2H, d), 1.74 (IH, m), 3.14 (2H, t), 3.28 (2H, t), 3.86 (2H, d), 7.60 (IH, s), 8.24 (IH, s), 8.29 (IH, s), 8.66 (IH, t), 8.99 (IH, s), 10.90 (IH, s). LC/MS, t = 3.63 min, Molecular ion observed [M-H]" = 527 consistent with the molecular formula d^Hn^BrFsN^.
Example 180:2-(3-Fluoro-5-ftrifluoromemvl)phenvlannno)-4-trifluoromemvl-pvrimidine-S-carboxvlic acid ftetrahydrotivran-4-ylmethvlVamide GW867015X
(Figure Removed)
In a manner similar to Example 166GW847367X(b) 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg) and 3-fluoro-5-(trifluoromethyl)aniline (138 mg, ex Fluorochem) afforded after stirring at reflux for 24 hours the title compound (44 mg).
NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.62 (2H, d), 1.75 (IH, m), 3.14 (2H, t), 3.28 (2H, t), 3.86 (2H, d), 7.32 (IH, d), 7.96 (IH, d), 8.06 (IH, s), 8.67 (IH, t), 8.90 (IH, s), 10.90 (IH, s). LC/MS, t = 3.45 min, Molecular ion observed [MH+] = 467 consistent with the molecular formula C19H17F7N4O2.
Example 181:2-(2-Fluoro-3-f1rifluoromemvl)Dhenvlammo'>-4-trifluoromethvl-pvrimidine-5-carboxvlic acid ftetrahvdropvran-4-vlmethvlVamide GW867018X
(Figure Removed)
In a manner similar to Example 166GW847367X(b) 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg) and 2-fluoro-3-(trifluoromethyl)aniline (138 mg, ex Aldrich) afforded, after stirring at reflux for 80 hours and purification by mass-directed autopreparation technique, the title compound (15 mg). NMR (DMSO-d6) 8 1.1-1.25 (2H, m), 1.60 (2H, d), 1.73 (IH, m), 3.11 (2H, t), 3.26 (2H, t), 3.85 (2H, d), 7.43 (IH, t), 7.61 (IH, t), 7.92 (IH, s), 8.63 (IH, t), 8.72 (IH, s), 10.30 (IH, s). LC/MS, t = 3.28 min, Molecular ion observed [Mff*"] = 467 consistent with the molecular formula C19H17F7N4O2.
Example 182: 2-(2-Memvlthio-3-(lrifluoromemvl>phenvlammoV4^ carboxvlic acid ftetrahvdropvran^-vlmethvlVamide GW868558X
(Figure Removed)
SCH3 2-CMoro-4-1rifluoromemyl-pyrimidm-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg), 2-methylthio-3-(trifluoromethyl)aiiiline (125 mg, ex Maybridge) and acetonitrile (0.5ml) were heated at 190° under microwave irradiation for 30 minutes. The solvent was evaporated in vacuo and the residue purified by mass-directed autopreparation technique, to give the title compound (11 mg).
NMR (DMSO-d6) S 1.1-1.25 (2H, m), 1.60 (2H, d), 1.73 (1H, m), 2.24 (3H, s), 3.12 (2H, t), 3.26 (2H, t), 3.85 (2H, d), 7.65 (2H, d), 8.11 (1H, t), 8.64 (1H, t), 8.72 (1H, s), 9.81 (1H, s). LC/MS, t = 3.53 min, Molecular ion observed [MH4"] = 495 consistent with the molecular formula C2oH2oF6N402S.
Example 183: 2-f5-Chloro-2-methvlphenvlamino)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid fcvclopentvlmethvlVamide GW868561X
(a). To a solution of 2-chloro-4-trifluoromethyl-pvrimidin-5-carbonyl chloride (1.0 g, ex Maybridge) in dichloromethane (7 ml) at -2° was added a dropwise a solution of cyclo-pentanemethanamine hydrochloride (0.55 g) and triethylamine (1.4 ml) in dichloromethane (13 ml) and the solution stirred at 0° for 1 hour. Dichloromethane was removed under reduced pressure and ethyl acetate (20 ml) added. The solution was washed with 2N hydrochloric acid (3 x 15 ml), dried (MgS04), evaporated and triturated with isohexane to afford 2-chloro-4-trifluoromemyl-pyrimidin-5-carboxylic acid (cyclopentylmethyl)-amide ((GW848813X, 838 mg). NMR (DMSO-d6) 8 1.1-1.3 (2H, m), 1.45-1.65 (4H, m), 1.65-1.8 (2H, m), 2.07 (1H, quintuplet), 3.20 (2H, t), 8.78 (1H, t), 9.17 (1H, s).
LC/MS, t = 3.22 min, Molecular ion observed [M-H]" = 306 consistent with the molecular formula C12H,335C1F3N30. CI (b). In a manner similar to Example 166GW847367X(b) 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethylamide (47.5 mg) and 5-chloro-2-methylaniline (110 mg, ex Aldrich) afforded after stirring at reflux for 30 hours the title compound (41 mg). NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.4-1.6 (4H, m), 1.65-1.75 (2H, m), 2.06 (1H, quintuplet), 2.20 (3H, s), 3.14 (2H, t), 7.19 (1H, d), 7.29 (1H, d), 7.48 (1H, s), 8.55 (1H, t), 8.63 (1H, s), 9.83 (1H, s).
LC/MS, t = 3.68 min, Molecular ion observed [MH"1"] = 413 consistent with the molecular formula CsH^ClFjN^.
(Figure Removed)
Example 184:2-f3-Chloro-4-methvlphenvlamino^-4-trifluoromethvl-pvrimidine-5-carboxvlic acid ftetrahvdropvran-4-vlmethvP-amide GW870025X
(Figure Removed)
In a manner similar to Example 166GW847367X(b) 2-cWoro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg) and 3-chloro-4-methyl-aniline (109
mg) afforded, after stirring at reflux for 24 hours and purification by mass-directed
autopreparation technique, the title compound (35 mg).
NMR (DMSO-d6) 5 1.15-1.3 (2H, m), 1.61 (2H, d), 1.74 (IH, m), 2.28 (3H, s), 3.13 (2H, t), 3.27
(2H, t), 3.86 (2H, d of d), 7.31 (IH, d), 7.56 (IH, d), 7.94 (IH, s), 8.61 (IH, t), 8.79 (IH, s), 10.50
(1H,S).
LC/MS, Molecular ion observed [MH+] = 429 consistent with the molecular formula
Cls>H2o35ClF3N402.
Example 185:2-f3-Chloro-2-memvlphenvlammo^-4-trifluoromefcvl-pvrimidme-5-carboxvlic acid ftetrahvdropvran-4-vlmethvlVamide GW870030X
(Figure Removed)
In a manner similar to Example 166GW847367X(b) 2-cUoro-4-trifluoromemyl-pyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmemyl)-amide (50 mg) and 3-chloro-2-methyl-aniiine (109 mg, GR20291IX, known compound CAS No 87-60-5) afforded, after stirring at reflux for 24 hours and purification by mass-directed autopreparation technique, the title compound (30 mg). NMR (DMSO-d6) 5 1.1-1.25 (2H, m), 1.59 (2H, d), 1.72 (IH, m), 2.21 (3H, s), 3.10 (2H, t), 3.26 (2H, t), 3.84 (2H, d of d), 7.24 (IH, t), 7.3 (2H, m), 8.56 (IH, t), 8.61 (IH, s), 9.99 (IH, s). LC/MS, t = 3.19 min, Molecular ion observed [MET1"] = 429 consistent with the molecular formula QSHJO^CIFSN^.
Example 186: 2-f4-C!hloro-3-memoxvphenvlammoM-trifluorome&vl-Pvrimidme-5-car^ acid (tetrahvdropvran-4-vlmethvl")-amide GW870034X
(Figure Removed)
in a manner similar to Example 166GW847367X(b) 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmetfayl)-amide (50 mg) and 4-chloro-3-methoxy-aniline (122 mg GR251112X) afforded, after stirring at reflux for 24 hours and purification by mass-directed autopreparation technique, the title compound (33 mg).
NMR (DMSO-d6) 8 1.1-1.25 (2H, m), 1.61 (2H, d), 1.73 (IH, m), 3.13 (2H, t), 3.27 (2H, t), 3.83 (3H, S), 3.86 (2H, d), 7.27 (IH, d), 7.37 (IH, d), 7.81 (IH, s), 8.63 (IH, t), 8.80 (IH, s), 10.50 (1H,S).
LC/MS, t = 3.26 min, Molecular ion observed [MH+] = 445 consistent with the molecular formula CJ^O^CIFJN^.
Example 187: 2-f4-Chloro-3-memvlphenvlamino)-4-trifluoromethvl-Dvrimidme-5-carboxvlic acid ftetrahvdropvran-^-vlmethvn-amide GW872977X
(Figure Removed)
In a manner similar to Example 166GW847367X(b) 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg) and 4-chloro-3-methyl-aniline (109
mg, ex Lancaster) afforded, after stirring at reflux for 24 hours and purification by mass-directed
autopreparation technique, the title compound (33 mg).
NMR (DMSO-d6) 8 1.15-1.3 (2H, m), 1.61 (2H, d), 1.73 (IH, m), 2.31 (3H, s), 3.12 (2H, t), 3.27
(2H, t), 3.86 (2H, d), 7.37 (IH, d), 7.62 (IH, d), 7-72 (IH, s), 8.61 (IH, t), 8.77 (IH, s), 10.45
(IH, s).
LC/MS, t = 3.41 min, Molecular ion observed [MH"1"] = 429 consistent with the molecular
formula CHJHM^CIFSN^.
Example 188:2-(3-CMorophenvlaininoM-trifluoromethvl-Pvrimidine-5-carboxvlic acid cvclobutvlmethvl-methvl-amide GW 848S55X
a)GW848545XN-(Cyclobutylmethyl)-2,2,2-trifluoroacetamide
C-cyclobutyl-methylamine hydrochloride (1.82g) was added to a solution of N,N-diisopropylethylamine (4.14g) in dry tetrahydrofuran (30ml) at 0°C. The mixture was stirred at 0°C for 5mins then cooled to -20°C. A solution of trifluoroacetic anhydride (3.57g) in
tetrahydrofuran (10ml) was added dropwise over lOmins and the mixture was then allowed to stir
at room temperature for 1 hour. The solution was diluted with ether (100ml) and water (75ml),
separated and the organic layer washed with water, dilute hydrochloric acid, water and brine,
dried (MgS04) and evaporated to give the title compound (2.63g)
NMR (CDClj) 8 1.70 (2H, m excess), 1.93 (2H, m), 2.10 (2H, m), 2.53 (1H, m), 3.39 (2H, t), 6.2
(lH,brs).
b)GW848547XNK N-(Cyclobutylmethyl)-2,2,2-trifluoroacetamide (2.62g) (GW848545X) and iodomethane (3.6ml) were dissolved in dry acetone (75ml). Powdered potassium hydroxide (3.2g) was added and the mixture heated at reflux for 5 mins. The excess iodomethane and acetone were removed under reduced pressure, water (75ml) added and the solution heated at reflux for 1 hour. The mixture was cooled and ether (75ml) added. The layers were separated and the organic layer was extracted with dilute hydrochloric acid (75ml). The aqueous extract was washed with ether, then made strongly basic with sodium hydroxide and extracted with ether (2 x 75ml). The extracts were dried (K2C03) and evaporated to give the title compound (517mg) NMR (CDCI3) 8 1.3 (1H, m excess), 1.65 (2H, m), 1.9 (2H, m), 2.05 (2H, m), 2.45 (4H, m), 2.55 (2H,d).
c) 2-(3-CMorophenylammo)^trifluorome1hyl-pyrimidine-5-carboxylic acid cyclobutylmethyl -methyl-amide GW 848555X


(Figure Removed)
To a solution of N-(cyclobutylmethyl)-N-methylamine (17mg)GW848547X in
dimethylformamide (1.5 ml) was added successively, 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg), N,N-diisopropylethylamine(38ul), 1-
hydroxybenzotriazole hydrate (23 mg) and l-(3-dimemylarnino-propyl)-3-ethylcarbodiimide
hydrochloride (25 mg). The solution was stirred overnight. Dimethylformamide was removed
under reduced pressure and ethyl acetate (10 ml) added. The solution was washed sequentially
with 10ml portions of water, saturated sodium bicarbonate solution, water, dilute hydrochloric
acid, water and brine, dried (MgS04) and evaporated to give the title compound (31 mg).
NMR (DMSO-d6) Rotamers in 60:40 ratio 8 1.5-2.1 (6H, m), 2.50 (0.4H, m excess), 2.65 (0.6H,
m), 2.84 (1.8H, s), 2.94 (1.2H, s), 3.22 (0.4H, d), 3.50 (1.6H, br s), 7.09 (1H, d), 7.36 (1H, m),
7.66 (1H, m), 7.96 (1H, s), 8.76 (1H, d), 10.5 (1H, s).
LC/MS t = 3.66 min, Molecular ion observed (MH*) = 399 consistent with the molecular formula Cl8Hl835ClF3N40
Example 189:2-f3-QiloropherwlammoV4-1rifluoromemvl-Dvrirnidine-5-carboxvlic acid cvclohexvlmethvl-methvl-amide. GW 848546X
a) N-(Cyclohexylmethyl)-2,2,2-trifluoroacetamide GI182467X
In a manner similar to Example 188a) GW848545X cyclohexanemethanamine (2.83g)
(Lancaster) gave the title compound (5.09g).
NMR (CDCI3) 8 0.95 (2H, m), 1.22 (3H, m), 1.54 (IH, m excess), 1.70 (5H, m), 3.21 (2H, t), 6.3
(lH,brs).
b) N-(Cyclohexylmethyl)-N-methylamine
GW407975X
In a manner similar to Example 188b) GW848547XN-(cyclohexylmethyl)-2,2,2-
trifluoroacetamide (2.98g) GI182467X gave the title compound (1.41g).
NMR (CDCI3) F6496 8 0.9 (2H, m), 1.23 (4H, m), 1.46 (IH, m excess), 1.72 (5H, m), 2.4 (5H,
m).
c) 2-(3-CMoTophenylammo)^trifluoromemyl-pyrimidine-5-carboxylic acid cyclohexylmethyl -
methyl-amide.
In a manner similar to Example 188c) GW848555X 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and N-(cyclohexylmethyl)-N-methylamine (21nig)
GW407975X gave the title compound.
NMR (DMSO-d6) Rotamers in 63:37 ratio 8 0.65-1.30 (5H, m), 1.5-1.8 (6H, m), 2.87 (1.9H, s),
2.97 (1.1H, s), 3.03 (0.7H, d), 3.30 (1.3H, d excess), 7.09 (IH, d), 7.36 (IH, m), 7.66 (IH, d),
7.96 (IH, m), 8.73 (0.37H, s), 8.78 (0.63H, s), 10.6 (IH, s).
LC/MS t = 3.87 min, Molecular ion observed (MH*) = 427 consistent with the molecular formula
C20H2235ClF3N4O
(Figure Removed)
Example 190:2-(3-CMorophenvlamino^-4-trifluorome1hvl-pvrinuQ^ne-5-carboxvlic acid cvclopentvlmethvl-methvl-amide GW848556X
a) N-(Cyclopentylmethyl)-2,2,2-trifluoroacetamide GW848549X
In a manner similar to Example 188a)GW848545X (cyclopentylmethyl)amine (1.02g) (Example
2) gave the title compound (1.47g).
NMR (CDCI3) 8 1.21 (2H, m), 1.4 (4H, m), 1.78 (2H, m), 2.10 (lH,m), 3.31 (2H, t), 6.3 (IH, br
s).
b) N-(Cyclopentylmethyl)-N-metiiylamine hydrochloride GW848552A
In a manner similar to Example 188b)GW848547X N-(cyclopentylmethyl)-2,2,2-trifluoroacetamide(1.46g) gave, after treatment with hydrogen chloride in 1,4-dioxan, the title compound (0.77g). NMR (D20) 8 1.12 (2H, m), 1.5 (4H, m), 1.75 (2H, m), 2.08 (1H, m), 2.61 (3H, s), 2.90 (2H, d).
c) 2-(3-Chlorophenylammo)^-trifluoromemyl-pyrimidme-5-carboxylic acid cyclopentylmethyl -
methyl-amide GW 848556X
(Figure Removed)
In a manner similar to Example 188c) GW848555X 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35 mg) and N-(cyclopentylmethyl)-N-methylamine hydrochloride
(21mg) (Example 190b)GW848552A) together with an additional equivalent of N,N-
diisopropylethylamine gave the title compound (42mg)
NMR (DMSO-d6) Rotamers in 65:35 ratio 5 1.0-1.8 (8H, m), 2.13 (0.35H, m), 2.27 (0.65H, m),
2.88 (1.95H, s), 2.99 (1.05H, s), 3.14 (0.7H, d), 3.41 (1.3H, br s), 7.09 (1H, d), 7.36 (1H, t), 7.66
(1H, d), 7.96 (1H, m), 8.77 (1H, s), 10.6 (1H, s).
LC/MS t = 3.77 min, Molecular ion observed (MH*) = 413 consistent with the molecular
formula Ci9H2035ClF3N4O
Example 191:2-(5-Chloro-2-fluorophenvlaminoM-1rifluoromemvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 849408X
a) 2-Qiloro-4-trifluoromethyl-pvrimidine-5-carboxylic acid cyclobutylmethyl-amide
GW849406X
(Figure Removed)
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine-5-carbonyl chloride (613mg) (Maybridge) and C-cyclobutylmethylamine hydrochloride (304mg) in dry dichloromethane (10ml) was cooled to -30°C and N,N-diisopropylethylamine (958ul) was added dropwise. The mixture was stirred at room temp for 1 hour. Water (10ml) was added, the layers separated and the organic layer was washed sequentially with 10ml portions of water, dilute hydrochloric acid, water, dilute sodium bicarbonate solution and water, dried (MgS04) and evaporated. Purification by chromatography on silica gel (dichloromethane/ether 25:1) gave the title compound (449 mg). NMR (CDC13) 5 1.75 (2H, m), 1.93 (2H, m), 2.10 (2H, m), 2.57 (1H, m), 3.50 (2H, t), 5.86 (1H,
br s), 8.90 (1H, s).
b) 2-(5-CMoro-2-fluorophenylammo)^-1rifluoromemyl-pyrimidme-5-carboxylic acid cyclobutylmethyl-amide
GW 849408X
(Figure Removed)
In a manner similar to Example 166, GW 847367X, S-chloro-2-fluoroaniline (109mg) (Avacado)
and 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide (44 mg)
GW849406X gave the title compound (45mg).
NMR (DMSO-d6) 5 1.7 (2H, m), 1.8 (2H, m), 1.99 (2H, m), 2.47 (1H, m excess), 3.25 (2H, t),
7.3 (2H, m), 7.76 (1H, m), 8.56 (1H, t), 8.70 (1H, s), 10.2 (1H, s)
LC/MS t = 3.52 min, Molecular ion observed (MET) = 403 consistent with the molecular
formula CnH^SciF^O
Example 192:2-f3.5-Difluorophenvlammo)-4-trifluoromemvl-p\Timidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 849409X
(Figure Removed)

Li a manner similar to Example 166, GW 847367X, 3,5-difluoroaniline (97mg) (Lancaster) and
2-chloro-4-1rifluoromemyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide (44 mg) gave
the title compound (46mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.27 (2H, t),
6.88 (1H, m), 7.55 (2H, m), 8.60 (1H, t), 8.83 (1H, s), 10.8 (1H, s)
LC/MS t = 3.54 min, Molecular ion observed (MET) = 387 consistent with the molecular formula C17H15F5N4O
Example 193:2-(3-Oiloro-4-trifluoromemoxvphenvlammo^-trifluoromelJivl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850292X
(Figure Removed)
In a manner similar to Example 166, GW847367X 3-chloro-4-trifluoromethoxy aniline (159mg) (Lancaster) and 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide (44 mg) gave the title compound (59mg).
NMR (DMS0-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.27 (2H, t), 7.56 (1H, d), 7.76 (1H, m), 8.16 (1H, d), 8.59 (1H, t), 8.81 (1H, s), 10.8 (1H, s) LC/MS t = 3.82 min, Molecular ion observed (MH*) = 469 consistent with the molecular formula CjgH1s^ClFsN^
Example 194:2-f3-Chloro^fluorophenvlanimoM-1rifluoromemvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850297X
In a manner similar to Example 166, GW847367X 3-chloro-4-fluoroamline (109mg) (Lancaster)
and 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cycloburylmethyl-amide (44 mg)
gave the title compound (50mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.27 (2H, t),
7.42 (1H, t), 7.67 (1H, m), 8.04 (1H, m), 8.57 (1H, t), 8.77 (1H, s), 10.6 (1H, s)
LC/MS t = 3.60 min, Molecular ion observed (MH4) = 403 consistent with the molecular
formula C17H1535C1F4N40
Example 195: 2-(3-CMoro-2-fluorophenvlanu^o^^1rifluoromethvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850299X
In a manner similar to Example 166, GW847367X3-chloro-2-fluoroaniline (109mg) (Acres) and
2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide (44 mg) gave
the title compound (47mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.23 (2H, t),
7.22 (1H, t), 7.42 (1H, t), 7.54 (1H, t), 8.55 (1H, t), 8.65 (1H, s), 10.2 (1H, s)
LC/MS t = 3.49 min, Molecular ion observed (MH4) = 403 consistent with the molecular formula
C17H1535C1F4N40
Example 196: 2-f3-Fluoro-4-1rifluoromemvlphenvlaminoV4-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850302X
(Figure Removed)
In a manner similar to Example 166, GW847367X, 3-fluoro-4-trifluoromethylaniline (134mg)
(ABCR) and 2-chloro^trifluoromethyl-pyrimidine-5-carboxylic acid C-cyclobutylmethyl-amide
(44 mg) gave the title compound (41mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.26 (2H, t),
7.67 (1H, d), 7.75 (1H, t), 8.02 (1H, d), 8.62 (1H, t), 8.87 (1H, s), 11.0 (1H, s)
LC/MS t = 3.71 min, Molecular ion observed (MH*) = 437 consistent with the molecular formula C i gHj 5F7N4O
Example 197:2-f3-Chloro-4-cvanophenvlammoV4-1rifluorome^ acid
cvclobutvlmethvl-amide GW 85031SX
In a manner similar to Example 166, GW847367X 3-chloro-4-cyanoaniline (114mg) (Lancaster)
and 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide (44 mg)
gave the title compound (26mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.27 (2H, t),
7.83 (1H, m), 7.93 (1H, d), 8.24 (1H, s), 8.62 (1H, t), 8.89 (1H, s), 11.1 (1H, s)
LC/MS t = 3.50 min, Molecular ion observed (MH4) = 410 consistent with the molecular
formula C18H1s^Cn^NsO
Example 198:2-f3-FluorophenvlamuioM-trifluoromethvl-pvriniidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850629X
In a manner similar to Example 188, GW 848555X2-(3-fluorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (30 mg) and C-cyclobutylmethylamine hydrochloride (18mg) gave
the title compound (31mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.26 (2H, t),
6.86 (1H, m), 7.37 (1H, m), 7.50 (1H, d), 7.76 (1H, m), 8.58 (1H, t), 8.78 (1H, s), 10.6 (1H, s)
LC/MS t = 3.42 min, Molecular ion observed (MH4) = 369 consistent with the molecular formula
C17H16F4N4O
Example 199: 2-G-Bromophenvlamino')-4-trifluoromethvl-pvriniidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850630X
(Figure Removed)
m a manner similar to Example 188, GW 848SSSX 2-(3-bromophenylamino)-4-trifluoromethyl-
pyrimidine-S-carboxylic acid (36 mg) and C-cyclobutylmethylamine hydrochloride (18mg) gave
the title compound (33mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.26 (2H, t),
7.22 (1H, d), 7.31 (1H, t), 7.70 (1H, d), 8.10 (1H, t), 8.57 (1H, t), 8.78 (1H, s), 10.6 (1H, s)
LC/MS t = 3.60 min, Molecular ion observed (MH*) = 431 consistent with the molecular formula
Ci7H168lBrF3N40
Example 200:2-f2.3-Dichlorophenvlamino')-4-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 85063IX
(Figure Removed)
In a manner similar to Example 188.GW 848555X 2-(2,3-dichlorophenylamino)-4-
trifluoromethyl-pyrmiidine-5-carboxylic acid (36 mg) and C-cyclobutylmethylamine
hydrochloride (18mg) gave the title compound (36mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.24 (2H, t),
7.40 (1H, t), 7.54 (2H, m), 8.54 (1H, t), 8.63 (1H, s), 10.1 (1H, s)
LC/MS t = 3.61 min, Molecular ion observed (MH*) = 419 consistent with the molecular formula
c17H1535cl2F3N4°
Example 201:2-(2.4-DichlorophenvlaminoV4-trifluoromethvl-pvrimidine-5-carboxYlic acid cvclobutvlmethvl-amide GW 850632X
(Figure Removed)
In a manner similar to Example 188,GW 848555X 2-(2,4-dichlorophenylamino)-4-
trifluoromethyl-pyrimidine-5-carboxylic acid (36 mg) and C-cyclobutylmethylamine
hydrochloride (18mg) gave the title compound (37mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.24 (2H, t),
7.47 (1H, m), 7.58 (1H, d), 7.72 (1H, d), 8.54 (1H, t), 8.65 (1H, s), 10.0 (1H, s)
LC/MS t = 3.66 min, Molecular ion observed (MH4) = 419 consistent with the molecular formula
CnH^SSc^N^
Example 202:2-f2.5-DicMoTOphmvlaminoV4-1rifluon^ acid
cvclobutvlmethvl-amide GW 850633X
(Figure Removed)
In a manner similar to Example 188, GW 848SSSX 2-(2,5-dichlorophenylamino)-4-
trifluoromethyl-pyrimidine-5-carboxylic acid (36 mg) and C-cyclobutylmethylamine
hydrochloride (18mg) gave the title compound (33mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (IH, m excess), 3.24 (2H, t),
7.34 (IH, m), 7.58 (IH, d), 7.72 (IH, d), 8.55 (IH, t), 8.66 (IH, s), 10.0 (IH, s)
LC/MS t = 3.65 min, Molecular ion observed (MH4) = 419 consistent with the molecular formula
Cl7Hl535Cl2F3N40
Example 203:2-(2.6-DicMorophenvlaminoM-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850634X
(Figure Removed)

In a manner similar to Example 188, GW 848555X 2-(2,6-dichlorophenylamino)-4-
trifluoromethyl-pyrimidine-5-carboxylic acid (36 mg) and C-cyclobutylmethylamine
hydrochloride (18mg) gave the title compound (35mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (IH, m excess), 3.22 (2H, t),
7.39 (IH, t), 7.59 (2H, d), 8.56 (2H, m), 10.1 (IH, s).
LC/MS t = 3.38 min, Molecular ion observed (MH*) = 419 consistent with the molecular formula
Ci7H1535ci2F3N40
Example 204:2-G.4-IMchlorophenvlamino')-4-trifluoromethvl-Pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850635X
(Figure Removed)
In a manner similar to Example 188, GW 848555X 2-(3,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidiiie-5-carboxylic acid (36 mg) and C-cyclobutylmethylamine hydrochloride (18mg) gave the title compound (36mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.26 (2H, t),
7.60 (1H, d), 7.69 (1H, m), 8.16 (1H, d), 8.58 (1H, t), 8.80 (1H, a), 10.7 (1H, s)
LC/MS t = 3.77 min, Molecular ion observed (MH*) = 419 consistent with the molecular formula
Cl7Hl535Cl2F3N40
Example 205:2-(3-MethoxvphenvlairdnoM-trifluorome1hvl-pvrimidine-5-carboxvlic acid
cvclobutvlmethvl-amide GW 850640X

(Figure Removed)
In a manner similar to Example 188, GW 848555X 2-(3-metnoxyphenylamino)-4-
trifluorometiiyl-pyrimidine-5-carboxylic acid (31 mg) and C-cyclobutylmethylamine
hydrochloride (18mg) gave the title compound (38mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.26 (2H, t),
3.74 (3H, s), 6.63 (1H, d), 7.24 (2H, m), 7.52 (1H, s), 8.56 (1H, t), 8.72 (1H, s), 10.4 (1H, s)
LC/MS t = 3.35 min, Molecular ion observed (MH*) = 381 consistent with the molecular formula
C18H19F3N4O2
Example 206:2-(3.5-Dichlorophenvlamino")-4-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 850642X
(Figure Removed)
In a manner similar to Example 188, GW 848555X 2-(3,5-dichlorophenylamino)-4-
trifluoromethyl-pyrimidine-5-carboxylic acid (36 mg) and C-cyclobutylmethylamine
hydrochloride (18mg) gave the title compound (36mg).
NMR (DMSO-d6) 8 1.7 (2H, m), 1.8 (2H, m), 2.0 (2H, m), 2.47 (1H, m excess), 3.26 (2H, t),
7.60 (1H, d), 7.69 (1H, m), 8.16 (1H, d), 8.58 (1H, t), 8.80 (1H, s), 10.7 (1H, s)
LC/MS t = 3.84 min, Molecular ion observed (MH4) = 419 consistent with the molecular formula
C17H1535ci2F3N40
Example 207: 2-(3-Bromophenvlamino^-4-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclopentvlamide GW 853718X
(Figure Removed)
in a manner similar to Example 188, GW 84855SX 2-(3-bromophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (36 mg) and cyclopentylamine (18mg) gave the title compound
(28mg).
NMR (DMSO-d6) 8 1.5 (4H, m), 1.66 (2H, m), 1.86 (2H, m), 4.16 (1H, m), 7.22 (1H, d), 7.31
(1H, t), 7.70 (1H, d), 8.10 (1H, t), 8.53 (1H, d), 8.79 (1H, s), 10.6 (1H, s)
LC/MS t = 3.39 min, Molecular ion observed (MH4) = 431 consistent with the molecular
formula Ci7Hj681BrF3N40
Example 208:2-f2.4-DichlorophenvlaminoV4-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclopentvlamide GW 853719X
(Figure Removed)
In a manner similar to Example 188, GW 848555X 2-(2,4-dichlorophenylamino)-4-
trifluoromethyl-pyrimidine-5-carboxylic acid (26 mg) and cyclopentylamine (18mg) gave the title
compound (21mg).
NMR (DMSO-d6) 8 1.5 (4H, m), 1.63 (2H, m), 1.84 (2H, m), 4.14 (1H, m), 7.47 (1H, m), 7.56
(1H, d), 7.71 (1H, d), 8.50 (1H, d), 8.62 (1H, s), 10.0 (1H, s)
LC/MS t = 3.40 min, Molecular ion observed (MH4) = 419 consistent with the molecular formula
CnH^Sc^^o
Example 209: 2-f3-CMorophenvlaiiunoM-trifluorome1hvl-Pvrimidine-5-carboxvlic acid cvclopropvlamide GW 842159X:
(Figure Removed)
In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (35mg) and cyclopropylamine (9mg, ex Lancaster) afforded the title
compound (32mg).
NMR (DMSO-d6) 8 0.49-0.52 (2H, m), 0.69-0.74 (2H, m), 2.78 (1H, m), 7.09 (1H, d), 7.36 (1H,
t), 7.65 (1H, d), 7.95 (1H, s), 8.65 (1H, d), 8.80 (1H s), 10.60 (1H, s)
LC/MS, t = 3.25 min, Molecular ion observed (MH4) = 357 consistent with the molecular formula
C15H12N4 0F335C1
F.yampla 210: 2-(3-CMorophenvlammoM-trifluoTomemvl-pvrimid^ine-S-carboxvlic acid C3.3-dimethvlbutvlVamide GW 847199X
(Figure Removed)
in a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (50mg) and 3,3-dimethylbutylamine (17mg, ex Aldrich) afforded
the title compound (32mg).
NMR (DMSO-d6) 8 0.96 (6H, d), 1.85 (1H, m), 3.12 (2H, t), 7.16 (1H, d), 7.42 (1H, t), 7.71 (1H,
d), 8.02 (1H, s), 8.65 (1H, t), 8.86 (1H s), 10.70 (1H, s)
LC/MS, t = 3.49 min, Molecular ion observed (MET) = 373 consistent with the molecular formula
C,6H16N4OF335Cl
Example 211: 2-f3-ChlorophenvlaminoV4-trifluoromethvl-pvrimidine-5-carboxvlic acid methvl-ftetrahvdro-pvran-4-vlmethvn-amide GW 851353X:
(a). To a solution of 4-aminomethyltetrahydropyran (500mg, ex Combi-Blocks, Inc.) in dichloromethane (10ml) at 0°C was added triethylamine (1.2ml) followed by a solution of di-tert-butyl dicarbonate (1.14g) in dichloromethane (4ml). The reaction was stirred at 0°C for lh. Dichloromethane was removed under reduced pressure and ethyl acetate added (10ml). The solution was washed sequentially with 2N hydrochloric acid (10ml), water (10ml), 5% sodium bicarbonate solution (10ml), and water (10ml), dried (MgS04) and evaporated. The residue was purified by chromatography eluting with 2% MeOH/CH2Cl2, to afford N-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (809mg). NMR (DMSO-d6) 8 1.15 (2H, m), 1.45 (9H, s), 1.80-1.95 (3H, d,m), 2.87 (2H, t), 3.30 (2H, t), 3.90 (2H, d,d),6.95(lH,t).
(Figure Removed)
(b). To a solution of N-(te1rahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (800mg) in THF (10ml) at room temperature under nitrogen was added 60% sodium hydride (164mg, ex Aldrich) . portionwise. The reaction was stirred until effervescence had ceased and then methyl iodide (280 ul, ex Lancaster) was added. Stirring was continued at room temperature overnight. THF was removed under reduced pressure and ethyl acetate was added (10ml). This was washed three times with water (10ml), dried (MgS04) and evaporated. The residue was purified by chromatography eluting with 3% MeOH/CH2Cl2, to affoniN-memyl-N-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (745mg).
**\OD
NMR (DMSO-d6) 8 1.15 (2H, m), 1.45 (9H, s), 1.50 (2H, m), 1.80 (1H, m) 2.80 (3H, d), 3.08 (2H, d), 3.28 (2H, t), 3.85 (2H, d).
(Figure Removed)
(c). A solution of N-memyl-N-(ten^ydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (740mg) in 4N hydrochloric acid in 1,4-dioxan (10ml, ex Aldrich) was stirred at room temperature for lh. The dioxan was removed under reduced pressure and the residue triturated with ether. The solid was filtered onto a sinter, washed with ether and dried, to afford N-methyl-N-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (460mg).
NMR (DMSO-d6) 8 1.15 (2H, m), 1.65 (2H, d), 1.95 (IH, m) 2.50 (3H, d), 2.80 (2H, d), 3.30 (2H, t), 3.85 (2H, d), 9.0 (2H, s).
(Figure Removed)
(d). In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (50mg) and N-methyl-N-(tetrahydro-pyran-4-yl methyl) amine
hydrochloride (39mg) afforded, after Biotage chromatography over silica gel, eluting with 1%
MeOH/CH2Cl2, the title compound (33mg).
NMR (DMSO-d6) Rotamers in 65:35 ratio 6 1.05 (0.7H, m), 1.23 (1.3H, m), 1.45 (0.7H, d), 1.58
(1.3H, d), 1.85 (0.35H, m), 2.0 (0.65H, m), 2.89 (1.95H, s), 2.98 (1.05H; s), 3.10-3.40 (4H, m),
3.80 (0.7H, d), 3.88 (1.3H, d), 7.10 (IH, d), 7.36 (IH, t), 7.65 (IH, t), 7.97 (IH, s), 8.75 (0.35H,
s), 8.80 (0.65H, s), 10.6 (IH, s)
LC/MS, t = 3.29 min, Molecular ion observed (MH*) = 429 consistent with the molecular formula
C,9H2oN402F335Cl
(Figure Removed)
Example 212: 2-f2-Fluoro-3-chloro-phenvlaminoV4-trifluoromethvl-pvrimidine-5-carboxvlic acid ftetrahvdro-pvran-4-vlmethvn-amide GW 8S1360X
(Figure Removed)
In a manner similar to Example 166, W847367X, 2-chloro-4-trifiuoromemyl-pyrimidine-5-
carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (lOOmg) and 2-fluoro-3-chloroaniline
(225mg, ex Acros) afforded the title compound (85mg) after purification by trituration with
isohexane.
NMR (DMSO-d6) 8 1.14-1.23 (2H, m), 1.6 (2H, d), 1.72 (IH, m), 3.1 (2H, t), 3.25 (2H, m), 3.85
(2H, d), 7.24 (IH, t), 7.42 (IH, t), 7.55 (IH, t), 8.61 (IH, t), 8.70 (IH, s), 10.20 (IH, s)
LC/MS, t = 3.14 min, Molecular ion observed (MH*) = 433 consistent with the molecular formula
C,8H,7N402F435C1
Example 213:2-f2-Fluoro-5-chloro-phenvlamino')-4-trifluoromethvl-pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmemvlVamide GW 851361X:

(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (lOOmg) and 2-fluoro-S-chloroaniline . (22Smg, ex Avocado) afforded the title compound (96mg) after purification by trituration with isohexane.
NMR (DMSO-d6) 8 1.17-1.23 (2H, m), 1.6 (2H, d), 1.72 (1H, m), 3.1 (2H, t), 3.25 (2H, m), 3.85 (2H, d), 7.27-7.37 (2H, t^n), 7.76 (1H, dd), 8.62 (1H, t), 8.73 (1H, s), 10.15 (1H, s) LC/MS, t = 3.15 min, Molecular ion observed (MH4) = 433 consistent with the molecular formula ClgH17N402F435Cl
Example 214: 2-f3.5-Difluorophenvlamino")-4-trifluoromethvl-pvrimidine-5-carboxvlic acid ftetrahvdro-pvran-^vlmethvlVamide GW 851362X:
(Figure Removed)
m a manner similar to Example 167, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (lOOmg) and 3,5-difluoroaniline (199mg, ex Lancaster) afforded the title compound (98mg) after purification by trituration with isohexane. NMR (DMSO-d6) 8 1.18-1.25 (2H, m), 1.61(2H, d), 1.74 (1H, m), 3.13 (2H, t), 3.27 (2H, m), 3.85 (2H, d), 6.88 (1H, t,), 7.52 7.55 (2H, m), 8.66 (1H, t), 8.86 (1H, s), 10.80 (1H, s) LC/MS, t = 3.18 min, Molecular ion observed (MH4) = 417 consistent with the molecular formula CgHn^OzFs
Example 215: 2-(4-Fluoro-3-chloro-phenvlamino^-4-trifluoiXHnethvl-pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmethvn-amide GW 851363X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (lOOmg) and 4-fluoro-3-chloroaniline (225mg, ex Lancaster) afforded the title compound (134mg) after purification by trituration with isohexane.
NMR (DMS0-d6) 8 1.18-1.23 (2H, m), 1.61 (2H, d), 1.75 (IH, m), 3.1 (2H, t), 3.25 (2H, m), 3.85 (2H, d), 7.42 (IH, t), 7.65 (IH, m), 8.05 (IH, dd), 8.63 (IH, t), 8.80 (IH, s), 10.65 (IH, s) LC/MS, t = 3.25 min, Molecular ion observed (MH*) = 433 consistent with the molecular formula CI8H17N402F435C1
Example 216: 2-(4-Trifluoixmiemoxv-3-chloro-phenvlanuno^^trifluoromemvl-Pvrimidine-5-carboxvlic acid (tetrahvdro-pvran^-vlmethvD-amide GW 851365X:

(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (lOOmg) and 4-trifiuoromethoxy-3-chloroaniline (327mg, ex Lancaster) afforded the title compound (135mg) after purification by trituration with isohexane.
NMR (DMSO-d6) 5 1.18-1.23 (2H, m), 1.61 (2H, d), 1.74 (IH, m), 3.13 (2H, t), 3.25 (2H, m), 3.85 (2H, d), 7.57 (IH, d), 7.75 (IH, dd), 8.14 (IH, d), 8.63 (IH, t), 8.84 (IH, s), 10.74 (IH, s) LC/MS, t = 3.51 min, Molecular ion observed (MH*) = 499 consistent with the molecular formula C19H,7N4 03F635C1
Example 217:2-(4-Cvano-3-cMoro-phenvlamino)-4-1rifluoromemvl-pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmethvn-amide GW 851366X:
F
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (lOOmg) and 4-cyano-3-chloroaniline (236mg, ex Lancaster) afforded the title compound (8mg). Sample purified by mass directed auto-prep.
LC/MS, t = 3.51 min, Molecular ion observed (MH*) = 440 consistent with the molecular formula C19H17Ns02F335Cl
Example 218:2-f4-Trifluoromemvl-3-fluOTO-phenvlammoM-trifluoromethvl-Pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmethvl)-amide GW 851367X
(Figure Removed)
in a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (lOOmg) and 4-trifluoromethyl-3-fluoroaniline (277mg, ex ABGR) afforded the title compound (125mg) after purification by trituration with isohexane.
NMR (DMSO-d6) 8 1.16-1.25 (2H, m), 1.61 (2H, d), 1.73 (1H, m), 3.14 (2H, t), 3.25 (2H, m), 3.85 (2H, d), 7.67 (1H, d), 7.75 (1H, t), 8.02 (1H, d), 8.68 (1H, t), 8.90 (1H, s), 11.00 (1H, s) LC/MS, t = 3.38 min, Molecular ion observed (MET) = 467 consistent with the molecular formula C19H,7N402F7
Example 219: 2-f4-C^ano-3-chloro-phenvlaminoM-1rifluoromethvl-Pvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide GW 856462X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclopentylmethylamide (70mg) and 4-cyano-3-chloroaniline (173mg, ex
Lancaster) afforded the title compound (125mg). Purified by chromatography eluting with 1:1
ethyl acetate:hexane.
NMR(DMSO-d6) 8 1.20-1.25 (2H, m), 1.48-1.73 (6H, m), 2.08 (1H, m), 3.18 (2H, t), 7.83 (1H,
dd), 7.84 (1H, d), 8.24 (1H, d), 8.66 (1H, t), 8.90 (1H s), 11.10 (1H, s) -
LC/MS, t = 3.68 min, Molecular ion observed (MH4) = 424 consistent with the molecular
formula C19 H17 N5 O F3 35C1
Example 220:2-(2.4-DicMoro-phenvlamino)-4-1rifluoromethvl-pvrimidine-5-carboxvlic acid a.l-dioxo-hexahvdro-1 f - thiopvran-4-vn-amide GW 864873X:
(Figure Removed)
In a manner similar to Reference Example 1 (c) 2-(2,4-Dichlorophenylamino)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (50mg) and (l,l-dioxo-tetrahydro-2H-thiopyran-4-yl)amine
hydrochloride (40mg) (Ref. WO 02/18380) afforded the title compound (64mg). Purified by
chromatography eluting with 2% MeOH/CH2Cl2.
NMR (DMSO-d6) 8 1.97 (2H, m), 2.13 (2H, m), 3.13 (2H, m), 3.27 (2H, m), 4.10 (lH,m), 7.47
(1H, dd), 7.56 (1H, d), 7.72 (1H, d), 8.67 (1H t), 8.7 (1H, s), 10.05 (1H, s)
LC/MS, t = 3.22 min, Molecular ion observed (MH*) = 483 consistent with the molecular formula
C17H15N403F335C12S
Example 221:2-(2.4-Difluoro-DhenvlaminoM-trifluoromethvl-pvrimidine-5-carboxvlic acid
cvclohexvhnethvl-amide GW 865283X
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidme-5-carboxylic acid cyclohexylmethyl-amide (80mg) and 2,4-difluoroaniline (160mg, ex Lancaster) afforded the title compound (77mg) after purification by trituration with isohexane / diethylether. NMR (DMSO-d6) 8 0.89-0.95 (2H, m), 1.15-1.20 (3H, m), 1.46-1.47 (IH, m), 1.60-1.72 (5H, m), 3.05 (2H, t), 7.10 (IH, t), 7.35 (IH, m), 7.52 (IH, m), 8.53 (IH t), 8.62 (IH, s), 10.00 (IH, s) LC/MS, t = 3.63 min, Molecular ion observed (MH*) = 433 consistent with the molecular formula Q9H19 N4 O F5
Example 222:2-(2-Chloro-4-fluoro-phenvlarm^o)-4-trifluo«)methvl-pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide GW 865286X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclohexylmethyl-amide (80mg) and 2-chloro-4-fluoroaniline (181mg, ex
Lancaster) afforded the title compound (91mg).
NMR (DMSO-d6) S 0.89-0.95 (2H, m), 1.15-1.20 (3H, m), 1.44-1.46 (IH, m), 1.62-1.72 (5H, m),
3.05 (2H, t), 7.27 (IH, m), 7.55 (2H, m), 8.52 (IH t), 8.60 (IH, s), 10.00 (IH, s)
LC/MS, t = 3.73 min, Molecular ion observed (MH*) = 431 consistent with the molecular
formula C19H19 N4 O F4 35C1
Example 223:2-f2.4-Difluoro-phenvlamino)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid
cvclobutvlmethvl-amide GW 865291X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidiiie-5-carboxylic acid cyclobutylmethyl-amide (80mg) and 2,4-difluoroaniline (198mg, ex Lancaster) afforded the title compound (82mg) after purification by trituration with isohexane / diethylether.

NMR (DMS0-d6) 8 1.67-2.01 (6H, m), 2.47 (IH, m), 3.23 (2H, t), 7.10 (IH, t), 7.35 (IH, m), 7.52 (IH, m), 8.53 (IH t), 8.62 (IH, s), 10.00 (IH, s)
LC/MS, t = 3.40 min, Molecular ion observed (MH4) = 386 consistent with the molecular formula C17H,S N4 OFj
Example 224:2-(2-CMoro-4-fluoro-phenvlaniinoM-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 865294X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclobutylmethyl-amide (80mg) and 2-chloro-4-fluoroaniline (198mg, ex
Lancaster) afforded the title compound (80mg) after purification by trituration with 2N
hydrochloric acid.
NMR (DMSO-d6) S 1.67-2.00 (6H, m), 2.46 (IH, m), 3.23 (2H, t), 7.27 (IH, m), 7.55 (2H, m),
8.52 (IH t), 8.58 (IH, s), 9.90 (IH, s)
LC/MS, t = 3.51 min, Molecular ion observed (MET) = 403 consistent with the molecular
formula C17H15 N4 O F435C1
Example 225:2-(2-Chloro-4-bromo-phenvlammo)-4-trifluoromemvl-pvi±nidine-5-carboxvlic acid cvclohexvlmethvl-arnide GW 866677X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (80mg) and 2-chloro-4-bromoaniline (257 mg, ex Lancaster) afforded the title compound (96mg) after purification by trituration with 2N hydrochloric acid.
NMR (DMSO-d6) 5 0.89-0.95 (2H, m), 1.15-1.20 (3H, m), 1.44-1.46 (IH, m), 1.62-1.72 (5H, m), 3.05 (2H, t), 7.52 (IH, d), 7.58 (IH, dd), 7.82 (IH, d), 8.55 (IH t), 8.63 (IH, s), 10.00 (IH, s) LC/MS, t = 3.97 min, Molecular ion observed (MH*) = 493 consistent with the molecular formula C19H,9 N4 O F3 35C181Br
Example 226: 2-f2-Fluoro-4-chloro-phenvlammo)-4-trifluoTomemvl-pwimidine-5-carpoxvlic acid cvclohexvlmethvl-amide GW 866678X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (80mg) and 2-fluoro-4-chloroaniline (180mg, ex Lancaster) afforded the title compound (73mg) after purification by trituration with 2N hydrochloric acid.
NMR (DMSO-d6) 8 0.95-0.98 (2H, m), 1.15-1.20 (3H, m), 1.44-1.46 (IH, m), 1.66-1.72 (5H, m), 3.05 (2H, t), 7.31 (IH, d), 7.53 (IH, dd), 7.60 (IH, t), 8.55 (IH t), 8.66 (IH, s), 10.00 (IH, s) LC/MS, t = 3.79 min, Molecular ion observed (MH*) = 431 consistent with the molecular formula C19 H,9 N4 O F4 35C1
Example 227:2-f2-CMoro-4-bromo-phenvlammo^-1rifluoromemvl-pyrimidme-5-carboxvlic acid cvclobutvlmethvl-amide GW 867720X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclobutylmethyl-amide (80mg) and 2-chloro-4-bromoaniline (281mg, ex
Lancaster) afforded the title compound (103mg) after purification by trituration with 2N
hydrochloric acid.
NMR (DMSO-d6) 8 1.67-2.00 (6H, m), 2.45 (IH, m), 3.23 (2H, t), 7.50 (IH, d), 7.58 (IH, dd),
7.82 (IH, d), 8.53 (lHt), 8.61 (IH, s), 10.00 (IH, s)
LC/MS, t = 3.77 min,' Molecular ion observed (MH+) = 465 consistent with the molecular formula C
N4OF335Cl8IBr
Example 228:2-(2-Fluoro-4-chloro-phenvlammo)-4-trifluoromemYl-pvrimidme-5-carboxvlic acid cvclobutvlmethvl-amide GW 867723X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide (80mg) and 2-fluoro-4-chloroaniline (198mg, ex Lancaster) afforded the title compound (94mg) after purification by trituration with 2N hydrochloric acid.
NMR (DMS0-d6) 8 1.67-2.08 (6H, m), 2.45 (1H, m), 3.23 (2H, t), 7.31 (1H, d), 7.53 (1H, dd),
7.60 (1H, t), 8.53 (1H t), 8.64 (1H, s), 10.00 (1H, s)
LC/MS, t = 3.59 min, Molecular ion observed (MH*) = 403 consistent with the molecular formula CnH1s
N4OF435Cl
Example 229:2-f2-Fluoro-4-bromo-phenvlanu^o)-4-trifluoromemvl-pvrinn^ine-5-carboxvlic acid cvclobutvlmethvl-amide GW 867725X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclobutylmethyl-amide (80mg) and 2-fluoro-4-bromoaniline (259mg, ex
Lancaster) afforded the title compound (95mg) after purification by trituration with 2N
hydrochloric acid.
NMR (DMSO-d6) 8 1.67-2.00 (6H, m), 2.45 (1H, m), 3.23 (2H, t), 7.43 (1H, d), 7.54 (1H, t), 7.63
(1H, dd), 8.53 (1H t), 8.64 (1H, s), 10.00 (1H, s)
LC/MS, t = 3.63 min, Molecular ion observed (MH*) = 449 consistent with the molecular formula CpH1s
N4OF481Br
Example 230: 2-(2-Bromo-4-chloro-phenvlaminoM-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 867780X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclobutylmethyl-amide (80mg) and 2-bromo-4-chloroaniline (281mg, ex
Lancaster) afforded the title compound (105mg) after purification by trituration with 2N
hydrochloric acid.
NMR (DMSO-d6) 8 1.67-2.08 (6H, m), 2.45 (1H, m), 3.23 (2H, t), 7.52 (2H, m), 7.85 (1H, s),
8.53 (1H t), 8.60 (1H, s), 10.00 (1H, s)
LC/MS, t = 3.75 min, Molecular ion observed (MH+) = 465 consistent with the molecular formula Ci7H1S
N4OF335a8IBr
Example 231 2-f2-Fluoro-4-bromo-phenvlammo)-4-1rifluoromemvl-pvrinu'd^e-5-carboxvlic acid cvclohexvlmethvl-amide GW 867784X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (80mg) and 2-fluoro-4-bromoaniline (236mg, ex Lancaster) afforded the title compound (96mg) after purification by trituration with 2N hydrochloric acid.
NMR (DMSO-d6) 6 0.90-0.92 (2H, m), 1.15-1.20 (3H, m), 1.44-1.46 (IH; m), 1.63-1.72 (5H, m), 3.05 (2H, t), 7.44 (IH, d), 7.55 (IH, t), 7.64 (IH, dd), 8.55 (IH t), 8.66 (IH, s), 10.00 (IH, s) LC/MS, t = 3.83 min, Molecular ion observed (MET) = 477 consistent with the molecular formula Ci9 Ht9 N4 O F4 glBr
Example 232: 2-(2-Fluoro-4-bromo-phenvlammo)-4-trifluoromemvl-pvrimidine-5-carboxvlic acid ftelrahvdro-pvran-4-vlmethvn-amide GW 867785X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimiduie-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (80mg) and 2-fluoro-4-bromoaniline (235mg, ex Lancaster) afforded the title compound (lOOmg) after purification by trituration with 2N hydrochloric acid.
NMR (DMSO-d6) 8 1.16-1.23 (2H, m), 1.60 (2H, d), 1.71 (IH, m), 3.1 (2H, t), 3.25 (2H, m), 3.85 (2H, d), 7.43 (IH, d), 7.55 (IH, t), 7.64 (IH, dd), 8.60 (IH, t), 8.65 (IH, s), 10.10 (IH, s) LC/MS, t = 3.28 min, Molecular ion observed (MH*) = 479 consistent with the molecular formula ClgH17N4 02F48IBr
Example 233:2-(2-C3iloro-4-fluoTO-phenvlamino)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid ftetrahvdro-Pvran-4-vlmethylVamide GW 868105X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (80mg) and 2-chloro-4-fluoroaniline (180mg, ex Lancaster) afforded the title compound (95mg) after purification by trituration with 2N hydrochloric acid.
NMR (DMS0-d6) 8 1.14-1.23 (2H, m), 1.59 (2H, d), 1.71 (IH, m), 3.1 (2H, t), 3.25 (2H, m), 3.85
(2H, d), 7.27 (IH, m), 7.55 (2H, m), 8.58 (IH, t), 8.61 (IH, s), 10.00 (IH, s)
LC/MS, t = 3.14 min, Molecular ion observed (MH*) = 433 consistent with the molecular formula
CIgH17N402F435Cl
Example 234:2-f2-Chloro-4-bromo-phenvlammo)-4-trifluoromemvl-pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmethvn-amide GW 868123X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (80mg) and 2-chloro-4-bromoaniline (255mg, ex Lancaster) afforded the title compound (102mg) after purification by trituration with 2N hydrochloric acid.
NMR (DMSO-d6) 8 1.14-1.23 (2H, m), 1.58 (2H, d), 1.72 (IH, m), 3.1 (2H, t), 3.28 (2H, m), 3.84 (2H, d), 7.51 (IH, d), 7.59 (IH, dd), 7.82 (IH, d), 8.58 (IH, t), 8.63 (IH, s), 10.00 (IH, s) LC/MS, t = 3.42 min, Molecular ion observed (MH*) = 495 consistent with the molecular formula C18H,7N4Q2F335Cl81Br
Example 23 5: 2-f2-CMoro-4-cvano-phenvlamino)-4-trifluoromethYl-pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmethyl>amide GW 868124X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (80mg) and 2-chloro-4-cyanoaniline (188mg, ex Lancaster) afforded the title compound (22mg). Sample purified by mass directed auto-prep.
NMR (DMSO-d6) 5 1.14-1.23 (2H, m), 1.59 (2H, d), 1.72 (IH, m), 3.12 (2H, t), 3.23 (2H, m), 3.85 (2H, d), 7.87 (IH, d), 7.92 (IH, d), 8.14 (IH, s), 8.65 (IH, t), 8.75 (IH, s), 10.20 (IH, s) LC/MS, t = 3.11 min, Molecular ion observed (MH*) = 440 consistent with the molecular formula C19H17NS02F335C1
Example 236:2-f2-CMoro-4-trifluoromemvl-phenvlammoM-trifluoromethvl-pvrimidine-5-carboxvlic acid (tetrahvdro-pvran-4-vlmemvlVamide GW 868125X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (80mg) and 2-chloro-4-trifluoromethylaniline (241mg, ex Lancaster) afforded the title compound (48mg). Sample purified by mass directed auto-prep.
NMR (DMSO-d6) 5 1.17-1.23 (2H, m), 1.59 (2H, d), 1.72 (IH, m), 3.12 (2H, t), 3.23 (2H, m), 3.85 (2H, d), 7.77 (IH, d), 7.88 (IH, d), 7.96 (IH, s), 8.63 (IH, t), 8.72 (IH, s), 10.15 (IH, s) LC/MS, t = 3.47 min, Molecular ion observed (MET) = 483 consistent with the molecular formula C19H17N402F635C1
Example 237:2-(2-CMoro-4-cvano-phenvlamino')-4-trifluoromethvl-Pvrirnidine-5-carboxvlic acid cvclohexvlmethvl-amide GW 869220X:
(Figure Removed)
m a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (80mg) and 2-chloro-4-cyanoaniline (189mg, ex Lancaster) afforded the title compound (15mg). Sample purified by mass directed auto-prep. NMR (DMSO-d6) 5 0.90 (2H, m), 1.15-1.23 (3H, m), 1.44-1.46 (IH, m), 1.67-1.73 (5H, m), 3.06 (2H, t), 7.87 (IH, dd), 7.92 (IH, d), 8.14 (IH, d), 8.58 (IH t), 8.74 (IH, s), 10.10 (IH, s) LC/MS, t = 3.67 min, Molecular ion observed (MH*) = 438 consistent with the molecular formula CM H19 N5 O F3 3SC1
Example 238:2-f2-Bromo-4-chloro-phenvlammo)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide GW 869241X :
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluorometfayl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (80mg) and.2-bromo-4-chloroaniline (257mg, ex Lancaster) afforded the title compound (23mg). Sample purified by mass directed auto-prep. NMR (DMSO-d6) 8 0.89-0.95 (2H, m), 1.15-1.20 (3H, m), 1.44-1.46 (IH, m), 1.62-1.72 (5H, m), 3.04 (2H, t), 7.52 (2H, m), 7.85 (IH, d), 8.53 (IH t), 8.61 (IH, s), 10.00 (IH, s)
LC/MS, t = 3.94 min, Molecular ion observed (MH*) = 493 consistent with the molecular formula C19 H19 N4 O F3 35C181Br
Example 239: 2-f2-Bromo-4-chloro-phenvlammo')-4-trifluoromethvl-pvrimidine-5-carboxvlic acid rtetrahvdro-Pvran-4-vlmethvn-amide GW 870000X:
(Figure Removed)
In a manner similar to Example 166, GW847367X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (80mg) and 2-bromo-4-chloroaniline (255mg, ex Lancaster) afforded the title compound (6mg). Sample purified by mass directed auto-prep.
NMR (DMSO-d6) 8 1.14-1.23 (2H, m), 1.58 (2H, d), 1.72 (IH, m), 3.1 (2H, t), 3.28 (2H, m), 3.84 (2H, d), 7.50 (2H, m), 7.82 (IH, d), 8.58 (IH, t), 8.63 (IH, s), 10.00 (IH, s) LC/MS, t = 3.40 min, Molecular ion observed (MH*) = 495 consistent with the molecular formula C1gH,7N402F335Cl81Br
Example 240: 2-(3-Brom (Figure Removed)
in a manner similar to Reference Example 1 (c) 2-(3-bromophenylamino)-4-trifluoromethyl-
pyrimidme-5-carboxylic acid (80mg) and cyclopropylmethylamine (19mg, ex Lancaster) afforded
the title compound (24mg). Sample purified by mass directed auto-prep.
NMR (DMSO-d6) 8 0.22 (2H, m), 0.45 (2H, m), 1.67 (IH, m), 3.13 (2H, t), 7.23 (IH, d), 7.30
(IH, t), 7.72 (IH, d), 8.10 (IH, m), 8.68 (IH, t), 8.80 (IH s), 10.60 (IH, s)
LC/MS, t = 3.49 min, Molecular ion observed (MH4) = 417 consistent with the molecular formula
C,6H,4N4 0F38,Br
Example 241: 2-(2.4-Dichlorophenvlamino)-4-trifluoromemvl-pvrimidine-5-carboxvlic acid cyclopropvlmethvl-amide GW 871909X:
(Figure Removed)
In a manner similar to Reference Example 1 (c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (80mg) and cyclopropylmethylamine (19mg, ex Lancaster) afforded the title compound (58mg).
NMR (DMSO-d6) 8 0.22 (2H, m), 0.45 (2H, m), 1.67 (1H, m), 3.13 (2H, t), 7.23 (1H, d), 7.30 (1H, t), 7.72 (1H, d), 8.10 (1H, m), 8.68 (1H, t), 8.80 (1H s), 10.60 (1H, s) LC/MS, t - 3.56 min, Molecular ion observed (MET) = 405 consistent with the molecular formula C16H13N4OF335CI
Example 242:2-(2.3-Difluorophenvlamino')-4-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide. GW 867104X
(Figure Removed)
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (GW 87706lAExample 166a) (50mg) in 1,4-dioxan (1ml) was added 2,3-difluoroaniline (Aldrich) (113mg) and the mixture was stirred at reflux for 47 hours using a Radleys Greenhouse Parallel Synthesiser. The dioxan was removed using a nitrogen blow down unit. The residue was ' taken up into methanol (0.5ml) and dimethylsulfoxide (0.5ml) and purified using a mass directed auto-preparative system to give the title compound (16mg)
NMR (Chloroform-d6) 8 0.94-1.08 (2H, m), 1.15-1.34 (3H, m), 1.5-1.6 (>lH,m & water) 1.65-1:73 (1H, m), 1.73-1.83 (4H, m), 3.30 (2H, t,), 5.91 (1H, bs) 6.88- 6.98 (1H, m) 7.08-7.1 (1H, m), 7.66 (1H, bs), 8.16-8.25 (1H, m), 8.75 (1H, s). LC/MS t = 3.66min, [MH+] 415 consistent with the molecular formula C19H19FjN40
Example 243: 2-(2-Fluoro-3-1rifluoromemvl-phenvlaminoM-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide. (GW 867105X)
In a manner similar to Example 242, GW 867104X, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (GW 877061A Example 166a) (50mg) in 1,4-dioxan (lml) and 2-fluoro-3-trifluoromethylphenylamine (Aldrich) (156mg) were reacted to give the title compound (GW 867105X) (llmg)
NMR (Chloroform-d6) 8 0.94-1.08 (2H, m), 1.15-1.34 (3H, m), 1.55- 1.59 (IH, m), 1.65-1.73 (IH, m), 1.73-1.83 (4H, m), 3.30 (2H, t,), 5.91 (IH, bs), 7.28- 7.37 (2H, m), 7.74 (IH, bs), 8.65-8.73 (IH, m), 8.77-8.80 (IH, m) LC/MS t= 3.66min [MH+] = 465 consistent with the molecular formula C20H19F7N4O
Example 244:2-f2-CMoro-4-memvlphenvlanimoV4-irifluoromemvl-Pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide. GW 869341X

(Figure Removed)
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (GW 877061AExample 166a) (50mg) in 1,4-dioxan (1ml) was added 2-chloro-4-methylphenylamine (Aldrich) (109mg) the mixture was stirred at reflux for 24 hours using a Radleys Greenhouse Parallel Synthesiser. The dioxan was removed using a nitrogen blow down unit. The residue was taken up into methanol (0.5ml) and dimethylsulfoxide (0.5ml) and purified using mass directed auto-preparative system to give the title compound (GW 86934IX) (24mg) NMR (Methanol-d6) 6 1.50-1.60 (2H, m), 1.70-1.89 (3H, m), 2.06-215 (IH, m), 2.2-2.26 (IH, m), 2.27-2.38 (4H, m), 2.88 (3H, s), 3.71 (2H, d), 7.68 (IH, d), 7.85 (IH, s), 8.31 (IH, d), 9.10 (lH,s). LC/MS t = 3.81min, [MH+] = 427 consistent with the molecular formula C2oH2235Cl F3N4O
Example 245:2-(4-Cliloro-3-memoxvphenvlamino)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclohexvlmethvl-amide. GW 869346X
(Figure Removed)
In a manner similar to Example 243, GW 867104X, 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclohexylmethyl-amide (GW 877061A, Example 166a) (50mg) in 1,4-dioxan
(lml) and 4-chloro-3-methoxy-phenylamine (Wychem) (122mg) were reacted to give the title
compound (33mg)
NMR (Methanol-d6) 8 0.95-1.06 (2H, m), 1.20-1.34 (3H, m), 1.55-1.64 (IH, m), 1.65-171 (IH,
m), 1.72-1.85(4H, m), 3.19 (2H, d), 3.90 (3H, s), 7.18 (IH, dd), 7.27 (IH, d), 7.80 (IH, bs), 8.64
(lH,s).
LC/MS t = 3.79min, \MH+] 443 consistent with the molecular formula C2oH2235Cl F3N4O2
Example 246:2-f5-Chloro-2-methvlphenvlarmno)-4-1rifluoromemvl-Pvrimidme-5-carboxvlic acid cvclohexvlmethvl-amide. GW 869355X
(Figure Removed)
In a manner similar to Example 243, GW 867104X 2-chloro-4-trifluoromethyl-pyrimidine-5-
carboxylic acid cyclohexylmethyl-amide (GW 87706 lAExample 166a) (SOmg) in 1,4-dioxan
(1ml) and S-chloro-2-methyl aniline (Aldrich) (1 lOmg) were reacted to give the title compound
(36mg)
NMR (Methanol-d6) 81.47-1.59 (2H, m), 1.72-1.89 (3H, m), 2.05-2.18 (IH, m) 2.19-2.25 (IH,
m), 2.31 (4H, t), 2.79 (3H, s), 3.71 (2H, d), 7.76 (IH, dd), 7.76 (IH, d), 8.17 (IH, d), 9.09 (IH, s)
LC/MS t =3.77min [MH4] = 427 consistent with the molecular formula QJOH^CI F3N40
Example 247: 2-f3-Chloro-4-fluoro-phenvlamino)-4-1rifluon)memYl-pvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide GW 848814X
(Figure Removed)
2:CWoro-4-1rifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-amide (GW 848813X,116mg Example 183a), 3-chloro-4-fluoroaniline (ex-Aldrich, 275mg), and 1,4-dioxan (1.2ml) were stirred at 100°C under nitrogen for 6h. The cooled reaction mixture was evaporated in vacuo, treated with ethyl acetate ( 5ml), washed with aqueous 2M hydrochloric acid (2 x 3ml), followed by brine, and dried ( Na2S04). The solution was evaporated in vacuo to give the title compound (104mg).
NMR 5 (DMSO-d6)l.15-1.32 (2H,m), 1,46-1.66 (4H,m) 1.66-1.78 (2H, m), 2.1 (IH, q), 3.17 (2H,t), 7.4 (IH, t), 7.63-7.7 (IH, m), 8.05(1H, dd), 8.61 (IH, t), 8.79 (IH, s), 10.6 (lH,s). LC/MS t = 3.7 min, Molecular ion observed [MH+] =417 consistent with the molecular formula C1jHI7ClF4N40.
Example 248:2-f3-Chloro-2-fluoro-phenvlamino)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide GW 848815X
(Figure Removed)
In a manner similar to Example 247, GW 848814X, 3-chloro-2-fluoroaniline (ex-Acros, 275mg). was reacted for 18h, worked up analogously, then stirred in isohexane (6 ml), and filtered off to give the title compound (82mg).
NMR 8 (CDC13) 1.2-1.34 (2H, m), 1.55-1.76 (>4H, m + H20), 1.78-1.89 (2H, m), 2.16 (IH, q), 3.41 (IH, t), 5.83-5.95 (IH, brt), 7.1-7.18 (2H, m), 7.28 (IH, s), 7.66 (IH, brs), 8.3-8.4 (IH, m), 8.75 (IH, s).
LC/MS t = 3.7 min, Molecular ion observed [MH*] 417 consistent with the molecular formula CgHnCUW).
Example 249:2-(2-Chloro-5-fluoro-phenvlano)-4-trifluoromet^ acid cvclopentvlmethvl-amide GW 871627
(Figure Removed)
2-Chloro^-1rifluoromemyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-amide (GW 848813X,100mg Example 183a), 2-chloro-5-fluoroaniline (ex-Fluorochem, 237mg), and 1,4-dioxan (1 ml) were stirred at 100°C under nitrogen for 18h. The cooled reaction mixture was evaporated in vacuo, treated with ethyl acetate (5 ml), washed with aqueous 2M hydrochloric acid (2 x 3ml), followed by water (2x3 ml), and dried (Na2S04). The solution was evaporated in vacuo and the residue purified by mass directed autopreparative purification to give the title compound (35mg).
NMR 8 (CDC13) 1.2-1.35 (2H, m), 1.53-1.76 (>4H, m + H20), 1.78-1.90 (2H, m), 2.17 (IH, q), 3.41 (2H, dd), 5.9 (IH, brt), 7.0-7.11 (2H, m), 7.65-7.7 (IH, m) 8.56 (IH, dd), 8.79 (IH, s). LC/MS t = 3.67 min, Molecular ion observed [MlT] 417 consistent with the molecular formula C1gH,7ClF4N40.
Example 250GW 842iyOX: 2-f3.4-Dichlorophenvlamino)-4-trifluoromethvlpvrimidine-5-carboxvlic acid ftetrahvdro-Pvran-4-vlmethvlVamide
(Figure Removed)
In a manner similar to. Reference Example 1(c) 2-(3,4-dichlorophenylammo)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid (30mg) and 4-aminomethyltetrahydropyran (20mg, ex
CombiBlocks) afforded the title compound (38mg).
NMR (DMSO-d6) 8 1.18-1.25 (2H, m), 1.62 (2H, d), 1.74 (IH, m), 3.1 (2H, t), 3.25 (2H, m), 3.85
(2H, d), 7.60 (IH, t), 7.69 (IH, m), 8.16 (IH, dd), 8.64 (IH, t), 8.84 (IH, s), 10.70 (IH, s)
LC/MS, t = 3.45 min, Molecular ion observed (MH4) = 449 consistent with the molecular formula
ClgH17N40235Cl2F3
Example 251:2-(Phenvlamino')-4-trifluoromethvl-Pvrimidine-5-carboxvlic acid cvclopentvlmethvl-amide GW 855149X
(Figure Removed)
in a manner similar to Reference Example 1 (c), 2-(Phenylamino)-4-trifluoromethyl-pyrimidine-
5-carboxylic acid (30mg) and cyclopentylmethylamine hydrochloride (21mg) afforded the title
compound (32mg) after purification by trituration with diethylefher.
NMR (DMSO-d6) 8 1.20-1.25 (2H, m), 1.48-1.72 (6H, m), 2.07 (1H, m), 3.13 (2H, t), 7.04 (1H,
t), 7.34 (2H, t), 7.74 (2H, d), 8.58 (1H, t), 8.70 (1H s), 10.35 (1H, s)
LC/MS, t = 3.52 min, Molecular ion observed (MH4) = 365 consistent with the molecular formula
CIgH19N4OF3
Example 252: 2-f2-Fluoro-3-1rifluoromethvl-phenvlamino')-4-trifluoromethvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 873896X
(Figure Removed)
2-Chloro-4-trifluoromethyl-pvrimidin-5-carboxylic acid cyclobutylmethyl-amide (200mg) in 2-fluoro-3-(trifluoromethyl)aniline (0.5ml) was heated at 180°C under microwave irradiation for 30 minutes. The residue was dissolved in dichloromethane and purified over silica gel (Merck 9385) using the Biotage Horizon system eluting with 10% ethylacetate / isohexane to 100% ethyl acetate gradient to afford the title compound.
NMR (CDC13) 81.70-1.81 ( 2H, m), 1.86-2.00 (2H, m), 2.07-2.17 (2H, m), 2.51-2.65 (1H, m), 3.48 (2H, dd), 5.78-5.86 (1H, m), 7.25-7.36 (2H, m), 7.70-7.76(lH, bs), 8.64-8.72 (1H, m), 8.75-8.79 (1H, s)
LC/MS, t = 3.64min, Molecular ion observed (MH4) = 437 consistent with the molecular formula Cjg H15 F7 N4 O
Example 253:2-f2-Memvl-4-cliloro-phenvlamino)-4-trifluoromemvl-pvrimidine-5-carboxvlic acid cvclobutvlmethvl-amide GW 873900X
(Figure Removed)
to a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid cyclobutylmethyl-amide
(50mg) in 1,4-dioxan (1.0ml) was added 2-methyl-4-chloroaniline (120mg) and the solution
heated at 180°C under microwave irrdiation for 30 x 2 minutes. The residue was dissolved in 1:1
DMSO : methanol (1.0ml) and purified by Mass Directed Auto-Purification to afford the title
compound (36mg).
NMR (CDC13) 8 1.79-1.80 (2H, m), 1.85-1,99 (2H, m), 2.05-2.16 (2H, m), 2.25-2.63 91H, m),
5.74-5.83 (IH, m), 7.15 (IH, bs), 7.2-7.78 (2H, m), 7.81 (IH, d), 8.66 (IH, s)
LC/MS, t= 3.6min, Molecular ion observed (MH+)= 398 consistent with the molecular formula C18H18ClF3N40
Example 254:2-f2-Trifluoromemvl-4-bromo-phenvlammo)-4-1rifluoromethvl-pvrimidine-5-carboxvlic acid (tefrahvdro-pvran-4-vlmemvlVamide GW 874234X
(Figure Removed)
2-Qiloro-4-trifluoromemyl-pyrimidin-5-carboxylicacid(tetrahydro-pynm-4-ylmethyl)-amide
(80mg) in 2- trifluoromethyl-4-bromoaniline (0.5ml) was heated at 190°C under microwave
irradiation for 20 minutes. The sample was purified by mass directed auto-purification to afford
the title compound (21mg).
NMR (DMSO-d6) 5 1.15-1.23 (2H, m), 1.57 (2H, d), 1.60 (IH, m), 3.09 (2H, t), 3.26 (2H, t), 3.84
(2H, d), 7.51 (IH, d), 7.95 (2H, m), 8.58 (2H, s,t), 10.00 (IH, s)
LC/MS, t = 3.41 min, Molecular ion observed (MH*) = 529 consistent with the molecular
formula C19 H17 N4 O2 F6 81Br
Example 255:2-f3-Chlorophenvlamino)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid ftetrahvdrothiopvran^vlmethvl) amide GW875763X
a) 4-(Aniinomethyl)tetrahydrothiopyran GW876857X
A solution of borane-tetrahydrofuran complex (1M in tetrahydrofuran, 11ml) was added over 5minutes to a solution of tetrahydro-2H-thiopyran-4-carbonitrile (1.27g) [Heimgartner et al, Helv. Chim. Acta 80(5), 1528 (1997)] in dry tetrahydrofuran (5ml) under nitrogen at room temperature. The solution was heated at reflux overnight, then cooled to 20°C. Methanol (15ml) was added dropwise keeping the temperature below 25°C, then the mixture was cooled to 0°C and dry hydrogen chloride was bubbled through for 15mins. The resulting mixture was heated at reflux for 1.5 hours, evaporated and the residue re-evaporated twice from methanol. Ether (30ml) was added giving a white oily solid. The ether was decanted and the residue was dissolved in water (30ml) and extracted with dichloromethane (2 x 30ml). The remaining aqueous was made strongly basic with sodium hydroxide and extracted with dichloromethane (2 x 30ml). The
combined extracts were dried over potassium carbonate and evaporated to give the title compound (390mg)
NMR (DMSO) 5 1.2 (5H, m), 2.0 (2H, m), 2.36 (2H, m), 2.55 (4H, m). 5
b) 2-(3-CMorophenylammo)^trifluoromemyl-pyrmiidine-5-carboxylic acid
(tetrahydromiopyran-4-ylmethyl) amide GW875763X
H In a manner similar to Reference Example lb)GW848555X 2-(3-chlorophenylamino)-4-) trifluoromethylpyrimidine-5-carboxylic acid (95 mg) and 4-(aminomethyl)tetrahydrothiopyran (79mg) (above)GW8768S7X gave the title compound (92mg).
NMR (DMSO-d6) 6 1.26 (2H, m), 1.55 (1H, m), 2.01 (2H, m), 2.60 (4H, m), 3.10 (2H, t), 7.09 (1H, m), 7.37 (1H, t), 7.65 (1H, m), 7.96 (1H, m), 8.63 (1H, t), 8.81 (1H, s), 10.6 (1H, s). • LC/MS CF111437, t = 3.61 min, Molecular ion observed (MH*) = 431 consistent with the molecular formula C18H1g35ClF3N4OS
Example 256:2-r2.4-Pichlorophenvlamino)-4-trifluoromethvl-pvrimidine-5-carboxvlic acid
(tetrahvdrothiopvran-4-vlmethvl') amide GW875765X
(Figure Removed)
In a manner similar to Reference Example lb)GW848SSSX 2-(2,4-dichlorophenylamino)-4-Mfluoromemyl-pyrimidine-5-carboxylic acid (106 mg) and 4-(aminomethyl)tetrahydrothiopyran (79mg) (Example 255a)GW8768S7X gave the title compound (82mg).
NMR (DMSO-d6) 5 1.27 (2H, m), 1.55 (1H, m), 2.00 (2H, m), 2.59 (4H, m), 3.08 (2H, t), 7.47 (1H, m), 7.57 (1H, d), 7.72 (1H, m), 8.59 (1H, t), 8.64 (1H, s), 10.0 (1H, s). LC/MS CF111493, t = 3.70 min, Molecular ion observed (MH*) = 465 consistent with the molecular formula C18H1735Cl2F3N4OS
Example 263:2-(3-CMorophenvlammoM-trifluoTomemyl-pvrimidine-5-carboxvlic acid (2-oxo-propvn-amide GW 876307X
To a stirred solution of 2-(3-chloro-phenylamino)-trifluorome11ryl-pyrimidine-5-carboxylic acid (2-hydroxy-propyl)-amide (200mg) in dimethylsulfoxide (6.0ml) and triethylamine (324mg) at 0°C was added a solution of sulphur trioxide-pyridine complex (250mg) in dimethylsulfoxide (6.0ml). This was allowed to warm to room temperature and after 2 hours the mixture was diluted with dichloromethane and washed twice with 0.1N hydrochloric acid. The organic layer was dried (Na2S04) and evaporated. The sample was purified by mass directed auto-purification to afford the title compound (91mg).
NMR (DMSO-d6) 8 2.15 (3H, s), 4.13 (2H, d), 7.10 (1H, d), 7.36 (1H, t), 7.67 (1H, d), 7.96 (1H, s), 8.84 (1H, s), 8.94 (1H, t), 10.55 (1H, s)
LC/MS, t = 3.18 min, Molecular ion observed (MH*) = 373 consistent with the molecular formula C15H12N4 02F335C1
Example 264: 2-f3-ChlorophenvlammoV4-trifluoromethvlpvrimidine-5-carboxvlic acid fdioxo-hexahvdro-1 /^-thiopvran-4-vlmethvl)-amide
2-(3-C!hlorophenylammo)-4-1rifluoromethylpyrimidine-5-carboxylic acid (tetrahydro-thiopyran-4-
ylmethyl)-amide ( Example 255) (82mg) was dissolved in dichloromethane (15ml) and cooled in an ice bath. A solution of 3-chloroperbenzoic acid (95mg; Lancaster 50-56%) in dichloromethane (5ml) was added dropwise over 5 mins. The resulting solution was stirred at room temp for 2 hrs men a saturated solution of sodium sulphite (10ml) was added and the mixture was stirred for 15 mins. Dichloromethane (20ml), saturated sodium bicarbonate solution (20ml) and water (30ml) were added, separated and the organics were washed with water (2 x 30ml), dried over magnesium sulphate and evaporated to an oil. Purification by chromatography on silica gel (dichloromethane/methanol 10:l)gave the title compound (17 mg).
LC/MS t = 3.09 min, Molecular ion observed (MH4) = 463 consistent with the molecular formula Cl8Hl835ClF3N4035
Example 265: 2-f2.4-Dichlorophenvlamino')-4-trifluoromethvlpvrimidine-5-carboxvlic acid fdioxo-hexahvdro-1 ^-thiopvran^vlmethvlVamide
In a similar manner to Example 264,2-(2,4-dichlorophenylamino)-4-trifluoromethylpyrimidirie-5-carboxylic acid (tetrahydro-thiopyran-4-ylmethyl)-amide ( Example 256) (72mg) and 3-chloroperbenzoic acid (146mg) gave the title compound (63mg)
LC/MS t = 3.21 min, Molecular ion observed (MH*) = 497 consistent with the molecular formula C18H1735Cl2F3N4O35
Example 266: Preparation of Nanomilled Compound
2.S g of compound of example 176 GW851393X was weighed into a 10 ml centrifuge tube. 25 ml of 0.3mm yttrium zirconium (YTZ) ceramic milling beads (Manufacturer: Tosoh, Japan; Supplier: Glen Creston Ltd., batch no. 5280130030)") was weighed into a 50 ml milling pot. 22.5 ml of aqueous 1.5% HPMC was measured with a measuring cylinder into a 100 ml beaker. This solution was homogenised for 3 seconds with an Ultra Turrax T25 homogeniser. Approximately 200 mg of the 2.5 g of the compound was added to the HPMC solution and homogenised at the lowest speed setting until the powder was wetted. This was repeated until all the compound had been added. The speed of the homogeniser was then increased to maximum and the suspension was homogenised for a further 3 minutes. This suspension was allowed to stand for 30 minutes in order to allow some of the foam to disperse. The suspension was then poured into the 50 ml pot containing the YTZ milling beads, stirring to release any trapped air. The lid to the pot was then fitted and the pot sealed with some Nesco film. This procedure was repeated for a second 50 ml nanomilling pot and both pots were placed on a Retsch mill and milled for a total of 8 hours.
The milling pots were removed from the Retsch mill and left to cool and for the foam to disperse overnight. In the morning the suspension and bead mixture was passed through a 200u, 40 mm diameter screen. The contents from each 50 ml pot was washed with aqueous 1.5% HPMC: 10% of the original suspension volume (i.e. 2.5 ml). The suspension from the 2 pots was combined to make 1 batch. The suspension obtained from the method above was named the concentrate.
A sample of the concentrate was diluted 1 in 4 with aqueous 1.5% HPMC to give a nominal concentration of 25 mg/ml. This first dilution was assayed by HPLC. The concentration of the concentrate was calculated to be 91.21 mg/ml.
HPLC conditions
Column: Symmetry Cjg 5u. 3.9x150 mm column; flow rate 1.0 ml/min; column temp 40°C; UV detection at 280nm.
Mobile phase gradient: A: water + 0.1% trifluoro acetic acid (TFA)
B: acetonitrile + 0.1% TFA
Table A:
(Table Removed)
A particle size analysis was carried out on the Lecotrac laser particle size analyser. The results are shown in Table B along with the results from the starting material for comparison:

Table B:

Particle Size Analysis


(Table Removed)
A dilution of nominally 15.0 mg/ml was prepared using 21.36 ml of the concentrate and (100 ■ 20.34) ml = 83.64 ml of diluent (aqueous 1.5% HPMC).
Compounds of Examples 19,34,194,217,228,247 were nanomilled on a 1 g scale using the process described above and the particle size analysed pre and post nanomilling. The results are given in Table C.
Table C.
(Table Removed)
Formulations for pharmaceutical use incorporating compounds of the present.invention either pre or post nanomilling can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Example 7.67: Tnbalant Formulation
A compound of formula (I) or a pharmaceutically acceptable derivative thereof, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
Example 268: Tablet Formulation
Tablets/Ingredients Per Tablet
1. Active ingredient 40 mg (Compound of formula (I) or pharmaceutically acceptable derivative)
2. Corn Starch 20 mg
3. Alginicacid 20 mg
4. Sodium Alginate 20 mg
5. Mgstearate 1.3 mg
Procedure for tablet formulation:
Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender: Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 140°F (60°C) until dry. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.
Example 269: Parenteral Formulation
A pharmaceutical composition for parenteral administration is prepared by dissolving an
appropriate amount of a compound of formula (J) in polyethylene glycol with heating. This
solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then
rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile
containers.






WE CLAIM:
1. 2-(2,4-Dichlorophenylamino)-4-trifluoromet±iylpyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide or a pharmaceutically acceptable salt thereof of the kind such as herein described.
2. 2-(2,4-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide.
3. A compound as claimed in claim 1 or claim 2 wherein said compound is in nanoparticulate form.

Documents:

295-delnp-2005-abstract.pdf

295-delnp-2005-claims.pdf

295-delnp-2005-complete specification(as files).pdf

295-delnp-2005-complete specification(granted).pdf

295-delnp-2005-correspondence-others.pdf

295-delnp-2005-correspondence-po.pdf

295-delnp-2005-description (complete).pdf

295-delnp-2005-form-1.pdf

295-delnp-2005-form-13.pdf

295-delnp-2005-form-18.pdf

295-delnp-2005-form-2.pdf

295-delnp-2005-form-3.pdf

295-delnp-2005-form-5.pdf

295-delnp-2005-gpa.pdf

295-delnp-2005-pct-101.pdf

295-delnp-2005-pct-210.pdf

295-delnp-2005-pct-220.pdf

295-delnp-2005-pct-301.pdf

295-delnp-2005-pct-304.pdf

295-delnp-2005-pct-308.pdf

295-delnp-2005-pct-332.pdf

295-delnp-2005-pct-401.pdf

295-delnp-2005-pct-409.pdf

295-delnp-2005-pct-416.pdf

295-delnp-2005-petition-137.pdf

295-delnp-2005-petition-138.pdf


Patent Number 243175
Indian Patent Application Number 295/DELNP/2005
PG Journal Number 40/2010
Publication Date 01-Oct-2010
Grant Date 28-Sep-2010
Date of Filing 25-Jan-2005
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GREENFORD, MIDDLESEX UB6 0NN, ENGLAND
Inventors:
# Inventor's Name Inventor's Address
1 GERARD MARTIN PAUL GIBLIN C/O GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM19 5AW, ENGLAND
2 ANDREW JOHN EATHERTON C/O GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM19 5AW, ENGLAND
3 RICHARD HOWARD GREEN (DECEASED) C/O GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY, ENGLAND
4 WILLIAM LEONARD MITCHELL C/O GLAXOSMITHKLINE, NEW FRONTIERS, SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM19 5AW, ENGLAND
5 ALAN NAYLOR C/O GLAXOSMITHKLINE, NEW FRONTIERS, SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM19 5AW, ENGLAND
6 DEREK ANTHONY RAWLINGS C/O GLAXOSMITHKLINE, NEW FRONTIERS, SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM19 5AW, ENGLAND
7 BRIAN PETER SLINGSBY C/O GLAXOSMITHKLINE, NEW FRONTIERS, SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM19 5AW, ENGLAND
8 ANDREW RICHARD WHITTINGTON C/O GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE, SG1 2NY, ENGLAND
PCT International Classification Number C07D 239/42
PCT International Application Number PCT/EP2003/009217
PCT International Filing date 2003-08-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0309326.7 2003-04-24 U.K.
2 0219501.4 2002-08-21 U.K.