SUBSTITUTED PYRIMIDINE DERIVATIVES AS NICOTINIC ACETYLCHOLINESTERASE RECEPTOR ALPHA 6 MODULATOR

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof wherein in, R.sup.1, R.sup.2, R.sup.3, L and X are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy particularly for use in treating disorders associated with nicotinic acetylcholine receptor 6 (nAChR6) activity.

##STR00001##

Claims

1. A compound of formula (I): ##STR00190## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: X is N or CR.sup.4; L is a bond, C(O), C(O)C(R.sup.5).sub.2, C(R.sup.5).sub.2, or C(R.sup.5).sub.2C(R.sup.5).sub.2; each R.sup.1 is independently selected from halo, cyano, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, and C.sub.3-C.sub.6 halocycloalkoxy; m is 2, 3, 4 or 5; R.sup.2 is selected from halo, cyano, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, and C.sub.3-C.sub.6 halocycloalkoxy; R.sup.3 is selected from a C.sub.3-C.sub.6 cycloalkyl and 4- to 10-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted with one, two, three, four or five substituents independently selected from halo, cyano, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, C.sub.3-C.sub.6 halocycloalkoxy, N(R.sup.6).sub.2, and SO.sub.2(R.sup.6); R.sup.4 is selected from hydrogen, halo, cyano, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, and C.sub.3-C.sub.6 halocycloalkoxy; each R.sup.5 is independently selected from hydrogen, CH.sub.3, CH.sub.2CH.sub.3, and CF.sub.3; and each R.sup.6 is independently selected from hydrogen and C.sub.1-C.sub.3 alkyl, or two R.sup.6 together with the nitrogen to which they are attached form a 3- to 6-membered saturated heterocyclic group; provided the compound is not: 4-methoxy-5-(2-methyl-4-(trifluoromethoxy)phenyl)-N-((1s,4s)-4-methylcyclohexyl)pyrimidin-2-amine; 4-methoxy-5-(2-methoxy-4-(trifluoromethoxy)phenyl)-N-((1s,4s)-4-methylcyclohexyl)pyrimidin-2-amine; or N-cyclopropyl-5-(3,4-dimethoxyphenyl)-4-methyl-pyrimidin-2-amine.

2. The compound as claimed in claim 1, wherein X is N.

3. The compound as claimed in claim 1, wherein X is CR.sup.4.

4. The compound as claimed in claim 3, wherein R.sup.4 is selected from hydrogen, halo, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy, and cyclopropoxy.

5. The compound as claimed in claim 1, wherein each R.sup.1 is independently selected from halo, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, an C.sub.1-C.sub.3 haloalkoxy.

6. The compound as claimed in claim 1, wherein m is 2.

7. The compound as claimed in any one of the claim 1, wherein R.sup.2 is selected from halo, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy, and cyclopropoxy.

8. The compound as claimed in any one of the claim 1, wherein L is a bond, C(O), C(O)CH.sub.2, C(O)CH(CH.sub.3), C(O)CH(CF.sub.3), CH.sub.2, CH(CH.sub.3), CH(CF.sub.3), CH.sub.2CH.sub.2, CH.sub.2CH(CH.sub.3), CH.sub.2CH(CF.sub.3), CH(CH.sub.3)CH.sub.2, or CH(CF.sub.3)CH.sub.2.

9. The compound as claimed in claim 1, wherein R.sup.3 is selected from a C.sub.3-C.sub.6 cycloalkyl group, a 4-, 5- or 6-membered saturated monocyclic heterocyclic group, a 7-, 8-, 9- or 10-membered saturated bicyclic heterocyclic group, and a 5- or 6-membered heteroaryl group, each of which is optionally substituted.

10. The compound as claimed in any one of the claim 1, wherein the cycloalkyl or heterocyclic group of R.sup.3 is optionally substituted with one, two, three, four or five substituents independently selected from halo, cyano, hydroxy, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy, N(R.sup.6).sub.2, and SO.sub.2(R.sup.6), wherein each R.sup.6 is independently selected from hydrogen and C.sub.1-C.sub.3 alkyl.

11. The compound as claimed in claim 1, wherein the compound is selected from: 4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5-phenylpyrimidin-2-amine; N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5-phenylpyrimidin-2-amine; 5-(4-fluorophenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine; 5-(4-fluorophenyl)-N-((1-methylpiperidin-3-yl)methyl)pyrimidin-2-amine; 5-(4-fluorophenyl)-N-(1-methylpiperidin-3-yl)pyrimidin-2-amine; 5-(4-fluorophenyl)-N-(1-isopropylpiperidin-3-yl)pyrimidin-2-amine; N.sup.1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N.sup.3,N.sup.3-dimethylcyclohexane-1,3-diamine; 5-(4-fluorophenyl)-N-((1-methylpiperidin-2-yl)methyl)pyrimidin-2-amine; 5-(4-fluorophenyl)-N-(1-isopropylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-((1-ethylpiperidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-((1-(dimethylamino)cyclopentyl)methyl)-4-methyl-pyrimidin-2-amine; N-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine; 5-(2,4-difluorophenyl)-4-methyl-N-((1-methylpyrrolidin-3-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine; 6-(2,4-difluorophenyl)-5-methyl-N-((1-methylpyrrolidin-2-yl)methyl)-1,2,4-triazin-3-amine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-2-yl)methyl)pyrimidin-2-amine; 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpyrrolidin-2-yl)methyl)-1,2,4-triazin-3-amine; 5-(2,4-difluorophenyl)-2-(((1-methylpyrrolidin-2-yl)methyl)amino)pyrimidine-4-carbonitrile; 6-(2,4-difluorophenyl)-5-methyl-N-((1-methylpiperidin-2-yl)methyl)-1,2,4-triazin-3-amine; 6-(2,4-difluorophenyl)-5-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,4-triazin-3-amine; 5-(2,4-difluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-4-methyl-pyrimidin-2-amine; 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,4-triazin-3-amine; 5-(2,4-difluorophenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-2-(((1-methylpiperidin-2-yl)methyl)amino)pyrimidine-4-carbonitrile; 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpiperidin-2-yl)methyl)-1,2,4-triazin-3-amine; 5-(2-fluoro-4-methoxyphenyl)-2-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)pyrimidine-4-carbonitrile; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(1-methylpyrrolidin-3-yl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-3-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-2-(((1-methylpyrrolidin-3-yl)methyl)amino)pyrimidine-4-carbonitrile; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-3-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-5-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-2-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-5-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-3-yl)methyl)pyrimidin-2-amine; 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-2-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-2-yl)methyl)pyrimidin-2-amine; 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)pyrimidin-2-amine; 2-((3-(dimethylamino)cyclopentyl)amino)-5-(2-fluoro-4-methoxyphenyl)pyrimidine-4-carbonitrile; N.sup.1-(6-(2,4-difluorophenyl)-5-methyl-1,2,4-triazin-3-yl)-N.sup.3,N.sup.3-dimethylcyclohexane-1,3-diamine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-N-(1-isopropylpiperidin-4-yl)-4-methyl-pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(pyridin-3-ylmethyl)pyrimidin-2-amine; N.sup.1-(5-(2-fluoro-4-methoxyphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)-N.sup.3,N.sup.3-dimethylcyclopentane-1,3-diamine; N.sup.1-(5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidin-2-yl)-N.sup.3,N.sup.3-dimethylcyclopentane-1,3-diamine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(tetrahydro-2H-pyran-3-yl)pyrimidin-2-amine; 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-N-(1-isopropylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-N-((1-isopropylpiperidin-3-yl)methyl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-N-((1-isopropylpiperidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((tetrahydro-2H-pyran-3-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(3-(methylsulfonyl)cyclopentyl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-N-(3-methoxycyclohexyl)-4-methyl-pyrimidin-2-amine; N.sup.1-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)-N.sup.3,N.sup.3-dimethylcyclohexane-1,3-diamine; 2-((3-(dimethylamino)cyclohexyl)amino)-5-(2-fluoro-4-methoxyphenyl)pyrimidine-4-carbonitrile; 5-(2,4-difluorophenyl)-2-((3-(dimethylamino)cyclopentyl)amino)pyrimidine-4-carbonitrile; 5-(2,4-difluorophenyl)-2-((3-(dimethylamino)cyclohexyl)amino)pyrimidine-4-carbonitrile; 5-(2,4-difluorophenyl)-4-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyrimidin-2-amine; 5-(2-fluoro-5-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-3-yl)methyl)pyrimidin-2-amine; 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-3-yl)methyl)pyrimidin-2-amine; 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((1-methyl-1H-imidazol-5-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(1-(1-methylpyrrolidin-3-yl)ethyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-2-((1-isopropylpiperidin-4-yl)amino)pyrimidine-4-carbonitrile; 5-(2,4-difluorophenyl)-2-((1-methylpiperidin-4-yl)amino)pyrimidine-4-carbonitrile; 5-(2,4-difluorophenyl)-N-(1-isopropylpiperidin-4-yl)-4-methyl-pyrimidin-2-amine; N.sup.1-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)-N.sup.3,N.sup.3-dimethylcyclobutane-1,3-diamine; 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine; 5-(2-fluoro-4-methoxyphenyl)-4,6-dimethyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-(1-isopropylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-4-methoxy-6-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 6-(2-fluoro-4-methoxyphenyl)-N-(1-isopropylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(1-methylpiperidin-3-yl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-((4-methylmorpholin-3-yl)methyl)pyrimidin-2-amine; N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-methoxyphenyl)-2-((1-isopropylpiperidin-4-yl)amino)pyrimidine-4-carbonitrile; 5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-((3,3-difluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine; N-((3,3-difluoro-1-methylpyrrolidin-2-yl)methyl)-5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-((1-ethylpyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine; N-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)hexahydro-1H-pyrrolizin-1-amine; 5-(2,4-difluorophenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethoxy)phenyl)-N-(1-isopropylpiperidin-4-yl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(4-fluoro-2-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-((1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-((3-fluoro-1-methylpyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine; N-(5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-pyrimidin-2-yl)hexahydro-1H-pyrrolizin-1-amine; N-((1-ethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-3-yl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(1-isopropylpyrrolidin-3-yl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methyl-4-piperidinyl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-piperidinylmethyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methyl-3-piperidinyl)methyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((4-methylmorpholin-2-yl)methyl)pyrimidin-2-amine; N.sup.1-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-N.sup.2,N.sup.2-dimethyl-cyclohexane-1,2-diamine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-3-yl)pyrimidin-2-amine; N.sup.3-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)cyclopentane-1,3-diamine; N-(4-fluoropyrrolidin-3-yl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((3-piperidinyl)methyl)pyrimidin-2-amine; 4-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)amino)pyrrolidin-3-ol; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(3-piperidinyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine; N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)quinuclidin-3-amine; N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-amine; N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-amine; N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-6-azaspiro[2.5]octan-1-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-4-methyl-pyrimidin-2-amine; N.sup.1-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)cyclohexane-1,3-diamine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(piperidin-3-ylmethyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(piperidin-3-yl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(1-(pyrrolidin-2-yl)ethyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(1-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-((3-fluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((2-methyl-pyrrolidin-2-yl)methyl)pyrimidin-2-amine; N-((1,2-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine; N-((1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine; and N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-1-methylpyrrolidine-2-carboxamide; or an enantiomer of any of the foregoing; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.

12. The compound as claimed in claim 1, wherein the compound is selected from: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-amine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*S)-1-((2S)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine; and N-(((2*S,5*R)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.

13. The compound as claimed in claim 1, wherein the compound is selected from: (S)-5-(2,4-difluorophenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; (R)-5-(2,4-difluorophenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-N-(1-isopropylpiperidin-4-yl)-4-methyl-pyrimidin-2-amine; (R)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine; (S)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; 5-(2,4-difluorophenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine; (S)-5-(2,4-difluorophenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine; (R)-5-(2,4-difluorophenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine; (R)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; (S)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine; and 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((3S)-3-piperidinyl)pyrimidin-2-amine; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.

14. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein the process comprises: (a) reacting a compound of formula (II) or a salt thereof, with a compound of formula (III) or a salt thereof, to provide a compound of formula (IV) or a salt thereof: ##STR00191## wherein m, R.sup.1, R.sup.2 and X are as defined in claim 1; R.sup.7 is independently selected from hydroxy, C.sub.1-C.sub.5 alkyl, and C.sub.1-C.sub.5 alkoxy, or two R.sup.7 together with the boron to which they are attached form an optionally substituted 3- to 12-membered heterocyclic group; and LG.sup.1 and LG.sup.2 are leaving groups, or a sulfonate group; (b) reacting a compound of formula (IV) or a salt thereof, with a compound of formula (V) or a salt thereof, to provide a compound of formula (I) or a salt thereof: ##STR00192## wherein R.sup.3 and L are as defined in claim 1; and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (I) into another compound of formula (I); removing any protecting groups; forming a pharmaceutically acceptable salt, solvate or prodrug.

15. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

16. (canceled)

17. A method of treating or preventing a disease, disorder or condition, wherein the method comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I): ##STR00193## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: X is N or CR.sup.4; L is a bond, C(O), C(O)C(R.sup.5).sub.2, C(R.sup.5).sub.2, or C(R.sup.5).sub.2C(R.sup.5).sub.2; each R.sup.1 is independently selected from halo, cyano, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, and C.sub.3-C.sub.6 halocycloalkoxy; m is 0, 1, 2, 3, 4 or 5; R.sup.2 is selected from hydrogen, halo, cyano, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, and C.sub.3-C.sub.6 halocycloalkoxy; R.sup.3 is selected from a C.sub.3-C.sub.6 cycloalkyl and 4- to 10-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted with one, two, three, four or five substituents independently selected from halo, cyano, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, C.sub.3-C.sub.6 halocycloalkoxy, N(R.sup.6).sub.2, and SO.sub.2(R.sup.6); R.sup.4 is selected from hydrogen, halo, cyano, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, and C.sub.3-C.sub.6 halocycloalkoxy; each R.sup.5 is independently selected from hydrogen, CH.sub.3, CH.sub.2CH.sub.3, and CF.sub.3; and each R.sup.6 is independently selected from hydrogen and C.sub.1-C.sub.3 alkyl, or two R.sup.6 together with the nitrogen to which they are attached form a 3- to 6-membered saturated heterocyclic group; wherein the disease, disorder or condition is associated with nicotinic acetylcholine receptor 6 (nAChR6) activity: or wherein the disease, disorder or condition has dysregulation of dopamine, noradrenaline or serotonin as a key pathological mechanism; or wherein the disease, disorder or condition is selected from a movement disorder, dystonia, dyskinesia, Parkinson's disease, Huntington's disease, a psychiatric disorder, an addiction disorder, and a non-motor symptom of Parkinson's disease.

18-21. (canceled)

22. The method of claim 17, wherein the movement disorder is tremor; or wherein the dyskinesia is L-DOPA induced dyskinesia in Parkinson's disease; or wherein the psychiatric disorder is selected from schizophrenia, psychotic disorder, psychosis, schizoaffective disorder, bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and Tourettes syndrome; or wherein the addiction disorder is selected from substance or drug dependence, alcohol dependence, nicotine dependence, binge eating, and gambling disorder; or wherein the non-motor symptom of Parkinson's disease is selected from apathy, anhedonia, and depression.

23. The method of claim 22, wherein the tremor is selected from a resting tremor in Parkinson's disease and essential tremor including essential tremor in isolation, essential tremor in Parkinson's disease, essential tremor in Alzheimer's disease, and essential tremor in other neurodegenerative diseases; or wherein the bipolar disorder is selected from bipolar I, bipolar IL, bipolar mania, and bipolar depression; or wherein the autism spectrum disorder (ASD) is Fragile X syndrome.

Description

[0375] The generic schemes below describe the routes used to synthesize the examples herein.

[0376] FIG. 1

##STR00007##

[0377] FIG. 2

##STR00008##

[0378] FIG. 3

##STR00009##

[0379] FIG. 4

##STR00010##

[0380] FIG. 5

##STR00011##

[0381] FIG. 6

##STR00012##

[0382] FIG. 7

##STR00013##

[0383] FIG. 8

##STR00014##

[0384] FIG. 9

[0385] ##STR00015##

[0386] For FIGS. 1 to 9 above, where there are reaction conditions described, such as reagents, solvents, temperatures and reaction durations, it is to be understood that these reaction conditions, in particular solvents, temperatures and reaction durations, are not essential to the reaction being carried out and may be varied.

1. INTERMEDIATES

[0387] Commercial intermediates were used in preparation of the examples except for the following intermediates which were prepared using standard procedures as outlined below.

Intermediate 1: 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine

[0388] ##STR00016##

[0389] K.sub.2CO.sub.3 (1.01 g, 7.35 mmol) was added to a solution of 5-bromo-2-chloro-4-methyl-pyrimidine (1.00 g, 4.82 mmol) and 2,4-difluorophenylboronic acid (0.76 g, 4.82 mmol) in dioxane (10 mL) and H.sub.2O (2 mL) in a glass tube and purged with argon for 10 min. The mixture was treated with a PdCl.sub.2-dppf DCM complex (0.40 g, 0.49 mmol), purged with argon for 10 min, sealed and heated to 110 C. for 5 h. The solvent was evaporated from the mixture and the residue diluted with ice cold H.sub.2O (10 mL) and extracted with EtOAc (325 mL). The combined organic layers were dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. The residue was purified by column chromatography in an automated purification system (Grace, 8-10% EtOAc/petrol ether) to obtain the title compound (400 mg, 35%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.39 (s, 1H), 7.21-7.23 (m, 1H), 6.96-6.97 (m, 2H), 2.44 (s, 3H). MS ES.sup.+: 241.1.

Intermediate 2: 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine

[0390] ##STR00017##

[0391] Prepared as described for Intermediate 1 using 5-bromo-2-chloro-4-methyl-pyrimidine (0.6 g, 2.89 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (0.55 g, 3.23 mmol) to afford the title compound (0.65 g, 89%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.39 (s, 1H), 7.14 (t, J=8.4 Hz, 1H), 6.83 (d, J=6.4 Hz, 1H), 6.76 (d, J=11.6 Hz, 1H), 3.87 (s, 3H), 2.50 (s, 3H). MS ES.sup.+: 253.0.

Intermediate 3: 5-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile

[0392] ##STR00018##

[0393] Step 1: To a stirred solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (2.0 g, 8.0 mmol) and ammonium chloride (2.56 g, 40 mmol) in DMF (20 mL) was added EDC HCl (2.3 g, 12 mmol), morpholine (0.002 mL, 0.023 mmol) and HOBt (1.62 g, 12 mmol) at RT. The mixture was stirred for 16 h at RT, quenched with ice cold H.sub.2O and extracted with EtOAc (225 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was triturated with pentane to obtain 5-bromo-2-(methylthio)pyrimidine-4-carboxamide (1.50 g, 75%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.91 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 2.54 (s, 3H). MS ES.sup.+: 247.8.

[0394] Step 2: A stirred solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxamide (0.75 g, 3.0 mmol), 2,4-difluorophenylboronic acid (0.52 g, 3.3 mmol) and K.sub.2CO.sub.3 (1.24 g, 9 mmol) in dioxane/H.sub.2O (4:1, 15 mL) in a sealed tube was purged with N.sub.2 for 10 min, treated with Pd(dppf)Cl.sub.2 (0.21 g, 0.3 mmol), sealed and heated at 100 C. for 1 h (microwave). The mixture was treated with H.sub.2O and extracted with EtOAc (230 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. The crude compound was purified by column chromatography (on Grace instrument, 0-50% EtOAc/petrol ether) to afford 5-(2,4-difluorophenyl)-2-(methylthio)pyrimidine-4-carboxamide (0.6 g, 71%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.72 (s, 1H), 8.15 (s, 1H), 7.76 (s, 1H), 7.60-7.50 (m, 1H), 7.45-7.35 (m, 1H), 7.25-7.2 (m, 1H), 2.62 (s, 3H). MS ES.sup.+: 282.14.

[0395] Step 3: To a stirred solution of 5-(2,4-difluorophenyl)-2-(methylthio)pyrimidine-4-carboxamide (0.60 g, 2.13 mmol) and triethylamine (0.75 mL) in DCM (15 mL) was added trichloroacetyl chloride (0.80 mL, 4.26 mmol) at 0 C. The mixture was warmed to RT, stirred for 4 h, diluted with H.sub.2O and extracted with EtOAc (250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to obtain 5-(2,4-difluorophenyl)-2-(methylthio)pyrimidine-4-carbonitrile (0.5 g), which was used in the next step without further purification.

[0396] Step 4: To a stirred solution of 5-(2,4-difluorophenyl)-2-(methylthio)pyrimidine-4-carbonitrile (0.5 g, 1.9 mmol) in acetone/H.sub.2O (1:1, 12 mL) was added oxone (0.60 g, 3.8 mmol) at RT. The mixture was stirred at RT for 4 h and extracted with EtOAc (220 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (in Grace instrument, 0-50% EtOAc/petrol ether) to obtain the title compound (0.32 g, 58%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.2 (s, 1H), 7.58-7.53 (m, 1H), 7.20-7.00 (m, 2H), 3.45 (s, 3H). MS ES.sup.+: 296.14.

Intermediate 4: 5-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile

[0397] ##STR00019##

[0398] Prepared as described for Intermediate 3 using 5-bromo-2-(methylthio)pyrimidine-4-carboxamide (2 g, 8 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (1.36 g, 8 mmol) in step 2 to afford the title compound (0.6 g, 24%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.18 (s, 1H), 6.98-6.92 (m, 1H), 6.87 (d, J=12.4 Hz, 2H), 3.91 (s, 3H), 3.45 (s, 3H). MS ES.sup.+: 308.20.

Intermediate 5: 2-chloro-5-(2-fluoro-5-methoxyphenyl)-4-methyl-pyrimidine

[0399] ##STR00020##

[0400] Prepared as described for Intermediate 1 using 5-bromo-2-chloro-4-methyl-pyrimidine (0.2 g, 1.0 mmol) and (2-fluoro-5-methoxyphenyl)boronic acid (0.17 g, 1.0 mmol) to afford the title compound (0.1 g, 41%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.42 (s, 1H), 7.15-7.10 (t, J=9.2 Hz, 1H), 6.98-6.95 (m, 1H), 6.74-6.72 (m, 1H), 3.83 (s, 3H), 2.47 (s, 3H). MS ES.sup.+: 253.47.

Intermediate 6: 2-chloro-5-(2-chloro-4-methoxyphenyl)-4-methyl-pyrimidine

[0401] ##STR00021##

[0402] Prepared as described for Intermediate 1 using 5-bromo-2-chloro-4-methyl-pyrimidine (0.45 g, 2.2 mmol) and (2-chloro-4-methoxyphenyl)boronic acid (0.409 g, 2.0 mmol) to afford the title compound (0.23 g, 40%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.34 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.94-6.91 (dd, J=2.4 Hz and 8.8 Hz, 1H), 3.87 (s, 3H), 2.38 (s, 3H). MS ES.sup.+: 269.18.

Intermediate 7: 2-chloro-4-cyclopropyl-5-(2,4-difluorophenyl)pyrimidine

[0403] ##STR00022##

[0404] Step 1: A solution of 5-bromo-2-chloropyrimidine (5 g, 25.9 mmol) in a mixture of ACN/H.sub.2O (1:1, 100 mL) was treated with cyclopropanecarboxylic acid (2.22 g, 25.9 mmol), ammonium persulfate (37.2 g, 167.17 mmol) and silver nitrate (1.32 g, 7.77 mmol) under N.sub.2 at RT, stirred for 16 h and evaporated. The residue was extracted with EtOAc (250 mL) and the combined organic layers were washed with H.sub.2O followed by brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (on Grace instrument, 2% EtOAc in petrol ether) to afford 5-bromo-2-chloro-4-cyclopropylpyrimidine (2.5 g, 48%) as a colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.49 (s, 1H), 2.47-2.44 (m, 1H), 1.31-1.24 (m, 4H). MS ES.sup.+: 233.06.

[0405] Step 2: To a solution of 5-bromo-2-chloro-4-cyclopropylpyrimidine (0.90 g, 3.9 mmol) in dioxane/H.sub.2O (3:1, 20 mL) was added (2,4-difluorophenyl)boronic acid (0.677 g, 4.29 mmol) and K.sub.2CO.sub.3 (1.61 g, 11.7 mmol). The mixture was purged with N.sub.2, treated with Pd(dppf)Cl.sub.2 (0.16 g, 0.19 mmol), sealed and stirred at 100 C. for 2 h. The solvent was evaporated and the mixture extracted with EtOAc (250 mL). The combined organic layers were washed with H.sub.2O followed by brine, dried over Na.sub.2SO.sub.4 and concentrated to obtain crude product. The crude product was purified by column chromatography (on Grace instrument, 5% EtOAc in petrol ether) to afford the title compound (0.45 g, 38%) as a colourless gum. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.28 (s, 1H), 7.35-7.31 (m, 1H), 7.06-6.96 (m, 2H), 1.82-1.79 (m, 1H), 1.34-1.30 (m, 2H), 1.10-1.07 (m, 2H). MS ES.sup.+: 267.0.

Intermediate 8: 2-chloro-4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)pyrimidine

[0406] ##STR00023##

[0407] Step 1: A solution of 5-bromo-2-chloropyrimidine (5 g, 25.9 mmol) in a mixture of ACN/H.sub.2O (1:1, 100 mL) was treated with cyclopropanecarboxylic acid (2.22 g, 25.9 mmol), ammonium persulfate (37.2 g, 167.17 mmol) and silver nitrate (1.32 g, 7.77 mmol) under N.sub.2 at RT, stirred for 16 h and evaporated. The residue was extracted with EtOAc (250 mL) and the combined organic layers were washed with H.sub.2O followed by brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (on Grace instrument, 2% EtOAc in petrol ether) to afford 5-bromo-2-chloro-4-cyclopropylpyrimidine (2.5 g, 48%) as a colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.49 (s, 1H), 2.47-2.44 (m, 1H), 1.31-1.24 (m, 4H). MS ES.sup.+: 233.06.

[0408] Step 2: A solution of 5-bromo-2-chloro-4-cyclopropylpyrimidine (2.5 g, 10.8 mmol) in dioxane/H.sub.2O (3:1, 100 mL) was treated with (2-fluoro-4-methoxyphenyl)boronic acid (2.01 g, 11.88 mmol) and K.sub.2CO.sub.3 (4.47 g, 32.4 mmol), purged with N.sub.2, treated with Pd(dppf)Cl.sub.2 (0.44 g, 0.54 mmol), sealed and stirred at 100 C. for 2 h. The solvent was evaporated and the residue extracted with EtOAc (250 mL). The combined organic layers were washed with H.sub.2O followed by brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (on Grace instrument, 5% EtOAc in petrol ether) to afford the title compound (1.60 g, 42%) as a colourless gum. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.30 (s, 1H), 7.28-7.23 (m, 1H), 6.86-6.84 (m, 1H), 6.80-6.76 (m, 1H), 3.88 (s, 3H), 1.92-1.88 (m, 1H), 1.35-1.30 (m, 2H), 1.10-1.07 (m, 2H). MS ES.sup.+: 279.22.

Intermediate 9: 2-chloro-5-(2-fluoro-4-trifluoromethoxy)phenyl)-4-methyl-pyrimidine

[0409] ##STR00024##

[0410] Prepared as described for Intermediate 1 using 5-bromo-2-chloro-4-methyl-pyrimidine (0.1 g, 0.5 mmol) and (2-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (0.112 g, 0.5 mmol) to afford the title compound (0.045 g, 30%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.41 (s, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.20-7.18 (m, 1H), 7.17-7.12 (m, 1H), 2.46 (s, 3H). MS ES.sup.+: 307.09.

Intermediate 10: 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine

[0411] ##STR00025##

[0412] A solution of 5-bromo-2-chloro-4-methyl-pyrimidine (0.6 g, 2.9 mmol), (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (0.7 g, 3.2 mmol) and K.sub.2CO.sub.3 (0.8 g, 5.8 mmol) in H.sub.2O and dioxane in a glass tube was purged with N.sub.2 for 10 min, treated with Pd(dppf)Cl.sub.2.Math.DCM (0.2 g, 0.2 mmol) and purged with N.sub.2. The tube was sealed and the mixture heated at 90-100 C. for 14 h, cooled, diluted with EtOAc and washed with H.sub.2O and brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (on Grace instrument, 60% MeOH in H.sub.2O) to afford the title compound (0.36 g, 43%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.34 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.22-7.16 (m, 1H), 7.14-7.10 (m, 1H), 2.40 (s, 3H). MS ES.sup.+: 291.09.

Intermediate 11: 2-chloro-5-(4-fluoro-2-(trifluoromethyl)phenyl)-4-methyl-pyrimidine

[0413] ##STR00026##

[0414] Prepared as described for Intermediate 1 using 5-bromo-2-chloro-4-methyl-pyrimidine (0.3 g, 1.5 mmol) and (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid (0.4 g, 1.8 mmol) to afford the title compound (0.21 g, 49%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.42 (s, 1H), 7.21 (m 1H), 7.29-7.10 (m, 1H), 7.10-7.01 (m, 1H), 2.42 (s, 3H). MS ES.sup.+: 291.01.

Intermediate 12: 6-(2,4-difluorophenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine

[0415] ##STR00027##

[0416] Step 1: A stirred solution of 1-(2,4-difluorophenyl)propan-1-one (1.5 g, 8.8 mmol) in DCM was treated with TMSCl (1.91, 17.6 mmol) followed by isoamyl nitrite (2.06 g, 17.6 mmol) at 20 C., allowed to warm to RT and stirred at RT for 16 h. The mixture was quenched with ice cold H.sub.2O (100 mL) and extracted with DCM (250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (2-3% EtOAc in petrol ether) to obtain (E)-1-(2,4-difluorophenyl)-2-(hydroxyimino)propan-1-one (900 mg, 51.4%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.07 (s, 1H), 7.56-7.50 (m, 1H), 6.96-6.91 (m, 1H), 6.87-6.81 (m, 1H), 2.14 (s, 3H). MS ES.sup.+: 200.06.

[0417] Step 2: Carbon disulfide (12.5 mL, 0.2 mol) was added dropwise to an ice cooled mixture of hydrazine hydrate (85%, 10 mL, 0.2 mol) in aq. KOH (13.4 g, 0.24 mol) and 2-propanol (50 mL). The mixture was allowed to stir at 10 C. for 1.5 h, dropwise treated with methyl iodide (12.5 mL, 0.20 mol) and continued to stir at 0 C. for 1 h. The precipitated solid was filtered and washed with ice H.sub.2O. The crude material was purified by column chromatography (20-45% EtOAc in petrol ether) to give methyl hydrazinecarbodithioate (4.0 g, 65%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.86-8.31 (m, 1H), 4.70 (s, 1H), 4.17 (s, 1H), 2.66 (s, 3H). MS ES.sup.+: 123.0.

[0418] Step 3: A stirred solution of (E)-1-(2,4-difluorophenyl)-2-(hydroxyimino)propan-1-one (2.5 g, 12.6 mmol) and methyl hydrazinecarbodithioate (1.69 g, 13.7 mmol) in EtOH (10 mL) at 0 C. was treated with conc. HCl (1.2 mL), allowed to warm to RT and stirred for 16 h. The precipitated solid was filtered, washed with petrol ether and dried in vacuo to obtain methyl (Z)-2-((E)-1-(2,4-difluorophenyl)-2-(hydroxyimino)propylidene)hydrazine-1-carbodithioate (2.1 g, 55%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.63 (s, 1H), 7.64 (s, 1H), 7.21-7.15 (m, 1H), 7.08-7.03 (m, 1H), 7.01-6.95 (m, 1H), 2.65 (s, 3H), 2.28 (s, 3H). MS ES.sup.+: 304.0.

[0419] Step 4: A solution of methyl (Z)-2-((E)-1-(2,4-difluorophenyl)-2-(hydroxyimino) propylidene)hydrazine-1-carbodithioate (2.5 g, 8.3 mmol) in aq. 20% potassium carbonate solution (30 mL) was refluxed at 110 C. for 1 h and allowed to cool to RT. The precipitated solid was filtered, washed with petrol ether and Et.sub.2O, and dried in vacuo to obtain 6-(2,4-difluorophenyl)-3-mercapto-5-methyl-1,2,4-triazine-4-oxide (1.8 g, 85%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.61-7.55 (m, 1H), 7.42-7.36 (m, 1H), 7.25-7.20 (m, 1H), 2.06 (s, 3H). MS ES.sup.+: 256.0.

[0420] Step 5: Methyl iodide (2.08 g, 14.7 mmol) was added to a stirred solution of 6-(2,4-difluorophenyl)-3-mercapto-5-methyl-1,2,4-triazine-4-oxide (2.5 g, 9.8 mmol) and potassium carbonate (2.7 g, 19.6 mmol) in DMF (20 mL) at 0 C. The mixture was allowed to stir at RT for 2 h, quenched with ice cold H.sub.2O (100 mL) and extracted with EtOAc (270 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (10-12% EtOAc in petrol ether) to give 6-(2,4-difluorophenyl)-5-methyl-3-(methylthio)-1,2,4-triazine-4-oxide (1.0 g, 38.2%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.64-7.57 (m, 1H), 7.12-7.09 (m, 1H), 7.08-6.97 (m, 1H), 2.73 (s, 3H), 2.44 (s, 3H). MS ES.sup.+: 270.0.

[0421] Step 6: A stirred solution of 6-(2,4-difluorophenyl)-5-methyl-3-(methylthio)-1,2,4-triazine-4-oxide (0.05 g, 0.2 mmol) in triethyl phosphite (1 mL) was stirred at 160 C. for 4 h, cooled to RT, loaded onto a silica gel column and purified by chromatography (2-3% EtOAc in petrol ether) to give 6-(2,4-difluorophenyl)-5-methyl-3-(methylthio)-1,2,4-triazine (0.03 g, 63%) as a colourless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.59-7.54 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.95 (m, 1H), 2.71 (s, 3H), 2.45 (s, 3H). MS ES.sup.+: 254.17.

[0422] Step 7: Oxone (0.491 mg, 1.6 mmol) was added to a stirred solution of 6-(2,4-difluorophenyl)-5-methyl-3-(methylthio)-1,2,4-triazine (0.2 g, 0.8 mmol) in acetone/H.sub.2O (1:1, 10 mL) at 0 C. The mixture was allowed to stir at RT for 3 h, quenched with ice H.sub.2O (20 mL) and extracted with EtOAc (220 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (50-60% EtOAc in petrol ether) to give the title compound (0.2 g, 90/%) as a pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.61-7.52 (m, 1H), 7.09-7.01 (m, 1H), 7.00-6.92 (m, 1H), 4.01 (s, 3H), 2.47 (s, 3H). MS ES.sup.+: 286.89.

Intermediate 13: N.SUP.1.-(5-bromo-4-(trifluoromethyl)pyrimidin-2-yl)-N.SUP.3.,N.SUP.3.-dimethylcyclopentane-1,3-diamine

[0423] ##STR00028##

[0424] A stirred solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine (0.3 g, 1.15 mmol) in dioxane (10 mL) was treated with DIPEA (0.28 g, 2.3 mmol) and N.sup.1,N.sup.1-dimethylcyclopentane-1,3-diamine (0.14 g, 1.15 mmol) and stirred at 105 C. for 16 h. The solvent was evaporated under reduced pressure to yield crude title compound (0.4 g), which was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.73 (m, 1H), 8.26 (br s, 1H), 4.20-4.12 (m, 2H), 3.16-3.02 (m, 2H), 2.40-2.25 (m, 2H), 2.00-1.62 (m, 6H), 1.30-1.22 (m, 2H). MS ES.sup.+: 353.20.

Intermediate 14: 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4,6-dimethylpyrimidine

[0425] ##STR00029##

[0426] A solution of 5-bromo-2-chloro-4,6-dimethylpyrimidine (0.5 g, 2.25 mmol) in dioxane/H.sub.2O (3:1, 20 mL) was treated with K.sub.2CO.sub.3 (0.624 g, 4.5 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (0.382 g, 2.21 mmol), purged with N.sub.2 for 10 min, treated with Pd(dppf)Cl.sub.2 (0.054 g, 0.03 mmol), sealed and stirred at 100 C. for 16 h. The solvent was evaporated under reduced pressure and the residue dissolved in H.sub.2O and extracted with EtOAc (330 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography (on Grace instrument, 12% EtOAc in petrol ether) to give the title compound (0.10 g, 17%) as a colourless gum. MS ES.sup.+: 267.10

Intermediate 15: (S)-5-bromo-4-methoxy-6-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0427] ##STR00030##

[0428] Step 1: A solution of 5-bromo-2,4-dichloro-6-methyl pyrimidine (1.00 g, 4.13 mmol) in THF (10 mL) at 0 C. was treated with NaOMe (0.21 g, 3.72 mmol) and stirred for 30 min at 0 C. The mixture was diluted with EtOAc and washed with H.sub.2O followed by brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine (0.90 g, 92%) as a yellow solid, which was used in the next step without further purification.

[0429] Step 2: A stirred solution of 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine (0.60 g, 2.55 mmol) in 1,4-dioxane (5 mL) was treated with (S)-(1-methylpyrrolidin-2-yl)methanamine (0.35 g, 3.06 mmol) under N.sub.2 at RT, then treated with DIPEA (1.8 ml, 10.2 mmol), heated to 100 C. and stirred for 16 h. The mixture was cooled to RT, treated with H.sub.2O and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (60% MeOH/H.sub.2O) to give the title compound (0.35 g, 50%) as an off-white gummy solid. MS ES.sup.+: 317.23.

Intermediate 16: 5-bromo-4-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine

[0430] ##STR00031##

[0431] A mixture of 5-bromo-2-chloro-4-methyl-pyrimidine (0.40 g, 1.9 mmol), tetrahydro-2H-pyran-4-amine (0.19 g, 1.92 mmol) and DIPEA (0.367 g, 2.85 mmol) in dioxane (5 mL) was stirred for 16 h at 105 C. in a sealed tube. The mixture was cooled to RT, treated with H.sub.2O and extracted with EtOAc. The organic layer was evaporated under reduced pressure. The residue was purified by column chromatography (0-50% EtOAc in petrol ether) to afford the title compound (0.30 g, 58%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.26 (s, 1H), 7.34 (br s, 1H), 3.86-3.84 (m, 3H), 3.38-3.32 (m, 2H), 2.33 (s, 3H), 1.80-1.76 (m, 2H), 1.49-1.45 (m, 2H). MS ES.sup.+: 274.16.

Intermediate 17: 5-bromo-4-methyl-N-tetrahydro-2H-pyran-3-yl)pyrimidin-2-amine

[0432] ##STR00032##

[0433] Prepared as described for Intermediate 16 using 5-bromo-2-chloro-4-methyl-pyrimidine (0.40 g, 1.9 mmol) and tetrahydro-2H-pyran-3-amine (0.19 g, 1.92 mmol) to afford the title compound (0.30 g, 58%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.26 (s, 1H), 7.34 (br s, 1H), 3.86-3.84 (m, 3H), 3.38-3.32 (m, 1H), 3.10-3.00 (m, 1H), 2.34 (s, 3H), 2.00-1.95 (m, 1H), 1.80-1.76 (m, 1H), 1.49-1.45 (m, 2H). MS ES.sup.+: 274.03.

Intermediate 18: 5-bromo-4-methyl-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-2-amine

[0434] ##STR00033##

[0435] Prepared as described for Intermediate 16 using 5-bromo-2-chloro-4-methyl-pyrimidine (0.40 g, 1.9 mmol) and (tetrahydrofuran-2-yl)methanamine (0.19 g, 1.92 mmol) to afford the title compound (0.25 g, 48%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.24 (s, 1H), 7.3 (br s, 1H), 4.00-3.90 (m, 1H), 3.85-3.75 (m, 1H), 3.70-3.60 (m, 1H), 3.40-3.30 (m, 1H), 3.25-3.15 (m, 1H), 2.35 (s, 3H), 1.95-1.70 (m, 3H), 1.60-1.50 (m, 1H). MS ES.sup.+: 272.10.

Intermediate 19: 5-bromo-4-methyl-N-((4-methylmorpholin-3-yl)methyl)pyrimidin-2-amine

[0436] ##STR00034##

[0437] A solution of 5-bromo-2-chloro-4-methyl-pyrimidine (0.3 g, 1.5 mmol), (4-methylmorpholin-3-yl)methanamine (0.214 g, 1.65 mmol) and DIPEA (0.58 g, 6 mmol) in dioxane (10 mL) was allowed to stir for 24 h at 110 C. The mixture was diluted with H.sub.2O and extracted with EtOAc (330 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound (0.39 g, 90%) as sticky solid. MS ES.sup.+: 301.0.

Intermediate 20: (R)-1-(4,4-difluoro-1-methylpyrrolidin-2-yl)-N-(4 methoxybenzyl) methanamine

[0438] ##STR00035##

[0439] Step 1: A solution of (R)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (1 g, 4 mmol) and (4-methoxyphenyl)methanamine (0.66 g, 4.8 mmol) in THF (20 mL) was treated with HATU (2.28 g, 6.0 mmol) and DIPEA (1.54 g, 12 mmol) and allowed to stir for 24 h at RT. The mixture was quenched with ice cold H.sub.2O and extracted with 10% MeOH/DCM (240 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (60-70% EtOAc in petrol ether) to afford tert-butyl (R)-4,4-difluoro-2-((4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate (1.3 g, 88%) as thick liquid.

[0440] Step 2: A solution of tert-butyl (R)-4,4-difluoro-2-((4-methoxybenzyl)carbamoyl) pyrrolidine-1-carboxylate (0.50 g, 1.4 mmol) in THF was treated at 0 C. with an LiAlH.sub.4 solution (6.5 mL, 2M in THF) and stirred for 30 min. The mixture was warmed to 60 C. and continued to stir for 2 h, cooled to 0 C., quenched with a paste of Na.sub.2SO.sub.4 in H.sub.2O (0.5 mL) and allowed to stir for 5 min. Excess EtOAc was added to the mixture and filtered through Celite. The filtrate was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine-silica Davisil, 20-25% EtOAc in petrol ether) to afford the title compound (0.09 g, 25%) as thick liquid.

Intermediate 21: tert-butyl 2-(((5-bromo-4-methyl-pyrimidin-2-yl)amino)methyl)-3,3-difluoropyrrolidine-1-carboxylate

[0441] ##STR00036##

[0442] Step 1: A solution of 1-(tert-butyl) 2-ethyl 3-oxopyrrolidine-1,2-dicarboxylate (8.00 g, 31.1 mmol) in DCM (160 mL) was treated with DAST (15.04 g, 93.28 mmol, 12.32 mL) at 0 C. under N.sub.2 and stirred at 25 C. for 16 h. The mixture was diluted with DCM (300 mL), treated with sat. aq. NaHCO.sub.3 (800 mL) and extracted with DCM (500 mL). The combined organic layers were washed with H.sub.2O (400 mL) and brine (400 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford 1-(tert-butyl) 2-ethyl 3,3-difluoropyrrolidine-1,2-dicarboxylate (4.9 g, 56%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 4.40 (m, 1H), 4.25 (m, 2H), 3.75 (m, 1H), 3.55 (m, 1H), 2.41 (m, 2H), 1.45 (s, 9H), 1.3 (m, 3H).

[0443] Step 2: A solution of 1-(tert-butyl) 2-ethyl 3,3-difluoropyrrolidine-1,2-dicarboxylate (5.1 g, 18.3 mmol) in anhydrous THF (50 mL) at 0 C. was treated with LiAlH.sub.4 (762 mg, 20.1 mmol) in portions and stirred for 30 min at 0 C. The mixture was quenched with H.sub.2O (75 L), NaOH (15% 75 L) and H.sub.2O (150 L), filtered, and the filtrate concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford tert-butyl 3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.42 g, 78.9%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 4.0-3.6 (m, 4H), 3.5 (m, 2H), 2.45 (m, 2H), 1.5 (s, 9H).

[0444] Step 3: A solution of tert-butyl 3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.50 g, 14.8 mmol) in EtOAc (50 mL) (ice-bath) was treated with Et.sub.3N (2.24 g, 22.1 mmol, 3.08 mL) and MsCl (2.21 g, 19.29 mmol, 1.49 mL) and stirred at 25 C. for 1 h. The mixture was filtered and washed with EtOAc (20 mL) and the filtrate concentrated under reduced pressure, resulting in crude tert-butyl 3,3-difluoro-2-(((methylsulfonyl)oxy) methyl)pyrrolidine-1-carboxylate (5.5 g, 99%) as yellow oil, which was used in the next step without further purification.

[0445] Step 4: A solution of tert-butyl 3,3-difluoro-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (5.50 g, 14.7 mmol) in DMSO (50 mL) was treated with NaN.sub.3 (1.49 g, 22.9 mmol) and stirred at 70 C. for 16 h. The mixture was added into ice H.sub.2O (200 mL) and extracted with MTBE (350 mL). The combined organic layers were washed with H.sub.2O (25 mL) and dried over MgSO.sub.4. The resulting solution was treated with Pd/C (300 mg, 14.7 mmol, 10%/6), purged with H.sub.2 (3) and stirred at 25 C. for 20 h under H.sub.2. The mixture was filtered and concentrated under reduced pressure. The residue tert-butyl 2-(aminomethyl)-3,3-difluoropyrrolidine-1-carboxylate (3.1 g, 88.9%) was used in the next step without further purification.

[0446] Step 5: A solution of tert-butyl 2-(aminomethyl)-3,3-difluoropyrrolidine-1-carboxylate (3.00 g, 12.7 mmol) in DMF (60 mL) was treated with Cs.sub.2CO.sub.3 (8.27 g, 25.40 mmol) and 5-bromo-2-chloro-4-methyl-pyrimidine (3.42 g, 16.51 mmol) and stirred at 70 C. for 8 h. The mixture was quenched with cold H.sub.2O (200 mL) and extracted with EtOAc (2100 mL). The combined organic layers were washed with H.sub.2O (2100 mL) and brine (200 mL), dried over MgSO.sub.4 and evaporated. The residue was purified by flash silica gel chromatography to afford the title compound (2.2 g, 42.5%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.19 (s, 1H), 5.5 (br s, 1H), 4.1 (m, 1H), 3.7-3.40 (m, 4H), 2.4 (s, 3H), 2.4-2.3 (m, 2H), 1.4 (s, 9H).

Intermediate 22: tert-butyl 2-(aminomethyl)-3-fluoropyrrolidine-1-carboxylate

[0447] ##STR00037##

[0448] Step 1: A stirred solution of 1-(tert-butyl) 2-ethyl 3-oxopyrrolidine-1,2-dicarboxylate (1.50 g, 5.83 mmol) in MeOH (50 mL) was treated with NaBH.sub.4 (0.44 g 11.7 mmol) at 0 C., stirred at RT for 2 h and evaporated under reduced pressure. The residue was diluted with H.sub.2O and extracted with EtOAc (230 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to give 1-(tert-butyl) 2-ethyl 3-hydroxypyrrolidine-1,2-dicarboxylate (1.46 g) as an off-white solid, which was used in the next step without further purification.

[0449] Step 2: A stirred solution of 1-(tert-butyl) 2-ethyl 3-hydroxypyrrolidine-1,2-dicarboxylate (1.46 g, 5.6 mmol) in DCM (60 mL) was treated with DAST (1.80 g, 11.2 mmol) at 0 C., allowed to warm to RT and stirred for 16 h. The solvent was evaporated under reduced pressure and the residue diluted with H.sub.2O and extracted with EtOAc (230 ml). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated. Purification of the residue on amine silica (Davisil, 30% EtOAc in petrol ether) gave 1-(tert-butyl) 2-ethyl 3-fluoropyrrolidine-1,2-dicarboxylate (1.30 g, 90%) as an off-white gummy solid.

[0450] Step 3: A stirred solution of 1-(tert-butyl) 2-ethyl 3-fluoropyrrolidine-1,2-dicarboxylate (1.1 g, 4.2 mmol) in THF (50 mL) was treated with lithium borohydride (0.183 g, 8.4 mmol) at 0 C. and then stirred at RT for 3 h. The solvent was evaporated from the mixture, and the residue diluted with H.sub.2O and extracted with EtOAc (230 ml). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to give crude tert-butyl 3-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.55 g) as an off-white solid, which was used in the next step without further purification.

[0451] Step 4: A stirred solution of tert-butyl 3-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.25 g, 1.14 mmol) in toluene (50 mL) was treated with triphenyl phosphine (0.449 g, 1.71 mmol) and phthalimide (0.251 g, 1.71 mmol) at 0 C., stirred for 5 min, treated with DIAD (0.345 g, 1.71 mmol) and stirred at RT for 2.5 h. The mixture was then treated with hydrazine hydrate in EtOH (1:1, 5 mL) at 0 C. and stirred for 3 h at 85 C. The solvent was evaporated under reduced pressure and the residue diluted with H.sub.2O and extracted with EtOAc (230 ml). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by reverse phase column chromatography (30% MeOH/H.sub.2O) to give the title compound (0.12 g, 50%) as a pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 6.36 (s, 2H), 5.01 (m, 3H), 3.50 (s, 2H), 2.85-2.70 (m, 1H), 2.20-2.00 (m, 2H), 1.48 (s, 9H). ELSD MS: 219.1.

2. EXAMPLES

Example 1: 4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5-phenylpyrimidin-2-amine

[0452] ##STR00038##

[0453] A solution of 2-chloro-4-methyl-5-phenylpyrimidine (0.20 g, 1.00 mmol) in dry DMF was treated with 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.16 g, 1.25 mmol), stirred at 150 C. for 15 h, cooled to RT, quenched with ice H.sub.2O and extracted with EtOAc (220 mL). The combined organic layers were washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the residue by column chromatography on amine silica (Davisil) gave the title compound (0.053 g, 18%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.52 (s, 2H), 7.49-7.42 (m, 3H), 7.36-7.33 (m, 1H), 5.83 (s, 1H), 3.59-3.48 (m, 2H), 3.10 (t, J=7.6 Hz, 1H), 2.94 (s, 3H), 2.36 (s, 3H), 2.36-2.20 (m, 1H), 2.20-2.13 (q, J=9.2 Hz, 1H), 2.05-1.90 (m, 2H), 1.85-1.55 (m, 4H). MS ES.sup.+: 296.42.

Example 2: N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5-phenylpyrimidin-2-amine

[0454] ##STR00039##

[0455] A solution of 2-chloro-5-phenylpyrimidine (0.20 g, 1.05 mmol) in dry DMF was treated with 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.16 g, 1.248 mmol), stirred at 150 C. for 15 h, cooled to RT, quenched with ice H.sub.2O and extracted with EtOAc (220 mL). The combined organic layers were washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the residue by column chromatography on amine silica (Davisil) gave the title compound (0.053 g, 18%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.52 (s, 2H), 7.49-7.42 (m, 4H), 7.36-7.33 (m, 1H), 5.83 (s, 1H), 3.59-3.48 (m, 2H), 3.10 (t, J=7.6 Hz, 1H), 2.36 (s, 3H), 2.36-2.20 (m, 1H), 2.20-2.13 (q, J=9.2 Hz, 1H), 2.05-1.90 (m, 2H), 1.85-1.55 (m, 4H). MS ES.sup.+: 283.32.

Example 3: 5-(4-fluorophenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine

[0456] ##STR00040##

[0457] Prepared as described for Example 2 using 2-chloro-5-(4-fluorophenyl)pyrimidine (0.20 g, 0.96 mmol) and 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.16 g, 1.25 mmol) to afford the title compound (0.072 g, 25%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60 (s, 2H), 7.69-7.63 (m, 2H), 7.37 (br t, 1H), 7.29-7.24 (m, 2H), 3.40 (m, 2H), 3.25-3.10 (m, 1H), 2.50-2.28 (m, 5H), 2.10-1.90 (m, 2H), 1.80-1.68 (m, 2H), 1.65-1.50 (m, 2H). MS ES.sup.+: 301.31.

Example 4: 5-(4-fluorophenyl)-N-((1-methylpiperidin-3-yl)methyl)pyrimidin-2-amine

[0458] ##STR00041##

[0459] Prepared as described for Example 2 using 2-chloro-5-(4-fluorophenyl)pyrimidine (0.20 g, 0.96 mmol) and (1-methylpiperidin-3-yl)methanamine (0.16 g, 1.13 mmol) to afford the title compound (0.070 g, 24%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.58 (s, 2H), 7.68-7.62 (m, 2H), 7.41 (t, J=6.0 Hz, 1H), 7.29-7.24 (m, 2H), 3.30-3.15 (m, 2H), 2.90-2.65 (m, 2H), 2.25 (br s, 3H), 2.05-1.75 (m, 3H), 1.72-1.60 (m, 2H), 1.55-1.40 (m, 1H), 1.00-0.90 (m, 1H). MS ES.sup.+: 301.32.

Example 5: 5-(4-fluorophenyl)-N-(1-methylpiperidin-3-yl)pyrimidin-2-amine

[0460] ##STR00042##

[0461] Prepared as described for Example 2 using 2-chloro-5-(4-fluorophenyl)pyrimidine (0.22 g, 1.08 mmol) and 3-amino-1-methylpiperidine (0.135 g, 1.19 mmol) to afford the title compound (0.033 g, 12%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60 (s, 2H), 7.68-7.64 (m, 2H), 7.30-7.25 (m, 2H), 7.18-7.12 (m, 1H), 3.95-3.88 (m, 1H), 2.90-2.80 (m, 1H), 2.65-2.55 (m, 1H), 2.19 (br s, 3H), 1.90-1.78 (m, 3H), 1.72-1.65 (m, 1H), 1.58-1.48 (m, 1H), 1.35-1.20 (m, 1H). MS ES.sup.+: 287.24.

Example 6: 5-(4-fluorophenyl)-N-(1-isopropylpiperidin-3-yl)pyrimidin-2-amine

[0462] ##STR00043##

[0463] Prepared as described for Example 2 using 2-chloro-5-(4-fluorophenyl)pyrimidine (0.30 g, 1.44 mmol) and (1-isopropylpiperidin-3-yl)amine (0.340 g, 1.58 mmol) to afford the title compound (0.090 g, 20%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60 (s, 2H), 7.68-7.64 (m, 2H), 7.30-7.25 (t, J=6.6 Hz, 2H), 7.12-7.02 (br s, 1H), 3.95-3.85 (br s, 1H), 2.95-2.85 (m, 1H), 2.70-2.55 (m, 2H), 2.20-2.00 (m, 2H), 1.85-1.78 (m, 1H), 1.75-1.60 (m, 1H), 1.55-1.40 (m, 1H), 1.40-1.30 (m, 1H), 1.10-0.90 (br s, 6H). MS ES.sup.+: 315.31.

Example 7: N.SUP.1.-(5-(4-fluorophenyl)pyrimidin-2-yl)-N.SUP.3.,N.SUP.3.-dimethylcyclohexane-1,3-diamine

[0464] ##STR00044##

[0465] Prepared as described for Example 2 using 2-chloro-5-(4-fluorophenyl)pyrimidine (0.20 g, 0.96 mmol) and 3-(amino)-N,N-dimethylcyclohexanamine (0.16 g, 1.05 mmol) to afford the title compound (0.065 g, 21%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.65 (s, 1H), 8.62 (s, 1H), 7.69-7.65 (m, 2H), 7.50 (s, 1H), 7.30-7.25 (m, 2H), 4.30-3.90 (m, 1H), 3.40-3.20 (m, 1H), 2.75 (s, 6H), 2.20-2.10 (m, 1H), 1.95-1.85 (m, 1H), 1.80-1.70 (m, 2H), 1.60 (s, 1H), 1.50-1.20 (m, 1H), 1.10-0.90 (br s, 2H). MS ES.sup.+: 315.39.

Example 8: 5-(4-fluorophenyl)-N-((1-methylpiperidin-2-yl)methyl)pyrimidin-2-amine

[0466] ##STR00045##

[0467] Prepared as described for Example 2 using 2-chloro-5-(4-fluorophenyl)pyrimidine (0.22 g, 1.1 mmol) and (1-methylpiperidin-2-yl)methanamine (0.162 g, 1.3 mmol) to afford the title compound (0.072 g, 25%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60 (s, 2H), 7.70-7.65 (m, 2H), 7.27 (t, J=8.8 Hz, 2H), 7.10-6.90 (br s, 1H), 3.65-3.58 (m, 1H), 3.25 (br s, 1H), 2.85-2.70 (m, 1H), 2.40-1.90 (m, 5H), 1.75-1.60 (m, 2H), 1.55-1.15 (m, 4H). MS ES.sup.+: 301.29.

Example 9: 5-(4-fluorophenyl)-N-(1-isopropylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine

[0468] ##STR00046##

[0469] Prepared as described for Example 2 using 2-chloro-5-(4-fluorophenyl)-4-methyl-pyrimidine (0.22 g, 1.1 mmol) and 1-isopropylpiperidin-3-amine (0.222 g, 1 mmol) to afford the title compound (0.07 g, 25%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.07 (s, 1H), 7.40-7.37 (m, 2H), 7.25 (t, J=8.4 Hz, 2H), 6.92-6.82 (br s, 1H), 3.95-3.85 (br s, 1H), 2.90-2.80 (m, 1H), 2.75-2.65 (m, 1H), 2.65-2.60 (m, 1H), 2.25 (s, 3H), 2.15-2.08 (m, 1H), 2.02 (t, J=9.2 Hz, 1H), 1.85-1.75 (m, 1H), 1.70-1.62 (m, 1H), 1.55-1.40 (m, 1H), 1.35-1.25 (m, 1H), 0.95 (d, J=6.4 Hz, 6H). MS ES.sup.+: 329.10.

Example 10: 5-(2,4-difluorophenyl)-N-((1-ethylpiperidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0470] ##STR00047##

[0471] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.1 g, 0.4 mmol) and (1-ethylpiperidin-2-yl)methanamine (0.056 g, 0.40 mmol) to afford 5-(2,4-difluorophenyl)-N-((1-ethylpiperidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine (0.12 g, 57%) as a pale brown liquid. A solution of 5-(2,4-difluorophenyl)-N-((1-ethylpiperidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine (0.12 g, 0.35 mmol) in dioxane (2 mL) at 0 C. was treated with 4M HCl in dioxane (2 mL) and stirred at RT for 2 h. Solvent was evaporated from the mixture under reduced pressure and the remaining solid was triturated with diethyl ether and decanted to afford the title compound as a pale yellow sticky solid (0.12 g, 99%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.85 (s, 1H), 8.14 (s, 1H), 7.64 (t, J=5.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.22-7.17 (dt, J=2.4 Hz and 8.4 Hz, 1H), 3.65-3.10 (m, 6H), 3.05-2.95 (m, 1H), 2.17 (s, 3H), 2.05-1.95 (m, 1H), 1.85-1.40 (m, 5H), 1.35-1.20 (m, 3H). MS ES.sup.+: 347.28.

Example 11: 5-(2,4-difluorophenyl)-N-((1-(dimethylamino)cyclopentyl)methyl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0472] ##STR00048##

[0473] Prepared as described for Example 10 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.20 g, 0.80 mmol) and 1-(aminomethyl)-N,N-dimethyl-cyclopentanamine (0.102 g, 0.8 mmol) to afford the title compound (0.065 g, 30%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.28 (s, 1H), 8.17 (s, 1H), 7.68 (t, J=6.4 Hz, 1H), 7.48-7.35 (m, 2H), 7.22-7.17 (dt, J=2.0 Hz and 8.0 Hz, 1H), 3.72 (d, J=6.8 Hz, 2H), 2.82 (d, J=4.8 Hz, 6H), 2.18 (s, 3H), 1.95-1.85 (m, 4H), 1.80-1.70 (m, 4H). MS ES.sup.+: 347.10.

Example 12: N-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine, hydrochloride salt

[0474] ##STR00049##

[0475] Prepared as described for Example 10 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.2 g, 0.8 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine (0.112 g, 0.8 mmol) to afford the title compound (0.077 g, 30%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.14 (s, 1H), 8.16 (s, 1H), 7.76 (br s, 1H), 7.48-7.35 (m, 2H), 7.25-7.17 (dt, J=2.4 Hz and 6.0 Hz, 1H), 4.12 (br s, 1H), 3.95-3.80 (m, 2H), 2.90-2.60 (m, 1H), 2.65 (br d, 2H), 2.30-2.10 (m, 7H), 2.05-1.95 (m, 4H). MS ES.sup.+: 345.29.

Example 13: 5-(2,4-difluorophenyl)-4-methyl-N-((1-methylpyrrolidin-3-yl)methyl) pyrimidin-2-amine, hydrochloride salt

[0476] ##STR00050##

[0477] Prepared as described for Example 10 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.2 g, 0.8 mmol) and (1-methylpyrrolidin-3-yl)methanamine (0.091 g, 0.8 mmol) to afford the title compound (0.068 g, 24%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.50 (s, 1H), 8.10 (s, 1H), 7.65 (br s, 1H), 7.46-7.35 (m, 2H), 7.22-7.17 (dt, J=2.4 Hz and 8.4 Hz, 1H), 3.60-3.40 (m, 3H), 3.15-2.98 (m, 2H), 2.85-2.75 (m, 4H), 2.70-2.60 (m, 1H), 2.25-2.00 (m, 1H), 2.15 (s, 3H), 1.90-1.60 (m, 1H). MS ES.sup.+: 319.10.

Example 14: 5-(2,4-difluorophenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl) pyrimidin-2-amine, hydrochloride salt

[0478] ##STR00051##

[0479] Prepared as described for Example 10 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.2 g, 0.8 mmol) and 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.102 g, 0.8 mmol) to afford the title compound (0.17 g, 68%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.35 (s, 1H), 8.10 (s, 1H), 7.65 (br s, 1H), 7.46-7.35 (m, 2H), 7.20-7.10 (m, 1H), 3.60-3.50 (m, 3H), 3.30 (m, 1H), 3.10-2.95 (m, 1H), 2.80 (s, 3H), 2.30-2.20 (m, 1H), 2.10 (m, 4H), 2.00-1.80 (m, 3H), 1.80-1.70 (m, 1H). MS ES.sup.+: 333.31.

Example 15: 6-(2,4-difluorophenyl)-5-methyl-N-((1-methylpyrrolidin-2-yl)methyl)-1,2,4-triazin-3-amine

[0480] ##STR00052##

[0481] A stirred solution of 6-(2,4-difluorophenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.3 g, 1.1 mol) and (1-methylpyrrolidin-2-yl)methanamine (0.15 g, 1.32 mol) in 1,4-dioxane was refluxed at 110 C. and evaporated under reduced pressure. Purification of the residue by prep-HPLC gave the title compound (150 mg, 44%) as a pale brown liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.00-7.70 (br s, 1H), 7.60 (q, J=6.80 Hz, 1H), 7.42 (dt, J=2.40 Hz and 9.2 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 3.60 (br s, 1H), 3.30-3.15 (m, 1H), 3.00-2.90 (m, 1H), 2.40 (br s, 1H), 2.32 (s, 3H), 2.20-2.10 (m, 4H), 1.95-1.80 (m, 1H), 1.70-1.55 (m, 3H). MS ES.sup.+: 320.32.

Example 16: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl) ethyl)pyrimidin-2-amine, hydrochloride salt

[0482] ##STR00053##

[0483] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.20 g, 0.80 mmol) and 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.12 g, 0.9 mmol) to afford the title compound (0.09 g, 33%) as a pale yellow sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.00 (s, 1H), 8.10 (s, 1H), 7.55 (s, 1H), 7.26 (t, J=8.8 Hz, 1H), 6.94 (dd, J=2.4 Hz and 12.0 Hz, 1H), 6.87 (dd, J=2.4 Hz and 12.0 Hz, 1H), 3.81 (s, 3H), 3.60-3.50 (m, 11H), 3.45-3.35 (m, 2H), 3.35-3.25 (m, 1H), 3.05-2.98 (m, 1H), 2.79 (d, J=5.2 Hz, 3H), 2.35-2.28 (m, 1H), 2.25-2.15 (m, 4H), 2.00-1.85 (m, 2H), 185-1.75 (m, 1H), 1.72-1.60 (m, 1H). MS ES.sup.+: 345.10.

Example 17: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-2-yl)methyl) pyrimidin-2-amine

[0484] ##STR00054##

[0485] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.2 g, 0.8 mmol) and (1-methylpiperidin-2-yl)methanamine (0.12 g, 0.90 mmol) to afford the title compound (0.094 g, 35%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.92 (s, 1H), 8.13 (s, 1H), 7.60 (t, J=6.1 Hz, 1H), 7.26 (t, J=8.8 Hz, 1H), 6.95 (dd, J=2.4 Hz and 12.0 Hz, 1H), 6.89 (dd, J=2.4 Hz and 8.4 Hz, 1H), 3.81 (s, 3H), 3.60-3.45 (m, 2H), 3.40-3.32 (m, 1H), 3.25-3.12 (m, 1H), 3.05-2.95 (m, 1H), 2.92-2.70 (m, 3H), 2.18 (s, 3H), 1.97 (d, J=13.2 Hz, 1H), 1.80-1.60 (m, 3H), 1.50-1.35 (m, 1H). MS ES.sup.+: 345.10.

Example 18a/b: 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpyrrolidin-2-yl) methyl)-1,2,4-triazin-3-amine

[0486] ##STR00055##

[0487] Prepared as described for Example 15 using 6-(2-fluoro-4-methoxyphenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.70 g, 2.4 mmol) and (1-methylpyrrolidin-2-yl) methanamine (0.301 g, 2.64 mmol) to afford the title compound as racemate which was subjected to separation of enantiomers by SFC (YMC-SC (30 mm250 mm, 5 m); CO.sub.2: 60%, co-solvent: 40% of 0.2% 7M NH.sub.3 in MeOH; total flow: 110.0 g/min; T=30 C.; UV detection at: 250 nm) to obtain isomer 1 (0.175 g, 23%) and isomer 2 (0.17 g, 23%) as pale brown sticky solids.

[0488] Example 18a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.75 (br s, 1H), 7.43 (t, J=8.80 Hz, 1H), 6.97 (dd, J=2.40 Hz, 12.0 Hz, 1H), 6.93 (dd, J=2.4 Hz and 8.4 Hz, 1H), 3.85 (s, 3H), 3.61 (br s, 1H), 3.25-3.15 (m, 1H), 2.98-2.92 (m, 1H), 2.45-2.35 (br s, 1H), 2.32 (s, 3H), 2.20 (s, 3H), 2.15-2.08 (m, 1H), 1.90-1.82 (m, 1H), 1.70-1.55 (m, 3H). MS ES.sup.+: 332.29. Chiral HPLC: 99.8, 3.49 min. SOR: 54.3 (c 0.1, MeOH).

[0489] Example 18b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.70 (br s, 1H), 7.43 (t, J=8.40 Hz, 1H), 6.97 (dd, J=2.40 Hz, 12.0 Hz, 1H), 6.93 (dd, J=2.4 Hz and 8.4 Hz, 1H), 3.85 (s, 3H), 3.61 (br s, 1H), 3.25-3.15 (m, 1H), 2.98-2.92 (m, 1H), 2.45-2.35 (br s, 1H), 2.32 (s, 3H), 2.20 (s, 3H), 2.15-2.08 (m, 1H), 1.90-1.82 (m, 1H), 1.70-1.55 (m, 3H). MS ES.sup.+: 332.29. Chiral HPLC: 99.7, 6.4 min. SOR: +54.7 (c 0.1, MeOH).

Example 19: 5-(2,4-difluorophenyl)-2-(((1-methylpyrrolidin-2-yl)methyl)amino) pyrimidine-4-carbonitrile

[0490] ##STR00056##

[0491] A mixture of 5-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.20 g, 0.7 mmol) and (1-methylpyrrolidin-2-yl)methanamine (0.087 g, 0.21 mmol) were heated at 100 C. for 2 h (microwave), cooled to RT, treated with H.sub.2O and extracted with EtOAc (250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. Purification of the residue by prep-HPLC gave the title compound (0.12 g, 52%) as a pale yellow gummy solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.61 (d, J=18.00 Hz, 1H), 7.97 (br s, 1H), 7.68-7.62 (q, J=8.4 Hz, 1H), 7.51-7.45 (dt, J=2.4 Hz and 9.4 Hz, 1H), 7.30-7.25 (dt, J=2.0 Hz and 8.4 Hz, 1H), 3.55-3.45 (m, 1H), 3.25-3.15 (m, 1H), 3.00-2.90 (m, 1H), 2.40-2.30 (m, 3H), 2.32 (s, 1H), 2.20-2.10 (m, 1H), 1.95-1.80 (m, 1H), 1.70-1.55 (m, 3H). MS ES.sup.+: 330.30.

Example 20: 6-(2,4-difluorophenyl)-5-methyl-N-((1-methylpiperidin-2-yl)methyl)-1,2,4-triazin-3-amine

[0492] ##STR00057##

[0493] Prepared as described for Example 15 using 6-(2,4-difluorophenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.25 g, 0.87 mmol) and (1-methylpiperidin-2-yl)methanamine (0.15 g, 1.2 mmol) to afford the title compound (0.12 g, 41%) as a pale brown sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.76 (br s, 1H), 7.64-7.57 (q, J=7.6 Hz, 1H), 7.45-7.39 (dt, J=2.4 Hz and 9.8 Hz, 1H), 7.30-7.25 (dt, J=2.0 Hz and 8.8 Hz, 1H), 3.66 (br s, 1H), 3.22 (s, 3H), 2.76 (d, J=8.00 Hz, 1H), 2.25 (s, 3H), 2.15-2.05 (s, 1H), 2.05-1.95 (m, 2H), 1.72-1.62 (m, 2H), 1.55-1.38 (m, 2H), 1.25-1.15 (m, 2H). MS ES.sup.+: 334.10.

Example 21: 6-(2,4-difluorophenyl)-5-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,4-triazin-3-amine

[0494] ##STR00058##

[0495] Prepared as described for Example 15 using 6-(2,4-difluorophenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.25 g, 0.87 mmol) and 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.126 g, 1.2 mmol) to afford the title compound (0.13 g, 44%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.85 (br s, 1H), 7.64-7.57 (q, J=7.6 Hz, 1H), 7.45-7.39 (dt, J=2.4 Hz and 9.6 Hz, 1H), 7.28-7.22 (dt, J=2.0 Hz and 8.8 Hz, 1H), 3.45 (br s, 2H), 2.95-2.90 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 2.15-2.00 (m, 2H), 1.95-1.85 (m, 2H), 1.68-1.58 (m, 2H), 1.55-1.40 (m, 2H). MS ES.sup.+: 334.33.

Example 22: 5-(2,4-difluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-4-methyl-pyrimidin-2-amine

[0496] ##STR00059##

[0497] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.13 g, 0.54 mmol) and 1-isopropylpyrrolidin-3-amine (0.083 g, 0.65 mmol) to afford the title compound (0.067 g, 42%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.45-7.33 (m, 3H), 7.25-7.16 (m, 1H), 4.32 (s, 1H), 2.95-2.85 (m, 1H), 2.65-2.50 (m, 2H), 2.40-2.30 (m, 2H), 2.15-2.05 (m, 4H), 1.75-1.65 (m, 1H), 1.01 (d, J=12.80 Hz, 6H). MS ES.sup.+: 333.39.

Example 23: 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-(2-(1-methylpyrrolidin-2-yl) ethyl)-1,2,4-triazin-3-amine

[0498] ##STR00060##

[0499] Prepared as described for Example 15 using 6-(2-fluoro-4-methoxyphenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.27 g, 0.9 mmol) and 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.126 g, 1.2 mmol) to afford the title compound (0.2 g, 68%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.693 (br, 1H), 7.43 (t, J=8.80 Hz, 1H), 6.95 (dd, J=2.00 Hz and 8.0 Hz, 1H), 6.93 (dd, J=2.40 Hz and 8.4 Hz, 1H), 3.84 (s, 3H), 3.40 (s, 2H), 2.95-2.90 (t, J=3.20 Hz, 1H), 2.21 (s, 3H), 2.20 (s, 3H), 2.15-2.20 (m, 2H), 1.95-1.85 (m, 2H), 1.68-1.58 (m, 2H), 1.55-1.40 (m, 2H). MS ES.sup.+: 346.42.

Example 24a: (S)-5-(2,4-difluorophenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl) pyrimidin-2-amine

[0500] ##STR00061##

[0501] A stirred solution of 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.15 g, 0.63 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanamine (0.107 g, 0.93 mmol) in dioxane (9 mL) and DIPEA (1 mL) was stirred at 90 C. for 16 h in a sealed tube, cooled to RT and evaporated. The residue was diluted with DCM and washed with H.sub.2O. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the residue by reverse phase column chromatography gave the title compound (90 mg, 46%) as an off-white semi-solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.45-7.32 (m, 2H), 7.18 (m, 1H), 7.03 (s, 1H), 3.55-3.50 (m, 1H), 3.15-3.10 (m, 1H), 2.95-2.90 (m, 1H), 2.40-2.32 (m, 1H), 2.30 (s, 3H), 2.15-2.10 (m, 4H), 1.84 (m, 1H), 1.60 (m, 3H). MS ES.sup.+: 319.23. Chiral HPLC: 99.43%, 4.70 min. SOR: 51.5 (c 0.1, MeOH).

Example 24b: (R)-5-(2,4-difluorophenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl) pyrimidin-2-amine

[0502] ##STR00062##

[0503] Prepared as described for Example 24a using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.15 g, 0.63 mmol) and (R)-(1-methylpyrrolidin-2-yl)methanamine (0.107 g, 0.93 mmol) to afford the title compound (88 mg, 45%) as an off-white semi-solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.45-7.32 (m, 2H), 7.22-7.15 (dt, J=2.4 Hz and 8.0 Hz, 1H), 7.05-6.98 (br s, 1H), 3.58-3.50 (m, 1H), 3.18-3.08 (m, 1H), 2.98-2.90 (m, 1H), 2.40-2.32 (m, 1H), 2.30 (s, 3H), 2.15-2.08 (m, 4H), 1.90-1.80 (m, 1H), 1.65-1.52 (m, 3H). MS ES.sup.+: 319.23. Chiral HPLC: 96.75%, 5.65 min. SOR: +48.9 (c 0.1, MeOH).

Example 25: 5-(2-fluoro-4-methoxyphenyl)-2-(((1-methylpiperidin-2-yl)methyl)amino) pyrimidine-4-carbonitrile

[0504] ##STR00063##

[0505] A solution of 5-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.15 g, 0.5 mmol) and (1-methylpiperidin-2-yl)methanamine (0.064 g, 0.5 mmol) in dioxane (3 ml) was heated at 100 C. (microwave) for 1 h and evaporated under reduced pressure. Purification of the residue by column chorography (Grace instrument, 0-5% MeOH in DCM) gave the title compound (0.06 g, 33%) as a pale yellow sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.58 (d, J=13.60 Hz, 1H), 7.78 (d, J=21.60 Hz, 1H), 7.48 (t, J=8.80 Hz, 1H), 7.03 (dd, J=2.40 Hz and 12.40 Hz, 1H), 6.94 (dd, J=2.40 Hz and 8.40 Hz, 1H), 3.83 (s, 3H), 3.65-3.50 (m, 1H), 3.30-3.20 (m, 1H), 2.80-2.70 (d, J=11.20 Hz, 1H), 2.25 (s, 3H), 2.10-2.02 (m, 2H), 1.70-1.60 (m, 2H), 1.55-1.40 (m, 2H), 1.30-1.10 (m, 2H). MS ES.sup.+: 356.10.

Example 26: 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpiperidin-2-yl) methyl)-1,2,4-triazin-3-amine, hydrochloride salt

[0506] ##STR00064##

[0507] Prepared as described for Example 15 using 6-(2-fluoro-4-methoxyphenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.27 g, 0.9 mmol) and (1-methylpiperidin-2-yl)methanamine (0.127 g, 1.0 mmol) to afford 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpiperidin-2-yl)methyl)-1,2,4-triazin-3-amine (0.15 g, 48%) as a pale brown sticky solid. .sup.1H NMR (400 MHz, DMSO-de): 7.70-7.40 (br s, 1H), 7.44 (t, J=8.80 Hz, 1H), 7.00-6.96 (dd, J=2.4 Hz and 12.4 Hz, 1H), 6.94-6.91 (dd, J=2.4 Hz and 8.4 Hz, 1H), 3.84 (s, 3H), 3.70-3.60 (br s, 1H), 3.35-3.22 (m, 1H), 2.76 (d, J=11.60 Hz, 1H), 2.27 (s, 3H), 2.19 (s, 3H), 2.10 (s, 1H), 2.05-1.95 (t, J=3.20 Hz, 1H), 1.75-1.60 (m, 2H), 1.55-1.40 (m, 2H), 1.35-1.10 (m, 2H). MS ES.sup.+: 346.41.

[0508] 4M HCl in dioxane was added to a solution of 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpiperidin-2-yl)methyl)-1,2,4-triazin-3-amine (0.1 g) in dioxane at 0 C. and stirred for 2 h. The solvent was evaporated and the residual solids triturated with Et.sub.2O and concentrated under vacuum to obtain the title compound (90 mg, 82%) as a pale brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.43 (t, J=8.80 Hz, 1H), 6.97 (m, 2H), 3.84 (s, 3H), 3.80 (s, 1H), 3.568 (s, 0.5H), 3.39 (d, J=7.60 Hz, 2H), 3.28 (s, 0.5H), 3.10-3.09 (m, 1H), 2.96 (d, J=4.80 Hz, 3H), 2.243 (m, 3H), 1.99 (d, J=14.40 Hz, 1H), 1.70-1.30 (m, 6H). MS ES.sup.+: 346.39.

Example 27: 5-(2-fluoro-4-methoxyphenyl)-2-((2-(1-methylpyrrolidin-2-yl)ethyl)amino) pyrimidine-4-carbonitrile

[0509] ##STR00065##

[0510] Prepared as described for Example 15 using 5-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.2 g, 0.7 mmol) and 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (0.127 g, 1.0 mmol) to afford the title compound (0.10 g, 56%) as a pale brown sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.59 (d, J=12.8 Hz, 1H), 8.07 (t, J=5.60 Hz, 1H), 7.47 (t, J=8.80 Hz, 1H), 7.03 (dd, J=2.40 Hz and 12.2 Hz, 1H), 6.94 (dd, J=2.0 Hz and 8.6 Hz, 1H), 3.83 (s, 3H), 3.15 (s, 3H), 2.43-2.35 (m, 5H), 2.10-1.95 (m, 2H), 1.80-1.70 (m, 2H), 1.54-1.50 (m, 2H). MS ES.sup.+: 356.41.

Example 28a/b: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl) methyl)pyrimidin-2-amine

[0511] ##STR00066##

[0512] A solution of 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (3.00 g, 11.9 mmol) and (1-methylpyrrolidin-2-yl)methanamine (1.83 g, 14.28 mmol) in dioxane (10 mL) was treated with DIPEA (6.0 mL, 36 mmol), stirred at 100 C. for 24 h, cooled to RT and treated with H.sub.2O. The mixture was extracted with EtOAc (250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. Purification of the residue by column chromatography (0-20% MeOH/DCM) gave the title compound (1.25 g, 40%) as a thick gummy liquid. The racemic compound was subjected to separation of enantiomers by prep-SFC. Each enantiomer was subjected to HCl salt formation. A mixture of compound in 4M HCl in dioxane was stirred for 2 h at RT and evaporated under reduced pressure, then lyophilized to give isomer 1 (0.6 g, 91%) and isomer 2 (0.55 g, 84%) as brown sticky solids.

[0513] Example 28a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.60 (s, 1H), 8.18 (s, 1H), 7.78 (s, 1H), 7.28 (t, J=8.80 Hz, 1H), 6.96 (dd, J=2.40, 12.00 Hz, 1H), 6.89 (dd, J=2.40, 8.40 Hz, 1H), 3.85-3.70 (m, 5H), 3.60-3.50 (m, 2H), 3.08-3.02 (m, 1H), 2.88 (d, J=4.80 Hz, 3H), 2.26-2.15 (m, 4H), 2.05-1.75 (m, 3H). MS ES.sup.+: 331.35. Chiral HPLC: 99.9%, 4.73 min.

[0514] Example 28b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.60 (s, 1H), 8.18 (s, 1H), 7.78 (s, 1H), 7.28 (t, J=8.80 Hz, 1H), 6.96 (dd, J=2.40, 12.00 Hz, 1H), 6.89 (dd, J=2.40, 8.40 Hz, 1H), 3.85-3.70 (m, 5H), 3.60-3.50 (m, 2H), 3.08-3.02 (m, 1H), 2.88 (d, J=4.80 Hz, 3H), 2.26-2.15 (m, 4H), 2.05-1.75 (m, 3H). MS ES.sup.+: 331.35. Chiral HPLC: 99.7%, 5.63 min.

Example 29: 5-(2,4-difluorophenyl)-4-methyl-N-(1-methylpyrrolidin-3-yl)pyrimidin-2-amine

[0515] ##STR00067##

[0516] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.3 g, 1.25 mmol) and 1-methylpyrrolidin-3-amine (0.137 g, 1.37 mmol) to afford the title compound (0.05 g, 13%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.45-7.33 (m, 3H), 7.18 (t, J=2.00 Hz, 1H), 4.34 (br s, 1H), 2.78 (t, J=6.80 Hz, 1H), 2.55 (s, 1H), 2.45-2.45 (m, 1H), 2.41-2.43 (m, 1H), 2.31 (s, 3H), 2.18-2.10 (m, 4H), 1.75-1.675 (m, 1H). MS ES.sup.+: 305.30.

Example 30: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-3-yl)methyl) pyrimidin-2-amine, hydrochloride salt

[0517] ##STR00068##

[0518] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.25 g, 1.0 mmol) and (1-methylpiperidin-3-yl)methanamine (0.128 g, 1.00 mmol) to afford the title compound (0.06 g, 18%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.99 (s, 1H), 8.09 (s, 1H), 7.56 (s, 1H), 7.26 (t, J=8.80 Hz, 1H), 6.94 (dd, J=2.40, 12.00 Hz, 1H), 6.88 (dd, J=2.40, 8.60 Hz, 1H), 3.81 (s, 3H), 3.40-3.23 (m, 4H), 2.80-2.67 (m, 5H), 2.20 (m, 4H), 1.90-1.65 (m, 3H), 1.15-1.05 (m, 1H). MS ES.sup.+: 345.33.

Example 31: 5-(2-fluoro-4-methoxyphenyl)-2-(((1-methylpyrrolidin-3-yl)methyl)amino) pyrimidine-4-carbonitrile

[0519] ##STR00069##

[0520] Prepared as described for Example 15 using 5-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.1 g, 0.3 mmol) and (1-methylpyrrolidin-3-yl)methanamine (0.034 g, 0.3 mmol) to afford the title compound (0.05 g, 49%) as a pale yellow sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.57 (d, J=15.20 Hz, 1H), 8.13 (s, 1H), 7.47 (t, J=8.80 Hz, 1H), 7.03 (dd, J=2.40, 12.40 Hz, 1H), 6.94 (dd, J=2.80, 8.60 Hz, 1H), 3.85 (s, 3H), 3.26-3.20 (m, 2H), 2.50-2.44 (m, 3H), 2.35-2.30 (m, 2H), 2.22 (s, 3H), 1.90-1.82 (m, 1H), 1.50-1.40 (m, 1H). MS ES.sup.+: 342.31.

Example 32: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-3-yl) methyl)pyrimidin-2-amine, hydrochloride salt

[0521] ##STR00070##

[0522] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.30 g, 1.2 mmol) and (4-methylmorpholin-3-yl)methanamine (0.125 g, 0.96 mmol) to afford the title compound (0.1 g, 23%) as an off-white sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.70 (s, 1H), 8.13 (s, 1H), 7.59 (m, 1H), 7.26 (t, J=17.60 Hz, 1H), 6.95 (d, J=14.80 Hz, 1H), 6.88 (d, J=11.20 Hz, 1H), 4.06 (m, 1H), 3.93-3.70 (m, 6H), 3.66-3.50 (m, 2H), 3.50-3.39 (m, 2H), 3.20-3.10 (m, 1H), 2.95 (s, 3H), 2.19 (s, 3H). MS ES.sup.+: 347.32.

Example 33: 5-(2-fluoro-5-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-2-yl)methyl) pyrimidin-2-amine, hydrochloride salt

[0523] ##STR00071##

[0524] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-5-methoxyphenyl)-4-methyl-pyrimidine (0.30 g, 1.2 mmol) and (1-methylpiperidin-2-yl)methanamine (0.184 g, 1.44 mmol) to afford the title compound (0.19 g, 42%) as a pale brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.87 (s, 1H), 8.17 (s, 1H), 7.61 (t, J=11.60 Hz, 1H), 7.24 (t, J=9.20 Hz, 1H), 6.98-6.90 (m, 1H), 6.88-6.82 (m, 1H), 3.77 (m, 5H), 3.37 (d, J=13.60 Hz, 1H), 3.28-3.20 (m, 1H), 3.05-3.02 (m, 1H), 2.82 (d, J=5.20 Hz, 3H), 2.20 (s, 3H), 1.97 (d, J=13.60 Hz, 1H), 1.65-1.55 (m, 4H), 1.44 (s, 1H). MS ES.sup.+: 345.34.

Example 34: 5-(2-fluoro-5-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-3-yl)methyl) pyrimidin-2-amine, hydrochloride salt

[0525] ##STR00072##

[0526] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-5-methoxyphenyl)-4-methyl-pyrimidine (0.27 g, 1.1 mmol) and (1-methylpiperidin-3-yl)methanamine (0.169 g, 1.32 mmol) to afford the title compound (0.19 g, 42%) as a pale brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.89 (s, 1H), 8.14 (s, 1H), 7.57 (s, 1H), 7.23 (t, J=9.20 Hz, 1H), 7.00-6.96 (m, 1H), 6.90-6.88 (m, 1H), 3.77 (s, 3H), 3.45-3.31 (m, 4H), 2.85-2.60 (m, 5H), 2.25-2.10 (m, 4H), 1.90-1.60 (m, 3H), 1.20-1.05 (d, J=3.20 Hz, 1H). MS ES.sup.+: 345.1.

Example 35: 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((1-methylpiperidin-2-yl)methyl) pyrimidin-2-amine, hydrochloride salt

[0527] ##STR00073##

[0528] Prepared as described for Example 10 using 2-chloro-5-(2-chloro-4-methoxyphenyl)-4-methyl-pyrimidine (0.27 g, 1.0 mmol) and (1-methylpiperidin-2-yl)methanamine (0.14 g, 1.1 mmol) to afford the title compound (0.13 g, 30%) as a pale brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.99 (s, 1H), 8.06 (d, J=4.00 Hz, 1H), 7.60 (t, J=6.00 Hz, 1H), 7.26 (d, J=8.80 Hz, 1H), 7.18 (d, J=2.40 Hz, 1H), 7.01 (dd, J=1.20, 4.80 Hz, 1H), 3.80-3.70 (m, 3H), 3.68-3.65 (m, 2H), 3.37 (d, J=14.80 Hz, 1H), 3.25-3.21 (m, 1H), 3.18 (d, J=6.80 Hz, 1H), 2.82 (d, J=5.20 Hz, 3H), 2.11 (s, 3H), 1.97 (d, J=14.00 Hz, 1H), 1.63-1.66 (m, 4H), 1.42-1.45 (m, 1H). MS ES.sup.+: 361.1.

Example 36: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-2-yl) methyl)pyrimidin-2-amine, hydrochloride salt

[0529] ##STR00074##

[0530] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.3 g, 1.2 mmol) and (4-methylmorpholin-2-yl)methanamine (0.187 g, 1.44 mmol) to afford the title compound (0.1 g, 26%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d&): 10.81 (s, 1H), 8.11 (s, 1H), 7.50 (s, 1H), 7.27 (t, J=8.80 Hz, 1H), 6.95 (dd, J=2.80, 12.00 Hz, 1H), 6.88 (dd, J=2.80, 8.60 Hz, 1H), 4.03-4.00 (m, 2H), 3.79-3.72 (m, 4H), 3.50-3.35 (m, 4H), 3.02-3.00 (m, 1H), 2.80-2.75 (m, 4H), 2.17 (s, 3H). MS ES.sup.+: 347.32.

Example 37: 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-N-((1-methylpyrrolidin-3-yl) methyl)pyrimidin-2-amine

[0531] ##STR00075##

[0532] A stirred solution of 2-chloro-4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)pyrimidine (0.15 g, 0.50 mmol) in dioxane (5 mL) was treated with (1-methylpyrrolidin-3-yl)methanamine (0.06 g, 0.55 mmol) and DIPEA (0.193 g, 1.5 mmol), stirred at 100 C. in a sealed tube for 16 h and evaporated. The residue was diluted with EtOAc, washed with H.sub.2O followed by brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Purification of the residue in automated instrument (GRACE, in reverse phase) gave the title compound (0.06 g, 36%) as a pale yellow gummy mass. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.94 (s, 1H), 7.28 (t, J=8.40 Hz, 1H), 7.14 (s, 1H), 6.94 (dd, J=2.40, 12.00 Hz, 1H), 6.88 (dd, J=2.40, 8.40 Hz, 1H), 3.81 (s, 3H), 3.19 (m, 2H), 2.50-2.21 (m, 8H), 1.85-1.81 (m, 1H), 1.66 (t, J=4.40 Hz, 1H), 1.42-1.44 (m, 1H), 1.01 (s, 2H), 0.98-0.85 (m, 2H). MS ES.sup.+: 357.36.

Example 38a/b: 2-((3-(dimethylamino)cyclopentyl)amino)-5-(2-fluoro-4-methoxyphenyl) pyrimidine-4-carbonitrile

[0533] ##STR00076##

[0534] Prepared as described for Example 19 using 5-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.31 g, 1.0 mmol) and N.sup.1,N.sup.1-dimethylcyclopentane-1,3-diamine (0.13 g, 1.0 mmol) to afford the racemic title compound which was subjected to separation of isomers by chiral SFC to give isomer 1 (0.07 g, 48%) and isomer 2 (0.05 g, 42%) as off-white solids.

[0535] Example 38a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.57 (d, J=12.40 Hz, 1H), 8.10 (s, 1H), 7.46 (t, J=8.80 Hz, 1H), 7.03 (dd, J=2.40, 12.00 Hz, 1H), 6.94 (dd, J=2.40, 8.60 Hz, 1H), 4.17 (br s, 1H), 3.83 (s, 3H), 2.45-2.40 (m, 1H), 2.18-2.12 (m, 7H), 2.00-1.95 (m, 1H), 1.76 (d, J=7.60 Hz, 1H), 1.54-1.56 (m, 2H), 1.43-1.40 (m, 1H). MS ES.sup.+: 356.1.

[0536] Example 38b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.57 (d, J=12.00 Hz, 1H), 8.10 (s, 1H), 7.46 (t, J=8.80 Hz, 1H), 7.03 (dd, J=2.40 Hz and 12.00 Hz, 1H), 6.94 (dd, J=2.40 Hz and 8.60 Hz, 1H), 4.17 (br s, 1H), 3.83 (s, 3H), 2.50-2.45 (m, 1H), 2.20-2.10 (m, 7H), 2.00-1.90 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.50 (m, 2H), 1.45-1.35 (m, 1H). MS ES.sup.+: 356.1.

Example 39a/b: N.SUP.1.-(6-(2,4-difluorophenyl)-5-methyl-1,2,4-triazin-3-yl)-N.SUP.3.,N.SUP.3.-dimethylcyclohexane-1,3-diamine

[0537] ##STR00077##

[0538] Prepared as described for Example 15 using 6-(2,4-difluorophenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.50 g, 1.8 mmol) and N.sup.3,N.sup.3-dimethylcyclohexane-1,3-diamine (0.28 g, 1.98 mol) to afford the title compound, which was subjected to separation of isomers by SFC to obtain isomer 1 (0.045 g, 12%) and isomer 2 (0.041 g, 11%) as off-white solids.

[0539] Example 39a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.80 (br m, 1H), 7.64 (m, 1H), 7.42 (t, J=2.40 Hz, 1H), 7.25 (t, J=2.00 Hz, 1H), 4.25 (s, 1H), 2.33 (s, 1H), 2.20-2.17 (m, 9H), 1.96-1.94 (m, 1H), 1.80-1.45 (m, 7H). MS ES.sup.+: 348.15.

[0540] Example 39b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.77 (br m, 1H), 7.60 (m, 1H), 7.42 (t, J=2.40 Hz, 1H), 7.25 (t, J=8.40 Hz, 1H), 3.87 (s, 1H), 2.30 (t, J=11.60 Hz, 1H), 2.20-2.00 (m, 10H), 1.95-1.85 (m, 1H), 1.70-1.60 (t, J=12.80 Hz, 2H), 1.35-1.05 (m, 4H). MS ES.sup.+: 348.29.

Example 40: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(1-methylpiperidin-4-yl) pyrimidin-2-amine

[0541] ##STR00078##

[0542] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.45 g, 1.70 mmol) and 1-methylpiperidin-4-amine (0.2 g, 1.36 mmol) to afford the title compound (0.05 g, 9%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.01 (s, 1H), 7.24 (t, J=8.80 Hz, 1H), 7.09 (d, J=7.20 Hz, 1H), 6.92 (dd, J=2.40 Hz and 11.80 Hz, 1H), 6.86 (dd, J=2.40 Hz and 8.40 Hz, 1H), 3.81 (s, 3H), 3.75-3.65 (br s, 1H), 2.74 (d, J=11.20 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.95 (t, J=11.20 Hz, 2H), 1.80 (d, J=3.20 Hz, 2H), and 1.55-1.40 (m, 2H). MS ES.sup.+: 331.25.

Example 41: 5-(2-fluoro-4-methoxyphenyl)-N-(1-isopropylpiperidin-4-yl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0543] ##STR00079##

[0544] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.35 g, 1.38 mmol) and 1-isopropylpiperidin-4-amine (0.16 g, 1.38 mmol) to afford the title compound (0.10 g, 40%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.01 (m, 1H), 8.17 (s, 1H), 7.82 (d, J=13.20 Hz, 1H), 7.30-7.25 (m, 1H), 6.96 (dd, J=2.40 Hz and 12.00 Hz, 1H), 6.89 (dd, J=2.40 Hz and 8.40 Hz, 1H), 4.00 (s, 1H), 3.82 (s, 3H), 3.50-3.35 (m, 3H), 3.30-3.20 (m, 1H), 3.15-3.00 (m, 1H), 2.20-2.10 (m, 5H), 2.05-1.85 (m, 2H), and 1.35-1.30 (m, 6H). MS ES.sup.+: 359.31.

Example 42: 5-(2,4-difluorophenyl)-4-methyl-N-(pyridin-3-ylmethyl)pyrimidin-2-amine

[0545] ##STR00080##

[0546] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.1 g, 0.42 mmol) and pyridin-3-ylmethanamine (0.058 g, 0.55 mmol) to afford the title compound (0.08 g, 61%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.56 (s, 1H), 8.43 (dd, J=1.60 Hz and 4.80 Hz, 1H), 8.07 (s, 1H), 7.95-7.85 (br s, 1H), 7.78 (d, J=8.00 Hz, 1H), 7.44-7.29 (m, 3H), 7.17 (t, J=2.00 Hz, 1H), 4.54 (d, J=6.40 Hz, 2H), 2.14 (s, 3H). MS ES.sup.+: 313.0.

Example 43: N.SUP.1.-(5-(2-fluoro-4-methoxyphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)-N.SUP.3.,N.SUP.3.-dimethylcyclopentane-1,3-diamine

[0547] ##STR00081##

[0548] A stirred solution of N.sup.1-(5-bromo-4-(trifluoromethyl)pyrimidin-2-yl)-N.sup.3,N.sup.3-dimethylcyclopentane-1,3-diamine (0.40 g, 1.13 mmol) in dioxane/H.sub.2O (12 mL) was treated with K.sub.2CO.sub.3 (0.455 g, 3.39 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (0.192 g, 1.13 mmol), degassed with N.sub.2 for 10 min, treated with Pd(dppf)Cl.sub.2-DCM adduct (0.044 g, 0.056 mmol) degassed with N.sub.2 for 10 min, sealed and stirred at 105 C. for 3 h. The mixture was cooled to RT, filtered through Celite, washed with EtOAc, and the filtrate was concentrated under reduced pressure. Purification of the residue by prep-HPLC gave the title compound (0.06 g, 13%) as a pale brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.41 (s, 1H), 8.06 (m, 1H), 7.27 (t, J=8.8 Hz, 1H), 6.94 (dd, J=2.4 Hz and 11.60 Hz, 1H), 6.86 (dd, J=2.4 Hz and 8.40 Hz, 1H), 4.21 (s, 1H), 3.81 (s, 3H), 2.42 (s, 1H), 2.21-2.12 (m, 7H), 2.00-1.90 (s, 1H), 1.80-1.70 (m, 1H), 1.65-1.52 (m, 2H), 1.50-1.35 (m, 1H). MS ES.sup.+: 399.38.

Example 44a/b: N.SUP.1.-(5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidin-2-yl)-N.SUP.3.,N.SUP.3.-dimethylcyclopentane-1,3-diamine

[0549] ##STR00082##

[0550] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-'s methyl-pyrimidine (0.45 g, 1.8 mmol) and N.sup.1,N.sup.1-dimethylcyclopentane-1,3-diamine (0.414 g, 1.8 mmol) to afford the title compound as mixture of diastereomers. The diastereomers were separated by SFC (column/dimensions: Lux Amylose-2 (21 mm250 mm, 5 m); CO.sub.2 (75%) and co-solvent (25%, 0.2% 7M methanolic NH.sub.3 in ACN/MeOH 7:3); total flow: 65.0 g/min; T=30 C.; UV detection at 250 nm) to obtain isomer 1 (0.157 g, 22%) and isomer 2 (0.073 g, 11%) as off-white solids.

[0551] Example 44a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.01 (s, 1H), 7.21-7.22 (m, 2H), 6.92 (d, J=2.40 Hz, 1H), 6.86 (d, J=2.40 Hz, 1H), 4.19-4.21 (m, 1H), 3.81 (s, 3H), 2.38-2.30 (m, 1H), 2.12 (m, 10H), 1.95-1.92 (m, 1H), 1.78-1.73 (m, 1H), 1.59-1.52 (m, 2H), 1.57-1.53 (m, 1H). MS ES.sup.+: 345.38.

[0552] Example 44b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.01 (s, 1H), 7.29-7.22 (m, 2H), 6.92 (d, J=2.40 Hz, 1H), 6.86 (d, J=2.80 Hz, 1H), 4.19-4.10 (m, 1H), 3.81 (s, 3H), 2.38-2.30 (m, 1H), 2.16 (m, 10H), 1.99-1.93 (m, 1H), 1.83-1.73 (m, 1H), 1.60-1.52 (m, 2H), 1.37-1.32 (m, 1H). MS ES.sup.+: 345.38.

Example 45: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl) pyrimidin-2-amine

[0553] ##STR00083##

[0554] A solution of 5-bromo-4-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.25 g, 0.9 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (0.15 g, 0.9 mmol) and K.sub.2CO.sub.3 (0.372 g, 2.7 mmol) in dioxane/H.sub.2O (8:2, 10 mL) was purged with N.sub.2 for 5 min, treated with Pd(dppf)Cl.sub.2 (0.036 mg, 0.045 mmol) and heated for 3 h at 105 C. The mixture was cooled to RT, filtered through Celite and the filtrate concentrated under reduced pressure. Purification of the residue by column chromatography (0-50% EtOAc in petrol ether) gave the title compound (0.12 g, 42%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.03 (s, 1H), 7.23-7.20 (m, 2H), 6.93 (dd, J=2.40 Hz and 12.00 Hz, 1H), 6.86 (dd, J=2.40 Hz and 8.80 Hz, 1H), 3.96-3.80 (m, 6H), 3.45-3.36 (m, 2H), 2.12 (s, 3H), 1.83 (d, J=10.80 Hz, 2H), 1.49-1.50 (m, 2H). MS ES.sup.+: 318.1.

Example 46: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-(tetrahydro-2H-pyran-3-yl) pyrimidin-2-amine

[0555] ##STR00084##

[0556] Prepared as described for Example 45 using 5-bromo-4-methyl-N-(tetrahydro-2H-pyran-3-yl)pyrimidin-2-amine (0.250 g, 0.9 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (0.153 g, 0.9 mmol) to afford the title compound (0.16 g, 56%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.03 (s, 1H), 7.25 (t, J=8.80 Hz, 1H), 7.10 (d, J=5.20 Hz, 1H), 6.93 (dd, J=2.80, 12.00 Hz, 1H), 6.86 (dd, J=2.80, 8.60 Hz, 1H), 3.87-3.73 (m, 6H), 3.27-3.25 (m, 1H), 3.08 (t, J=11.20 Hz, 1H), 2.13 (s, 3H), 1.98-1.90 (m, 1H), 1.72-1.5 (m, 3H). MS ES.sup.+: 318.28.

Example 47: 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((tetrahydrofuran-2-yl)methyl) pyrimidin-2-amine

[0557] ##STR00085##

[0558] Prepared as described for Example 45 using 5-bromo-4-methyl-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-2-amine (0.250 g, 0.9 mmol) and (2-chloro-4-methoxyphenyl)boronic acid (0.153 g, 0.9 mmol) to afford the title compound (0.16 g, 56%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.95 (s, 1H), 7.26 (d, J=8.80 Hz, 1H), 7.16 (d, J=2.80 Hz, 2H), 6.99 (dd, J=2.40 Hz and 8.60 Hz, 1H), 4.05-3.95 (m, 1H), 3.85-3.76 (m, 4H), 3.65-3.55 (m, 1H), 3.45-3.35 (m, 1H), 3.30-3.25 (m, 1H), 2.06 (s, 3H), 1.95-1.75 (m, 3H), 1.65-1.55 (m, 1H). MS ES.sup.+: 334.25.

Example 48: 5-(2-fluoro-4-methoxyphenyl)-N-(1-isopropylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0559] ##STR00086##

[0560] A solution of 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.27 g, 1.07 mmol) in NMP (5 mL), 1-isopropylpiperidin-3-amine (0.23 g, 1.68 mmol) and triethylamine (0.8 ml, 5.3 mmol) was stirred at 180 C. for 4 h (microwave). The mixture was cooled to RT, treated with H.sub.2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification of the residue by prep-HPLC gave 5-(2-fluoro-4-methoxyphenyl)-N-(1-isopropylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine as a sticky solid. The compound was subjected to HCl salt formation by stirring a solution of the material in dioxane (4 mL) with 2 mL of 4M HCl in dioxane at RT for 3 h. The solution was evaporated in vacuo and lyophilized to obtain the title compound as hydrochloride (0.20 g, 93%) as a brown solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 10.1 (s, 1H), 8.12 (s, 1H), 7.79-7.49 (m, 1H), 7.29-7.24 (m, 1H), 6.95 (dd, J=2.80 Hz and 12.00 Hz, 1H), 6.88 (dd, J=2.40 Hz and 8.40 Hz, 1H), 4.25 (s, 1H), 3.85 (s, 3H), 3.51-3.46 (m, 2H), 3.39-3.31 (m, 1H), 2.95-2.83 (m, 1H), 2.73-2.65 (m, 11H), 2.17 (s, 3H), 2.01-1.81 (m, 3H), 1.61-1.55 (m, 1H), and 1.31-1.20 (m, 6H). MS ES.sup.+: 359.38.

Example 49: 5-(2-fluoro-4-methoxyphenyl)-N-((1-isopropylpiperidin-3-yl)methyl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0561] ##STR00087##

[0562] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.25 g, 0.992 mmol) and (1-isopropylpiperidin-3-yl)methanamine (0.24 g, 1.48 mmol) to afford the title compound (0.21 g, 51%) as an off-white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.85 (s, 1H), 8.13 (s, 1H), 7.72 (s, 1H), 7.28 (t, J=8.80 Hz, 1H), 6.95 (dd, J=2.40 Hz and 12.00 Hz, 1H), 6.88 (dd, J=2.80 Hz and 9.60 Hz, 1H), 3.81 (s, 3H), 3.45-3.28 (m, 5H), 2.85-2.75 (m, 1H), 2.75-2.65 (m, 1H), 2.30-2.15 (m, 4H), 1.90-1.75 (m, 3H), and 1.30-1.15 (m, 7H). MS ES.sup.+: 373.41.

Example 50: 5-(2-fluoro-4-methoxyphenyl)-N-((1-isopropylpiperidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0563] ##STR00088##

[0564] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.3 g, 1.19 mmol) and (1-isopropylpiperidin-2-yl)methanamine (0.28 g, 1.78 mmol) to afford the title compound (0.2 g, 49%) as a brown solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.75 (s, 1H), 8.10 (d, J=3.20 Hz, 1H), 7.62 (t, J=6.00 Hz, 1H), 7.28-7.24 (m, 1H), 6.95 (dd, J=2.40 Hz and 12.00 Hz, 1H), 6.88 (dd, J=2.80 Hz and 8.60 Hz, 1H), 4.10 (m, 1H), 3.80 (s, 4H), 3.50-3.30 (m, 3H), 2.84 (t, J=2.80 Hz, 1H), 2.15 (s, 3H), 2.02 (d, J=12.40 Hz, 1H), 1.75-1.60 (m, 4H), 1.55-1.45 (m, 1H), 1.35-1.20 (m, 6H). MS ES.sup.+: 373.41.

Example 51: 5-(2-fluoro-4-methoxyphenyl)-4-methyl-N-((tetrahydro-2H-pyran-3-yl) methyl)pyrimidin-2-amine

[0565] ##STR00089##

[0566] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.18 g, 0.7 mmol) and (tetrahydro-2H-pyran-3-yl)methanamine (0.088 g, 0.77 mmol) to afford the title compound (0.055 g, 21%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.10 (s, 1H), 7.60 (s, 1H), 7.27 (t, J=8.80 Hz, 1H), 6.95 (dd, J=2.80 Hz and 12.00 Hz, 1H), 6.88 (dd, J=2.80 Hz and 8.60 Hz, 1H), 3.79 (m, 4H), 3.75-3.65 (m, 1H), 3.34 (t, J=8.00 Hz, 1H), 3.23 (s, 2H), 3.12 (m, 1H), 2.17 (s, 3H), 1.90-1.75 (m, 2H), 1.65-1.55 (m, 1H), 1.50-1.40 (m, 1H), 1.30-1.20 (m, 1H). MS ES.sup.+: 332.10.

Example 52: 5-(2,4-difluorophenyl)-4-methyl-N-(3-(methylsulfonyl)cyclopentyl) pyrimidin-2-amine

[0567] ##STR00090##

[0568] A solution of 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.10 g, 0.40 mmol) in toluene (3 mL) was treated with 3-(methylsulfonyl)cyclopentan-1-amine (0.74 g, 0.4 mmol) and Cs.sub.2CO.sub.3 (0.19 g, 0.6 mmol), purged with N.sub.2 for 5-10 min, treated with Pd(OAc).sub.2 (0.002 g, 0.012 mmol) and BINAP (0.007 g, 0.012 mmol) and stirred for 16 h at 100 C. in a sealed tube. The solvent was evaporated and the residue was treated with H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Purification of the residue by reverse phase column chromatography (60-65% of MeOH in a 0.1% solution of ammonium bicarbonate in H.sub.2O) gave the title compound (0.75 g, 51%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (d, J=3.4 Hz, 1H), 7.48-7.30 (m, 3H), 7.25-7.15 (m, 11H), 4.35 (m, 1H), 3.70-3.65 (m, 1H), 2.95 (s, 3H), 2.45-1.60 (m, 9H). MS ES.sup.+: 368.27.

Example 53a/b: 5-(2-fluoro-4-methoxyphenyl)-N-(3-methoxycyclohexyl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0569] ##STR00091##

[0570] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4-methyl-pyrimidine (0.30 g, 1.2 mmol) and 3-methoxycyclohexan-1-amine (0.17 g, 1.32 mmol). The crude product was purified by column chromatography on amine silica (Davisil) to afford the individual diastereomers of the title compound, which were subjected to hydrochloride salt formation to afford isomer 1 (0.03 g, 10%) and isomer 2 (0.035 g, 12%) as off-white sticky solids.

[0571] Example 53a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.09 (s, 1H), 7.43 (s, 1H), 7.27 (t, J=8.80 Hz, 1H), 6.95 (dd, J=2.40, 12.00 Hz, 1H), 6.88 (dd, J=2.40, 8.40 Hz, 1H), 4.07 (s, 1H), 3.81 (s, 3H), 3.57 (s, 1H), 3.24 (s, 3H), 2.16 (s, 3H), 2.01 (s, 1H), 1.81 (s, 1H), 1.68 (s, 1H), 1.55-1.49 (m, 4H), 1.40-1.25 (m, 2H). MS ES.sup.+: 346.31.

[0572] Example 53b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.07 (s, 1H), 7.38 (s, 1H), 7.25 (t, J=3.60 Hz, 1H), 6.94 (dd, J=2.40, 12.00 Hz, 1H), 6.87 (dd, J=2.40, 8.40 Hz, 1H), 3.81 (s, 4H), 3.25 (s, 4H), 2.22 (s, 1H), 2.15 (s, 3H), 1.97 (s, 1H), 1.86 (s, 1H), 1.71-1.72 (m, 1H), 1.17-1.19 (m, 5H). MS ES.sup.+: 346.31.

Example 54a/b: 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpyrrolidin-2-yl) methyl)-1,2,4-triazin-3-amine

[0573] ##STR00092##

[0574] A stirred solution of 6-(2-fluoro-4-methoxyphenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.70 g, 2.4 mmol) and (1-methylpyrrolidin-2-yl)methanamine (0.30 g, 2.64 mmol) in dioxane was heated in a sealed tube at 110 C. for 1.5 h and evaporated. Purification of the residue by prep-HPLC followed by SFC (YMC-SC (30 mm250 mm, 5 m); CO.sub.2 (60%), co-solvent (40%, 0.2% 7M NH.sub.3 in MeOH); total flow=110.0 g/min, T=30 C.; UV detection at 250 nm) to obtain both enantiomers as pale brown sticky solids: isomer 1 (0.175 g, 23%) and isomer 2 (0.171 g, 23.1%).

[0575] Example 54a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.64 (br s, 1H), 7.43 (t, J=8.80 Hz, 1H), 6.97 (dd, J=2.40 Hz and 8.40 Hz, 1H), 6.91 (dd, J=2.4 Hz and 8.4 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 1H), 3.25-3.15 (m, 1H), 3.00-2.95 (m, 1H), 2.49 (s, 1H), 2.32 (s, 3H), 2.20-2.10 (m, 4H), 1.90-1.85 (m, 1H), 1.70-1.55 (m, 3H). MS ES.sup.+: 332.29. Chiral HPLC: 99.8%, 3.49 min. SOR: 54.3 (c 0.1, MeOH).

[0576] Example 54b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.65 (br s, 1H), 7.43 (t, J=8.80 Hz, 1H), 6.95 (dd, J=2.40 Hz and 8.40 Hz, 1H), 6.92 (dd, J=2.40 Hz and 8.4 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 1H), 3.26-3.22 (m, 1H), 3.00-2.90 (m, 1H), 2.40 (br s, 1H), 2.32 (s, 3H), 2.20-2.10 (m, 4H), 1.92-1.86 (m, 1H), 1.68-1.53 (m, 3H). MS ES.sup.+: 332.29. Chiral HPLC: 99.7%, 6.4 min. SOR: +54.7 (c 0.1, MeOH).

Example 55a/b: N.SUP.1.-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)-N.SUP.3.,N.SUP.3.-dimethylcyclohexane-1,3-diamine

[0577] ##STR00093##

[0578] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.21 g, 0.875 mmol) and N.sup.1,N.sup.1-dimethylcyclohexane-1,3-diamine (0.150 g 1.05 mmol) to afford the title compound, which was subjected to separation of isomers by SFC to afford isomer 1 (0.05 mg, 17%) and isomer 2 (0.05 mg, 16%) as off-white solids.

[0579] Example 55a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.047 (s, 1H), 7.45-7.32 (m, 2H), 7.19-7.11 (m, 2H), 4.16 (t, d, J=8.00 Hz, 1H), 2.37-2.32 (m, 1H), 2.21 (s, 6H), 2.11 (s, 3H), 1.90-1.88 (m, 1H), 1.68-1.46 (m, 7H). MS ES.sup.+: 347.36.

[0580] Example 55b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.057 (s, 1H), 7.44-7.27 (m, 3H), 7.19-7.16 (m, 1H), 3.81 (s, 1H), 2.69 (s, 1H), 2.41 (s, 6H), 2.12 (m, 4H), 1.90-1.75 (m, 1H), 1.40-1.10, (m, 6H). MS ES.sup.+: 347.28.

Example 56a/b: 2-((3-(dimethylamino)cyclohexyl)amino)-5-(2-fluoro-4-methoxyphenyl) pyrimidine-4-carbonitrile

[0581] ##STR00094##

[0582] Prepared as described for Example 19 using 5-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.20 g, 0.70 mmol) and N.sup.1,N.sup.1-dimethylcyclohexane-1,3-diamine (0.10 g, 0.70 mmol) to afford the title compound, which was subjected to separation of isomers by SFC to afford isomer 1 (0.07 g, 48%) and isomer 2 (0.05 g, 42%) as off-white solids.

[0583] Example 56a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.56 (d, J=13.20 Hz, 1H), 7.99 (s, 1H), 7.46 (t, J=8.80 Hz, 1H), 7.03 (dd, J=2.40, 12.40 Hz, 1H), 6.94 (dd, J=2.40, 8.80 Hz, 1H), 3.83-3.77 (m, 4H), 2.28-2.17 (m, 7H), 2.02 (d, J=11.20 Hz, 1H), 1.89-1.70 (m, 3H), 1.30-1.05 (m, 4H). MS ES.sup.+: 370.28.

[0584] Example 56b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.56 (s, 1H), 7.93 (s, 1H), 7.47 (t, J=8.80 Hz, 1H), 7.03 (dd, J=2.40, 12.40 Hz, 1H), 6.94 (dd, J=2.40, 8.40 Hz, 1H), 4.19-4.09 (m, 1H), 3.83 (s, 3H), 2.32 (m, 1H), 2.19-2.15 (m, 6H), 2.00-1.40 (m, 8H). MS ES.sup.+: 370.21.

Example 57a/b: 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-((1-methylpiperidin-2-yl) methyl)-1,2,4-triazin-3-amine

[0585] ##STR00095##

[0586] Prepared as described for Example 15 using 6-(2-fluoro-4-methoxyphenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.54 g, 1.82 mmol) and (1-methylpiperidin-2-yl)methanamine (0.254 g, 2.00 mmol) to afford the title compound as a light brown gummy solid, which was subjected to separation of enantiomers by SFC (Chiralpak AD-H (30 mm250 mm, 5 m); CO.sub.2 (70%), co-solvent (30%, 0.2% 7M ammonia in MeOH/ACN 1:1); total flow=110.0 g/min; T=30 C.; UV detection at 230 nm) to give isomer 1 (0.255 g, 33%) and isomer 2 (0.265 g, 33%) as light brown sticky solids.

[0587] Example 57a (isomer U: .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.61 (br s, 1H), 7.41 (t, J=8.40 Hz, 1H), 6.95 (dd, J=2.40, 8.40 Hz, 2H), 3.81 (s, 3H), 3.61 (s, 1H), 3.35 (s, 1H), 2.76 (d, J=11.20 Hz, 1H), 2.27 (s, 3H), 2.20 (s, 3H), 2.15-2.00 (m, 2H), 1.75-1.60 (m, 2H), 1.55-1.40 (m, 2H), 1.35-1.15 (m, 2H). MS ES.sup.+: 346.35. Chiral HPLC: 99.51%, 5.93 min.

[0588] Example 57b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.60 (br s, 1H), 7.41 (t, J=8.8 Hz, 1H), 6.95 (dd, J=2.40, 8.40 Hz, 2H), 3.84 (s, 3H), 3.65 (s, 1H), 3.32 (s, 1H), 2.77 (d, J=11.20 Hz, 1H), 2.30 (s, 3H), 2.20 (s, 3H), 2.15-1.99 (m, 2H), 1.72-1.65 (m, 2H), 1.55-1.40 (m, 2H), 1.35-1.15 (m, 2H). MS ES.sup.+: 346.35. Chiral HPLC: 99.3%, 9.44 min.

Example 58a/b: 5-(2,4-difluorophenyl)-2-((3-(dimethylamino)cyclopentyl)amino) pyrimidine-4-carbonitrile

[0589] ##STR00096##

[0590] Prepared as described for Example 19 using 5-(2,4-difluorophenyl)-2-(methylsulfonyl) pyrimidine-4-carbonitrile (1.2 g, 4.0 mmol) and N.sup.1,N.sup.1-dimethylcyclopentane-1,3-diamine (0.70 g, 5.4 mmol) to afford the title compound, which was subjected to separation of isomers by SFC to afford isomer 1 (0.337 g, 24%) and isomer 2 (0.244 g, 18%) as off-white solids.

[0591] Example 58a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.04 (s, 1H), 7.45-7.25 (m, 3H), 7.18 (t, J=2.00 Hz, 1H), 4.21 (d, J=6.80 Hz, 1H), 2.45 (t, J=6.80 Hz, 1H), 2.12 (s, 7H), 1.89-1.91 (m, 1H), 1.74 (q, J=10.40 Hz, 1H), 1.54-1.55 (m, 2H), 1.42-1.30 (m, 1H). MS ES.sup.+: 333.32.

[0592] Example 58b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.04 (s, 1H), 7.45-7.28 (m, 3H), 7.18 (t, J=2.00 Hz, 1H), 4.20 (s, 1H), 2.42-2.38 (m, 1H), 2.16 (s, 7H), 1.90-1.91 (m, 1H), 1.72 (m, 1H), 1.60-1.50 (m, 2H), 1.42-1.30 (m, 1H). MS ES.sup.+: 333.10.

Example 59a/b: 5-(2,4-difluorophenyl)-2-((3-(dimethylamino)cyclohexyl)amino) pyrimidine-4-carbonitrile

[0593] ##STR00097##

[0594] Prepared as described for Example 19 using 5-(2,4-difluorophenyl)-2-(methylsulfonyl) pyrimidine-4-carbonitrile (0.3 g, 1 mmol) and N.sup.1,N.sup.1-dimethylcyclohexane-1,3-diamine (0.17 g, 1.35 mmol) to afford the title compound, which was subjected to separation of isomers by SFC (Lux Amylose-2 (21 mm250 mm, 5 m); CO.sub.2 (82%), co-solvent (18% of 0.2% DIPEA in ACN/.sup.iPrOH 1:1); total flow=60.0 g/min; T=30 C.; UV detection at 260 nm) to afford isomer 1 (0.023 g, 24%) and isomer 2 (0.010 g, 18%) as off-white solids.

[0595] Example 59a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60 (s, 1H), 8.04 (s, 1H), 7.68-7.60 (m, 1H), 7.50-7.42 (m, 1H), 7.30-7.22 (m, 1H), 4.16 (m, 1H), 2.40-2.20 (m, 7H), 2.00-1.40 (m, 8H). MS ES.sup.+: 358.28.

[0596] Example 59b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.62 (d, J=11.60 Hz, 1H), 8.14 (d, J=6.80 Hz, 1H), 7.65-7.61 (m, 1H), 7.52-7.45 (m, 1H), 7.32-7.25 (m, 1H), 3.81 (d, J=14.40 Hz, 1H), 2.55 (m, 1H), 2.40-2.25 (m, 6H), 2.15-2.05 (m, 1H), 1.90-1.75 (m, 3H), 1.40-1.10 (m, 4H). MS ES.sup.+: 358.28.

Example 60: 5-(2,4-difluorophenyl)-4-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl) pyrimidin-2-amine

[0597] ##STR00098##

[0598] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.150 g, 0.6 mmol) and 1-(2,2,2-trifluoroethyl)piperidin-3-amine (0.091 g, 0.60 mmol) to afford the title compound (0.04 g, 17%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.07 (s, 1H), 7.45-7.32 (m, 2H), 7.20-7.08 (m, 2H), 3.99 (s, 1H), 3.25-3.17 (m, 2H), 3.06 (d, J=8.00 Hz, 1H), 2.82 (d, J=11.20 Hz, 1H), 2.33 (t, J=5.20 Hz, 1H), 2.24 (q, J=10.00 Hz, 1H), 2.12 (s, 3H), 1.85-1.75 (m, 1H), 1.72-1.62 (m, 1H), 1.62-1.45 (m, 1H), 1.35-1.20 (m, 1H). MS ES.sup.+: 387.32.

Example 61: 5-(2-fluoro-5-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-3-yl) methyl)pyrimidin-2-amine, hydrochloride salt

[0599] ##STR00099##

[0600] Prepared as described for Example 45 using 5-bromo-4-methyl-N-((4-methylmorpholin-3-yl)methyl)pyrimidin-2-amine (0.20 g, 0.70 mmol) and (2-fluoro-5-methoxyphenyl)boronic acid (0.138 g, 0.77 mmol) to afford the title compound (0.07 g, 30%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.78 (s, 1H), 8.18 (s, 1H), 7.62 (t, J=5.9 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 6.99 (m, J=3.2 Hz, 1H), 6.89 (q, J=3.1 Hz, 1H), 4.07 (t, J=6.4 Hz, 1H), 3.94 (d, J=10.3 Hz, 1H), 3.77 (s, 5H), 3.60 (m, J=6.1 Hz, 2H), 3.39 (t, J=14.0 Hz, 2H), 3.22 (m, J=7.3 Hz, 1H), 2.98 (d, J=4.0 Hz, 3H), 2.21 (s, 3H). MS ES.sup.+: 347.32.

Example 62: 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((4-methylmorpholin-3-yl) methyl)pyrimidin-2-amine

[0601] ##STR00100##

[0602] Prepared as described for Example 45 using 5-bromo-4-methyl-N-((4-methylmorpholin-3-yl)methyl)pyrimidin-2-amine (0.2 g, 0.7 mmol) and (2-chloro-4-methoxyphenyl)boronic acid (0.128 g, 0.77 mmol) to afford the title compound (0.05 g, 20%) as a brown sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.96 (s, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 7.01 (m, J=4.4 Hz, 2H), 3.82 (s, 3H), 3.76 (q, J=4.6 Hz, 1H), 3.66 (d, J=11.0 Hz, 1H), 3.60 (t, J=13.9 Hz, 1H), 3.47 (m, J=4.8 Hz, 1H), 3.26 (t, J=10.4 Hz, 1H), 3.16 (q, J=6.5 Hz, 1H), 2.64 (d, J=11.8 Hz, 1H), 2.30 (s, 3H), 2.20 (m, J=5.7 Hz, 2H), 2.06 (s, 3H). MS ES.sup.+: 363.32.

Example 63: 5-(2-chloro-4-methoxyphenyl)-4-methyl-N-((1-methyl-1H-imidazol-5-yl) methyl)pyrimidin-2-amine

[0603] ##STR00101##

[0604] Prepared as described for Example 2 using 2-chloro-5-(2-chloro-4-methoxyphenyl)-4-methyl-pyrimidine (0.15 g, 0.6 mmol) and (1-methyl-1H-imidazol-5-yl)methanamine (0.086 g, 0.78 mmol) to afford the title compound (0.019 g, 10%) as a brown sticky solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.99 (s, 1H), 7.59 (t, J=5.5 Hz, 1H), 7.52 (s, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 6.99 (q, J=3.7 Hz, 1H), 6.82 (s, 1H), 4.47 (d, J=5.6 Hz, 2H), 3.82 (s, 3H), 3.65 (s, 3H), 2.08 (s, 3H). MS ES.sup.+: 344.0.

Example 64a/b: 5-(2,4-difluorophenyl)-4-methyl-N-(1-(1-methylpyrrolidin-3-yl)ethyl) pyrimidin-2-amine

[0605] ##STR00102##

[0606] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.8 g, 3.33 mmol) and 1-(1-methylpyrrolidin-3-yl)ethan-1-amine (0.64 g, 4.99 mmol) to afford the title compound. The racemic compound was subjected to separation of isomers by SFC to obtain isomer 1 (0.05 g, 10%) and isomer 2 (0.05 g, 10%) as off-white solids.

[0607] Example 64a (isomer U: .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.03 (s, 1H), 7.45-7.32 (m, 2H), 7.20-7.10 (m, 2H), 3.91 (m, 1H), 2.59 (t, J=8.3 Hz, 1H), 2.43 (d, J=28.8 Hz, 1H), 2.30 (q, J=7.2 Hz, 2H), 2.20 (d, J=6.4 Hz, 3H), 2.11 (s, 4H), 1.84 (m, J=3.2 Hz, 1H), 1.51 (m, J=4.4 Hz, 1H), 1.09 (q, J=5.2 Hz, 3H). MS ES.sup.+: 333.28.

[0608] Example 64b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.03 (s, 1H), 7.45-7.32 (m, 2H), 7.21-7.10 (m, 2H), 3.91 (m, 1H), 2.60 (t, J=8.3 Hz, 1H), 2.43 (m, J=6.6 Hz, 1H), 2.29 (d, J=5.9 Hz, 2H), 2.20 (d, J=6.3 Hz, 3H), 2.11 (s, 4H), 1.90-1.80 (m, 1H), 1.55-1.45 (m, 1H), 1.09 (m, 3H). MS ES.sup.+: 333.32.

Example 65: 5-(2,4-difluorophenyl)-2-((1-isopropylpiperidin-4-yl)amino)pyrimidine-4-carbonitrile

[0609] ##STR00103##

[0610] A solution of 5-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.60 g, 2.0 mmol) and 1-isopropylpiperidin-4-amine (0.28 g, 0.21 mmol) in dioxane (10 ml) was stirred at 100 C. for 1 h (microwave) and evaporated. Purification of the residue by reverse phase column chromatography in automated instrument (Grace, 0.1% ammonium bicarbonate solution in H.sub.2O and MeOH) gave the title compound (0.36 g, 52%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60 (d, J=10.6 Hz, 1H), 8.08 (s, 1H), 7.64 (q, J=8.0 Hz, 1H), 7.48 (m, J=4.4 Hz, 1H), 7.28 (m, J=3.8 Hz, 1H), 3.69 (d, J=6.8 Hz, 1H), 2.78 (d, J=11.7 Hz, 2H), 2.75-2.65 (m, 1H), 2.19 (d, J=5.5 Hz, 2H), 1.85 (d, J=10.2 Hz, 2H), 1.49 (d, J=9.8 Hz, 2H), 0.97 (d, J=6.2 Hz, 6H). MS ES.sup.+: 358.33.

Example 66: 5-(2,4-difluorophenyl)-2-((1-methylpiperidin-4-yl)amino)pyrimidine-4-carbonitrile

[0611] ##STR00104##

[0612] Prepared as described for Example 10 using 5-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.30 g, 1.19 mmol) and 1-methylpiperidin-4-amine (0.15 g, 1.31 mmol) to afford the title compound (0.17 g, 58%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.61 (d, J=9.60 Hz, 1H), 8.08 (s, 1H), 7.68-7.61 (m, 1H), 7.52-7.45 (m, 1H), 7.32-7.25 (m, 1H), 3.68 (s, 1H), 2.75 (d, J=11.60 Hz, 2H), 2.16 (s, 3H), 1.96 (d, J=9.60 Hz, 2H), 1.83 (d, J=11.20, Hz, 2H), 1.61-1.51 (m, 2H). MS ES.sup.+: 330.26.

Example 67: 5-(2,4-difluorophenyl)-N-(1-isopropylpiperidin-4-yl)-4-methyl-pyrimidin-2-amine

[0613] ##STR00105##

[0614] Triethylamine (0.72 ml, 5.2 mmol) was added to a solution of 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.50 g, 2.1 mmol) and 1-isopropylpiperidin-4-amine (0.357 g, 2.52 mmol) in EtOH (10 mL). The mixture was stirred for 4 h at 140 C. (microwave) and evaporated. Purification of the residue by column chromatography in automated instrument (Grace, 2-5% DCM in MeOH) gave the title compound (0.3 g), which was further purified by prep-HPLC to obtain the title compound (0.23 g, 32%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.45-7.32 (m, 2H), 7.25-7.15 (m, 2H), 3.71 (s, 1H), 2.77 (s, 3H), 2.12 (s, 5H), 1.85 (s, 2H), 1.47 (s, 2H), 0.97 (s, 6H). MS ES.sup.+: 347.32.

Example 68a/b: N.SUP.1.-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)-N.SUP.3.,N.SUP.3.-dimethylcyclobutane-1,3-diamine, hydrochloride salt

[0615] ##STR00106##

[0616] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.30 g, 1.30 mmol) and N.sup.1,N.sup.1-dimethylcyclobutane-1,3-diamine hydrochloride (0.248 g, 1.60 mmol) to afford the title compound, which was subjected to separation of isomers by prep-HPLC in HCl medium to obtain isomer 1 (0.026 g, 8%) and isomer 2 (0.034 g, 10%) as off-white solids as hydrochloride salts.

[0617] Example 68a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.72 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.45-7.35 (m, 2H), 7.22-7.15 (m, 1H), 4.33 (s, 1H), 3.81 (t, J=7.7 Hz, 1H), 2.68 (d, J=4.9 Hz, 8H), 2.35 (m, J=3.3 Hz, 2H), 2.16 (s, 3H). MS ES.sup.+: 319.33.

[0618] Example 68b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.40 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.47-7.33 (m, 2H), 7.22-7.16 (m, 1H), 4.06 (s, 1H), 3.46 (d, J=8.2 Hz, 1H), 2.67 (d, J=4.9 Hz, 8H), 2.15 (m, 5H). MS ES.sup.+: 319.33.

Example 69a/b: 6-(2-fluoro-4-methoxyphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[0619] ##STR00107##

[0620] Prepared as described for Example 15 using 6-(2-fluoro-4-methoxyphenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (0.80 g, 2.7 mmol) and 1-methylpiperidin-3-amine (0.380 g, 2.97 mmol) to afford the title compound, which was subjected to separation of isomers by SFC (Chiralpak IC (30 mm250 mm, 5 m); CO.sub.2 (70%), co-solvent (30% of 0.2% 7M methanolic NH.sub.3 in EtOH); total flow=100.0 g/min; T=30 C.; UV detection at 254) to obtain isomer 1 (0.125 g, 15%) and isomer 2 (0.07 g, 9%) as off-white solids.

[0621] Example 69a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.43 (t, J=8.7 Hz, 2H), 6.95 (m, J=4.7 Hz, 2H), 4.00 (d, J=12.8 Hz, 1H), 3.84 (s, 3H), 2.87 (d, J=5.6 Hz, 1H), 2.62 (d, J=10.6 Hz, 1H), 2.18 (t, J=4.3 Hz, 6H), 1.86 (q, J=10.8 Hz, 3H), 1.69 (m, J=4.0 Hz, 1H), 1.53 (m, J=7.2 Hz, 1H), 1.31 (m, J=5.8 Hz, 1H). MS ES.sup.+: 332.32. Chiral HPLC: 99.98%, 7 min.

[0622] Example 69b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.43 (t, J=8.7 Hz, 2H), 6.95 (m, J=4.7 Hz, 2H), 4.02 (s, 1H), 3.84 (s, 3H), 2.87 (s, 1H), 2.63 (d, J=10.6 Hz, 1H), 2.19 (t, J=2.9 Hz, 6H), 1.88 (t, J=11.1 Hz, 3H), 1.70 (m, J=4.0 Hz, 1H), 1.53 (d, J=12.8 Hz, 1H), 1.31 (q, J=5.0 Hz, 1H). MS ES.sup.+: 332.32. Chiral HPLC: 99.32%, 10.01 min.

Example 70: 5-(2-fluoro-4-methoxyphenyl)-4,6-dimethyl-N-((1-methylpyrrolidin-2-yl) methyl)pyrimidin-2-amine, hydrochloride salt

[0623] ##STR00108##

[0624] Prepared as described for Example 10 using 2-chloro-5-(2-fluoro-4-methoxyphenyl)-4,6-dimethylpyrimidine (0.216 g, 0.81 mmol) and (1-methylpyrrolidin-2-yl)methanamine (0.109 g, 0.97 mmol) to obtain the title compound (0.040 g, 17%) as a gummy solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.38 (s, 1H), 7.67 (s, 1H), 7.21 (t, J=8.80 Hz, 1H), 6.95 (m, 1H), 6.85 (m, 1H), 3.85 (s, 3H), 3.80 (s, 2H), 3.60 (m, 2H), 3.15-3.05 (m, 1H), 2.95 (s, 3H), 2.15-2.10 (m, 1H), 2.05 (s, 6H), 2.00-1.95 (s, 1H), 1.90-1.80 (m, 2H). MS ES.sup.+: 345.34.

Example 71: 5-(2,4-difluorophenyl)-4-methyl-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine

[0625] ##STR00109##

[0626] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.05 g, 0.2 mmol) and 1-methylpiperidin-4-amine (0.26 g, 0.3 mmol) to obtain the title compound (0.02 g, 40%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.45-7.32 (m, 2H), 7.21-7.15 (m, 2H), 3.70 (br s, 1H), 2.74 (d, J=11.6 Hz, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.94 (t, J=10.8 Hz, 2H), 1.82 (d, J=10.0 Hz, 2H), 1.52 (m, J=5.9 Hz, 2H). MS ES.sup.+: 319.33.

Example 72: 5-(2,4-difluorophenyl)-N-(1-isopropylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine

[0627] ##STR00110##

[0628] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.10 g, 0.40 mmol) and 1-isopropylpiperidin-3-amine hydrochloride (0.106 g, 0.60 mmol) to obtain the title compound (0.05 g, 35%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.46-7.32 (m, 2H), 7.18 (m, J=3.3 Hz, 1H), 7.00 (s, 1H), 3.89 (s, 1H), 2.86 (d, J=7.6 Hz, 1H), 2.70 (q, J=6.7 Hz, 1H), 2.62 (d, J=10.9 Hz, 1H), 2.12 (s, 4H), 2.02 (t, J=9.8 Hz, 1H), 1.79 (m, J=4.0 Hz, 1H), 1.66 (m, J=4.0 Hz, 1H), 1.45 (q, J=11.6 Hz, 1H), 1.31 (m, J=5.4 Hz, 1H), 0.95 (q, J=2.7 Hz, 6H). MS ES.sup.+: 347.35.

Example 73: (R)-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine, fumarate salt

[0629] ##STR00111##

[0630] Step 1: A stirred solution of 2-chloro-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methylpyrimidine (300 mg, 0.98 mmol), tert-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate (294 mg, 1.47 mmol) in 1,4-dioxane (10 mL) was treated with DIPEA (190 mg, 1.47 mmol), stirred at 100 C. for 16 h and concentrated under reduced pressure. Purification of the residue by column chromatography (0 to 40% EtOAc/petrol ether) gave tert-butyl (R)-2-(((5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)pyrrolidine-1-carboxylate (320 mg, 82%) as a thick liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.07 (s, 1H), 7.53-7.49 (m, 2H), 7.34-7.32 (m, 2H), 3.96 (s, 1H), 3.55 (s, 1H), 3.25 (s, 3H), 2.14 (s, 3H), 1.85-1.76 (m, 4H), 1.39 (s, 9H).

[0631] Step 2: A stirred solution of tert-butyl (R)-2-(((5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)pyrrolidine-1-carboxylate (320 mg, 0.68 mmol) in 1,4-dioxane (10 mL) was treated with 4M HCl in 1,4-dioxane (10 mL), stirred at RT for 3 h, and concentrated under reduced pressure. The residue was neutralized with an aq. NaOH solution and extracted with EtOAc (310 mL). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by prep-HPLC to afford (R)-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine as a thick liquid.

[0632] Step 3: A stirred solution of (R)-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (140 mg, 0.378 mmol) in Et.sub.2O (5 mL) was treated with fumaric acid (44 mg, 0.378 mmol, as a solution in MeOH, 2 mL) slowly and stirred at RT for 5 h. The mixture was concentrated under reduced pressure and the residue was triturated with n-pentane, filtered and dried under vacuum to give the title compound (180 mg, 54%) as an off-white solid. .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.16 (s, 1H), 7.68 (br s, 11H), 7.55-7.50 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 6.48 (s, 2H), 3.70-3.50 (m, 3H), 3.20-3.10 (m, 2H), 2.17 (s, 3H), 2.08-2.00 (m, 1H), 1.95-1.75 (m, 2H), 1.70-1.60 (m, 1H). MS ES.sup.+: 372.3. SFC: 98.9%, 1.57 min.

Example 74a/b: 6-(2,4-difluorophenyl)-5-methyl-N-((1-methylpyrrolidin-2-yl)methyl)-1,2,4-triazin-3-amine

[0633] ##STR00112##

[0634] Prepared as described for Example 15 using 6-(2,4-difluorophenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (1.0 g, 3.5 mmol) and (1-methylpyrrolidin-2-yl)methanamine (0.48 g, 4.2 mmol) to obtain the title compound, which was subjected to separation of enantiomers by SFC (Chiralpak IC (30 mm250 mm, 5 m); CO.sub.2 (55%), co-solvent (45%, 0.2% 7M NH.sub.3 in MeOH); total flow=120.0 g/min; T=30 C.; UV detection at 250 nm) to obtain isomer 1 (0.35, 31%) as a pale brown gummy liquid and isomer 2 (0.35 g, 31%) as a pale brown gum.

[0635] Example 74a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.84 (br s, 1H), 7.65-7.57 (m, 1H), 7.45-7.38 (m, 1H), 7.28-7.22 (m, 1H), 3.61 (br s, 1H), 3.28-3.18 (m, 1H), 2.98-2.90 (m, 1H), 2.41 (br s, 1H), 2.32 (s, 3H), 2.20 (s, 3H), 2.18-2.10 (m, 1H), 1.92-1.82 (m, 1H), 1.68-1.58 (m, 3H). MS ES.sup.+: 320.21. Chiral HPLC: 99.93%, 2.33 min.

[0636] Example 74b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.84 (br s, 1H), 7.63-7.57 (m, 1H), 7.42 (t, J=2.40 Hz, 1H), 7.25 (t, J=2.40 Hz, 1H), 3.60 (br s, 1H), 3.30-3.18 (m, 1H), 2.98-2.90 (m, 1H), 2.40 (br s, 1H), 2.30 (s, 3H), 2.20 (s, 3H), 2.18-2.10 (m, 1H), 1.92-1.82 (m, 1H), 1.70-1.55 (m, 3H). MS ES.sup.+: 320.17. Chiral HPLC: 99.56%, 3.97 min.

Example 75: 5-(2-fluoro-4-methoxyphenyl)-4-methoxy-6-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0637] ##STR00113##

[0638] A solution of 5-bromo-4-methoxy-6-methyl-N-((1-methylpyrrolidin-2-yl)methyl) pyrimidin-2-amine (0.40 g, 1.27 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (0.26 g, 1.52 mmol) and K.sub.2CO.sub.3 (0.53 g, 3.82 mmol) in H.sub.2O and dioxane (4:1, 20 ml) in a glass tube was purged with N.sub.2 for 10 min, treated with Pd(PPh.sub.3).sub.4 (0.15 g, 0.1278 mmol), purged with N.sub.2, sealed, and heated at 90-100 C. for 1.5 h. The mixture was cooled to RT, diluted with EtOAc and washed with H.sub.2O and brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated, and the residue purified by prep-HPLC to afford the title compound (0.10 g, 36%) as an off-white gummy solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.14 (t, J=8.7 Hz, 1H), 7.05 (br s, 1H), 6.85 (m, 1H), 6.80 (m, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.60-3.52 (m, 1H), 3.15-3.00 (br s, 1H), 2.98-2.90 (m, 1H), 2.40-2.30 (m, 1H), 2.32 (s, 3H), 2.12 (q, J=8.4 Hz, 1H), 1.98 (s, 3H), 1.90-1.80 (m, 1H), 1.68-1.55 (m, 3H). MS ES.sup.+: 361.33. Chiral HPLC: 99.26%, 4.11 min. SOR: 56.1 (c 0.1, MeOH).

Example 76a/b: 6-(2-fluoro-4-methoxyphenyl)-N-(1-isopropylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine

[0639] ##STR00114##

[0640] Prepared as described for Example 15 using 6-(2-fluoro-4-methoxyphenyl)-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (1.0 g, 3.4 mmol) and 1-isopropylpiperidin-3-amine dihydrochloride (0.48 g, 3.74 mmol) to afford the title compound as the racemate, which was subjected to separation of enantiomers by SFC (Chiralpak IC (30 mm250 mm, 5 m); CO.sub.2 (65%), co-solvent (35%, 0.2% 7M methanolic NH.sub.3 in EtOH); total flow=110.0 g/min; T=35 C.; UV detection at 220 nm) to obtain isomer 1 (0.14 g, 12%) and isomer 2 (0.14 g, 12%) as off-white solids.

[0641] Example 76a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.60 (br s, 1H), 7.43 (t, J=8.7 Hz, 1H), 6.95 (m, J=4.7 Hz, 2H), 3.97 (br s, 1H), 3.84 (s, 3H), 2.92 (d, J=7.4 Hz, 1H), 2.73 (q, J=6.6 Hz, 1H), 2.65 (d, J=10.9 Hz, 1H), 2.19 (s, 3H), 2.18-2.00 (m, 2H), 1.85 (d, J=8.8 Hz, 1H), 1.69 (m, J=3.9 Hz, 1H), 1.48 (d, J=10.9 Hz, 1H), 1.35 (q, J=4.8 Hz, 1H), 0.96 (d, J=6.5 Hz, 6H). MS ES.sup.+: 360.33. Chiral HPLC: 99.94%, 5.05 min. SOR: +33.86 (c 0.1, MeOH).

[0642] Example 76b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.60 (br s, 1H), 7.43 (t, J=8.7 Hz, 1H), 6.95 (m, J=4.7 Hz, 2H), 3.99 (br s, 1H), 3.84 (s, 3H), 2.92 (d, J=8.2 Hz, 1H), 2.72 (t, J=6.6 Hz, 1H), 2.65 (t, J=5.4 Hz, 1H), 2.19 (s, 3H), 2.20-2.00 (m, 2H), 1.85 (d, J=8.8 Hz, 1H), 1.69 (q, J=5.4 Hz, 1H), 1.48 (d, J=11.1 Hz, 1H), 1.35 (q, J=4.9 Hz, 1H), 0.96 (d, J=6.5 Hz, 6H). MS ES.sup.+: 360.34. Chiral HPLC: 99.20%, 7.52 min. SOR: 34.00 (c 0.1, MeOH).

Example 77a/b: 5-(2,4-difluorophenyl)-4-methyl-N-(1-methylpiperidin-3-yl)pyrimidin-2-amine

[0643] ##STR00115##

[0644] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (1.0 g, 4.2 mmol) and 1-methylpiperidin-3-amine (0.62 g, 5.46 mmol) to afford the title compound, which was subjected to separation of enantiomers by SFC to obtain isomer 1 (0.27 g, 20%) and isomer 2 (0.295 g, 22%) as off-white solids.

[0645] Example 77a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.39 (m, J=4.5 Hz, 2H), 7.18 (m, J=3.2 Hz, 1H), 7.08 (br s, 1H), 3.92 (br s, 1H), 2.82 (d, J=9.0 Hz, 1H), 2.59 (d, J=10.4 Hz, 1H), 2.16 (s, 3H), 2.12 (s, 3H), 1.83 (m, J=11.2 Hz, 3H), 1.66 (m, J=4.1 Hz, 1H), 1.51 (m, J=6.6 Hz, 1H), 1.27 (t, J=11.2 Hz, 1H). MS ES.sup.+: 319.24. Chiral HPLC: 99.86%, 4.18 min. SOR: +31.00 (c 0.1, MeOH).

[0646] Example 77b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.39 (m, J=4.5 Hz, 2H), 7.18 (m, J=2.5 Hz, 1H), 7.08 (br s, 1H), 3.92 (br s, 1H), 2.82 (d, J=8.0 Hz, 1H), 2.59 (d, J=10.8 Hz, 1H), 2.14 (s, 3H), 2.12 (s, 3H), 1.83 (m, J=9.1 Hz, 3H), 1.66 (m, J=4.0 Hz, 1H), 1.52 (t, J=11.4 Hz, 1H), 1.27 (t, J=11.4 Hz, 1H). MS ES.sup.+: 319.24. Chiral HPLC: 99.91%, 6.34 min. SOR: 31.00 (c 0.1, MeOH).

Example 78a/b: 5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine

[0647] ##STR00116##

[0648] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.50 g, 2.1 mmol) and 1-ethylpiperidin-3-amine dihydrochloride (0.63 g, 3.1 mmol) to afford the title compound (0.7 g, 65%), which was subjected to separation of isomers by SFC to obtain isomer 1 (0.2 g, 29%) and isomer 2 (0.2 g, 29%) as off-white solids.

[0649] Example 78a (isomer 1 (R)): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.39 (m, J=4.5 Hz, 2H), 7.18 (m, J=3.9 Hz, 1H), 7.05 (br s, 1H), 3.91 (br s, 1H), 2.90 (d, J=10.0 Hz, 1H), 2.69 (d, J=11.5 Hz, 1H), 2.33 (q, J=7.1 Hz, 2H), 2.12 (s, 3H), 1.86 (m, 3H), 1.67 (m, 1H), 1.49 (q, J=11.9 Hz, 1H), 1.30 (m, J=6.0 Hz, 1H), 0.98 (t, J=7.1 Hz, 3H). MS ES.sup.+: 333.36. Chiral HPLC: 99.95%, 3.75 min. SOR: +21.12 (c 0.1, MeOH).

[0650] Example 78b (isomer 2 (S)): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.39 (m, J=4.5 Hz, 2H), 7.18 (m, J=3.9 Hz, 1H), 7.05 (br s, 1H), 3.91 (br s, 1H), 2.90 (d, J=8.9 Hz, 1H), 2.69 (d, J=11.6 Hz, 1H), 2.33 (q, J=7.1 Hz, 2H), 2.12 (s, 3H), 1.86 (m, J=10.6 Hz, 3H), 1.67 (q, J=4.4 Hz, 1H), 1.49 (d, J=11.8 Hz, 1H), 1.31 (q, J=7.4 Hz, 1H), 0.98 (t, J=7.1 Hz, 3H). MS ES.sup.+: 333.32. Chiral HPLC: 99.28%, 4.87 min. SOR: 21.12 (c 0.1, MeOH).

Example 78a: (R)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine, fumarate salt

[0651] ##STR00117##

[0652] Step 1: A stirred solution of 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (500 mg, 2.07 mmol) and (R)-1-ethylpiperidin-3-amine (399 mg, 3.11 mmol) in NMP (2.5 ml) was treated with DIPEA (2.14 g, 16.6 mmol) and allowed to stir for 1 h at 180 C. under microwave irradiation. The mixture was diluted with ice cold H.sub.2O and extracted with EtOAc (315 ml). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. Purification of the residue by prep-HPLC (XBridge C18, 19 mm250 mm, 5 m; mobile phase A: 10 mM ammonium bicarbonate in H.sub.2O, mobile phase B: CH.sub.3CN, 10-85% B) gave (R)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine (400 mg, 58%) as an off-white solid. MS ES.sup.+: 333.38.

[0653] Step 2: A stirred solution of (R)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine (400 mg, 1.20 mmol) in diethyl ether (5 ml) was treated with a solution of fumaric acid (139 mg, 1.20 mmol) in MeOH (0.1 ml) at RT, allowed to stir for 12 h and concentrated under reduced pressure. The residue was triturated with n-pentane and the remaining solids dried under vacuum to obtain the title compound (475 mg, 88%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.97 (br s, 1H), 8.07 (s, 1H), 7.45-7.33 (m, 2H), 7.20-7.10 (m, 2H), 6.58 (s, 2H), 3.97 (br s, 1H), 3.05-2.95 (m, 1H), 2.85-2.75 (m, 1H), 2.50-2.42 (m, 2H), 2.12 (s, 3H), 2.10-1.95 (m, 2H), 1.85-180 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.40-1.30 (m, 1H), 1.02 (t, J=7.2 Hz, 3H). MS ES.sup.+: 333.21. HPLC: 99.7%, 4.83 min. Chiral SFC: 99.9%, 1.89 min.

Example 78b: (S)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine, fumarate salt

[0654] ##STR00118##

[0655] Step 1: A stirred solution of (S)-1-ethylpiperidin-3-amine dihydrochloride (2.00 g, 9.94 mmol) in absolute EtOH (10 ml) was treated with K.sub.2CO.sub.3 (1.65 g, 11.9 mmol) and stirred at RT for 1 h. The suspension was filtered and the filtrate concentrated in vacuo. The resulting residue was dissolved in NMP (10 ml) and treated with 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (2.00 g, 8.40 mmol) and DIPEA (8.56 g, 66.5 mmol). The mixture was stirred for 1 h at 180 C. under microwave irradiation, cooled to RT, diluted with ice cold H.sub.2O and extracted with EtOAc (315 ml). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. Purification of the residue by prep-HPLC (XBridge C18, 19 mm250 mm, 5 m; mobile phase A: 10 mM ammonium bicarbonate in H.sub.2O, mobile phase B: CH.sub.3CN, 10-85% B) gave (S)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine (2.01 g, 75%) as an off-white solid. MS ES.sup.+: 333.17.

[0656] Step 2: A stirred solution of (S)-5-(2,4-difluorophenyl)-N-(1-ethylpiperidin-3-yl)-4-methyl-pyrimidin-2-amine (2.01 g, 6.33 mmol) in diethyl ether (20 ml) was treated with a solution of fumaric acid (0.70 g, 6.01 mmol) in MeOH (1 ml) at RT and stirred for 12 h at RT. Solvents were evaporated from the mixture under reduced pressure. The residue was triturated with n-pentane, the solids were collected and dried in vacuo to obtain the title compound (2.57 g, 91%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.97 (br s, 1H), 8.07 (s, 1H), 7.45-7.32 (m, 2H), 7.20-7.10 (m, 2H), 6.58 (s, 2H) 3.96 (br s, 1H), 3.05-2.95 (m, 1H), 2.85-2.75 (m, 1H), 2.50-2.30 (m, 2H), 2.12 (s, 3H), 2.10-1.95 (m, 2H), 1.87-1.77 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.40-1.30 (m, 1H), 1.02 (t, J=7.2 Hz, 3H). MS ES.sup.+: 333.34. HPLC: 98.5%, 3.15 min. Chiral SFC: 99.7%, 1.08 min.

Example 79a/b: 5-(2,4-difluorophenyl)-4-methyl-N-((4-methylmorpholin-3-yl)methyl) pyrimidin-2-amine

[0657] ##STR00119##

[0658] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.70 g, 2.91 mmol) and (4-methylmorpholin-3-yl)methanamine (0.60 g, 4.37 mmol) to afford the title compound, which was subjected to separation of enantiomers by SFC (Chiralpak IG (30 mm250 mm, 5 m); CO.sub.2 (60/6), co-solvent (40%, 0.2% 7M methanolic NH.sub.3 in MeOH); total flow=100.0 g/min; T=35 C.; UV detection at 250 nm) to afford isomer 1 (0.05 g, 5%) and isomer 2 (0.05 g, 5%) as off-white solids.

[0659] Example 79a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.39 (m, 2H), 7.18 (m, 1H), 7.05 (br s, 1H), 3.75 (m, 1H), 3.68 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 3.30-3.15 (m, 2H), 2.65 (m, 1H), 2.30 (s, 3H), 2.25-2.10 (m, 5H). MS ES.sup.+: 335.29. Chiral HPLC: 99.97%, 2.34 min. SOR: 51.48 (c 0.1, MeOH).

[0660] Example 79b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.07 (s, 1H), 7.39 (m, 2H), 7.18 (m, 11H), 7.05 (br s, 1H), 3.75 (m, 1H), 3.68 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 3.30-3.15 (m, 2H), 2.65 (m, 1H), 2.30 (s, 3H), 2.25-2.10 (m, 5H). MS ES.sup.+: 335.29. Chiral HPLC: 99.63%, 2.94 min. SOR: +48.40 (c 0.1, MeOH).

Example 80: (R)N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-amine

[0661] ##STR00120##

[0662] Step 1: A solution of (R)-1-(4,4-difluoro-1-methylpyrrolidin-2-yl)-N-(4-methoxybenzyl)methanamine (0.07 g, 0.3 mmol) and 2-chloro-5-(2,4-difluorophenyl).sub.4-methyl-pyrimidine (0.065 g, 0.27 mmol) in THF (1.5 mL) and toluene (1.5 mL) was treated with DIPEA (0.116 g, 0.90 mmol) and stirred for 16 h at 125 C. in a sealed tube. The mixture was cooled to RT and purified by flash column chromatography (amine silica Davisil, 12-15% EtOAc in petrol ether) to afford (R)N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-5-(2,4-difluorophenyl)-N-(4-methoxybenzyl)-4-methyl-pyrimidin-2-amine, the protected precursor of the title compound (0.07 g, 58%) as a gummy solid.

[0663] Step 2: A solution of (R)N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-5-(2,4-difluorophenyl)-N-(4-methoxybenzyl)-4-methyl-pyrimidin-2-amine (0.07 g, 0.10 mmol) in EtOAc was treated with PdC (0.15 g 10%) and degassed with N.sub.2, followed by H.sub.2 (60 psi). The mixture was stirred for 2 days at RT and filtered through Celite. The filtrate was dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by flash column chromatography (amine silica Davisil, 5-7% MeOH/DCM) to afford the title compound (10 mg, 20%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.23 (s, 1H), 7.45-7.37 (m, 2H), 7.23-7.18 (m, 1H), 6.37 (s, 1H), 4.55 (m, 1H), 4.20-4.10 (m, 1H), 3.95-3.80 (m, 1H), 3.20-3.00 (m, 11H), 2.90-2.80 (m, 1H), 2.75-2.50 (m, 2H), 2.50 (s, 3H), 2.20 (s, 3H). MS ES.sup.+: 355.10. Chiral HPLC: 96.83%, 2.47 min.

Example 81: 5-(2-fluoro-4-methoxyphenyl)-2-((1-isopropylpiperidin-4-yl)amino) pyrimidine-4-carbonitrile

[0664] ##STR00121##

[0665] Prepared as described for Example 19 using 5-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)pyrimidine-4-carbonitrile (0.10 g, 0.33 mmol) and 1-isopropylpiperidin-4-amine (0.46 g, 0.33 mmol) to afford the title compound (0.041 g, 34%) as an off-white solid. .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.57 (d, J=5.9 Hz, 1H), 7.99 (s, 1H), 7.46 (t, J=8.8 Hz, 1H), 7.03 (q, J=4.9 Hz, 1H), 6.94 (q, J=3.7 Hz, 1H), 3.83 (s, 3H), 3.68 (s, 1H), 2.73 (m, J=12.1 Hz, 3H), 2.18 (d, J=9.2 Hz, 2H), 1.85 (d, J=11.4 Hz, 2H), 1.48 (q, J=10.5 Hz, 2H), 0.96 (d, J=6.5 Hz, 6H). MS ES.sup.+: 370.1.

Example 82: 5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine

[0666] ##STR00122##

[0667] Step 1: Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.50 g, 2.1 mmol) and tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (0.92 g, 4.5 mmol) to afford tert-butyl 2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)pyrrolidine-1-carboxylate, the protected precursor of the title compound (0.3 g) as a yellowish gummy intermediate.

[0668] Step 2: A solution of tert-butyl 2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl) amino)methyl)pyrrolidine-1-carboxylate (0.3 g, 0.7 mmol) in dioxane (5 ml) at 0 C. was treated with 4M HCl in dioxane (0.12 mL) and stirred for 12 h at RT. The mixture was basified with sodium bicarbonate and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. Purification of the residue by reverse phase flash column chromatography (60-65% MeOH in H.sub.2O) gave the title compound (0.27 g, 91%) as a solid. .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.39 (m, J=4.5 Hz, 2H), 7.18 (m, J=3.8 Hz, 2H), 3.25 (d, J=10.5 Hz, 4H), 2.82 (m, J=4.6 Hz, 1H), 2.74 (m, J=6.0 Hz, 1H), 2.12 (s, 3H), 1.68 (m, J=5.0 Hz, 3H), 1.39 (m, J=5.2 Hz, 1H). MS ES.sup.+: 305.27.

Example 83a/b: 5-(2,4-difluorophenyl)-N-((3,3-difluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine

[0669] ##STR00123##

[0670] Step 1: A solution of tert-butyl 2-(((5-bromo-4-methyl-pyrimidin-2-yl)amino)methyl)-3,3-difluoropyrrolidine-1-carboxylate (1.6 g, 3.93 mmol), (2,4-difluorophenyl)boronic acid (0.931 g, 5.89 mmol), K.sub.2CO.sub.3 (1.09 g, 7.86 mmol) in dioxane (15 mL) and H.sub.2O (3 mL) was degassed with N.sub.2 (3), treated with Pd(dppf)Cl.sub.2 (0.158 g, 0.216 mmol) and stirred at 100 C. for 6 h under N.sub.2. The mixture was cooled to RT, diluted with H.sub.2O (50 mL) and extracted with EtOAc (240 mL). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. Purification of the residue by flash silica gel chromatography (5 to 30% EtOAc/petroleum ether) gave tert-butyl 2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)-3,3-difluoropyrrolidine-1-carboxylate (1.65 g, 95%) as a yellow oil.

[0671] Step 2: A solution of 0.25 g of this oil in dioxane (0.5 mL) was treated with HCl/dioxane (4M, 0.5 mL), stirred at 25 C. for 16 h and evaporated. The residue was dissolved in H.sub.2O, and adjusted pH=10 with aq. NaHCO.sub.3. The aqueous layer was extracted with DCM (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO.sub.4, filtered and concentrated. Purification of the residue by SFC (DAICEL CHIRALPAK AD-H (250 mm30 mm, 5 m); 0.1% NH.sub.3.Math.H.sub.2O in EtOH) gave isomer 1 (0.037 g, 29%) and isomer 2 (0.037 g, 29%) as yellow oils.

[0672] Example 83a (isomer 1): .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.1 (s, 1H), 7.39 (m, 1H), 7.01 (m, 2H), 5.5 (s, 1H), 3.70 (m, 1H), 3.6 (m, 1H), 3.5 (m, 1H), 3.25 (m, 2H), 2.3 (m, 5H). MS ES.sup.+: 341.0. Chiral HPLC: 99.00%, 3.83 min.

[0673] Example 83b (isomer 2): .sup.1H NMR (401 MHz, CDCl.sub.3): 8.1 (s, 1H), 7.3 (m, 1H), 6.9 (m, 2H), 5.5 (s, 1H), 3.60 (m, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 3.25 (m, 2H), 2.25 (m, 5H). MS ES.sup.+: 341.1. Chiral HPLC: 96.3%, 4.07 min.

Example 84a/b: N-((3,3-difluoro-1-methylpyrrolidin-2-yl)methyl)-5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-amine

[0674] ##STR00124##

[0675] A solution of tert-butyl 2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)amino) methyl)-3,3-difluoropyrrolidine-1-carboxylate (see Example 83, 0.65 g, 1.48 mmol) in THF (15 mL) was treated with LiAlH.sub.4 (0.168 g, 4.43 mmol) at 25 C. and stirred at 25 C. for 0.5 h. The mixture was filtered and concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography and the product was separated into enantiomers by SFC (DAICEL CHIRALPAK AD-H, 250 mm30 mm, 5 m; 25% of 0.1% aqueous NH.sub.3 solution in .sup.iPrOH), followed by SFC (DAICEL CHIRALPAK IG, 250 mm30 mm, 10 m; 20% of 0.1% aqueous NH.sub.3 solution in MEOH) to give isomers 1 and 2.

[0676] Example 84a (isomer 1): .sup.1H NMR (401 MHz, CDCl.sub.3): 8.06 (s, 1H), 7.25 (m, 1H), 6.95 (m, 2H), 5.53 (s, 1H), 3.95 (m, 1H), 3.5 (m, 1H), 3.1 (m, 1H), 2.6 (m, 1H), 2.5 (m, 4H), 2.25 (m, 5H). MS ES.sup.+: 355.1. Chiral HPLC: 100%, 2.94 min.

[0677] Example 84b (isomer 2): .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.2 (m, 1H), 6.95 (m, 2H), 5.53 (s, 1H), 3.95 (m, 1H), 3.5 (m, 1H), 3.1 (m, 1H), 2.6 (m, 1H), 2.45 (m, 4H), 2.30 (m, 5H). MS ES.sup.+: 355.1. Chiral HPLC: 99.66%, 3.42 min.

Example 85: 5-(2,4-difluorophenyl)-N-((1-ethylpyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine

[0678] ##STR00125##

[0679] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.20 g, 0.83 mmol) and (1-ethylpyrrolidin-2-yl)methanamine (0.213 g, 1.66 mmol) to afford the title compound (0.170 g, 60%) as a yellow gummy solid. .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.45-7.32 (m, 2H), 7.22-7.07 (m, 2H), 3.55-3.45 (m, 1H), 3.20-2.60 (m, 4H), 2.40-2.10 (m, 5H), 1.85 (br s, 1H), 1.70-1.55 (m, 3H), 1.15-1.00 (m, 3H). MS ES.sup.+: 333.29.

Example 86a/b: N-(5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)hexahydro-1H-pyrrolizin-1-amine

[0680] ##STR00126##

[0681] Prepared as described for Example 2 using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.72 g, 3.0 mmol) and hexahydro-1H-pyrrolizin-1-amine (0.45 g, 3.6 mmol) to afford the racemic title compound (0.20 g, 25%) as an off-white solid. This racemate was subjected to separation of diastereomers by SFC (Chiralpak AD-3 (4.6 mm150 mm, 5 m); CO.sub.2 (80%), co-solvent (20%, 0.2% DIPEA in MeOH); total flow=3 g/min; T=30 C.; UV detection at 220 nm) to afford isomer 1 (0.043 g) and isomer 2 (0.04 g) as yellow solids.

[0682] Example 86a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.12 (s, 1H), 7.39 (m, J=4.6 Hz, 2H), 7.19 (m, J=3.8 Hz, 1H), 3.73 (q, J=6.7 Hz, 1H), 3.46 (m, J=5.8 Hz, 1H), 3.15 (t, J=4.7 Hz, 1H), 3.00 (m, J=5.7 Hz, 2H), 2.71 (m, J=3.7 Hz, 1H), 2.62 (q, J=5.1 Hz, 1H), 2.15 (s, 3H), 2.01 (m, J=4.6 Hz, 1H), 1.64 (m, J=11.6 Hz, 2H), 1.49 (m, J=4.4 Hz, 1H), 1.24 (m, J=5.7 Hz, 1H). MS ES.sup.+: 331.36. Chiral HPLC: 50%, 2.45 min; 49.5%, 8.30 min.

[0683] Example 86b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.09 (s, 1H), 7.38 (m, J=4.6 Hz, 2H), 7.18 (m, J=3.8 Hz, 1H), 3.92 (m, J=4.2 Hz, 1H), 3.61 (m, J=3.9 Hz, 1H), 3.48 (m, J=6.2 Hz, 2H), 2.69 (m, J=4.8 Hz, 2H), 2.20-2.05 (m, 2H), 2.14 (s, 3H), 1.78 (m, J=3.7 Hz, 1H), 1.60 (m, J=7.4 Hz, 1H), 1.47 (q, J=4.4 Hz, 1H), 1.30 (m, J=8.0 Hz, 1H). MS ES.sup.+: 331.32. Chiral HPLC: 50.97%, 3.50 min; 48.30%, 5.03 min.

Example 87: 5-(2,4-difluorophenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl))methyl)pyrimidin-2-amine

[0684] ##STR00127##

[0685] A stirred solution of 5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (0.27 g, 0.90 mmol) in DMF (5 mL) was slowly treated at 0 C. with K.sub.2CO.sub.3 (0.42 g, 1.35 mmol) and CD.sub.3I (0.16 ml, 1.17 mmol), warmed to RT and stirred for 2 h. The mixture was diluted with ice cold H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated. Purification of the residue by column chromatography followed by prep-HPLC gave the title compound (0.10 g, 31%) as an off-white semi-solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.15 (s, 1H), 7.81 (s, 1H), 7.41 (m, J=4.1 Hz, 2H), 7.20 (m, J=3.8 Hz, 1H), 3.83 (t, J=6.7 Hz, 2H), 3.58 (m, J=6.2 Hz, 3H), 2.30 (m, J=4.9 Hz, 1H), 2.17 (s, 3H), 1.96 (m, J=8.4 Hz, 3H). MS ES.sup.+: 322.34.

Example 88: 5-(2-fluoro-4-(trifluoromethoxy)phenyl)-N-(1-isopropylpiperidin-4-yl)-4-methyl-pyrimidin-2-amine

[0686] ##STR00128##

[0687] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-pyrimidine (0.15 g, 0.50 mmol) and 1-isopropylpiperidin-4-amine (0.085 g, 0.60 mmol) to afford the title compound (0.10 g, 49%) as an off-white solid. .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.09 (s, 1H), 7.52 (t, J=8.6 Hz, 2H), 7.33 (d, J=8.6 Hz, 1H), 7.23 (s, 1H), 3.71 (d, J=6.8 Hz, 1H), 2.77 (d, J=11.7 Hz, 2H), 2.68 (m, J=6.6 Hz, 1H), 2.14 (d, J=14.2 Hz, 5H), 1.84 (d, J=10.1 Hz, 2H), 1.46 (m, J=5.5 Hz, 2H), 0.96 (d, J=6.6 Hz, 6H). MS ES.sup.+: 413.50.

Example 89: 5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine

[0688] ##STR00129##

[0689] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-pyrimidine (0.2 g, 1.0 mmol) and 1-methylpiperidin-4-amine (0.125 g, 1.1 mmol) to afford the title compound (0.040 g, 16.1%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.09 (s, 1H), 7.52 (t, J=8.6 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.23 (s, 1H), 3.70 (t, J=3.4 Hz, 1H), 2.74 (d, J=11.7 Hz, 2H), 2.16 (s, 3H), 2.13 (s, 3H), 1.94 (t, J=10.9 Hz, 2H), 1.82 (d, J=9.9 Hz, 2H), 1.53 (m, J=5.9 Hz, 2H). MS ES.sup.+: 385.26.

Example 90a: (S)-5-(2,4-difluorophenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0690] ##STR00130##

[0691] Step 1: A solution of 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.50 g, 2.1 mmol) and tert-butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate (0.50 g, 2.52 mmol) in dioxane (10 mL) was treated at RT with DIPEA (0.812 g, 6.30 mmol), sealed and stirred for 16 h at 100 C. The mixture was concentrated and the residue purified by column chromatography (15-20% EtOAc in petrol ether) to afford tert-butyl (S)-2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)pyrrolidine-1-carboxylate, the BOC-protected intermediate (0.3 g) as a yellowish gum.

[0692] Step 2: A stirred solution of tert-butyl (S)-2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)pyrrolidine-1-carboxylate (0.30 g, 0.7 mmol) in dioxane (5 mL) was slowly treated with 4M HCl in dioxane (0.12 mL) at 0 C. and stirred for 12 h at RT. The mixture was basified with sodium bicarbonate and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated. Purification of the residue by reverse phase flash column chromatography (60-65% of MeOH in H.sub.2O) gave (S)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (0.270 g, 91%) as pale yellow gum.

[0693] Step 3: A stirred solution of (S)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (0.27 g, 0.90 mmol) in DMF (5 mL) was slowly treated at 0 C. with K.sub.2CO.sub.3 (0.42 g, 1.35 mmol) followed by CD.sub.3I (0.16 ml, 1.17 mmol) and stirred at RT for 2 h. The mixture was diluted with ice cold H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography followed by prep-HPLC to give the title compound (0.10 g, 31%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.15 (s, 1H), 7.81 (s, 1H), 7.41 (m, J=4.1 Hz, 2H), 7.20 (m, J=3.8 Hz, 1H), 3.83 (t, J=6.7 Hz, 2H), 3.58 (m, J=6.2 Hz, 3H), 2.30 (m, J=4.9 Hz, 1H), 2.17 (s, 3H), 1.96 (m, J=8.4 Hz, 3H). MS ES.sup.+: 339.27 as NH.sub.3 adduct.

Example 90b: (R)-5-(2,4-difluorophenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0694] ##STR00131##

[0695] Prepared as described for Example 90a using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.50 g, 2.1 mmol) and tert-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate (0.50 g, 2.52 mmol) to afford in 3 steps the title compound (0.10 g, 31%) as an off-white semi-solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.15 (s, 1H), 7.84 (s, 1H), 7.41 (m, J=3.7 Hz, 2H), 7.20 (m, J=3.8 Hz, 1H), 3.83 (t, J=7.1 Hz, 2H), 3.58 (m, J=6.3 Hz, 3H), 2.30 (q, J=6.3 Hz, 1H), 2.17 (s, 3H), 1.98 (m, J=6.9 Hz, 3H). MS ES.sup.+: 339.31 as NH.sub.3 adduct.

Example 91a: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0696] ##STR00132##

[0697] A solution of 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (0.10 g, 0.30 mmol) in dioxane (20 mL) was treated with (R)-(1-methylpyrrolidin-2-yl)methanamine (0.04 g, 0.40 mmol) and DIPEA (0.08 g, 0.60 mmol), stirred at 100 C. for 16 h and cooled to RT. The mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Purification of the crude material by prep-HPLC gave the title compound (0.10 g, 83%) as a pale yellow solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz, 90 C.): 8.13 (s, 1H), 7.79 (d, J=10.1 Hz, 1H), 7.65 (m, J=5.5 Hz, 2H), 7.15 (s, 1H), 3.55 (m, J=3.3 Hz, 1H), 3.15 (m, J=6.4 Hz, 1H), 2.95 (m, J=3.0 Hz, 1H), 2.31 (m, 4H), 2.13 (t, J=8.6 Hz, 4H), 1.85 (m, J=3.8 Hz, 1H), 1.61 (m, J=4.3 Hz, 3H). MS ES.sup.+: 369.26. SOR: +52.7 (c 0.1, CHCl.sub.3).

Example 91b: (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0698] ##STR00133##

[0699] Prepared as described for Example 91a using 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (0.20 g, 0.60 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanamine (0.08 g, 0.80 mmol) to afford the title compound (120 mg, 52%) as a pale yellow solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz, 90 C.): 8.13 (s, 1H), 7.79 (d, J=10.1 Hz, 1H), 7.65 (m, J=5.5 Hz, 2H), 7.15 (s, 1H), 3.55 (m, J=3.3 Hz, 1H), 3.15 (m, J=6.4 Hz, 1H), 2.95 (m, J=3.0 Hz, 1H), 2.31 (m, 4H), 2.13 (t, J=8.6 Hz, 4H), 1.85 (m, J=3.8 Hz, 1H), 1.61 (m, J=4.3 Hz, 3H). MS ES.sup.+: 369.26. Chiral HPLC: 99.20%, 1.39 min. SOR: 49.68 (c 0.1, CHCl.sub.3).

Example 92a: (R)-5-(4-fluoro-2-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0700] ##STR00134##

[0701] Prepared as described for Example 91 using 2-chloro-5-(4-fluoro-2-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (0.10 g, 0.30 mmol) and (R)-(1-methylpyrrolidin-2-yl)methanamine (0.04 g, 0.4 mmol) to afford the title compound (0.060 g, 50%) as a pale yellow solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz, 90 C.): 7.94 (s, 1H), 7.75 (q, J=4.0 Hz, 1H), 7.61 (m, J=3.9 Hz, 1H), 7.49 (q, J=4.7 Hz, 1H), 6.99 (s, 1H), 3.54 (s, 1H), 3.13 (s, 1H), 2.95 (m, J=4.4 Hz, 1H), 2.30 (s, 4H), 2.12 (q, J=8.5 Hz, 1H), 1.96 (s, 3H), 1.87 (q, J=5.5 Hz, 1H), 1.61 (m, J=4.5 Hz, 3H). MS ES.sup.+: 369.29. Chiral HPLC: 97.5%, 4.99 min. SOR: +52.72 (c 0.1, CHCl.sub.3).

Example 92b: (S)-5-(4-fluoro-2-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0702] ##STR00135##

[0703] Prepared as described for Example 91 using 2-chloro-5-(4-fluoro-2-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (0.10 g, 0.30 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanamine (0.04 g, 0.4 mmol) to afford the title compound (0.05 g, 45%) as a pale yellow solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz, 90 C.): 7.94 (s, 1H), 7.75 (q, J=4.0 Hz, 1H), 7.61 (m, J=3.9 Hz, 1H), 7.49 (q, J=4.7 Hz, 1H), 6.99 (s, 1H), 3.54 (s, 1H), 3.13 (d, J=5.5 Hz, 1H), 2.95 (m, J=3.5 Hz, 1H), 2.30 (s, 4H), 2.12 (q, J=8.5 Hz, 1H), 1.96 (s, 3H), 1.86 (m, J=6.6 Hz, 1H), 1.60 (m, J=4.3 Hz, 3H). MS ES.sup.+: 369.28. Chiral HPLC: 99.41%, 6.09 min. SOR: 49.04 (c 0.1, CHCl.sub.3).

Example 93a: (R)-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0704] ##STR00136##

[0705] Prepared as described for Example 91 using 2-chloro-5-(2-fluoro-4-(trifluoromethoxy) phenyl)-4-methyl-pyrimidine (0.06 g, 0.20 mmol) and (R)-(1-methylpyrrolidin-2-yl) methanamine (0.034 g, 0.30 mmol) to afford the title compound (0.30 g, 30%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.09 (s, 1H), 7.52 (m, J=4.6 Hz, 2H), 7.33 (t, J=4.2 Hz, 1H), 7.09 (s, 1H), 3.54 (m, J=3.3 Hz, 1H), 3.14 (m, J=5.2 Hz, 1H), 2.95 (m, J=3.0 Hz, 1H), 2.31 (m 4H), 2.12 (d, J=10.4 Hz, 4H), 1.85 (m, J=4.5 Hz, 1H), 1.60 (m, J=4.5 Hz, 3H). MS ES.sup.+: 385.39.

Example 93b: (S)-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-N-((1-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0706] ##STR00137##

[0707] Prepared as described for Example 91 using 2-chloro-5-(2-fluoro-4-(trifluoromethoxy) phenyl)-4-methyl-pyrimidine (0.06 g, 0.20 mmol) and (S)-(1-methylpyrrolidin-2-yl) methanamine (0.034 g, 0.30 mmol) to afford the title compound (0.40 g, 42%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.09 (s, 1H), 7.52 (m, J=3.9 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.08 (s, 1H), 3.54 (m, J=3.3 Hz, 1H), 3.14 (m, J=6.4 Hz, 1H), 2.95 (t, J=6.4 Hz, 1H), 2.31 (m, 4H), 2.14 (m, 4H), 1.86 (m, J=5.2 Hz, 1H), 1.60 (m, J=4.6 Hz, 3H). MS ES.sup.+: 385.38.

Example 94a: (R)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine

[0708] ##STR00138##

[0709] Step 1: A solution of 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.50 g, 2.1 mmol) and ((R)-1-BOC-pyrrolidin-2-yl)methanamine (0.215 g, 1.90 mmol) in dioxane (10 mL) at RT was treated with DIPEA (0.82 g, 6.3 mmol) and stirred for 2 h at 120 C. (microwave). The solvent was evaporated and the residue purified by reverse phase flash column chromatography (50-55% MeOH in H.sub.2O) to afford the intermediate BOC compound.

[0710] Step 2: The intermediate from step 1 was stirred in 4M HCl in dioxane (10 mL) at RT for 6 h and evaporated. The residue was purified by reverse phase column chromatography to obtain the title compound (0.101 g, 17%) as a pale brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.05 (s, 1H), 7.45 (m, J=4.0 Hz, 1H), 7.35 (m, J=2.2 Hz, 11H), 7.25-7.10 (m, 2H), 3.24 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.05 (m, 4H), 1.80-1.58 (m, 3H), 1.4 (br s, 1H). MS ES.sup.+: 305.16. SOR: 5.03 (c 0.5, DMSO-d.sub.6).

Example 94b: (S)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine

[0711] ##STR00139##

[0712] Prepared as described for Example 94a using 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.50 g, 2.1 mmol), ((S)-1-BOC-pyrrolidin-2-yl)methanamine (0.215 g, 1.90 mmol) to afford the title compound (0.088 g, 15%) as a pale brown solid. .sup.1H NMR (401 MHz, DMSO-d.sub.6): 8.05 (s, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 3.31 (s, 3H), 2.85-2.70 (m, 2H), 2.12 (m, 4H), 1.80-1.55 (m, 3H), 1.40-1.30 (m, 1H). MS ES.sup.+: 305.16. SOR: 4.54 (c 0.5, DMSO-d.sub.6).

Example 95a: (R)-5-(2,4-difluorophenyl)-4-methyl-N-((1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0713] ##STR00140##

[0714] A solution of (R)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (0.10 g, 0.33 mmol) in DCM (10 mL) was treated with DIPEA (0.13 g, 0.99 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.15 g, 0.66 mmol) and stirred at RT for 4 h. The solvent was evaporated and the residue purified by prep-HPLC to obtain the title compound (0.035 g, 27%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.39 (m, 2H), 7.18 (m, J=2.8 Hz, 1H), 7.11 (t, J=5.9 Hz, 1H), 3.65-3.45 (m, 2H), 3.25-3.05 (m, 3H), 2.95-2.85 (m, 1H), 2.45 (m, 1H), 2.21 (s, 3H), 1.90-1.80 (m, 1H), 1.75-1.65 (m, 2H), 1.65-1.55 (m, 1H). MS ES.sup.+: 387.28.

Example 95b: (S)-5-(2,4-difluorophenyl)-4-methyl-N-((1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine

[0715] ##STR00141##

[0716] Prepared as described for Example 95a using (S)-5-(2,4-difluorophenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (0.10 g, 0.33 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.15 g, 0.66 mmol) to obtain the title compound (0.025 g, 20%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.06 (s, 1H), 7.40 (m, 2H), 7.18 (m, J=2.8 Hz, 1H), 7.11 (t, J=5.9 Hz, 1H), 3.65-3.45 (m, 2H), 3.25-3.05 (m, 3H), 2.95-2.85 (m, 1H), 2.45 (m, 1H), 2.21 (s, 3H), 1.90-1.80 (m, 1H), 1.75-1.65 (m, 2H), 1.65-1.55 (m, 1H). MS ES.sup.+: 387.28.

Example 96a/b: 5-(2,4-difluorophenyl)-N-((3-fluoro-1-methylpyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine

[0717] ##STR00142##

[0718] Step 1: A solution of 2-chloro-5-(2,4-difluorophenyl)-4-methyl-pyrimidine (0.24 g, 1.0 mmol) and tert-butyl 2-(aminomethyl)-3-fluoropyrrolidine-1-carboxylate (0.22 g, 1.0 mmol) in dioxane (10 mL) at RT under N.sub.2 was treated with DIPEA (0.17 g, 1.33 mmol) and stirred at 100 C. for 16 h. The mixture was cooled to RT, treated with H.sub.2O and extracted with EtOAc (220 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give crude tert-butyl 2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)-3-fluoropyrrolidine-1-carboxylate (0.40 g) as an off-white solid, which was used in the next step without further purification.

[0719] Step 2: A solution of tert-butyl 2-(((5-(2,4-difluorophenyl)-4-methyl-pyrimidin-2-yl)amino)methyl)-3-fluoropyrrolidine-1-carboxylate (0.40 g, 0.94 mmol) in dioxane was treated at 0 C. with 4M HCl in dioxane (3 mL) and stirred at RT for 2 h. The solvent was evaporated under reduced pressure to obtain the crude product, which was dissolved in EtOAc (25 mL). The pH of the solution was adjusted to pH=9 using aq. NaOH solution and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain 5-(2,4-difluorophenyl)-N-((3-fluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine (0.38 g) as a brown solid, which was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.08 (s, 1H), 7.39 (m, J=5.1 Hz, 3H), 7.18 (m, J=3.8 Hz, 1H), 5.05 (d, J=28.2 Hz, 1H), 3.45 (m, J=3.3 Hz, 1H), 3.35 (m, 1H), 3.15 (m, J=4.8 Hz, 1H), 2.93 (t, J=7.4 Hz, 2H), 2.15 (m, 4H), 1.95-1.80 (m, 2H). MS ES.sup.+: 323.28.

[0720] Step 3: A stirred solution of 5-(2,4-difluorophenyl)-N-((3-fluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine (0.38 g, 1.17 mmol) in DCM (20 mL) was treated at 0 C. with DIPEA (0.30 mg, 2.35 mmol), stirred at 0 C. for 10 min, treated with CH.sub.3I (0.167 mg, 1.17 mmol) and stirred at RT for 16 h. The mixture was diluted with DCM and washed with H.sub.2O (20 mL). The organic layer was dried over Na.sub.2SO.sub.4 and evaporated. Purification of the residue by reverse phase column chromatography (30% MeOH/H.sub.2O) gave the title compound as diastereomeric mixture. This material was subjected to separation of isomers by SFC (Chiralpak-IG (30 mm250 mm, 5 m); CO.sub.2 (75%), co-solvent (25%, 0.2% 7M methanolic ammonia in MEOH); total flow=100.0 g/min; T=30 C.; UV detection at 248 nm) to obtain isomer 1 (0.015 g, 4.5%) and isomer 2 (0.016 g, 5%) as pale yellow semi-solids.

[0721] Example 96a (isomer 1): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.08 (s, 1H), 7.39 (m, J=5.1 Hz, 3H), 7.18 (m, J=3.8 Hz, 1H), 5.05 (t, J=28.2 Hz, 1H), 3.54 (m, J=3.3 Hz, 1H), 3.13 (t, J=4.3 Hz, 1H), 2.93 (t, J=7.5 Hz, 1H), 2.60 (m, J=9.3 Hz, 1H), 2.40 (m, 4H), 2.14 (s, 3H), 1.89 (m. J=5.6 Hz, 2H). MS ES.sup.+: 337.31. Chiral HPLC: 99.74%, 1.97 min.

[0722] Example 96b (isomer 2): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.08 (s, 1H), 7.39 (m, J=5.1 Hz, 3H), 7.18 (m, J=3.8 Hz, 1H), 5.05 (t, J=28.2 Hz, 1H), 3.54 (m, J=3.3 Hz, 1H), 3.10 (m, J=4.8 Hz, 1H), 2.93 (t, J=7.4 Hz, 1H), 2.61 (m, J=9.5 Hz, 1H), 2.40 (m, 4H), 2.14 (s, 3H), 1.90 (m, J=4.9 Hz, 2H). MS ES.sup.+: 337.28. Chiral HPLC: 95.15%, 2.49 min.

Example 97a/b/c/d: N-(5-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-methyl-pyrimidin-2-yl)hexahydro-1H-pyrrolizin-1-amine

[0723] ##STR00143##

[0724] Prepared as described for Example 2 using 2-chloro-5-(2-fluoro-4-(trifluoromethoxy) phenyl)-4-methyl-pyrimidine (0.2 g, 0.65 mmol) and hexahydro-1H-pyrrolizin-1-amine (0.13 g, 1.05 mmol) to afford the title compound as a mixture of diastereomers (0.20 g, 77%) as an off-white solid. This material was subjected to separation of isomers by SFC (Lux Cellulose 2 (30 mm250 mm, 5 m); CO.sub.2 (80%), co-solvent (20%, 0.2% DIPEA in EtOH); total flow=100.0 g/min; T=30 C.; UV detection at 263 nm) to obtain two diastereomeric pairs of enantiomers: isomer 1a (0.010 g), isomer 1b (0.015 g), isomer 2a (0.016 g) and isomer 2b (0.008 g, 35%), respectively, as off-white solids.

[0725] Example 97a (isomer 1a): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.13 (s, 1H), 7.51 (t, J=8.6 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 3.91 (m, J=5.1 Hz, 1H), 3.61 (m, J=3.9 Hz, 1H), 3.49 (m, J=5.9 Hz, 2H), 3.20 (m, 1H), 2.67 (m, J=9.7 Hz, 2H), 2.15 (d, J=0.9 Hz, 5H), 1.78 (t, J=8.8 Hz, 1H), 1.60 (q, J=10.2 Hz, 1H), 1.46 (q, J=4.4 Hz, 1H), 1.29 (m, J=11.1 Hz, 1H). MS ES.sup.+: 397.41.

[0726] Example 97b (isomer 1b): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.13 (s, 1H), 7.51 (t, J=8.6 Hz, 2H), 7.33 (d, J=8.6 Hz, 1H), 3.89 (m, J=4.1 Hz, 1H), 3.61 (m, J=3.9 Hz, 1H), 3.48 (m, J=5.9 Hz, 2H), 3.21 (m, 1H), 2.65 (m, J=10.0 Hz, 2H), 2.15 (s, 5H), 1.76 (m, J=5.5 Hz, 1H), 1.59 (t, J=10.4 Hz, 1H), 1.46 (q, J=4.4 Hz, 1H), 1.28 (q, J=13.0 Hz, 1H). MS ES.sup.+: 397.41.

[0727] Example 97c (isomer 2a): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.17 (s, 1H), 7.52 (t, J=8.6 Hz, 2H), 7.34 (d, J=8.5 Hz, 1H), 3.74 (q, J=6.7 Hz, 1H), 3.47 (m, J=5.8 Hz, 1H), 3.15 (d, J=8.9 Hz, 1H), 3.04 (d, J=9.8 Hz, 2H), 2.75 (m, J=6.7 Hz, 2H), 2.64 (m, J=5.0 Hz, 1H), 2.17 (d, J=0.9 Hz, 3H), 2.03 (m, J=5.6 Hz, 1H), 1.66 (m, J=11.5 Hz, 2H), 1.52 (m, J=5.7 Hz, 1H), 1.28 (m, J=6.3 Hz, 1H). MS ES.sup.+: 397.40.

[0728] Example 97d (isomer 2b): .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.16 (s, 1H), 7.52 (t, J=8.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 3.72 (q, J=6.7 Hz, 1H), 3.46 (m, J=5.8 Hz, 1H), 3.15 (d, J=11.8 Hz, 1H), 2.95 (m, J=5.8 Hz, 2H), 2.61 (m, J=7.1 Hz, 2H), 2.41 (s, 1H), 2.16 (d, J=0.8 Hz, 3H), 1.98 (q, J=5.6 Hz, 1H), 1.61 (m, J=11.1 Hz, 2H), 1.47 (m, J=4.9 Hz, 1H), 1.25 (m, J=6.5 Hz, 1H). MS ES.sup.+: 397.40.

Example 98: N-((1-ethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, formate salt

[0729] ##STR00144##

[0730] A solution of 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (50 mg, 0.172 mmol), (1-ethylpyrrolidin-2-yl)methanamine (33 mg, 0.26 mmol) and DIPEA (44 mg, 0.34 mmol, 60 L) in dioxane (0.5 mL) was stirred at 110 C. for 3 h, cooled to RT and extracted with DCM (35 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated. Purification of the residue by prep-HPLC (Phenomenex Luna C18 (80 mm40 mm, 3 m); mobile phase A: 0.2% aq. HCOOH, mobile phase B: ACN; flow rate: 25 mL/min; gradient from 17% to 57% B). The desired material was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to dryness to give the title compound (30 mg, 40%, 98.6% purity by HPLC) as light yellow gummy solid. MS ES.sup.+: 383.1.

Example 99: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methylpyrrolidin-3-yl)methyl)pyrimidin-2-amine, formate salt

[0731] ##STR00145##

[0732] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and (1-methylpyrrolidin-3-yl)methanamine (19 mg, 0.17 mmol) to afford the title compound (30 mg, 41%, 97.6% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 369.1.

Example 100: (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(1-isopropylpyrrolidin-3-yl)-4-methyl-pyrimidin-2-amine, formate salt

[0733] ##STR00146##

[0734] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and (3S)-1-isopropylpyrrolidin-3-amine (33 mg, 0.26 mmol) to afford the title compound (34 mg, 45%, 97.4% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 383.1.

Example 101: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methyl-4-piperidinyl)methyl)pyrimidin-2-amine, formate salt

[0735] ##STR00147##

[0736] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and (1-methyl-4-piperidinyl)methanamine (33 mg, 0.26 mmol) to afford the title compound (26 mg, 35%, 98.7% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 383.1.

Example 102: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine, semi-fumarate salt

[0737] ##STR00148##

[0738] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (200 mg, 0.69 mmol) and tert-butyl (2R)-2-(aminomethyl)pyrrolidine-1-carboxylate (138 mg, 0.69 mmol) to afford (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (108 mg, 44%) as a yellow gummy solid. A solution of (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine (108 mg, 0.305 mmol) and fumaric acid (17.7 mg, 0.153 mmol) in EtOH (2 mL) was stirred at 25 C. for 1 h. The formed precipitate was collected by filtration and dried to give the title compound (80 mg, 63%) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.16 (s, 1H), 7.66-7.56 (m, 3H), 7.53-7.43 (m, 1H), 6.47 (d, J=1.0 Hz, 1H), 3.91 (dq, J=3.6, 7.9 Hz, 1H), 3.82-3.75 (m, 1H), 3.64-3.57 (m, 1H), 3.35-3.25 (m, 2H), 2.24 (s, 3H), 2.21-2.14 (m, 1H), 2.10-1.94 (m, 2H), 1.90-1.75 (m, 1H). MS ES.sup.+: 354.9. Analyt. SFC: 100%, 3.26 min.

Example 103: (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-2-ylmethyl)pyrimidin-2-amine, semi-fumarate salt

[0739] ##STR00149##

[0740] Prepared as described for Example 102 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (209 mg, 0.72 mmol) and tert-butyl (2S)-2-(aminomethyl)pyrrolidine-1-carboxylate (187 mg, 0.935 mmol) to afford the title compound (108 mg, 36%) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.09 (s, 1H), 7.59-7.49 (m, 3H), 7.47-7.36 (m, 1H), 6.41 (s, 1H), 3.92-3.79 (m, 1H), 3.76-3.66 (m, 1H), 3.63-3.52 (m, 1H), 3.34-3.17 (m, 2H), 2.17 (s, 3H), 2.15-2.07 (m, 1H), 2.06-1.88 (m, 2H), 1.84-1.70 (m, 1H). MS ES.sup.+: 355.1. Analyt. SFC: 99.5%, 3.48 min.

Example 104: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-piperidinylmethyl) pyrimidin-2-amine, hydrochloride salt

[0741] ##STR00150##

[0742] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and tert-butyl 2-(aminomethyl) piperidine-1-carboxylate (37 mg, 0.17 mmol) to afford the title compound (25 mg, 34%, 95.2% purity by HPLC) as a yellow gummy solid. MS ES.sup.+: 369.1.

Example 104a/b: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-piperidinylmethyl)pyrimidin-2-amine semi-fumarate salt and (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-piperidinylmethyl)pyrimidin-2-amine semi-fumarate salt

[0743] ##STR00151##

[0744] Step 1: To a solution of 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (300 mg, 1.03 mmol) and tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (441 mg, 2.06 mmol) in 1,4-dioxane (0.5 ml) was added DIPEA (266 mg, 2.06 mmol). The mixture was stirred at 110 C. for 16 h. The mixture cooled to RT, diluted with EtOAc (5 ml), washed with H.sub.2O (10 ml) and extracted with EtOAc (35 ml). The combined organic layers were washed with brine (10 ml), dried (Na.sub.2SO.sub.4) and evaporated. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, 050% EtOAc/petroleum ether) to give rac-tert-butyl 2-[[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-pyrimidin-2-yl]amino]methyl]piperidine-1-carboxylate (370 mg, 0.755 mmol, 73%, 95.6% HPLC purity) as a colourless gummy solid. MS ES.sup.+: 469.4.

[0745] Step 2: The rac-tert-butyl 2-[[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-pyrimidin-2-yl]amino]methyl]piperidine-1-carboxylate (370 mg 0.755 mmol) was purified by SFC (DAICEL CHIRALPAK AD, 250 mm30 mm, 10 m; mobile phase: A: supercritical CO.sub.2, B: 0.1% NH.sub.3. H.sub.2O in EtOH, A:B=4:1) to give isomer 1 (170 mg, 0.361 mmol, 47%, 99.4% HPLC purity) as a white solid and isomer 2 (160 mg, 0.341 mmol, 44%, 99.7% HPLC purity) as a white solid.

[0746] Step 3a: A solution of (*R)-tert-butyl 2-[[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-pyrimidin-2-yl]amino]methyl]piperidine-1-carboxylate (170 mg, 0.363 mmol) was dissolved into HCl/dioxane (4M, 3 mL), stirred at 25 C. for 1 h and concentrated to afford a residue which was dissolved into CH.sub.2Cl.sub.2 (5 ml) and H.sub.2O (5 ml). The aqueous phase was basified to pH=8 using sat. aq. NaHCO.sub.3 and the mixture was extracted with CH.sub.2Cl.sub.2 (55 ml). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give an off-white gummy solid. The residue was dissolved in EtOH (1 ml), treated with fumaric acid (21 mg, 0.18 mmol) and stirred at 25 C. for 0.5 h. White precipitates were formed, which were collected and dried to afford 104a semi-fumarate (R-enantiomer; 51.3 mg, 0.118 mmol, 32%, 98.1% HPLC purity) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.13 (s, 1H), 7.62-7.53 (m, 2H), 7.51-7.42 (m, 1H), 6.50 (s, 1H), 3.70-3.61 (m, 1H), 3.59-3.51 (m, 1H), 3.40-3.32 (m, 2H), 2.96-2.86 (m, 1H), 2.23-2.17 (m, 3H), 2.00-1.81 (m, 3H), 1.67-1.56 (m, 1H), 1.55-1.46 (m, 2H). MS ES.sup.+: 369.3. Chiral SFC: 100%, 2.40 min.

[0747] Step 3b: A solution of (*S)-tert-butyl 2-[[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-pyrimidin-2-yl]amino]methyl]piperidine-1-carboxylate (130 mg, 0.353 mmol) in EtOH (1 ml) was treated with fumaric acid (20.5 mg, 0.176 mmol). The mixture was stirred at 25 C. for 0.5 h. White precipitates were formed, which were collected to afford 104b semi-fumarate (S-enantiomer; 53.9 mg, 34.7%, 96.9% HPLC purity) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.13 (s, 1H), 7.62-7.52 (m, 2H), 7.50-7.42 (m, 1H), 6.51 (s, 1H), 3.70-3.61 (m, 1H), 3.60-3.51 (m, 1H), 3.43-3.31 (m, 2H), 2.99-2.84 (m, 1H), 2.25-2.17 (m, 3H), 2.00-1.81 (m, 3H), 1.65-1.56 (m, 1H), 1.55-1.44 (m, 2H). MS ES.sup.+: 369.3. Chiral SFC: 100%, 1.99 min.

Example 105: (S)N-((1-ethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidin-2-amine, formate salt

[0748] ##STR00152##

[0749] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and ((2S)-1-ethylpyrrolidin-2-yl) methanamine (33 mg, 0.26 mmol) to afford the title compound (20 mg, 27%, 99.6% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 383.1.

Example 106: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine, formate salt

[0750] ##STR00153##

[0751] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and 2-(1-methylpyrrolidin-2-yl)ethan-1-amine (33 mg, 0.26 mmol) to afford the title compound (20 mg, 27%, 99% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 383.1.

Example 106a/b: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine (fumarate, 2.5 equiv) and (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine (bis-fumarate)

[0752] ##STR00154##

[0753] Step 1: Racemic material of 106 free base (180 mg) was purified by SFC separation (DAICEL CHIRALPAK IC, 250 mm30 mm, 10 m; mobile phase: A: supercritical CO.sub.2, B: 0.1% NH.sub.3. H.sub.2O in EtOH, A:B=1:1 at 60 mL/min) to give the (R)-isomer 106a (70 mg, 27%) as a light yellow oil and the (S)-isomer 106b (40 mg, 15%) as a light yellow oil.

[0754] Step 2a: To a solution of (R)-isomer 106a (85 mg, 0.22 mmol) in EtOH (1 ml) was added fumaric acid (51.6 mg, 0.445 mmol). The mixture was stirred at 25 C. for 0.25 h, concentrated to afford a solid which was partitioned between CH.sub.3CN (2 ml) and H.sub.2O (10 ml) and lyophilized to give the (R)-isomer 106a fumarate (2.5 equiv, 70 mg, 46%, 99.2% HPLC purity) as an off-white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.19 (s, 1H), 7.57-7.50 (m, 2H), 7.48-7.37 (m, 1H), 6.65 (s, 5H), 3.62-3.55 (m, 1H), 3.54-3.47 (m, 2H), 3.37-3.25 (m, 1H), 3.09-2.99 (m, 1H), 2.81 (s, 3H), 2.40-2.30 (m, 1H), 2.24 (s, 3H), 2.12-1.85 (m, 3H), 1.84-1.68 (m, 2H). MS ES.sup.+: 383.3. Chiral SFC: 100%, 3.22 min.

[0755] Step 2b: To a solution of (S)-isomer 106b (70 mg, 0.18 mmol) in EtOH (1 ml) was added fumaric acid (42.5 mg, 0.366 mmol). The mixture was stirred at 25 C. for 0.25 h, concentrated to afford a solid which was partitioned between CH.sub.3CN (2 ml) and H.sub.2O (10 ml) and lyophilized to give the (S)-isomer 106b bis-fumarate (70 mg, 62%, 99.6% HPLC purity) as an off-white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.18 (s, 1H), 7.60-7.51 (m, 2H), 7.49-7.42 (m, 1H), 6.67-6.63 (m, 4H), 3.67-3.58 (m, 1H), 3.57-3.49 (m, 2H), 3.40-3.30 (m, 1H), 3.12-3.03 (m, 11H), 2.85 (s, 3H), 2.43-2.33 (m, 1H), 2.24 (s, 3H), 2.13-1.86 (m, 3H), 1.86-1.71 (m, 2H). MS ES.sup.+: 383.3. Chiral SFC: 97.8%, 3.35 min.

Example 107: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-methyl-3-piperidinyl)methyl)pyrimidin-2-amine, formate salt

[0756] ##STR00155##

[0757] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and (1-methyl-3-piperidinyl)methanamine (33 mg, 0.26 mmol) to afford the title compound (20 mg, 27%, 99.4% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 383.1.

Example 108: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((4-methylmorpholin-2-yl)methyl)pyrimidin-2-amine, formate salt

[0758] ##STR00156##

[0759] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and (4-methylmorpholin-2-yl)methanamine (22 mg, 0.17 mmol) to afford the title compound (20 mg, 27%, 94.4% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 385.1.

Example 108a/b: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((4-methylmorpholin-2-yl)methyl)pyrimidin-2-amine (bis-fumarate) and (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((4-methylmorpholin-2-yl)methyl)pyrimidin-2-amine (bis-fumarate)

[0760] ##STR00157##

[0761] Step 1: rac-5-(2-Fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((4-methylmorpholin-2-yl)methyl)pyrimidin-2-amine (190 mg) was purified by SFC (DAICEL CHIRALPAK AD, 250 mm30 mm, 10 m; mobile phase: 15% of 0.1% aq. NH.sub.3 in EtOH) to give isomer 108a (95 mg, 0.24 mmol, 48%, 97.5% HPLC purity) as a colourless oil and isomer 108b (96 mg, 0.25 mmol, 51%, 100% HPLC purity) as a colourless oil.

[0762] Step 2a: To a solution of isomer 108a (90 mg, 0.234 mmol) in EtOH (1 ml) was added fumaric acid (81.5 mg, 0.702 mmol). The mixture was stirred at 25 C. for 1 h and concentrated to afford a residue which was partitioned between CH.sub.3CN (10 ml) and H.sub.2O (20 ml). The solution was lyophilized to dryness to give the title compound as the bis-fumarate salt (enantiomerically pure with the absolute configuration not known; 70 mg, 46%, 95.9% HPLC purity) as an off-white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.21 (s, 1H), 7.62-7.56 (m, 2H), 7.52-7.46 (m, 1H), 6.71 (s, 4H), 4.18-4.11 (m, 1H), 4.06-3.99 (m, 1H), 3.84-3.76 (m, 1H), 3.71-3.62 (m, 2H), 3.61-3.54 (m, 1H), 3.49-3.42 (m, 1H), 3.17-3.08 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.86 (m, 3H), 2.29-2.25 (m, 3H). MS ES.sup.+: 385.3. Chiral SFC: 100%, 1.95 min.

[0763] Step 2b: To a solution of isomer 108b (90 mg, 0.23 mmol) in EtOH (1 ml) was added fumaric acid (81.5 mg, 0.702 mmol). The mixture was stirred at 25 C. for 1 h and concentrated to afford a residue which was partitioned between CH.sub.3CN (10 ml) and H.sub.2O (20 ml). The solution was lyophilized to dryness to give the title compound as the bis-fumarate salt (enantiomerically pure with the absolute configuration not known; 80 mg, 55%, 99.2% HPLC purity) as an off-white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.22 (s, 1H), 7.64-7.55 (m, 2H), 7.54-7.44 (m, 1H), 6.71 (s, 4H), 4.18-4.11 (m, 1H), 4.06-3.99 (m, 1H), 3.85-3.75 (m, 1H), 3.72-3.62 (m, 2H), 3.62-3.54 (m, 1H), 3.49-3.42 (m, 1H), 3.18-3.08 (m, 1H), 3.03-2.94 (m, 1H), 2.89 (s, 3H), 2.31-2.23 (m, 3H). MS ES.sup.+: 385.3. Chiral SFC: 100%, 2.12 min.

Example 109: (1S,2S)N.SUP.1.-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-N.SUP.2.,N.SUP.2.-dimethyl-cyclohexane-1,2-diamine, formate salt

[0764] ##STR00158##

[0765] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and (1S,2S)N.sup.2,N.sup.2-dimethylcyclohexane-1,2-diamine (29 mg, 0.21 mmol) to afford the title compound (15 mg, 32%, 97.5% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 397.1.

Example 110: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(pyrrolidin-3-yl)pyrimidin-2-amine, hydrochloride salt

[0766] ##STR00159##

[0767] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (48 mg, 0.26 mmol) to afford the title compound (5 mg, 8%, 98.6% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 341.0.

Example 111: (1S,3S)N.SUP.3.-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)cyclopentane-1,3-diamine, hydrochloride salt

[0768] ##STR00160##

[0769] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and tert-butyl N-((1S,3S)-3-aminocyclopentyl)carbamate (52 mg, 0.26 mmol) to afford the title compound (5.6 mg, 8.2%, 98.5% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 355.1.

Example 112: N-((cis)-4-fluoropyrrolidin-3-yl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0770] ##STR00161##

[0771] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and tert-butyl cis-3-amino-4-fluoro-pyrrolidine-1-carboxylate (35 mg, 0.17 mmol) to afford the title compound (6.7 mg, 9.7%, 98.3% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 359.0.

Example 113: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((3-piperidinyl) methyl)pyrimidin-2-amine, hydrochloride salt

[0772] ##STR00162##

[0773] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl (3S)-3-(aminomethyl) piperidine-1-carboxylate (44 mg, 0.21 mmol) to afford the title compound (10 mg, 23%, 97.7% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 369.1.

Example 114: N-((trans)-4-fluoropyrrolidin-3-yl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0774] ##STR00163##

[0775] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and tert-butyl (trans)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (35 mg, 0.17 mmol) to afford the title compound (10 mg, 14%, 98.0% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 359.0.

Example 115: (3R,4R)-4-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)amino)pyrrolidin-3-ol, hydrochloride salt

[0776] ##STR00164##

[0777] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (50 mg, 0.17 mmol) and tert-butyl (3R,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate (35 mg, 0.17 mmol) to afford the title compound (10 mg, 14%, 98.1% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 357.0.

Example 116: (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(3-piperidinyl) pyrimidin-2-amine, hydrochloride salt

[0778] ##STR00165##

[0779] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate (41 mg, 0.21 mmol) to afford the title compound (10 mg, 25%, 98.9% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 355.0.

Example 117: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine, fumarate salt

[0780] ##STR00166##

[0781] Step 1: A solution of tert-butyl N-(((2R)-pyrrolidin-2-yl)methyl)carbamate (1.00 g, 4.99 mmol) and DIPEA (1.29 g, 9.99 mmol, 1.74 mL) in DCM (10 mL) was dropwise treated with trideuterio(iodo)methane (724 mg, 4.99 mmol, 310 L) at 0 C. and stirred at 25 C. for 1 h. The mixture was extracted with DCM (320 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated and the residue purified by silica gel column chromatography (DCM/MeOH 10:1) to afford tert-butyl N-(((2R)-1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)carbamate (0.80 g, 63%, 85% purity by HPLC) as a yellow solid.

[0782] Step 2: A solution of tert-butyl N-(((2R)-1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)carbamate (0.80 g, 3.13 mmol, 85% purity by HPLC) in 4M HCl in dioxane (10 mL) was stirred at 25 C. for 0.5 h. The mixture was evaporated to dryness to give ((2R)-1-(trideuteriomethyl)pyrrolidin-2-yl)methanamine hydrochloride (0.56 g, crude) as a brown solid, which was used in the next step without further purification.

[0783] Step 3: A solution of ((2R)-1-(trideuteriomethyl)pyrrolidin-2-yl)methanamine hydrochloride (158 mg, 1.03 mmol), 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (150 mg, 0.516 mmol) and DIPEA (200 mg, 1.55 mmol) in dioxane (1 mL) was stirred at 110 C. for 8 h, cooled to RT and extracted with DCM (350 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and filtered.

[0784] The filtrate was evaporated to dryness. Purification of the residue by prep-TLC (DCM/MeOH 10:1) and prep-HPLC (Phenomenex Luna C18 (80 mm40 mm, 3 m); mobile phase A: 0.225% aq. HCOOH, mobile phase B: ACN; flow rate: 25 mL/min; gradient from 14% to 54% B) gave the product, which was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to dryness to give the product as a yellow gummy solid. This material was dissolved in H.sub.2O (10 mL) and the pH was adjusted pH=8 using sat. aq. NaHCO.sub.3. The mixture was extracted with DCM (310 mL). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated to dryness to give 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(((2R)-1-(trideuteriomethyl) pyrrolidin-2-yl)methyl)pyrimidin-2-amine (20 mg, 10%) as a yellow gummy solid. MS ES.sup.+: 372.2.

[0785] Step 4: A solution of 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(((2R)-1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine (20 mg, 0.53 mmol) and fumaric acid (6.25 mg, 0.53 mmol) in EtOH (1 mL) was stirred at 25 C. for 1 h. The mixture was evaporated to dryness and the residue suspended in H.sub.2O (10 mL). The solution was lyophilized to give the title compound (17.7 mg, 64%, 95.4% purity by HPLC) as a white powder. .sup.1H NMR (400 MHz, D.sub.2O): 7.85 (s, 1H), 7.38-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.19-7.11 (m, 1H), 6.44 (s, 2H), 3.76-3.43 (m, 3H), 3.18-2.95 (m, 1H), 2.20-2.05 (m, 1H), 2.01-1.68 (m, 6H). MS ES.sup.+: 372.0.

Example 118: (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1-(trideuteriomethyl)pyrrolidin-2-yl)methyl)pyrimidin-2-amine, fumarate salt

[0786] ##STR00167##

[0787] Prepared as described for Example 117 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (200 mg, 0.69 mmol) and ((2S)-1-(trideuteriomethyl) pyrrolidin-2-yl)methanamine (81 mg, 0.69 mmol) to afford the title compound (80 mg, 23%, 98.8% purity by HPLC) as a light yellow powder. .sup.1H NMR (400 MHz, D.sub.2O): 8.16 (s, 1H), 7.64-7.51 (m, 2H), 7.50-7.42 (m, 1H), 6.64 (s, 2H), 3.94-3.79 (m, 1H), 3.92-3.57 (m, 3H), 3.17-3.04 (m, 1H), 2.32-2.16 (m, 3H), 2.13-2.01 (m, 2H), 1.98-1.85 (m, 2H). MS ES.sup.+: 372.1. SFC: 100%, 2.18 min.

Example 119: (R)N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl) quinuclidin-3-amine, formate salt

[0788] ##STR00168##

[0789] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (300 mg, 1.03 mmol) and (3R)-quinuclidin-3-amine dihydrochloride (205 mg, 1.03 mmol) to afford the title compound (3 mg, 0.6%, 87% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 381.1.

Example 120: (S)N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl) quinuclidin-3-amine, formate salt

[0790] ##STR00169##

[0791] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and (3S)-quinuclidin-3-amine dihydrochloride (41 mg, 0.21 mmol) to give the title compound (5 mg, 10%, 89.7% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 381.1.

Example 121: (1R,3s,5S)N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-amine, hydrochloride salt

[0792] ##STR00170##

[0793] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl (1R,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (47 mg, 0.21 mmol) to give the title compound (10 mg, 22%, 96.7% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 381.1.

Example 122: N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-amine, formate salt

[0794] ##STR00171##

[0795] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (44 mg, 0.20 mmol) to give the title compound (10 mg, 23%, 96.3% purity by HPLC) as a white powder. MS ES.sup.+: 367.1.

Example 123: N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-6-azaspiro[2.5]octan-1-amine, hydrochloride salt

[0796] ##STR00172##

[0797] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl 1-amino-6-azaspiro[2.5]octane-6-carboxylate hydrochloride (27 mg, 0.10 mmol) to give the title compound (10 mg, 22%, 97.4% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 381.1.

Example 124: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)-4-methyl-pyrimidin-2-amine, hydrochloride salt

[0798] ##STR00173##

[0799] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl (3S,4S)-4-amino-3-fluoro-piperidine-1-carboxylate (45 mg, 0.20 mmol) to give the title compound (10 mg, 22%, 93% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 373.0.

Example 125: (1S,3S)N.SUP.1.-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)cyclohexane-1,3-diamine, hydrochloride salt

[0800] ##STR00174##

[0801] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl N-((1S,3S)-3-aminocyclohexyl)carbamate (44 mg, 0.20 mmol) to give the title compound (10 mg, 26%, 97% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 369.1

Example 126: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-2-amine, formate salt

[0802] ##STR00175##

[0803] Prepared as described for Example 98 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and 2,2,6,6-tetramethylpiperidin-4-amine (32 mg, 0.20 mmol) to give the title compound (15 mg, 32%, 99.8% purity by HPLC) as a light yellow gummy solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.38 (s, 1H), 8.16 (s, 1H), 7.85-7.74 (m, 1H), 7.71-7.59 (m, 2H), 7.47 (br s, 1H), 4.30 (s, 1H), 2.16 (s, 3H), 1.89 (d, J=11.5 Hz, 2H), 1.48-1.18 (m, 14H). MS ES.sup.+: 411.1.

Example 127: (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(piperidin-3-ylmethyl)pyrimidin-2-amine, hydrochloride salt

[0804] ##STR00176##

[0805] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mmol) and tert-butyl (3R)-3-(aminomethyl)piperidine-1-carboxylate (44 mg, 0.20 mmol) to give the title compound (10 mg, 23%, 97% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 369.0.

Example 128: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(piperidin-3-yl) pyrimidin-2-amine, hydrochloride salt

[0806] ##STR00177##

[0807] Prepared as described for Example 82 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (30 mg, 0.10 mol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (41 mg, 0.206 mmol) to give the title compound (10 mg, 24%, 97.1% purity by HPLC) as a light yellow gummy solid. MS ES.sup.+: 355.0.

Example 129a/b: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(1-((2R)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine

[0808] ##STR00178##

[0809] Step 1: A mixture of tert-butyl (2R)-2-acetylpyrrolidine-1-carboxylate (600 mg, 2.81 mmol), NH.sub.4OAc (1.08 g, 14.05 mmol) and NaBH.sub.3CN (441.45 mg, 7.03 mmol) in MeOH (7 mL) was sealed, heated at 80 C. for 2 h (microwave) and concentrated. The resulting yellow solid was dissolved in H.sub.2O (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give (2R)-tert-butyl 2-(1-aminoethyl)pyrrolidine-1-carboxylate (780 mg) as a yellow gummy solid, which was used in the next step without further purification.

[0810] Step 2: A solution of 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (1.24 g, 4.26 mmol) and (2R)-tert-butyl 2-(1-aminoethyl)pyrrolidine-1-carboxylate (760 mg, 3.55 mmol) in dioxane (3.5 mL) was treated with DIPEA (916 mg, 7.10 mmol), stirred at 110 C. for 16 h, cooled to RT and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO, 25 g SepaFlash Silica Flash Column, 040% EtOAc/petroleum ether) to give (2R)-tert-butyl 2-(1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)amino)ethyl)-pyrrolidine-1-carboxylate (520 mg, 24%, 78% purity by HPLC) as a brown gummy solid. MS ES.sup.+: 469.2.

[0811] Step 3: The material from step 2 was purified by SFC separation (DAICEL CHIRALPAK AD, 250 mm30 mm10 m); mobile phase: A (supercritical CO.sub.2), B (0.1% NH.sub.3.Math.H.sub.2O in EtOH), A:B=85:15, flow=60 mL/min) to give diastereomer 1 (420 mg, 96% purity by HPLC) and diastereomer 2 (460 mg, 96% purity by HPLC) as brown gummy solids.

Example 129a (isomer 1): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2R)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine, semi-fumarate salt

[0812] Step 1: A solution of diastereomer 1, (R)-tert-butyl 2-((*R)-1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)amino)ethyl)pyrrolidine-1-carboxylate (420 mg, 0.897 mmol) was treated with HCl/dioxane (4M, 4 mL), stirred at 25 C. for 1 h and concentrated. The resulting gummy solid was dissolved in H.sub.2O (5 mL) and EtOAc (5 mL), treated with sat. aq. NaHCO.sub.3 (to adjust to pH=8) and the layers were separated. The aqueous phase was extracted with EtOAc (35 mL). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to give 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N((*R)-1-((R)-pyrrolidin-2-yl) ethyl)pyrimidin-2-amine (290 mg, 83%, 94.7% purity by HPLC) as a yellow gummy solid, which was used in the next step without further purification.

[0813] Step 2: A solution of 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N((*R)-1-((R)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine (40 mg, 0.109 mmol) in EtOH (0.5 mL) was treated with fumaric acid (6.30 mg, 0.054 mmol), stirred at 25 C. for 1 h and concentrated to afford a white solid, which was partitioned between ACN (2 mL) and H.sub.2O (10 mL). The mixture was lyophilized to dryness to give isomer 1 (17 mg, 35%, 95.7% purity by HPLC) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.15 (s, 1H), 7.71-7.54 (m, 2H), 7.54-7.41 (m, 1H), 6.49 (s, 11H), 4.30-4.13 (m, 1H), 3.78-3.55 (m, 1H), 3.46-3.19 (m, 2H), 2.28-2.18 (m, 4H), 2.17-1.80 (m, 3H), 1.38-1.26 (m, 3H). MS ES.sup.+: 369.2. SFC: 90.8%, 2.32 min.

Example 129b (isomer 2): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*S)-1-((2R)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine, 0.7 eq. fumarate salt

[0814] Prepared as described for Example 129a using diastereomer 2 (460 mg, 0.94 mmol) to afford the title compound (36 mg, 8%, 97.1% purity by HPLC) as a light yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.18 (s, 1H), 7.67-7.56 (m, 2H), 7.55-7.47 (m, 1H), 6.58 (s, 1.4H), 4.57-4.43 (m, 1H), 3.91-3.75 (m, 1H), 3.37-3.07 (m, 2H), 2.25 (s, 3H), 2.21-1.89 (m, 4H), 1.35 (d, J=7.2 Hz, 3H). MS ES.sup.+: 369.3. SFC: 100%, 3.14 min.

Example 130a/b: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(1-((2S)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine

[0815] ##STR00179##

Example 130a (isomer 1): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2S)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine, fumarate salt

[0816] Prepared as described for Example 129a using tert-butyl (2S)-2-acetylpyrrolidine-1-carboxylate (500 mg, 2.34 mmol) to afford the title compound (25 mg, 2%, 96.8% purity by HPLC) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.00 (s, 1H), 7.49-7.39 (m, 2H), 7.36-7.29 (m, 1H), 6.39 (s, 2H), 4.16-4.00 (m, 1H), 3.59-3.43 (m, 1H), 3.29-3.07 (m, 2H), 2.16-2.09 (m, 1H), 2.09-2.04 (m, 3H), 2.01-1.79 (m, 2H), 1.72-1.57 (m, 1H), 1.15 (d, J=6.6 Hz, 3H). MS ES.sup.+: 369.2. SFC: 100%, 3.55 min.

Example 130b (isomer 2): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*S)-1-((2S)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine, semi-fumarate salt

[0817] Prepared as described for Example 129a using tert-butyl (2S)-2-acetylpyrrolidine-1-carboxylate (500 mg, 2.34 mmol) to afford the title compound (60 mg, 6%, 95.0% purity by HPLC) as a white powder. .sup.1H NMR (400 MHz, D.sub.2O) 7.90 (s, 1H), 7.46-7.10 (m, 3H), 6.44 (s, 1H), 4.42-4.23 (m, 1H), 3.82-3.61 (m, 1H), 3.34-3.15 (m, 1H), 3.06 (td, J=7.4, 11.4 Hz, 1H), 2.20-1.69 (m, 7H), 1.21 (d, J=6.6 Hz, 3H). MS ES.sup.+: 369.1. SFC: 99.1%, 3.81 min.

Example 131a/b: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(1-((2R)-1-methylpyrrolidin-2-yl)ethyl) pyrimidin-2-amine

[0818] ##STR00180##

Example 131a (isomer 1: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2R)-1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine, 0.8 eq. fumarate salt

[0819] Step 1: A solution of 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2R)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine (150 mg, 0.41 mmol) and DIPEA (79 mg, 0.61 mmol) in THF (2 mL) was treated with Mel (75 mg, 0.53 mmol) and stirred at 0 C. for 2 h. The mixture was extracted with EtOAc (35 mL). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex Luna C18 7530 mm3 m, mobile phase A: 0.225% aq. HCOOH, mobile phase B: ACN; flow rate: 25 mL/min, gradient from 20% B to 50%). The product was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized. The product was dissolved in H.sub.2O (10 mL) and treated with sat. aq. NaHCO.sub.3 to adjust to pH=8. The mixture was extracted with DCM (310 mL). The combined organic layers were washed with brine 10 mL (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2R)-1-methyl-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine (120 mg, 77%) as a pale yellow gummy solid. MS ES.sup.+: 383.2.

[0820] Step 2: A solution of 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2R)-1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine (20 mg, 0.052 mmol) in EtOH (0.5 mL) was treated with fumaric acid (4.86 mg, 0.042 mmol), stirred at 25 C. for 1 h and concentrated. The resulting residue was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to give the title compound (22 mg, 87%, 97.1% purity by HPLC) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.22-8.13 (m, 1H), 7.65-7.54 (m, 2H), 7.54-7.40 (m, 1H), 6.62 (s, 1.6H), 4.34-4.17 (m, 1H), 3.80-3.51 (m, 2H), 3.40-3.12 (m, 1H), 3.10-2.67 (m, 3H), 2.43-2.29 (m, 1H), 2.27-2.21 (m, 3H), 2.20-1.84 (m, 3H), 1.30 (d, J=6.5 Hz, 3H). MS ES.sup.+: 383.2. SFC: 91.6%, 1.50 min.

Example 131b (isomer 2): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*S)-1-((2R)-1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine, 1.1 eq. fumarate salt

[0821] Prepared as described for Example 131a using 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*S)-1-((2R)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine (150 mg, 0.407 mmol) to afford the title compound (41 mg, 19%, 98.9% purity by HPLC) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.23-8.12 (m, 1H), 7.65-7.53 (m, 2H), 7.53-7.43 (m, 1H), 6.66 (s, 2.2H), 4.69-4.56 (m, 1H), 3.64-3.48 (m, 2H), 3.16-3.09 (m, 1H), 3.06 (s, 3H), 2.33-2.17 (m, 4H), 2.16-1.79 (m, 3H), 1.32 (d, J=6.9 Hz, 3H). MS ES.sup.+: 383.3. SFC: 99.4%, 1.63 min.

Example 132a/b: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-(1-((2S)-1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine

[0822] ##STR00181##

Example 132a (isomer 1): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2S)-1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine, fumarate salt

[0823] Prepared as described for Example 131a using 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*R)-1-((2S)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine (150 mg, 0.407 mmol) to afford the title compound (46 mg, 29%) as a light yellow solid. .sup.1H NMR (400 MHz, D.sub.2O) 8.16 (s, 1H), 7.62-7.51 (m, 2H), 7.49-7.38 (m, 1H), 6.66 (s, 2H), 4.41-4.14 (m, 1H), 3.79-3.47 (m, 2H), 3.35-3.08 (m, 1H), 2.91 (s, 3H), 2.41-2.27 (m, 1H), 2.26-2.17 (m, 3H), 2.16-1.97 (m, 2H), 1.96-1.81 (m, 1H), 1.34-1.18 (m, 3H). MS ES.sup.+: 383.1. SFC: 99.9%, 14.9 min.

Example 132b (isomer 2): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*S)-1-((2S)-1-methylpyrrolidin-2-yl)ethyl)pyrimidin-2-amine, semi-fumarate salt

[0824] Prepared as described for Example 131a using 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((1*S)-1-((2S)-pyrrolidin-2-yl)ethyl)pyrimidin-2-amine (150 mg, 0.407 mmol) to afford the title compound (35 mg, 18%, 94.7% purity by HPLC) as a light yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.20 (s, 1H), 7.64-7.53 (m, 2H), 7.52-7.42 (m, 1H), 6.73 (s, 1H), 3.77-3.51 (m, 3H), 3.20-3.01 (m, 4H), 2.34-2.20 (m, 2H), 2.13-1.81 (m, 2H), 1.34-1.30 (m, 2H), 1.29-1.26 (m, 3H). MS ES.sup.+: 383.1. SFC: 96%, 15.2 min.

Example 133a/b: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(((trans)-3-fluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine

[0825] ##STR00182##

Example 133a (isomer 1): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(((2*S,3*R)-3-fluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine, 1.4 eq. fumarate salt

[0826] Prepared as described for Example 96 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (1.1 g, 3.78 mmol) and trans-tert-butyl 2-(aminomethyl)-3-fluoro-pyrrolidine-1-carboxylate (826.08 mg, 3.78 mmol) to afford the title compound (123.41 mg, 6%, 96.70% purity by HPLC) as a light yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.20 (s, 1H), 7.71-7.54 (m, 2H), 7.54-7.42 (m, 1H), 6.68 (s, 2.8H), 5.49-5.29 (m, 1H), 4.34-4.19 (m, 1H), 3.84-3.45 (m, 4H), 2.53-2.28 (m, 2H), 2.25 (s, 3H). MS ES.sup.+: 373.2. SFC: 100%, 3.09 min.

Example 133b (isomer 2): 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(((2*R,3*S)-3-fluoropyrrolidin-2-yl)methyl)-4-methyl-pyrimidin-2-amine, fumarate salt

[0827] Prepared as described for Example 96 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (1.1 g, 3.78 mmol) and trans-tert-butyl 2-(aminomethyl)-3-fluoro-pyrrolidine-1-carboxylate (826.08 mg, 3.78 mmol) to afford the title compound (122.23 mg, 6%, 97.39% purity by HPLC) as a light yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.18 (s, 1H), 7.65-7.53 (m, 2H), 7.52-7.38 (m, 1H), 6.68 (s, 3H), 5.50-5.23 (m, 1H), 4.36-4.14 (m, 1H), 3.82-3.45 (m, 4H), 2.50-2.27 (m, 2H), 2.24 (s, 3H). MS ES.sup.+: 373.2. SFC: 99.8%, 3.44 min.

Example 134: (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((2-methyl-pyrrolidin-2-yl)methyl)pyrimidin-2-amine, fumarate salt

[0828] ##STR00183##

[0829] Prepared as described for Example 102 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (300 mg, 1.03 mmol) and tert-butyl (2S)-2-(aminomethyl)-2-methyl-pyrrolidine-1-carboxylate (221 mg, 1.03 mmol) to afford the title compound (102 mg, 20%, 98.2% purity by HPLC) as a light yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.20-8.04 (m, 11H), 7.63-7.34 (m, 3H), 6.53 (s, 2H), 3.82-3.47 (m, 3H), 3.39-3.21 (m, 2H), 2.28-1.90 (m, 6H), 1.88-1.78 (m, 1H), 1.51-1.31 (m, 3H). MS ES.sup.+: 369.1. SFC: 99.8%, 4.55 min.

Example 135: (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((2-methyl-pyrrolidin-2-yl)methyl)pyrimidin-2-amine, fumarate salt

[0830] ##STR00184##

[0831] Prepared as described for Example 134 using 2-chloro-5-(2-fluoro-4-(trifluoromethyl) phenyl)-4-methyl-pyrimidine (136 mg, 0.467 mmol) and tert-butyl (2R)-2-(aminomethyl)-2-methyl-pyrrolidine-1-carboxylate (100 mg, 0.467 mmol) to afford the title compound (130 mg, 57%, 98.6% purity by HPLC) as a light yellow powder. .sup.1H NMR (400 MHz, D.sub.2O): 7.91 (s, 1H), 7.41-7.15 (m, 3H), 6.55 (s, 2H), 3.75-3.42 (m, 3H), 3.40-3.19 (m, 2H), 2.27-1.88 (m, 6H), 1.85-1.74 (m, 1H), 1.27-1.27 (m, 1H), 1.35 (s, 3H). MS ES.sup.+: 369.1. SFC: 100%, 4.23 min.

Example 136: (S)N-((1,2-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, 1.5 eq. fumarate salt

[0832] ##STR00185##

[0833] Step 1: A solution of (S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((2-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine (100 mg, 0.271 mmol) and DIPEA (42 mg, 0.33 mmol) in THF (0.5 mL) was treated with Mel (46 mg, 0.33 mmol) at 0 C., stirred at 0 C. for 1.5 h, and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. The resulting yellow oil was purified by prep-TLC (DCM/MeOH=10:1) to give the free base product (52 mg, 48%, 96.28% purity by HPLC) as a light yellow gummy solid.

[0834] Step 2: A solution of (S)N-((1,2-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine (40 mg, 0.11 mmol) in EtOH (0.5 mL) was treated with fumaric acid (18 mg, 0.16 mmol), stirred at 25 C. for 1 h and concentrated. The resulting oil was dissolved in ACN (2 mL) and H.sub.2O (5 mL) and lyophilized to give the title compound (22 mg, 37%, 95.1% purity by HPLC) as a light yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.17 (s, 1H), 7.61-7.53 (m, 2H), 7.50-7.42 (m, 1H), 6.70-6.66 (m, 3H), 3.92-3.81 (m, 1H), 3.72-3.56 (m, 2H), 3.24-3.10 (m, 1H), 2.91-2.77 (m, 3H), 2.23 (s, 3H), 2.18-1.81 (m, 4H), 1.32 (s, 3H). MS ES.sup.+: 383.2. SFC: 99.2%, 11.4 min.

Example 137: (R)N-((1,2-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, di-fumarate salt

[0835] ##STR00186##

[0836] Prepared as described for Example 136 using (R)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-N-((2-methylpyrrolidin-2-yl)methyl)pyrimidin-2-amine (150 mg, 0.407 mmol) to afford the title compound (50 mg, 20%, 93.9% purity by HPLC) as a white powder. .sup.1H NMR (400 MHz, D.sub.2O): 8.24 (s, 1H), 7.68-7.54 (m, 2H), 7.48 (t, J=7.4 Hz, 1H), 6.74 (s, 4H), 3.95 (d, J=15.2 Hz, 1H), 3.66 (d, J=15.2 Hz, 2H), 3.29-3.13 (m, 1H), 2.84 (s, 3H), 2.28 (s, 3H), 2.21-2.05 (m, 2H), 2.04-1.83 (m, 2H), 1.33 (s, 3H). MS ES.sup.+: 383.2. SFC: 100%, 10.54 min.

Example 138a/b/c/d: N-((1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine

[0837] ##STR00187##

[0838] Step 1: A suspension of LiAlH.sub.4 (947 mg, 24.9 mmol) in THF (30 mL) was treated dropwise with a solution of 1,5-dimethylpyrrole-2-carbonitrile (3.00 g, 24.9 mmol) in THF (30 mL) under ice cooling, stirred at 85 C. for 1 h, cooled to 0 C. and treated dropwise with aq. NH.sub.3 (28%) until pH >8 was reached. The mixture was filtered and extracted with DCM (3100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated to give (1,5-dimethylpyrrol-2-yl)methanamine (3.00 g, 91.9%, 95% purity by HPLC) as a yellow oil. .sup.1H NMR (400 MHz, CD.sub.3Cl): 5.92 (d, J=3.3 Hz, 1H), 5.82 (d, J=3.3 Hz, 1H), 3.92-3.72 (m, 2H), 3.50 (s, 3H), 2.23 (s, 3H).

[0839] Step 2: A solution of (1,5-dimethylpyrrol-2-yl)methanamine (2.00 g, 16.1 mmol) in conc. aq. HCl (2 mL) and EtOH (20 mL) was treated with PtO.sub.2 (731 mg, 3.22 mmol) under N.sub.2. The suspension was purged with H.sub.2 (3) and stirred under H.sub.2 (50 psi) at 25 C. for 12 h. The mixture was filtered and the filtrate concentrated. The pH was adjusted to 9-10 by addition of 5M aq. NaOH solution and extracted with DCM/MeOH (10:1, 350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated to give (1,5-dimethylpyrrolidin-2-yl)methanamine (2.00 g, 97%) as a dark oil, which was used in the next step without further purification.

[0840] Step 3: A solution of 2-chloro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidine (0.7 0 g, 2.41 mmol), (1,5-dimethylpyrrolidin-2-yl)methanamine (617 mg, 4.82 mmol) and DIPEA (622 mg, 4.82 mmol) in dioxane (5 mL) was stirred at 110 C. for 8 h, cooled to RT and extracted with DCM (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by prep-HPLC (YMC-Triart Prep C18 (150 mm40 mm, 7 m); mobile phase A: 0.2% aq. HCOOH, mobile phase B: ACN; flow rate: 25 ml/min, gradient from 20% to 50% B). The product was dissolved in ACN (5 mL) and H.sub.2O (20 mL), lyophilized and separated into diastereomeric pairs of enantiomers by SFC (DAICEL CHIRALPAK IC (250 mm30 mm, 10 m); mobile phase A: supercritical CO.sub.2, B: 0.1% NH.sub.3.Math.H.sub.2O in EtOH, A:B=70:30; flow rate=70 mL/min; T: 38 C.; UV detection at 220 nm) to give diastereomeric pair of enantiomers 1 (600 mg, 65%, 99.3% purity by HPLC) and diastereomeric pair of enantiomer 2 (65 mg, 6.91%, 97.9% purity by HPLC) as yellow gummy solids.

[0841] The diastereomeric pair of enantiomers 1 was separated into enantiomers using chiral HPLC (CHIRALPAK IG-3 (IG30CD-WE016); mobile phase: EtOH/DIPEA=100/0.1; flow rate 0.5 mL/min; T=25 C.; UV detection at 254 nm) to give isomer 1 (236 mg) and isomer 2 (223 mg).

Example 138a (isomer U: N-(((2*R,5*R)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, fumarate salt

[0842] A solution of isomer 1 (160 mg, 0.418 mmol) in EtOH (2 mL) was treated with fumaric acid (107 mg, 0.92 mmol), stirred at 25 C. for 1 h and concentrated. The resulting residue was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to give N-(((2*R,5*R)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine fumarate (214 mg, 79%, 98.3% purity by HPLC) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.17 (s, 1H), 7.63-7.50 (m, 2H), 7.49-7.38 (m, 1H), 6.88-6.52 (m, 4.4H), 3.91-3.79 (m, 1H), 3.79-3.66 (m, 2H), 3.50-3.36 (m, 1H), 2.96 (s, 3H), 2.34-2.15 (m, 5H), 2.03-1.86 (m, 1H), 1.75-1.57 (m, 1H), 1.35 (d, J=6.5 Hz, 3H). MS ES.sup.+: 383.2. SFC: 99.4%, 1.22 min.

Example 138b (isomer 2): N-(((2*S,5*S)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, fumarate salt

[0843] A solution of isomer 2 (222 mg, 0.581 mmol) and fumaric acid (134.77 mg, 1.16 mmol) in EtOH (2 mL) was stirred at 25 C. for 1 h and evaporated. The residue was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to give N-(((2*S,5*S)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine fumarate (260 mg, 72%, 99.3% purity by HPLC) as an off-white solid. .sup.1H NMR (400 MHz, D.sub.2O): 7.97 (d, J=19.6 Hz, 1H), 7.44-7.11 (m, 3H), 6.63 (d, J=8.1 Hz, 4H), 3.68 (d, J=5.1 Hz, 3H), 3.37 (s, 1H), 3.09-2.84 (m, 3H), 2.30-1.96 (m, 5H), 1.85 (s, 1H), 1.55 (s, 1H), 1.38-1.22 (m, 3H). MS ES.sup.+: 383.3. SFC: 99.8%, 1.30 min.

[0844] The diastereomeric pair of enantiomers 2 was separated into enantiomers by SFC (DAICEL CHIRALPAK IC (250 mm30 mm, 10 m); mobile phase: A: supercritical CO.sub.2, B: 0.1% NH.sub.3H.sub.2O in EtOH, A:B=90:10; flow rate=60 mL/min; T=38 C.; UV detection at 220 nm). The enantiomerically pure products were dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to give isomer 3 (31 mg) and isomer 4 (31 mg).

Example 138c (isomer 3): N-(((2*R,5*S)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, fumarate salt

[0845] A solution of isomer 3 (31 mg, 0.08 mmol) and fumaric acid (9.4 mg, 0.08 mmol) in EtOH (1 mL) was stirred at 25 C. for 1 h and evaporated. The residue was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to give N-(((2*R,5*S)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine fumarate (22 mg, 47%, 97.7% purity by HPLC) as a yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.19-8.01 (m, 1H), 7.61-7.31 (m, 3H), 6.69-6.59 (m, 3H), 3.95-3.51 (m, 4H), 2.89-2.74 (m, 3H), 2.35-2.01 (m, 5H), 1.97-1.72 (m, 2H), 1.35-1.20 (m, 3H). MS ES.sup.+: 383.3.

Example 138d (isomer 4): N-(((2*S,5*R)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine, fumarate salt

[0846] A solution of isomer 4 (27 mg, 0.07 mmol) and fumaric acid (8.2 mg, 0.07 mmol) in EtOH (1 mL) was stirred at 25 C. for 1 h and evaporated. The residue was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to give N-(((2*S,5*R)-1,5-dimethylpyrrolidin-2-yl)methyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine fumarate (20 mg, 48%, 95.2% purity by HPLC) as a yellow solid. .sup.1H NMR (400 MHz, D.sub.2O): 8.21-8.01 (m, 1H), 7.63-7.31 (m, 3H), 6.64 (d, J=3.1 Hz, 3H), 3.93-3.53 (m, 4H), 2.81 (s, 3H), 2.40-2.08 (m, 5H), 1.96-1.64 (m, 2H), 1.33-1.16 (m, 3H). MS ES.sup.+: 383.3.

Example 139: (R)N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-1-methylpyrrolidine-2-carboxamide

[0847] ##STR00188##

[0848] Step 1: A mixture of (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (1.00 g, 4.81 mmol), 5-bromo-4-methyl-pyrimidin-2-amine (904 mg, 4.81 mmol), K.sub.2CO.sub.3 (1.33 g, 9.62 mmol) and 4-di(tert-butyl)phosphanyl-N,N-dimethyl-aniline-dichloropalladium (681 mg, 961 mol) in dioxane (10 mL) and H.sub.2O (5 mL) was de-gassed (N.sub.2), stirred at 110 C. for 10 h, cooled to RT and evaporated. The residue was purified by silica gel chromatography (EtOAc/petroleum ether 1:1) to afford 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine (0.95 g, 69%, 95% purity by HPLC) as a white solid. MS ES.sup.+: 272.1.

[0849] Step 2: A solution of 5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-amine (300 mg, 1.11 mmol), (2R)-1-methylpyrrolidine-2-carboxylic acid (143 mg, 1.11 mmol) and pyridine (892 L, 11.1 mmol) in DCM (1 mL) was treated dropwise with POCl.sub.3 (170 mg, 1.11 mmol) at 40 C. and stirred for 1 h. The mixture was poured into ice H.sub.2O (20 mL) and extracted with DCM (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated. Purification of the residue by prep-HPLC (Phenomenex Luna C18 (80 mm40 mm, 3 m); mobile phase A: H.sub.2O (0.225% HCOOH), mobile phase B: ACN; flow rate: 25 mL/min, gradient from 12% B to 42%). The product was dissolved in ACN (2 mL) and H.sub.2O (10 mL) and lyophilized to give the title compound (35 mg, 8%, 96.8% purity by HPLC) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.17 (s, 1H), 8.55 (s, 1H), 7.95-7.84 (m, 1H), 7.80-7.68 (m, 2H), 3.18-3.10 (m, 1H), 3.06-2.99 (m, 1H), 2.39 (s, 4H), 2.33-2.29 (m, 3H), 2.26-2.15 (m, 1H), 1.87-1.75 (m, 3H). MS ES.sup.+: 383.2. SFC: 99.6%, 1.59 min.

Example 140: (S)N-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-pyrimidin-2-yl)-1-methylpyrrolidine-2-carboxamide

[0850] ##STR00189##

[0851] Prepared as described for Example 139 using (2S)-1-methylpyrrolidine-2-carboxylic acid (105 mg, 811 mol) to afford the title compound (5.64 mg, 1.4%, 97.4% purity by HPLC) as a white solid. .sup.1H NMR (400 MHz, DMSO-de): 10.17 (s, 1H), 8.55 (s, 1H), 7.92-7.85 (m, 1H), 7.77-7.69 (m, 2H), 3.18-3.10 (m, 1H), 3.07-2.99 (m, 1H), 2.42-2.34 (m, 4H), 2.32-2.30 (m, 3H), 2.26-2.12 (m, 1H), 1.89-1.70 (m, 3H). MS ES.sup.+: 383.2. SFC: 96.8%, 1.40 min.

3. Biological Efficacy of Compounds of the Invention

[0852] The IC.sub.50 values for the compounds of the examples is shown in Table 1.

[0853] The ability of the test compounds to inhibit nicotine stimulated nAChR6 activity was determined in a fluorescence-based calcium assay. Compound activity was determined using a HEK cell line stably expressing a human nAChR6-3 chimera, in addition to 2 and 3.sup.V273S subunits (as in Capelli et al, Br J Pharmacol 163(2): 313-29 2011). In this cell line, nicotine stimulated an increase in intracellular calcium concentration, measured as an increase in fluorescence when cells were incubated with a calcium sensitive dye. Test compounds were pre-incubated with cells prior to nicotine stimulation to detect any reduction in the magnitude of the nicotine response.

[0854] The day prior to the assay, compounds were serially diluted in DMSO (200 final assay concentration (FAC)), in 384-well plates which were then stored in the dark at room temperature (RT) until use. Cells were seeded at 20 k/well in black, poly-D-lysine coated, clear bottom 384-well plates and incubated for 4 hours at 37 C., followed by overnight incubation at 30 C. The following day, the DMSO compound plate was diluted 1:20 (10FAC) in assay buffer (HEPES buffered saline solution with 10 mM HEPES, 0.1% bovine serum albumin, 1 mM probenecid). A nicotine solution was prepared in assay buffer (7FAC) and dispensed into a 384-well plate. The growth media was removed from the cell plate, replaced with 53 l calcium dye/well (Calcium 5; Molecular Devices) and the plate incubated at 30 C. for 45 minutes. Test compounds were then added to the cells (7 l of 10FAC) and incubated for 10 minutes, after which nicotine EC.sub.80 (10 l of 7FAC) was added and changes in fluorescence measured using a FLIPR plate reader (Molecular Devices).

[0855] Compound activity was examined using a 10-point, half-log concentration-response range and each concentration was tested in duplicate wells. Responses were calculated as changes in relative fluorescence units (max-min) and IC.sub.50 values were derived from this data using a four-parameter curve fit.

[0856] Results

TABLE-US-00001 TABLE 1 Example number IC.sub.50 (M) 1 0.048 2 0.302 3 0.331 4 0.211 5 0.635 6 0.123 7 0.59 8 0.286 9 0.264 10 0.201 11 0.246 12 0.108 13 0.05 14 0.042 15 1.943 16 0.075 17 0.02 18 0.526 18a 0.331 18b 0.442 19 0.216 20 0.49 21 0.599 22 0.05 23 0.233 24a 0.062 24b 0.005 25 0.034 26 0.156 27 0.056 28a 0.054 28b 0.01 29 0.095 30 0.082 31 0.082 32 0.099 33 0.045 34 0.13 35 0.029 36 0.14 37 0.103 38a 0.059 38b 0.07 39a 0.904 39b 0.901 40 0.068 41 0.081 42 1.196 43 0.178 44a 0.076 44b 0.088 45 1.311 46 2.175 47 1.25 48 0.083 49 0.069 50 0.103 51 1.104 52 1.531 53a 1.238 53b 0.734 54a 0.331 54b 0.442 55a 0.098 55b 0.081 56a 0.133 56b 0.162 57a 0.139 57b 0.144 58a 0.038 58b 0.056 59a 0.202 59b 0.134 60 1.181 61 0.533 62 0.064 63 0.141 64a 0.09 64b 0.088 65 0.084 66 0.094 67 0.066 68a 0.078 68b 0.067 69a 0.436 69b 0.309 70 0.072 71 0.054 72 0.052 73 nd 74a 0.693 74b 1.474 75 0.094 76a 0.118 76b 0.107 77a 0.07 77b 0.093 78a 0.061 78b 0.06 79a 0.42 79b 0.296 80 1.469 81 0.098 82 0.018 83a 1.151 83b 0.456 84a 1.528 84b 1.646 85 0.051 86a 0.122 86b 0.126 87 0.045 88 0.149 89 0.18 90a 0.211 90b 0.186 91a 0.008 91b 0.028 92a 0.033 92b 0.073 93a 0.05 93b 0.011 94a 0.005 94b 0.005 95a 0.048 95b 0.07 96a 0.151 96b 0.099 97a 0.184 97b 0.152 97c 0.18 97d 0.299 98 0.067 99 0.083 100 0.11 101 0.109 102 0.005 103 0.04 104 0.027 104a 0.104 104b 0.045 105 0.05 106 0.054 106a 0.105 106b 0.138 107 0.154 108 0.043 108a 0.086 108b 0.077 109 0.096 110 0.054 111 0.09 112 0.107 113 0.045 114 0.142 115 0.121 116 0.127 117 0.025 118 0.075 119 0.155 120 0.179 121 0.191 122 0.039 123 0.15 124 0.903 125 0.223 126 0.259 127 0.119 128 0.18 129a 0.065 129b 0.105 130a 0.118 130b 0.049 131a 0.172 131b 0.291 132a 0.092 132b 0.097 133a 0.305 133b 0.30 134 0.101 135 0.07 136 0.096 137 0.11 138a 0.207 138b 0.085 138c 0.069 138d 0.025 139 0.086 140 0.079

4. In Vivo Efficacy: Tacrine Studies

[0857] Resting tremor is one of the classic symptoms of Parkinson's disease. These characteristic tremors can be modelled pharmacologically in preclinical models using cholinomimetics such as the acetylcholine esterase inhibitor, tacrine (5 mg/kg, i.p.) (Salamone et al, Prog Neurobiol 56: 591-611 1998) to induce tremulous jaw movement behaviours. These tremulous jaw movements are thought to arise from an imbalance between cholinergic and dopaminergic neurotransmission and are thought to mimic the imbalances in neurotransmission resulting from the dopamine loss seen in Parkinson's disease (Aosaki et al, Geriatr Gerontol Int 10: s148-s157 2010). These tremors can be reversed by agents increasing the dopamine tone, such as dopamine agonists (Salamone et al, Behav Brain Res 156: 173-179 2005).

[0858] The objective of these studies was to evaluate the effects of oral administration of Example Compounds on tremulous jaw movements induced by tacrine in male C57BL/6J mice or Sprague-Dawley rats. Animals were administered vehicle (0.5% methylcellulose, p.o.) or Example Compound (across a range of doses; 10 mg/kg, p.o. data shown) 15 to 60 minutes prior to behavioural testing (n=10/group). Tacrine (5 mg/kg, i.p.) was administered to all animals immediately before behavioural assessment commenced. For each animal the latency to the first tremulous jaw movement and the total duration of the tremulous jaw movements post tacrine administration were recorded.

TABLE-US-00002 % Decrease from vehicle or percentage relative to vehicle (100%), Example (mean SEM) Species 24b 23.9 3.8*** mouse 78b 23.8 7.7*** mouse 94b 79.9 7.2 mouse 65 30.0 12.8* rat

[0859] illustrative data shown is percentage attenuation of tacrine-induced tremulous jaw movements relative to vehicle (100%). Each compound shown was tested at 10 mg/kg p.o.

[0860] Statistical significance was assessed using an unpaired student's t-test vs vehicle * p<0.05, ***p<0.001.

[0861] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.