5-Fluoro-4N-phenyl-4-pyrimidineamine compounds
View Patent ↗The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
1. A compound according to structural Formula (II):
and salts, hydrates, solvates, N-oxides and prodrugs thereof wherein:
R 4 is selected from the group consisting of phenyl mono-substituted at the 3-position with an R 8 groups, phenyl di-substituted at the 3,4- or 3,5-positions with the same or different R 8 groups and phenyl trisubstituted at the 2,3,4-, 2,3,5- or 3,4,5-positions with the same or different R 8 groups;
R 8 is selected from the group consisting of R e , R b , or R e substituted with one or more of the same or different R a or R b , —OR a substituted with one or more of the same or different R a or R b , —B(OR a ) 2 , —B(NR c R c ) 2 , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —O—CHR a R b , —O—CR a (R b ) 2 , —O—(CHR a ) m —R b , —O—(CH 2 ) m —CH[(CH 2 ) m R b ]R b , —O—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —O—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —NH—(CH 2 ) m —R b , —NH—(CHR a ) m —R b , —NH[(CH 2 ) m R b ] and —N[(CH 2 ) m R b ] 2 ;
each R a is independently selected from the group consisting of hydrogen, (C1–C6) alkyl, (C3–C8) cycloalkyl, cyclohexyl, (C4–C11) cycloalkylalkyl, (C5–C10) aryl, phenyl, (C6–C16) arylalkyl, benzyl, 2–6 membered heteroalkyl, 3–9 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4–11 membered cycloheteroalkylalkyl, 5–10 membered heteroaryl and 6–16 membered heteroarylalkyl;
each R b is a suitable group independently selected from the group consisting of ═O, —OR d , (C1–C3) haloalkyloxy, —OCF 3 , —SR d , —NR c R c , halogen, —CF 3 , —CN, —NO 2 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —OC(O)R d , —OC(O)OR d and —OC(O)NR c R c ;
each R c is independently a protecting group or R a , or, alternatively, two R c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R d is independently a protecting group or R a ;
each R e is independently selected from the group consisting (C1–C6) alkyl, (C3–C8) cycloalkyl, cyclohexyl, (C4–C11) cycloalkylalkyl, (C5–C10) aryl, phenyl, (C6–C16) arylalkyl, benzyl, 2–6 membered heteroalkyl, 3–9 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4–11 membered cycloheteroalkylalkyl, 5–10 membered heteroaryl and 6–16 membered heteroarylalkyl;
each m is independently an integer from 1 to 3; and
LG is a leaving group.
2. The compound of claim 1 in which LG is chloro.
3. The compound of claim 1 in which LG is chloro and R 4 is phenyl monosubstituted at the 3-position with —OR d .
4. The compound of claim 3 in which R d is hydrogen, acetyl, ethyl, butyl, hexyl, trifluoromethyl or benzyl.
5. The compound of claim 4 which is selected from the group consisting of 2-chloro-N4-(2-hydroxyphenyl)-5-fluoro-4-pyrimidineamine, 2-Chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine, 2-chloro-N4-(3-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine, and 2-chloro-N4-(3-benzyloxyphenyl)-5-fluoro-4-pyrimidineamine.
6. The compound of claim 1 which is 2-chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.
7. The compound of claim 1 in which LG is chloro and R 4 is phenyl disubstituted at the 3,4- or 3,5-positions with the same or different R 8 groups.
8. A compound selected from the group consisting of 2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)- 5-fluoro- 4-pyrimidineamine, 2-chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine, N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)- 4-pyrimidineamine, N2-chloro-5-fluoro-N 4-[3-(N-morpholinomethyl)-4-methoxyphenyl]-4-pyrimidineamine, 2-chloro-N4-(3-carboxy-4-hydroxyphenyl)- 5-fluoro-2,4-pyrimidineamine, 2-chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine, and 2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine.
9. The compound of claim 1 , wherein R a and/or R e is (C3-C8) cycloalkyl.
10. The compound of claim 9 , wherein R a and/or R e is cyclohexyl.
11. The compound of claim 1 , wherein R a and/or R e is (C5-C10) aryl.
12. The compound of claim 11 , wherein R a and/or R e is phenyl.
13. The compound of claim 1 , wherein R a and/or R e is C6-C16) arylalkyl.
14. The compound of claim 13 , wherein R a and/or R e is benzyl.
15. The compound of claim 1 , wherein R a and/or R e is 3 - 8 membered cycloheteroalkyl.
16. The compound of claim 15 , wherein R a and/or R e is selected from the group consisting of morpholinyl, homopiperazinyl, and piperidinyl.
17. The compound of claim 1 , wherein R b is (C1-C3) haloalkyloxy.
18. The compound of claim 17 , wherein R b is —OCF 3 .