Pipecolic acid derivatives of proline threonine amides useful for the treatment of rheumatoid arthritis

A compound of Formula I:

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• wherein R1 is selected from alkyl, phenyl, cycloalkyl rings having four to ten ring-member carbon atoms, bicycloalkyl fused ring systems having seven to nine ring-member carbon atoms, heteroaryl, heteroarylalkyl, benzo-fused-heteroaryl and benzo-fused-heteroarylalkyl wherein said heteroaryl moiety or fragment is a 5- or 6-ring-member fully-unsaturated ring system having one hetero atom as a ring member, said hetero atom selected from oxygen, nitrogen and sulfur atoms, and wherein any of said heteroaryl, heteroarylalkyl, benzo-fused-heteroaryl and benzo-fused-heteroarylalkyl may be attached to the nucleus of Formula I as an R1 substituent through a bond formed at any said ring-member atom or any atom of the alkyl portion of said R1 substituent where said bond is capable of forming a stable compound;
• wherein R2 is selected from hydrido, lower alkyl, cyclohexyl and phenyl;
• wherein R3 is selected from hydrido, hydroxy, lower alkyl, phenyl, acetyl(Lys)NH—, acetyl(Tyr)NH—, acetyl(Thr)NH—, acetylamino, propionylamino and benzyloxycarbonylamino;
• wherein R4 is selected from hydrido, lower alkyl and phenyl;
• wherein R5 is selected from hydrido, lower alkyl, phenyl, benzyl, hydroxyphenyl, hydroxybenzyl, aminoalkyl, mono-alkyl-substituted-aminoalkyl and radicals provided by B-Het-A;
• wherein Het is selected from heteroaryl moieties consisting of monocyclic and fused bicyclic ring systems having a total of five to fourteen ring members and with one to six ring members being selected from hetero atoms provided by oxygen, nitrogen and sulfur atoms, wherein said monocyclic ring system and at least one ring system of said fused bicyclic ring system is fully unsaturated, and
• wherein Het is further selected from heterocyclic moieties consisting of monocyclic and fused polycyclic ring systems having a total of four to twelve ring members and with one to six ring members selected from hetero atoms provided by oxygen, nitrogen and sulfur atoms, wherein said monocyclic ring-system and at least one ring system of said fused polycyclic ring system is fully saturated or partially unsaturated,
• wherein A is a single covalent bond or is a divalent radical selected from
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• wherein R13 is lower alkyl;
• wherein B is one or more substituents attached at a substitutable position on Het of Het-A, said substituent selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, alkenyl, alkynyl, halo, haloalkyl, oxo, cyano, benzyl and phenyl;
• wherein R6 is selected from hydrido, lower alkyl, hydroxy, alkoxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonyloxy, aminoalkyl, mono-alkyl-substituted-aminoalkyl, amido and amidoalkyl;
• wherein R7 is selected from carboxyl, lower alkyl, amido and methylthiomethyl;
• wherein R8 is selected from hydrido, methyl and ethyl;
• wherein R9 is selected from hydrido, lower alkyl, alkoxy and phenyl;
• wherein R10 is hydrido or hydroxy;
• wherein R11 is hydrido or methyl;
• wherein R12 is selected from lower alkyl, phenyl, phenylalkyl, cycloalkyl, cycloalkylalkyl,
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• wherein each of R14 through R17 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, cyano, benzyl and phenyl;
• wherein each of R18 and R19 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, benzyl and phenyl;
• or a pharmaceutically-acceptable amide, ester or salt thereof.